666 receptors to reduce renal phosphate reabsorption. Treatment involves that causes increased O2 affinity; Chap.
uses increased O2 affinity; Chap. 59) have the paraneoplastic
removal of the tumor, if possible, and supplementation with phosphate
and vitamin D. Octreotide treatment reduces phosphate wasting in
some patients with tumors that express somatostatin receptor subtype 2.
Octreotide scans may also be useful in detecting these tumors.
■■CONSUMPTIVE HYPOTHYROIDISM
Newborns with hepatic hemangiomas can develop a rare form of
hypothyroidism caused by overexpression of type 3 deiodinase (D3),
an enzyme that degrades and inactivates T4 and T3. The very high
expression of D3, and consumption of thyroid hormones, apparently
outstrips the thyroid gland’s rate of hormone production. The disorder
is characterized by low T4, low T3, high TSH, and markedly elevated
reverse T3 (rT3), reflecting the degradation of T4 to rT3. In addition
to treating the underlying hemangioma (rarely other tumor types),
patients are treated with l-thyroxine replacement, titrated to normal-
ize TSH. Steroids and propranolol may provide benefit, perhaps by
inhibiting growth factor pathways thought to stimulate D3 production.
HEMATOLOGIC SYNDROMES
The elevation of granulocyte, platelet, and eosinophil counts in most
patients with myeloproliferative disorders is caused by the prolifer-
ation of the myeloid elements due to the underlying disease rather
PART 4
than to a paraneoplastic syndrome. The paraneoplastic hematologic
syndromes in patients with solid tumors are less well characterized
than are the endocrine syndromes because the ectopic hormone(s) or
cytokines responsible have not been identified in most of these tumors
(Table 89-2). The extent of the paraneoplastic syndromes parallels the
Oncology and Hematology
course of the cancer.
■■ERYTHROCYTOSIS
Ectopic production of erythropoietin by cancer cells causes most para-
neoplastic erythrocytosis. The ectopically produced erythropoietin
stimulates the production of red blood cells (RBCs) in the bone marrow
and raises the hematocrit. Other lymphokines and hormones produced
by cancer cells may stimulate erythropoietin release but have not been
proved to cause erythrocytosis.
Most patients with erythrocytosis have an elevated hematocrit
(>52% in men, >48% in women) that is detected on a routine blood
count. Approximately 3% of patients with renal cell cancer, 10% of
patients with hepatoma, and 15% of patients with cerebellar heman-
gioblastomas have erythrocytosis. In most cases, the erythrocytosis is
asymptomatic.
Patients with erythrocytosis due to a renal cell cancer, hepatoma, or
CNS cancer should have measurement of red cell mass. If the red cell
mass is elevated, the serum erythropoietin level should be measured.
Patients with an appropriate cancer, elevated erythropoietin levels,
and no other explanation for erythrocytosis (e.g., hemoglobinopathy
TABLE 89-2  Paraneoplastic Hematologic Syndromes
CANCERS TYPICALLY
SYNDROME PROTEINS ASSOCIATED WITH SYNDROME
Erythrocytosis Erythropoietin Renal cancers, hepatocarcinoma,
cerebellar hemangioblastomas
Granulocytosis G-CSF, GM-CSF, IL-6 Lung cancer, gastrointestinal
cancer, ovarian cancer,
genitourinary cancer, Hodgkin’s
disease
Thrombocytosis IL-6 Lung cancer, gastrointestinal
cancer, breast cancer, ovarian
cancer, lymphoma
Eosinophilia IL-5 Lymphoma, leukemia, lung cancer
Thrombophlebitis Unknown Lung cancer, pancreatic cancer,
gastrointestinal cancer, breast
cancer, genitourinary cancer,
ovarian cancer, prostate cancer,
lymphoma
Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-
macrophage colony-stimulating factor; IL, interleukin.
Harrisons_20e_Part4_p0435-p0858.indd 666
syndrome.
TREATMENT
Erythrocytosis
Successful resection of the cancer usually resolves the erythrocy-
tosis. If the tumor cannot be resected or treated effectively with
radiation therapy or chemotherapy, phlebotomy may control any
symptoms related to erythrocytosis.
■■GRANULOCYTOSIS
Approximately 30% of patients with solid tumors have granulocy-
tosis (granulocyte count >8000/μL). In about half of patients with
granulocytosis and cancer, the granulocytosis has an identifiable
nonparaneoplastic etiology (infection, tumor necrosis, glucocorticoid
administration, etc.). The other patients have proteins in urine and
serum that stimulate the growth of bone marrow cells. Tumors and
tumor cell lines from patients with lung, ovarian, and bladder cancers
have been documented to produce granulocyte colony-stimulating
factor (G-CSF), granulocyte-macrophage colony-stimulating factor
(GM-CSF), and/or interleukin 6 (IL-6). However, the etiology of gran-
ulocytosis has not been characterized in most patients.
Patients with granulocytosis are nearly all asymptomatic, and the
differential white blood cell count does not have a shift to immature
forms of neutrophils. Granulocytosis occurs in 40% of patients with
lung and gastrointestinal cancers, 20% of patients with breast cancer,
30% of patients with brain tumors and ovarian cancers, 20% of patients
with Hodgkin’s disease, and 10% of patients with renal cell carcinoma.
Patients with advanced-stage disease are more likely to have granulo-
cytosis than are those with early-stage disease.
Paraneoplastic granulocytosis does not require treatment. The gran-
ulocytosis resolves when the underlying cancer is treated.
■■THROMBOCYTOSIS
Some 35% of patients with thrombocytosis (platelet count >400,000/μL)
have an underlying diagnosis of cancer. IL-6, a candidate molecule for
the etiology of paraneoplastic thrombocytosis, stimulates the produc-
tion of platelets in vitro and in vivo. Some patients with cancer and
thrombocytosis have elevated levels of IL-6 in plasma. Another can-
didate molecule is thrombopoietin, a peptide hormone that stimulates
megakaryocyte proliferation and platelet production. The etiology of
thrombocytosis has not been established in most cases.
Patients with thrombocytosis are nearly all asymptomatic. Throm-
bocytosis is not clearly linked to thrombosis in patients with cancer.
Thrombocytosis is present in 40% of patients with lung and gastroin-
testinal cancers; 20% of patients with breast, endometrial, and ovarian
cancers; and 10% of patients with lymphoma. Patients with thrombocy-
tosis are more likely to have advanced-stage disease and have a poorer
prognosis than do patients without thrombocytosis. In ovarian cancer,
IL-6 has been shown to directly promote tumor growth. Paraneoplastic
thrombocytosis does not require treatment other than treatment of the
underlying tumor.
■■EOSINOPHILIA
Eosinophilia is present in ~1% of patients with cancer. Tumors and
tumor cell lines from patients with lymphomas or leukemia may
produce IL-5, which stimulates eosinophil growth. Activation of IL-5
transcription in lymphomas and leukemias may involve translocation
of the long arm of chromosome 5, to which the genes for IL-5 and other
cytokines map.
Patients with eosinophilia are typically asymptomatic. Eosinophilia
is present in 10% of patients with lymphoma, 3% of patients with lung
cancer, and occasional patients with cervical, gastrointestinal, renal,
and breast cancer. Patients with markedly elevated eosinophil counts
(>5000/μL) can develop shortness of breath and wheezing. A chest
radiograph may reveal diffuse pulmonary infiltrates from eosinophil
infiltration and activation in the lungs.
6/1/18 5:42 PM

TREATMENT
Eosinophilia
Definitive treatment is directed at the underlying malignancy:
Tumors should be resected or treated with radiation or chemo-
therapy. In most patients who develop shortness of breath related
to eosinophilia, symptoms resolve with the use of oral or inhaled
glucocorticoids. IL-5 antagonists exist but have not been evaluated
in this clinical setting.
■■THROMBOPHLEBITIS AND DEEP VENOUS
THROMBOSIS
Deep venous thrombosis and pulmonary embolism are the most com-
mon thrombotic conditions in patients with cancer. Migratory or recur-
rent thrombophlebitis may be the initial manifestation of cancer. Nearly
15% of patients who develop deep venous thrombosis or pulmonary
embolism have a diagnosis of cancer (Chap. 113). The coexistence of
peripheral venous thrombosis with visceral carcinoma, particularly
pancreatic cancer, is called Trousseau’s syndrome.
Pathogenesis  Patients with cancer are predisposed to thromboem-
bolism because they are often at bed rest or immobilized, and tumors
may obstruct or slow blood flow. Postoperative deep venous throm-
bosis is twice as common in cancer patients who undergo surgery.
Chronic IV catheters also predispose to clotting. In addition, clotting
may be promoted by release of procoagulants or cytokines from tumor
cells or associated inflammatory cells or by platelet adhesion or aggre-
gation. The specific molecules that promote thromboembolism have
not been identified.
Chemotherapeutic agents, particularly those associated with endo-
thelial damage, can induce venous thrombosis. The annual risk of
venous thrombosis in patients with cancer receiving chemotherapy
is about 11%, sixfold higher than the risk in the general population.
Bleomycin, l-asparaginase, nitrogen mustard, thalidomide analogues,
cisplatin-based regimens, and high doses of busulfan and carmustine
are all associated with an increased risk.
In addition to cancer and its treatment causing secondary thrombo-
sis, primary thrombophilic diseases may be associated with cancer. For
example, the antiphospholipid antibody syndrome is associated with
a wide range of pathologic manifestations (Chap. 350). About 20% of
patients with this syndrome have cancers. Among patients with cancer
and antiphospholipid antibodies, 35–45% develop thrombosis.
Clinical Manifestations  Patients with cancer who develop
deep venous thrombosis usually develop swelling or pain in the leg,
and physical examination reveals tenderness, warmth, and redness.
Patients who present with pulmonary embolism develop dyspnea,
chest pain, and syncope, and physical examination shows tachycardia,
cyanosis, and hypotension. Some 5% of patients with no history of
cancer who have a diagnosis of deep venous thrombosis or pulmonary
embolism will have a diagnosis of cancer within 1 year. The most com-
mon cancers associated with thromboembolic episodes include lung,
pancreatic, gastrointestinal, breast, ovarian, and genitourinary cancers;
lymphomas; and brain tumors. Patients with cancer who undergo
surgical procedures requiring general anesthesia have a 20–30% risk of
deep venous thrombosis.
Diagnosis  The diagnosis of deep venous thrombosis in patients
with cancer is made by impedance plethysmography or bilateral
compression ultrasonography of the leg veins. Patients with a noncom-
pressible venous segment have deep venous thrombosis. If compres-
sion ultrasonography is normal and there is a high clinical suspicion
for deep venous thrombosis, venography should be done to look for a
luminal filling defect. Elevation of d-dimer is not as predictive of deep
venous thrombosis in patients with cancer as it is in patients without
cancer; elevations are seen in people over age 65 years without concom-
itant evidence of thrombosis, probably as a consequence of increased
thrombin deposition and turnover in aging.
Harrisons_20e_Part4_p0435-p0858.indd 667
Patients with symptoms and signs suggesting a pulmonary embo- 667
lism should be evaluated with a chest radiograph, electrocardiogram,
arterial blood gas analysis, and ventilation-perfusion scan. Patients
with mismatched segmental perfusion defects have a pulmonary
embolus. Patients with equivocal ventilation-perfusion findings should
be evaluated as described above for deep venous thrombosis in their
legs. If deep venous thrombosis is detected, they should be antico-
agulated. If deep venous thrombosis is not detected, they should be
considered for a pulmonary angiogram.
Patients without a diagnosis of cancer who present with an initial
episode of thrombophlebitis or pulmonary embolus need no additional
tests for cancer other than a careful history and physical examina-
tion. In light of the many possible primary sites, diagnostic testing in
asymptomatic patients is wasteful. However, if the clot is refractory
to standard treatment or is in an unusual site or if the thrombophle-
bitis is migratory or recurrent, efforts to find an underlying cancer are
indicated.
TREATMENT
Thrombophlebitis and Deep Venous Thrombosis
Patients with cancer and a diagnosis of deep venous thrombosis or
CHAPTER 89
pulmonary embolism should be treated initially with IV unfraction-
ated heparin or low-molecular-weight heparin for at least 5 days,
and warfarin should be started within 1 or 2 days. The warfarin
dose should be adjusted so that the international normalized ratio
(INR) is 2–3. Patients with proximal deep venous thrombosis and
Paraneoplastic Syndromes: Endocrinologic/Hematologic
a relative contraindication to heparin anticoagulation (hemorrhagic
brain metastases or pericardial effusion) should be considered for
placement of a filter in the inferior vena cava (Greenfield filter) to
prevent pulmonary embolism. Warfarin should be administered for
3–6 months. An alternative approach is to use low-molecular-weight
heparin for 6 months. The new oral anticoagulants (factor Xa and
thrombin inhibitors) are attractive because they do not require close
monitoring of the prothrombin time and are not affected by dietary
factors. However, data on their use in patients with cancer are not
yet mature. Patients with cancer who undergo a major surgical pro-
cedure should be considered for heparin prophylaxis or pneumatic
boots. Breast cancer patients undergoing chemotherapy and patients
with implanted catheters should be considered for prophylaxis.
Guidelines recommend that hospitalized patients with cancer and
patients receiving a thalidomide analogue receive prophylaxis with
low-molecular-weight heparin or low-dose aspirin. Use of prophy-
laxis routinely during chemotherapy is controversial and not recom-
mended by the American Society of Clinical Oncology.
MISCELLANEOUS REMOTE EFFECTS OF CANCER
Patients with cancer can develop paraneoplastic autoimmune disor-
ders (e.g., thrombocytopenia) and dysfunction of organs not directly
invaded or involved with the cancer (rheumatologic and renal
abnormalities are among the most frequent). The pathogenesis of
these disorders is undefined, but often the conditions reverse if the
tumor is removed or successfully treated.
Cutaneous paraneoplastic syndromes are discussed in Chap. 54.
Neurologic paraneoplastic syndromes are discussed in Chap. 90.
■■FURTHER READING
Chong WH et al: Tumor-induced osteomalacia. Endocr Relat Cancer
18:R53, 2012.
De Groot JWB et al: Non-islet cell tumour-induced hypoglycaemia: A
review of the literature including two new cases. Endocr Relat Cancer
14:979, 2007.
Ellison DH, Berl T: The syndrome of inappropriate antidiuresis.
N Engl J Med 356:2064, 2007.
Isidori AM et al: The ectopic adrenocorticotropin syndrome: Clinical
features, diagnosis, management and long-term follow-up. J Clin
Endocrinol Metab 91:371, 2006.
6/1/18 5:42 PM
 ■■COMPLICATIONS
Perhaps no other condition in clinical medicine has caused otherwise
astute physicians to intervene inappropriately more often than throm-
bocytosis, particularly if the platelet count is >1 × 106/μL. It is com-
monly believed that a high platelet count causes thrombosis; however,
no controlled clinical study has ever established this association, and
in patients younger than age 60 years, the incidence of thrombosis was
not greater in patients with thrombocytosis than in age-matched con-
trols, and tobacco use appears to be the most important risk factor for
thrombosis in ET patients.
To the contrary, very high platelet counts are associated primarily
with hemorrhage due to acquired von Willebrand’s disease. This is not
meant to imply that an elevated platelet count cannot cause symptoms
in an ET patient, but rather that the focus should be on the patient, not
the platelet count. For example, some of the most dramatic neurologic
problems in ET are migraine-related and respond only to lowering of
the platelet count, whereas other symptoms such as erythromelalgia
respond simply to platelet cyclooxygenase-1 inhibitors such as aspirin
or ibuprofen, without a reduction in platelet number. Still others may
represent an interaction between an atherosclerotic vascular system
and a high platelet count, and others may have no relationship to the
platelet count whatsoever. Recognition that PV can present with throm-
bocytosis alone as well as the discovery of previously unrecognized
causes of hypercoagulability (Chap. 113) make the older literature on
the complications of thrombocytosis unreliable.
TREATMENT
Essential Thrombocytosis
Survival of ET patients is not different than the general population
regardless of their driver mutation. An elevated platelet count in
an asymptomatic patient without cardiovascular risk factors or
tobacco use requires no therapy. Indeed, before any therapy is initi-
ated in a patient with thrombocytosis, the cause of symptoms must
be clearly identified as due to the elevated platelet count. When the
platelet count rises above 1 × 106/μL, a substantial quantity of high-
molecular-weight von Willebrand multimers are removed from
the circulation and destroyed by the enlarged platelet mass, result-
ing in an acquired form of von Willebrand’s disease. This can be
identified by a reduction in ristocetin cofactor activity. In this sit-
uation, aspirin could promote hemorrhage. Bleeding in this situa-
tion is rarely spontaneous and usually responds to ε-aminocaproic
acid, which can be given prophylactically before and after elective
surgery. Plateletpheresis is at best a temporary and inefficient
remedy that is rarely required. Importantly, ET patients treated
with 32P or alkylating agents are at risk of developing acute leuke-
mia without any proof of benefit; combining either therapy with
hydroxyurea increases this risk. If platelet reduction is deemed
necessary on the basis of symptoms refractory to salicylates
alone, pegylated IFN-α, the quinazoline derivative, anagrelide, or
hydroxyurea can be used to reduce the platelet count, but none
of these is uniformly effective or without significant side effects.
Hydroxyurea and aspirin are more effective than anagrelide and
aspirin for prevention of TIA because hydroxyurea is an NO
donor, but not more effective for the prevention of other types of
arterial thrombosis and actually less effective for venous thrombo-
sis. The risk of gastrointestinal bleeding is also higher when aspi-
rin is combined with anagrelide. Normalizing the platelet count
does not prevent either arterial or venous thrombosis. Pegylated
interferon can produce a complete molecular remission in some
ET patients, but a role for it or ruxolitinib in ET management has
not yet been established.
As more clinical experience is acquired, ET appears more benign
than previously thought. Evolution to acute leukemia is more likely
to be a consequence of therapy than of the disease itself. In manag-
ing patients with thrombocytosis, the physician’s first obligation is
to do no harm.
Harrisons_20e_Part4_p0435-p0858.indd 739
■■FURTHER READING 739
Alvarez-Larran A et al: Antiplatelet therapy versus observation in
low-risk essential thrombocythemia with CALR mutation. Haemato-
logica 101:926, 2016.
Lamy T et al: Inapparent polycythemia vera: An unrecognized diagno-
sis. Am J Med 102:14, 1997.
Marchioli R et al: Cardiovascular events and intensity of treatment in
polycythemia vera. N Engl J Med 368:22, 2013.
Vannucchi AM et al: Ruxolitinib versus standard therapy for the treat-
ment of polycythemia vera. N Engl J Med 372:426, 2015.
Verstovsek S et al: A double-blind, placebo-controlled trial of ruxoli-
tinib for myelofibrosis. N Engl J Med 366:799, 2012.
100 Acute Myeloid Leukemia
William Blum, Clara D. Bloomfield
CHAPTER 100 Acute Myeloid Leukemia
INCIDENCE
Acute myeloid leukemia (AML) is a neoplasm characterized by infiltra-
tion of the blood, bone marrow, and other tissues by proliferative, clonal,
poorly differentiated cells of the hematopoietic system. These leukemias
comprise a spectrum of malignancies that, untreated, are uniformly fatal.
In 2016, the estimated number of new AML cases in the United States
was 19,950, comprising ~1.2% of all cancer cases. AML is the most com-
mon acute leukemia in older patients, with a median age at diagnosis of
67 years. Long-term survival is infrequent; U.S. registry data report that
only 27% of patients survive 5 years.
■■ETIOLOGY
Most cases of AML are idiopathic. Genetic predisposition, radiation,
chemical/other occupational exposures, and drugs have been implicated
in the development of AML, but AML cases with established etiology
are relatively rare. No direct evidence suggests a viral etiology. Genome
sequencing studies suggest that most cases of AML arise from a limited
number of mutations that accumulate with advancing age. Indeed,
genome sequencing is providing paradigm-shifting advances in our
understanding of leukemogenesis. The Cancer Genome Atlas (TCGA)
and other databases demonstrate that blood cells from up to 5–6% of
normal individuals aged >70 years contain potentially “premalignant”
mutations that are associated with clonal expansion. The additional
insults that subsequently direct “premalignant” blood cells to leukemia
are quite heterogeneous and still poorly understood.
Genetic Predisposition  Myeloid neoplasms typically occur spo-
radically in adults; inherited predisposition is rare. Yet, it is clear that
myeloid neoplasms with germline predisposition represent an impor-
tant and growing subset of disease. Germline mutations associated
with increased risk of developing a myeloid neoplasm include CEBPA,
DDX41, RUNX1, ANKRD26, ETV6, and GATA2 (Table 100-1). Likewise,
myeloid neoplasms with germline predisposition are a feature of sev-
eral well-described clinical syndromes, including bone marrow failure
disorders (e.g., Fanconi anemia, Shwachman-Diamond syndrome,
Diamond-Blackfan anemia), and telomere biology disorders (e.g., dys-
keratosis congenita). As new mutations and associations are added to a
rapidly growing list, it is increasingly clear that genetic predisposition
plays a larger role than has been previously understood.
Several genetic syndromes with somatic cell chromosome aneu-
ploidy, such as Down syndrome with trisomy 21, are associated with
an increased incidence of AML. Down syndrome–associated AML
in young children (<4 years) is typically of the acute megakaryocytic
subtype and is associated with mutation in the GATA1 gene. Such
patients have excellent clinical outcomes but require dose modification
of chemotherapy due to high treatment-related toxicities. Inherited
6/1/18 5:43 PM
 740 TABLE 100-1  WHO 2016 Classification of Myeloid Neoplasms
with Germline Predisposition
CLASSIFICATIONa
Myeloid neoplasms with germline predisposition without a preexisting
disorder or organ dysfunction
  Acute myeloid leukemia with germline CEBPA mutation
  Myeloid neoplasms with germline DDX41 mutationb
Myeloid neoplasms with germline predisposition and preexisting platelet
disorders
  Myeloid neoplasms with germline RUNX1 mutationb
  Myeloid neoplasms with germline ANKRD26 mutationb
  Myeloid neoplasms with germline ETV6 mutationb
Myeloid neoplasms with germline predisposition and other organ dysfunction
  Myeloid neoplasms with germline GATA2 mutation
  Myeloid neoplasms associated with bone marrow failure syndromes
  Myeloid neoplasms associated with telomere biology disorders
  Myeloid neoplasms associated with Noonan syndrome
  Myeloid neoplasms associated with Down syndromeb
a
Recognition of familial myeloid neoplasms requires that physicians take a
thorough patient and family history to assess for typical signs and symptoms
of known syndromes, including data on malignancies and previous bleeding
episodes. Molecular genetic diagnostics is guided by a detailed patient and family
history. Diagnostics should be performed in close collaboration with a genetic
PART 4
counselor; patients with a suspected heritable myeloid neoplasm, who test
negative for known predisposition genes, should ideally be entered on a research
study to facilitate new syndrome discovery. bLymphoid neoplasms also reported.
Source: Adapted from Peterson L et al: Myeloid Neoplasms with Germline
Predisposition, in World Health Organization Classification of Tumours of
Oncology and Hematology
Haematopoietic and Lymphoid Tissues, update to 4th ed. IARC, 2017.
diseases with defective DNA repair (e.g., Fanconi anemia, Bloom syn-
drome, and ataxia-telangiectasia) are also associated with AML. Each
syndrome is associated with unique clinical features and atypical toxic-
ities with chemotherapy, requiring expert care. Congenital neutropenia
(Kostmann syndrome), due to mutations in the genes encoding the
granulocyte colony-stimulating factor receptor and neutrophil elastase,
is another disorder that may evolve into AML.
Chemical, Radiation, and Other Exposures  Anticancer
drugs are the leading cause of therapy-associated AML. Alkylating
agent–associated leukemias occur on average 4–6 years after exposure,
and affected individuals often have multilineage dysplasia and mono-
somy/aberrations in chromosomes 5 and 7. Topoisomerase II inhibi-
tor–associated leukemias occur 1–3 years after exposure, and affected
individuals often have AML with monocytic features and aberrations
involving chromosome 11q23. Exposure to ionizing radiation, benzene,
chloramphenicol, phenylbutazone, and other drugs can uncommonly
result in bone marrow failure that may evolve into AML.
■■CLASSIFICATION
The current categorization of AML uses the World Health Organiza-
tion (WHO) classification (Table 100-2), which defines biologically
distinct groups based on cytogenetic and molecular abnormalities in
addition to clinical features and light microscope morphology. Mye-
loid neoplasms with germline predisposition, as introduced above,
are included as a new and important feature of this classification
(Table 100-1). The WHO classification enables the identification of
subsets of disease that may now (or in the future) be treated differently
and advances the care of AML patients by enhancing recognition of
the molecular basis of the disease from the time of diagnosis. Marrow
(or blood) blast count of ≥20% is required to establish the diagnosis of
AML, except for AML with the recurrent genetic abnormalities t(15;17),
t(8;21), inv(16), or t(16;16).
Clinical Features  Even with advances in molecular biology, rec-
ognizing clinical features remains important in understanding AML.
For example, therapy-related AML is a distinct entity that develops
following prior chemotherapy (e.g., alkylating agents, topoisomerase
II inhibitors) or ionizing radiation. AML with myelodysplasia-related
Harrisons_20e_Part4_p0435-p0858.indd 740
TABLE 100-2  WHO 2016 Classification of Acute Myeloid Leukemia
and Related Neoplasms
Acute myeloid leukemia (AML) with recurrent genetic abnormalities
  AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Acute promyelocytic leukemia with PML-RARA
  AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A
  AML with t(6;9)(p23;q34.1); DEK-NUP214
  AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
  AML (megakaryoblastic) with t(1;22)(p13.3;q13.3); RBM15-MKL1
  Provisional entity: AML with BCR-ABL1
  AML with mutated NPM1
  AML with biallelic mutations of CEBPA
  Provisional entity: AML with mutated RUNX1
AML with myelodysplasia-related changes
  Therapy-related myeloid neoplasms
AML, not otherwise specified (NOS)
  AML with minimal differentiation
  AML without maturation
  AML with maturation
  Acute myelomonocytic leukemia
  Acute monoblastic/monocytic leukemia
  Pure erythroid leukemia
  Acute megakaryoblastic leukemia
  Acute basophilic leukemia
  Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to Down syndrome
  Transient abnormal myelopoiesis (TAM)
  Myeloid leukemia associated with Down syndrome
Note: Marrow blast count of ≥20% is required, except for AML with the recurrent
genetic abnormalities t(15;17), t(8;21), inv(16), or t(16;16).
Source: Adapted from Arber DA et al: Acute myeloid leukaemia (AML) with
recurrent genetic abnormalities, in World Health Organization Classification of
Tumours of Haematopoietic and Lymphoid Tissues, update to 4th ed. IARC, 2017.
changes is recognized based in part on morphology but also on a
medical history of an antecedent myelodysplastic syndrome (MDS) or
myelodysplastic/myeloproliferative neoplasm. These clinical features
contribute to AML prognosis and have therefore been included in the
WHO classification.
Genetic Findings  Subtypes of AML are recognized based on
the presence or absence of specific, recurrent cytogenetic, and/or
genetic abnormalities. For example, the diagnosis of acute promyelo-
cytic leukemia (APL) is based on the presence of either the t(15;17)(q22;q12)
cytogenetic rearrangement or the PML-RARA fusion product of the
translocation. Similarly, core binding factor (CBF) AML is designated
based on the presence of t(8;21)(q22;q22), inv(16)(p13.1q22), or t(16;16)
(p13.1;q22) or the respective fusion products RUNX1-RUNX1T1 and
CBFB-MYH11. Each of these groups identifies patients with favorable
clinical outcomes when appropriately treated.
Several cytogenetic or genetic AML subtypes often associate with a
specific morphologic appearance, such as a complex karyotype and AML
with myelodysplasia-related changes. Patients with such changes typ-
ically fare poorly with standard treatments. However, only one cyto-
genetic abnormality is invariably associated with specific morphologic
features: t(15;17)(q22;q12) with APL. Other cytogenetic and genetic
findings may be commonly but not invariably associated with a mor-
phological description, highlighting the necessity of genetic and cyto-
genetic testing beyond simple morphology to most accurately diagnose
AML. Several chromosomal abnormalities often associate primarily
with one morphologic/immunophenotypic group. Examples include
inv(16)(p13.1q22) with AML with abnormal bone marrow eosino-
phils; t(8;21)(q22;q22) with slender Auer rods, expression of CD19,
and increased normal eosinophils; and t(9;11)(p22;q23), and other
6/1/18 5:43 PM
 translocations involving 11q23, with monocytic features. Recurring
chromosomal abnormalities in AML may also be loosely associated
with specific clinical characteristics. More commonly associated with
younger age are t(8;21) and t(15;17), and with older age, del(5q) and
del(7q). Myeloid sarcomas are associated with t(8;21); disseminated
intravascular coagulation (DIC) is associated with t(15;17). 11q23 aber-
rations and monocytic leukemia are associated with extramedullary
sites of involvement at presentation, especially gingival hypertrophy.
The WHO classification also incorporates molecular abnormalities
by recognizing fusion genes or specific genetic mutations with a role
in leukemogenesis. As a classic example, t(15;17) results in the fusion
gene PML-RARA that encodes a chimeric protein, promyelocytic leu-
kemia (Pml)–retinoic acid receptor α (Rarα), which is formed by the
fusion of the retinoic acid receptor α (RARA) gene from chromosome
17 and the promyelocytic leukemia (PML) gene from chromosome 15.
The RARA gene encodes a member of the nuclear hormone receptor
family of transcription factors. PML is important in many cellular
processes, including cell growth control, apoptosis, and senescence;
its effects are mediated at least in part by nuclear bodies that store a
myriad of proteins/enzymes that are involved in these functions. The
PML-RARA fusion protein suppresses gene transcription and blocks
differentiation beyond the promyelocyte stage. Pharmacologic concen-
trations of the Rarα ligand, achieved with the drug all-trans-retinoic
acid (tretinoin, ATRA), relieve the block and promote hematopoietic
cell differentiation. However, the effects of ATRA are not primarily
from direct restoration of gene transactivation via RA signaling. Rather,
drug treatment induces degradation of the fusion protein. Mechanistic
work has demonstrated that the RARA fusion partner PML is far more
important in the pathobiology than was initially understood. PML-
RARA disturbs nuclear body assembly. This impairs many PML func-
tions, culminating in enhanced self-renewal of leukemic cells. ATRA
and arsenic trioxide (ATO) both induce PML-RARA degradation (by
different mechanisms), leading to reformation of PML nuclear bodies
(or enhanced nuclear body activity). Restored PML functions include
the activation of p53 which triggers senescence in leukemic cells. Clin-
ical therapy with ATRA and ATO has revolutionized the care of APL
patients (see “Treatment of Acute Promyelocytic Leukemia” section).
Similar examples of molecular subtypes included in the category
of AML with recurrent genetic abnormalities are those characterized
by the leukemogenic fusion genes RUNX1-RUNX1T1, CBFB-MYH11,
MLLT3-KMT2A, and DEK-NUP214, resulting, respectively, from t(8;21),
inv(16) or t(16;16), t(9;11), and t(6;9)(p23;q34).
The WHO classification of AML continues to expand as knowledge
of specific genetic or cytogenetic aberrations grows. Several AML
subtypes are defined by the presence of genetic mutations rather than
chromosomal aberrations including, for example, AML with mutated
nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPM1) and AML
with biallelic mutated CEBPA, respectively. Both entities are associated
with more favorable clinical outcomes, though the NPM1 prognostic
impact is affected by coexisting mutation in fms-related tyrosine kinase
3 (FLT3). Activating mutations of FLT3 are present in ~30% of adult
AML patients, primarily due to internal tandem duplications (ITD) in
the juxtamembrane domain that have negative prognostic impact. In
contrast, point mutations of the activating loop of the kinase (called
tyrosine kinase domain [TKD] mutations) have uncertain prognostic
impact. Aberrant activation of the FLT3-encoded protein provides
increased proliferation and antiapoptotic signals to the myeloid pro-
genitor cell. FLT3-ITD, the more common of the FLT3 mutations, occurs
preferentially in patients with cytogenetically normal AML (CN-AML).
The importance of identifying FLT3-ITD at diagnosis relates to the
fact that is it useful not only as a prognosticator but also may predict
response to specific treatment such as a tyrosine kinase inhibitor (TKI);
several TKI are currently in clinical investigation (e.g., midostaurin,
quizartinib, gilteritinib, crenolanib, sorafenib). The FLT3 allelic ratio (of
the number of mutated alleles to wild type alleles) provides informa-
tion beyond the mere presence or absence of the mutation. The ratio is
affected by several mutational scenarios such as one mutated gene and
one wild type gene, or one mutated gene with no (deleted) wild type
gene, and the ratio of malignant to nonmalignant cells in the sample.
Harrisons_20e_Part4_p0435-p0858.indd 741
TABLE 100-3  2017 European LeukemiaNet Risk Stratification by 741
Genetics for Acute Myeloid Leukemiaa
RISK CATEGORYb GENETIC ABNORMALITY
Favorable t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1q22) or t(16;16)(p13.1;q22);
CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow(c)
Biallelic mutated CEBPA
Intermediate Mutated NPM1 and FLT3-ITDhigh(c)
Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow(c)
(w/o adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2Ad
Cytogenetic abnormalities not classified as favorable
or adverse
Adverse t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,
MECOM(EVI1)
–5 or del(5q); –7; –17/abn(17p)
Complex karyotype,e monosomal karyotypef
CHAPTER 100 Acute Myeloid Leukemia
Wild type NPM1 and FLT3-ITDhigh(c)
Mutated RUNX1g
Mutated ASXL1g
Mutated TP53h
a
This table excludes acute promyelocytic leukemia. Frequencies, response rates,
and outcome measures should be reported by risk category, and, if sufficient
numbers are available, by specific genetic lesions indicated. bPrognostic impact of
a marker is treatment-dependent and may change with new therapies. cLow, low
allelic ratio (<0.5); high, high allelic ratio (≥0.5); semiquantitative assessment
of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio
of the area under the curve (AUC) “FLT3-ITD” divided by AUC “FLT3-wild type”;
recent studies indicate that acute myeloid leukemia with NPM1 mutation and
FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients
should not routinely be assigned to allogeneic hematopoietic-cell transplantation.
d
The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent
adverse-risk gene mutations. eThree or more unrelated chromosome abnormalities
in the absence of one of the World Health Organization-designated recurring
translocations or inversions, i.e., t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)
(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1. fDefined by the presence
of one single monosomy (excluding loss of X or Y) in association with at least
one additional monosomy or structural chromosome abnormality (excluding core-
binding factor AML). gThese markers should not be used as an adverse prognostic
marker if they co-occur with favorable-risk AML subtypes. hTP53 mutations are
significantly associated with AML with complex and monosomal karyotype.
Source: Adapted from Döhner H et al: Diagnosis and management of acute
myeloid leukemia in adults: 2017 recommendations from an international expert
panel, on behalf of the European LeukemiaNet. Blood 129:424, 2017.
The allelic ratio affects the prognostic impact of the FLT3-ITD mutation;
patients with FLT3-ITD “low” allelic ratio (<0.5) fare better. Accord-
ingly, mutated NPM1 without FLT3-ITD or with FLT3-ITDlow are both
viewed as favorable-risk by the European LeukemiaNet (ELN) risk
stratification schema (Table 100-3). Conversely, FLT3-ITDhigh is known
to have an adverse prognostic impact; patients with mutated NPM1
and FLT3-ITD with an allelic ratio >0.5 are thus intermediate-risk by
ELN stratification. Involving a different tyrosine kinase, AML with
BCR-ABL1 fusion is a new WHO provisional entity, to recognize rare
cases that may benefit from BCR-ABL TKI therapy (Table 100-2).
Immunophenotypic Findings  The immunophenotype of
human leukemia cells can be studied by multiparameter flow cytome-
try after the cells are labeled with monoclonal antibodies to cell-surface
antigens. This can be important in quickly distinguishing AML from
acute lymphoblastic leukemia and for identifying some subtypes of
AML. For example, AML with minimal differentiation, characterized
by immature morphology and no lineage-specific cytochemical reac-
tions, may be diagnosed by flow-cytometric demonstration of the
myeloid-specific antigens cluster designation (CD) 13 and/or 117.
Similarly, acute megakaryoblastic leukemia can often be diagnosed
only by expression of the platelet-specific antigens CD41 and/or CD61.
6/1/18 5:43 PM
 742 Although flow cytometry is widely used, and in some cases essential TABLE 100-4  Molecular Prognostic Markers in AMLa
for the diagnosis of AML, it has only a supportive role in establishing
GENE SYMBOL GENE LOCATION PROGNOSTIC IMPACT
the different subtypes of AML through the WHO classification. Increas-
ingly, multiparameter flow cytometry is used for the measurement of Genes Included in the WHO Classification and ELN Reporting System
minimal residual disease (MRD) after remission is achieved. NPM1 mutations 5q35.1 Favorable
CEBPA mutations 19q13.1 Favorable
■■PROGNOSTIC FACTORS FLT3-ITD 13q12 Depends on allelic ratio
Several factors predict outcome of AML patients treated with che- and NPM1 mutational
motherapy; they should be used for risk stratification and treatment status
guidance. Genes Encoding Receptor Tyrosine Kinases
Chromosome findings at diagnosis currently provide the most KIT mutation 4q12 Adverse
important independent prognostic information. Several reports have FLT3-TKD 13q12 Unclear
categorized patients as having favorable, intermediate, or adverse Genes Encoding Transcription Factors
cytogenetic risk based on the presence of structural and/or numerical
RUNX1 mutations 21q22.12 Adverse
aberrations. Patients with t(15;17) have a very good prognosis (~85%
WT1 mutations 11p13 Adverse
cured), and those with t(8;21) and inv(16) have a good prognosis
(~55% cured), whereas those with no cytogenetic abnormality have Genes Encoding Epigenetic Modifiers
an intermediate outcome risk (~40% cured). Patients with a complex ASXL1 mutations 20q11.21 Adverse
karyotype, t(6;9), inv(3), or –7 have a very poor prognosis. Another DNMT3A mutations 2p23.3 Adverse
cytogenetic subgroup, the monosomal karyotype, has been suggested IDH mutations (IDH1 and 2q34 & 15q26.1 Adverse
to adversely impact the outcome of AML patients other than those IDH2)
with t(15;17), t(8;21), or inv(16) or t(16;16). The monosomal karyotype KMT2A-PTD 11q23 Adverse
subgroup is defined by the presence of at least two autosomal mono- TET2 mutations 4q24 Adverse
PART 4

somies (loss of chromosomes other than Y or X) or a single autosomal Deregulated Genes

monosomy with additional structural abnormalities.
BAALC overexpression 8q22.3 Adverse
For patients lacking prognostic cytogenetic abnormalities, such as
those with CN-AML, testing for several mutated genes can help to ERG overexpression 21q22.3 Adverse
risk-stratify. In addition to the NPM1 mutation and/or FLT3-ITD as MN1 overexpression 22q12.1 Adverse
Oncology and Hematology

described above, biallelic CEBPA mutations have prognostic value.
Such mutations predict favorable outcome. Given the proven prognos-
tic importance of NPM1, CEBPA, and FLT3, molecular assessment of
these genes at diagnosis has been incorporated into AML management
guidelines by the National Comprehensive Cancer Network (NCCN)
and the ELN. The same markers help to define genetic groups in the
ELN standardized reporting system, which is based on both cytoge-
netic and molecular abnormalities and is used for comparing clinical
features/treatment response among subsets of patients reported across
different clinical studies (Table 100-3). These genetic groups should be
used for risk stratification and treatment guidance.
In addition to NPM1 and CEBPA mutations and FLT3-ITD, molec-
ular aberrations in other genes may be routinely used for prognos-
tication in the future (Table 100-4). Among these mutated genes are
those encoding receptor tyrosine kinases (e.g., v-kit Hardy-Zuckerman
4 feline sarcoma viral oncogene homolog [KIT]), transcription factors
(i.e., RUNX1 and Wilms tumor 1 [WT1]), and epigenetic modifiers
(i.e., additional sex combs like transcriptional regulator 1 [ASXL1],
DNA (cytosine-5-)-methyltransferase 3 alpha [DNMT3A], isocitrate
dehydrogenase 1 [NADP+], soluble [IDH1], isocitrate dehydrogenase
2 (NADP+), mitochondrial [IDH2], lysine (K)–specific methyltrans-
ferase 2A [KMT2A, also known as MLL], and tet methylcytosine
dioxygenase 2 [TET2]). Although KIT mutations are almost exclusively
present in CBF AML and impact adversely the outcome, the remaining
markers have been reported primarily in CN-AML. These gene muta-
tions have been shown to be associated with outcome in multivariable
analyses independent of other prognostic factors. However, for some of
them, data remain unclear on the prognostic impact due to conflicting
reports (e.g., TET2, IDH1, IDH2). Increasingly, novel drugs that inhibit/
modulate aberrant pathways activated by some of these genes (e.g.,
IDH1, IDH2, KMT2A, among others) are being incorporated into clini-
cal trials to treat AML.
In addition to gene mutations, deregulation of the expression
levels of coding genes and of short noncoding RNAs (microRNAs)
also provide prognostic information (Table 100-4). Overexpression of
genes such as brain and acute leukemia, cytoplasmic (BAALC), v-ets
avian erythroblastosis virus E26 oncogene homologue (avian) (ERG),
meningioma (disrupted in balanced translocation) 1 (MN1), and MDS1
and EVI1 complex locus (MECOM, also known as EVI1) predict poor
outcome, especially in CN-AML. Similarly, deregulated expression lev-
els of microRNAs, naturally occurring noncoding RNAs that regulate
EVI1 overexpression 3q26.2 Adverse
Deregulated MicroRNAs
miR-155 overexpression 21q21.3 Adverse
miR-3151 overexpression 8q22.3 Adverse
miR-181a overexpression 1q32.1 and 9q33.3 Favorable
a
This table excludes acute promyelocytic leukemia.
Abbreviations: AML, acute myeloid leukemia; ELN, European LeukemiaNet; ITD,
internal tandem duplication; PTD, partial tandem duplication; TKD, tyrosine kinase
domain; WHO, World Health Organization.
the expression of proteins via degradation or translational inhibition of
their target coding RNAs, have also been associated with prognosis in
AML. Overexpression of miR-155 and miR-3151 predicts unfavorable
outcome in CN-AML, whereas overexpression of miR-181a predicts
favorable outcome both in CN-AML and cytogenetically abnormal
AML.
Because prognostic molecular markers in AML are not mutually
exclusive and often occur concurrently (>80% patients have at least
two or more prognostic gene mutations), the likelihood that distinct
marker combinations may be more informative than single markers is
increasingly clear.
Epigenetic changes (e.g., DNA methylation and/or post-translational
histone modification) and microRNAs are often involved in deregu-
lation of genes involved in hematopoiesis, contribute to leukemo-
genesis and may associate with the previously discussed prognostic
gene mutations. These changes have been shown to provide biologic
insights into leukemogenic mechanisms and also independent prog-
nostic information. Indeed, it is anticipated that with the enormous
progress made in DNA and RNA sequencing technology, additional
genetic and epigenetic aberrations will soon be discovered, further
improving classification and risk-stratification in AML patients.
In addition to cytogenetics and molecular aberrations, several other
factors are associated with outcome in AML. Age at diagnosis is one
of the most important risk factors. Advancing age is associated with a
poor prognosis for two reasons: (1) its influence on the ability to survive
induction therapy due to coexisting medical comorbidities, and (2) with
each successive decade of age, a greater proportion of patients have
intrinsically more resistant disease. A prolonged symptomatic interval
with cytopenias preceding AML diagnosis, or a history of antecedent

Harrisons_20e_Part4_p0435-p0858.indd 742 6/1/18 5:43 PM

 hematologic disorders including MDS or myeloproliferative neoplasms,
is often found in older patients. Cytopenia is a clinical feature associated
with a lower complete remission (CR) rate and shorter survival time.
The CR rate is lower in patients who have had anemia, leukopenia,
and/or thrombocytopenia for >3 months before the diagnosis of AML,
when compared to those without such a history. Responsiveness to
chemotherapy declines as the duration of the antecedent disorder
increases. Likewise, AML developing after treatment with cytotoxic
agents for other malignancies is usually difficult to treat successfully.
In addition, older patients less frequently harbor favorable cytogenetic
abnormalities (i.e., t[8;21], inv[16], and t[16;16]) and more frequently
harbor adverse cytogenetic (e.g., complex and monosomal karyotypes)
and/or molecular (e.g., ASXL1, p53) abnormalities.
Other factors independently associated with worse outcome are a
poor performance status that influences ability to survive induction
therapy and a high presenting leukocyte count that in some series is
an adverse prognostic factor for attaining a CR. Among patients with
hyperleukocytosis (>100,000/μL), early central nervous system bleed-
ing and pulmonary leukostasis contribute to poor outcomes.
Following administration of therapy, achievement of CR is asso-
ciated with better outcome and longer survival. CR is defined after
examination of both blood and bone marrow and essentially represents
both eradication of detectable leukemia and restoration of normal
hematopoiesis. The blood neutrophil count must be ≥1000/μL and the
platelet count ≥100,000/μL. Hemoglobin concentration is not consid-
ered in determining CR. Circulating blasts should be absent. Although
rare blasts may be detected in the blood during marrow regeneration,
they should disappear on successive studies. At CR, the bone marrow
should contain <5% blasts, and Auer rods should be absent. Extramed-
ullary leukemia should not be present.
■■CLINICAL PRESENTATION
Symptoms  Patients with AML usually present with nonspecific
symptoms that begin gradually, or abruptly, and are the consequence
of anemia, leukocytosis, leukopenia/leukocyte dysfunction, or throm-
bocytopenia. Nearly half have symptoms for ≤3 months before the
leukemia is diagnosed.
Fatigue is a frequent first symptom among AML patients. Anorexia
and weight loss are common. Fever with or without an identifiable
infection is the initial symptom in ~10% of patients. Signs of abnormal
hemostasis (bleeding, easy bruising) are common. Bone pain, lymph-
adenopathy, nonspecific cough, headache, or diaphoresis may also
occur.
Rarely, patients may present with symptoms from a myeloid sar-
coma (a tumor mass consisting of myeloid blasts occurring at anatomic
sites other than bone marrow). Sites involved are most commonly the
skin, lymph node, gastrointestinal tract, soft tissue, and testis. This
rare presentation, often characterized by chromosome aberrations
(e.g., monosomy 7, trisomy 8, 11q23 rearrangement, inv[16], trisomy 4,
t[8;21]), may precede or coincide with blood and/or marrow involve-
ment by AML. Patients who present with isolated myeloid sarcoma
typically develop blood and/or marrow involvement quickly thereaf-
ter and cannot be cured with local therapy (radiation or surgery) alone.
Physical Findings  Fever, infection, and hemorrhage are often
found at the time of diagnosis; splenomegaly, hepatomegaly, lymph-
adenopathy, and “bone pain” may also be present less commonly.
Hemorrhagic complications are most commonly and, classically,
found in APL. APL patients often present with DIC-associated
minor hemorrhage but may have significant gastrointestinal bleeding,
intrapulmonary hemorrhage, or intracranial hemorrhage. Likewise,
thrombosis is another less frequent but well recognized clinical fea-
ture of DIC in APL. Bleeding associated with coagulopathy may also
occur in monocytic AML and with extreme degrees of leukocytosis
or thrombocytopenia in other morphologic subtypes. Retinal hemor-
rhages are detected in 15% of patients. Infiltration of the gingiva, skin,
soft tissues, or meninges with leukemic blasts at diagnosis is charac-
teristic of the monocytic subtypes and those with 11q23 chromosomal
abnormalities.
Harrisons_20e_Part4_p0435-p0858.indd 743
Hematologic Findings  Anemia is usually present at diagnosis 743
though it is not typically severe. The anemia is usually normocytic
normochromic. Decreased erythropoiesis in the setting of AML often
results in a reduced reticulocyte count, and red blood cell (RBC) sur-
vival is decreased by accelerated destruction. Active blood loss may
rarely contribute to the anemia.
The median presenting leukocyte count is ~15,000/μL. Lower
presenting leukocyte counts are more typical of older patients and
those with antecedent hematologic disorders. Between 25 and 40% of
patients have counts <5000/μL, and 20% have counts >100,000/μL.
Fewer than 5% have no detectable leukemic cells in the blood. In AML,
the cytoplasm often contains primary (nonspecific) granules, and the
nucleus shows fine, lacy chromatin with one or more nucleoli charac-
teristic of immature cells. Abnormal rod-shaped granules called Auer
rods are not uniformly present, but when they are, AML is virtually
certain (Fig. 100-1).
Platelet counts <100,000/μL are found at diagnosis in ~75% of
patients, and ~25% have counts <25,000/μL. Both morphologic and
functional platelet abnormalities can be observed, including large and
bizarre shapes with abnormal granulation and inability of platelets to
aggregate or adhere normally to one another.
Pretreatment Evaluation  Once the diagnosis of AML is sus-
CHAPTER 100 Acute Myeloid Leukemia
pected, thorough evaluation and initiation of appropriate therapy
should follow. In addition to clarifying the subtype of leukemia, initial
studies should evaluate the overall functional integrity of the major
organ systems, including the cardiovascular, pulmonary, hepatic, and
renal systems (Table 100-5). Factors that have prognostic significance,
either for achieving CR or for predicting CR duration, should also be
assessed before initiating treatment, including cytogenetics and molec-
ular markers. Leukemic cells should be obtained from all patients and
cryopreserved for future investigational testing as well as potential
future use as new diagnostics and therapeutics become available. All
patients should be evaluated for infection.
Most patients are anemic and thrombocytopenic at presentation.
Replacement of the appropriate blood components, if necessary, should
begin promptly. Because qualitative platelet dysfunction or the pres-
ence of an infection may increase the likelihood of bleeding, evidence
of hemorrhage justifies the immediate use of platelet transfusion, even
if the platelet count is only moderately decreased.
About 50% of patients have a mild to moderate elevation of serum
uric acid at presentation. Only 10% have marked elevations, but renal
precipitation of uric acid and the nephropathy that may result is a seri-
ous but uncommon complication. The initiation of chemotherapy may
aggravate hyperuricemia, and patients are usually started immediately
on allopurinol and hydration at diagnosis. Rasburicase (recombinant
uric oxidase) is also useful for treating uric acid nephropathy and often
can normalize the serum uric acid level within hours with a single
dose of treatment, although its expense suggests that limiting its use
to patients with severe hyperuricemia and/or kidney injury may be
prudent. The presence of high concentrations of lysozyme, a marker for
monocytic differentiation, may be etiologic in renal tubular dysfunc-
tion for a minority of patients.
TREATMENT
Acute Myeloid Leukemia
Treatment of the newly diagnosed patient with AML is usually
divided into two phases, induction and postremission management
(consolidation) (Fig. 100-2). The initial goal is to induce CR. Once
CR is obtained, further therapy must be given to prolong survival
and achieve cure. The initial induction treatment and subsequent
postremission therapy are chosen based on the patient’s age, overall
fitness, and cytogenetic/molecular risk. Intensive therapy with cyta-
rabine and anthracyclines in younger patients (<60 years) increases
the cure rate of AML. In older patients, the benefit of intensive
therapy is controversial in all but favorable-risk patients; novel
approaches for selecting patients predicted to be responsive to treat-
ment and new therapies are being pursued.
6/1/18 5:43 PM
 744
A B
PART 4
Oncology and Hematology
C D
FIGURE 100-1  Morphology of acute myeloid leukemia (AML) cells. A. Uniform population of primitive myeloblasts with immature chromatin, nucleoli in some cells,
and primary cytoplasmic granules. B. Leukemic myeloblast containing an Auer rod. C. Promyelocytic leukemia cells with prominent cytoplasmic primary granules.
D. Peroxidase stain shows dark blue color characteristic of peroxidase in granules in AML.
INDUCTION CHEMOTHERAPY
The most commonly used induction regimens (for patients other
than those with APL) consist of combination chemotherapy with
cytarabine and an anthracycline (e.g., daunorubicin, idarubicin).
Cytarabine is a cell cycle S-phase–specific antimetabolite that
becomes phosphorylated intracellularly to an active triphosphate
form that interferes with DNA synthesis. Anthracyclines are DNA
intercalators. Their primary mode of action is thought to be inhibi-
tion of topoisomerase II, leading to DNA breaks.
In adults, cytarabine used at standard dose (100–200 mg/m2) is
administered as a continuous intravenous infusion for 7 days. With
cytarabine, anthracycline therapy generally consists of daunorubicin
(60–90 mg/m2) or idarubicin (12 mg/m2) intravenously on days
1, 2, and 3 (the 7 and 3 regimen). Other agents can be added (e.g.,
cladribine) when 60 mg/m2 of daunorubicin is used. With the 7 and
3 regimen, it is now clearly established that 45 mg/m2 dosing of
daunorubicin results in inferior outcomes; patients should receive
higher doses as described. Patients failing remission after one induc-
tion are offered reinduction with the same (or slightly modified)
therapy.
In older patients (age ≥60–65 years), the outcome is generally
poor due to a higher frequency of resistant disease and increased
rate of treatment-related mortality. This is especially true in
patients with prior hematologic disorders (MDS or myelopro-
liferative neoplasms), therapy-related AML, or cytogenetic and
genetic abnormalities that adversely impact on clinical outcome.
Harrisons_20e_Part4_p0435-p0858.indd 744
All older patients should be considered for clinical trials, but in
particular older patients in the adverse-risk groups delineated
above should be offered investigational approaches when possi-
ble. Conventional therapy for older patients is similar to that for
younger: the 7 and 3 regimen with standard-dose cytarabine and
idarubicin (12 mg/m2), or daunorubicin (60 mg/m2, or 90 mg/
m2 for those <65 years). For patients aged >65 years, high-dose
daunorubicin (90 mg/m2) has increased toxicity and is not recom-
mended. Older patients and those with adverse-risk genetics may
receive lower intensity therapy with a hypomethylating agent
(decitabine or azacitidine), clofarabine, or preferably investiga-
tional therapy (Table 100-6).
With the 7 and 3 regimen, 60–80% of younger and 33–60%
of older patients (among those who are candidates for intensive
therapy) with primary AML achieve CR. Of patients who do not
achieve CR, most have drug-resistant leukemia, although induction
death is more frequent with advancing age and medical comor-
bidity. Patients with refractory disease after induction should be
considered for salvage treatments, preferentially on clinical trials,
before receiving allogeneic hematopoietic stem cell transplantation
(HCT) that is usually reserved for patients in or near CR. However,
fit younger patients with primary refractory disease have ~15–20%
cure rates with allogeneic HCT (after myeloablative conditioning);
for this reason early consideration of future allogeneic HCT feasibil-
ity (including HLA typing, donor search, etc.) should be part of the
initial induction approach for most AML patients.
6/1/18 5:43 PM
 TABLE 100-5  Initial Diagnostic Evaluation and Management of
Adult Patients with AML
History
Increasing fatigue or decreased exercise tolerance (anemia)
Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
Fevers or recurrent infections (neutropenia)
Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia
or bleed)
Early satiety (splenomegaly)
Family history of AML (Fanconi, Bloom, or Kostmann syndromes or
ataxia-telangiectasia)
History of cancer (exposure to alkylating agents, radiation, topoisomerase II
inhibitors)
Occupational exposures (radiation, benzene, petroleum products, paint,
smoking, pesticides)
Physical Examination
Performance status (prognostic factor)
Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic
leukemia)
Fever and tachycardia (signs of infection)
Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
Poor dentition, dental abscesses
Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)
Skin infiltration or nodules (leukemia infiltration, most common in monocytic
leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly
Back pain, lower extremity weakness (spinal granulocytic sarcoma, most likely
in t[8;21] patients)
Laboratory and Radiologic Studies
CBC with manual differential cell count
Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid,
hepatic enzymes, bilirubin, LDH, amylase, lipase)
Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen,
d-dimer)
Viral serologies (CMV, HSV-1, varicella-zoster)
RBC type and screen
HLA typing for potential allogeneic HCT
Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry,
molecular studies for NPM1 and CEBPA mutations and FLT3-ITD)
Cryopreservation of viable leukemia cells
Myocardial function (echocardiogram or MUGA scan)
PA and lateral chest radiograph
Placement of central venous access device
Interventions for Specific Patients
Dental evaluation (for those with poor dentition)
Lumbar puncture (for those with symptoms of CNS involvement)
Screening spine MRI (for patients with back pain, lower extremity weakness,
paresthesias)
Social work referral for patient and family psychosocial support
Counseling for All Patients
Provide patients with information regarding their disease and genetic risks,
sperm banking or menstrual suppression, financial counseling, and support
group contact
Abbreviations: AML, acute myeloid leukemia; BUN, blood urea nitrogen; CBC,
complete blood count; CMV, cytomegalovirus; CNS, central nervous system;
DIC, disseminated intravascular coagulation; HLA, human leukocyte antigen;
HCT, hematopoietic stem cell transplantation; HSV, herpes simplex virus; IV,
intravenous; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging;
MUGA, multigated acquisition; PA, posteroanterior; RBC, red blood (cell) count.
POSTREMISSION THERAPY
Induction of a durable first CR (CR1) is critical to long-term survival
in AML. However, without further therapy virtually all patients
relapse. Thus, postremission therapy is designed to eradicate resid-
ual (typically undetectable) leukemic cells to prevent relapse and
prolong survival. As for induction, the type of postremission therapy
Harrisons_20e_Part4_p0435-p0858.indd 745
in AML is selected for each individual patient based on age, fitness, 745
and cytogenetic/molecular risk.
The choice between consolidation with chemotherapy or trans-
plantation is complex and based on age, risk, and practical consid-
erations. In younger patients receiving chemotherapy, postremission
therapy with intermediate/high-dose cytarabine for two to four
cycles is standard practice. Higher doses of cytarabine during post
remission therapy appear more effective than standard doses (as are
used in induction), at least for those who do not have adverse-risk
genetics. Recent studies suggest that the long-standing practice of
high-dose cytarabine (3 g/m2, every 12 h on days 1, 3, and 5) may
not improve survival over intermediate-dose cytarabine (IDAC,
1-1.5 g/m2) for such patients. Thus, the ELN has recommended
IDAC at 1–1.5 g/m2, every 12 h, on days 1–3, as the optimal post-
remission chemotherapy approach for favorable and intermedi-
ate-risk younger patients, for two to four cycles. While high-dose
cytarabine may not be necessary, it is important to note that younger
favorable-risk patients have worse outcomes when doses below
1g/m2 are used. In contrast to favorable-risk, intermediate- and
adverse-risk patients should be considered for allogeneic HCT CR1
when feasible (see transplant discussion below). As older patients
have increased toxicities with higher doses of cytarabine, ELN rec-
CHAPTER 100 Acute Myeloid Leukemia
ommends relatively attenuated cytarabine doses (0.5–1g/m2, every
12 h, on days 1–3) in favorable-risk older patients. There is no clear
value for intensive postremission therapy in non–favorable-risk
older patients; allogeneic HCT in CR1 (up to age 75 years) or inves-
tigational therapy is recommended. Indeed, postremission therapy
is an appropriate setting for introduction of new agents in both older
and younger patients (Table 100-6).
Allogeneic HCT is the best relapse-prevention strategy currently
available for AML. Allogeneic HCT is probably best understood as
an opportunity for immunotherapy; residual leukemia cells poten-
tially elicit an immunologic response from donor immune cells, the
so-called graft-versus-leukemia (GVL) effect. The benefit of GVL in
relapse risk reduction, unfortunately, is offset somewhat by increased
morbidity and mortality from complications of allogeneic HCT
including graft-versus-host disease (GVHD). Given that relapsed
AML is typically resistant to chemotherapy, allogeneic HCT in CR1 is
a favored strategy. It is recommended in patients age <75 years who
do not have favorable-risk disease and who have a human leukocyte
antigen (HLA)–matched donor (related or unrelated). We recom-
mend allogeneic HCT in CR1 for patients with intermediate-risk
disease (Table 100-3). However, considerable debate exists regarding
whether allogeneic HCT in CR1 is a requirement for younger patients
with intermediate-risk AML, as one large series from the Medical
Research Council reported that such patients have similar outcomes
if transplanted only after relapse (and achievement of CR2), sparing
some the long-term morbidity of transplantation. That said, alloge-
neic HCT is generally recommended as soon as possible after CR1
is achieved unless the patient is in a favorable-risk group. Selected
adverse-risk patients without HLA-matched donors are considered
for alternative donor transplants (e.g., HLA-mismatched unrelated,
haploidentical related, and umbilical cord blood) even in CR1.
Notably, more effective methods of in vivo T cell depletion (i.e., post-
transplant cyclophosphamide following haploidentical transplanta-
tion) have broadened the availability of potential allogeneic HCT
donors. Now, virtually any patient with a healthy parent or child
(i.e., haploidentical) has an available donor suitable for allogeneic
HCT if desired. Long-term outcomes with conventional chemother-
apy for older patients are dismal; transplantation for such patients
is expanding. For older patients, nonrandomized data demonstrate
benefit for older patients in CR1 treated with reduced-intensity con-
ditioning regimens and allogeneic HCT. Prospective data suggest
that 40% of older patients in CR1 who are candidates for allogeneic
HCT may be cured.
Trials comparing allogeneic HCT with intensive chemotherapy or
autologous HCT have shown improved duration of remission with
allogeneic HCT. However, the relapse risk reduction that is observed
with allogeneic HCT is partially offset by the increase in fatal
6/1/18 5:43 PM
 746
Diagnosis AML

Previously Refractory
a
untreated or relapsed

Salvage
Favorable-risk Intermediate-risk Adverse-risk treatment

Patient with primary induction

failure and candidate for
Either option Either option Either option
myeloablative allogeneic HCT
acceptable acceptable acceptable
or CR2 achieved with salvage
treatment, and has suitable
donor available
Induction therapy: Induction therapy: Induction therapy:
Daunorubicin+ Daunorubicin+ Daunorubicin+
Cytarabine-based Investigational Cytarabine-based Investigational Cytarabine-based Investigational
regimen therapyb regimenb,c therapyc regimenb,c therapyc Yes:
Allogeneic
HCT
If CR: If CR, If CR: If CR, If CR:
If CR, Consolidation
Investigational Consolidation therapy: Investigational Consolidation therapy: Investigational No:
therapy:
therapyd Allogeneic HCT (preferred), therapyd Allogeneic HCT (alternative therapyd Investigational
IDACd
or IDAC or autologous donor transplant if no HLA- therapy, autologous
HCT if age<60d matched donor available)d HCT considered
for favorable-risk
patients in CR2 with
prolonged CR1
PART 4

duration (>12
Refractory (No CR) months)
or relapsed

FIGURE 100-2  Flowchart for the therapy of newly diagnosed acute myeloid leukemia (AML). aRisk stratification according to the European LeukemiaNet (see
Table 100-3). bYounger patients (<60–65 years) should routinely be offered investigational therapy on a backbone of standard chemotherapy for induction and consolidation.
Oncology and Hematology

c
Older patients, especially those >65 years or with adverse-risk disease, or those who are unfit for intensive daunorubicin + cytarabine regimens, may be considered for
investigational therapy alone or in combination with lower intensity chemotherapy regimens (azacitidine, decitabine). dInvestigational therapy as maintenance should be
considered if available (after consolidation for younger patients and older patients with favorable-risk disease, and for all other older patients after induction).
  For all forms of AML except acute promyelocytic leukemia (APL), standard induction therapy includes a regimen based on a 7-day continuous infusion of cytarabine
(100–200 mg/m2/d) and a 3-day course of daunorubicin (60–90 mg/m2/d) with or without additional drugs. Idarubicin (12 mg/m2/d) could be used in place of
daunorubicin (not shown). The value of postremission/consolidation therapy for older patients (>60 years) who do not have favorable-risk disease is uncertain.
Patients who achieve complete remission (CR) undergo postremission consolidation therapy, including sequential courses of intermediate-risk cytarabine, allogeneic
HCT, autologous HCT, or novel therapies, based on their predicted risk of relapse (i.e., risk-stratified therapy). Patients with APL (see text for treatment) usually receive
tretinoin and arsenic trioxide–based regimens with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin. HCT, hematopoietic cell
transplantation; HLA, human leukocyte antigen; IDAC, intermediate dose cytarabine.

treatment-related toxicity (GVHD, organ toxicity). Despite this, there
is no debate that patients with adverse-risk AML have improved
long-term survival with early allogeneic HCT. Alternatively, high-
dose chemotherapy with autologous HCT rescue is another post-
remission approach in non-adverse risk subsets. Autologous HCT
patients receive their own stem cells (collected during remission
and cryopreserved), following administration of myeloablative che-
motherapy. The toxicity is relatively low with autologous HCT (5%
mortality rate), but the relapse rate is higher than with allogeneic
HCT, due to the absence of the GVL effect. Favorable and interme-
diate-risk patients may benefit from autologous HCT more so than
adverse-risk patients. Practically speaking, however, autologous
HCT in AML patients is less frequently employed currently due to
enhanced relapse risk reduction seen with allogeneic HCT and the
growing use of HLA mismatched donors (in novel transplantation
approaches).
Prognostic factors help to select the appropriate postremission
therapy in patients in CR1. Our approach includes allogeneic HCT
in first CR for patients without favorable cytogenetics or geno-
type (e.g., patients who do not have CEBPA biallelic mutations or
NPM1 mutations without FLT3-ITD/with FLT3-ITDlow). Patients
with adverse-risk disease should proceed to allogeneic HCT at CR1
if possible. The decision for allogeneic HCT for younger intermedi-
ate-risk patients is complex and individualized as described above;
we recommend it when an HLA-matched donor is available. Subsets
of patients may benefit from targeted therapy given during remis-
sion; emerging data demonstrate survival benefit from incorpora-
tion of the FLT3 inhibitor midostaurin, for example, into induction
and postremission therapies for patients with FLT3 mutated AML.
On April 28, 2017, the U.S. Food and Drug Administration (FDA)
approved midostaurin (RYDAPT, Novartis Pharmaceuticals Corp.)
for the treatment of adult patients with newly diagnosed AML who
are FLT3 mutation-positive (either ITD or TKD+), in combination
with standard cytarabine and daunorubicin induction and cytara-
bine consolidation. Allogeneic transplantation in CR1 is still recom-
mended for these patients.
For patients in morphologic CR, measurement of MRD remains
a very important and challenging research area. Cytogenetics are a
mainstay of disease assessment, and persistence of abnormal karyo-
type (in spite of morphologic CR) is clearly associated with poor clin-
ical outcomes. Immunophenotyping to detect minute populations of
blasts or sensitive molecular assays (e.g., reverse transcriptase poly-
merase chain reaction [RT-PCR]) to detect AML-associated molec-
ular abnormalities (e.g., NPM1 mutation, the CBF AML RUNX1/
RUNX1T1 and CBFB/MYH11 transcripts, the APL PML/RARA
transcript) can be performed to assess whether MRD is present at
sequential time points during or after treatment. Whether emerg-
ing next-generation sequencing or serial quantitative assessment
using flow or RT-PCR, performed during remission, can effectively
direct successful subsequent therapy and improve clinical outcome
remains to be determined. Currently, no consensus exists for the
optimal MRD measurement technique, or its application. Data
suggest that MRD measurement can in some settings be a reliable
discriminator between patients who will continue in CR or relapse,
but whether subsequent therapy (i.e., allogeneic HCT or additional
chemotherapy) can effectively eradicate disease in such patients is
not yet clear. In the subset of patients with APL, serial RT-PCR (for
the PML/RARA transcript) is a very useful and reliable tool to detect

Harrisons_20e_Part4_p0435-p0858.indd 746 6/1/18 5:43 PM

 TABLE 100-6  Novel Therapies in Clinical Development in Acute transfusion-associated GVHD. Cytomegalovirus (CMV)–negative 747
Myeloid Leukemia blood products should be used for CMV-seronegative patients who
Protein kinase •  FLT3 inhibitors (midostaurin, quizartinib, are potential candidates for allogeneic HCT; fortunately white blood
inhibitors gilteritinib, crenolanib, sorafenib) cell filtration is quite effective at reducing CMV exposure as well.
•  KIT inhibitors Neutropenia (neutrophils <500/μL or <1000/μL and predicted
•  PI3K/AKT/mTOR inhibitors to decline to <500/μL over the next 48 h) can be part of the initial
•  Aurora and polo-like kinase inhibitors, CDK4/6 presentation and/or a side effect of the chemotherapy treatment
inhibitors, CHK1, WEE1, and MPS1 inhibitors in AML patients. Thus, infectious complications remain the major
•  SRC and HCK inhibitors cause of morbidity and death during induction and postremission
•  Syk inhibitors chemotherapy for AML. Antibacterial (i.e., quinolones) and antifun-
Epigenetic modulators •  New DNA methyltransferase inhibitors (SGI-110)
gal (i.e., posaconazole) prophylaxis, especially in conjunction with
regimens that cause mucositis, is beneficial. For patients who are
•  Histone deacetylase (HDAC) inhibitors
herpes simplex virus or varicella-zoster seropositive, antiviral pro-
•  IDH1 and IDH2 inhibitors
phylaxis should be initiated (e.g., acyclovir, valacyclovir).
•  DOT1L inhibitors Fever develops in most patients with AML, but infections are doc-
•  BET-bromodomain inhibitors umented in only half of febrile patients. Early initiation of empirical
Chemotherapeutic •  CPX-351 (especially in secondary AML) broad-spectrum antibacterial and antifungal antibiotics has signifi-
agents •  Vosaroxin cantly reduced the number of patients dying of infectious complica-
•  Nucleoside analogues tions (Chap. 70). An antibiotic regimen adequate to treat gram-negative
Mitochondrial •  Bcl-2, Bcl-xL, and Mcl-1 inhibitors organisms should be instituted at the onset of fever in a neutropenic
inhibitors •  Caseinolytic protease inhibitors patient after clinical evaluation, including a detailed physical exami-
Therapies targeting •  Fusion transcripts targeting nation with inspection of the indwelling catheter exit site and a

CHAPTER 100 Acute Myeloid Leukemia

oncogenic proteins •  EVI1 targeting
•  NPM1 targeting
•  Hedgehog inhibitors (glasdegib)
Antibodies and •  Monoclonal antibodies against CD33, CD44,
immunotherapies CD47, CD123, CLEC12A
•  Immunoconjugates (e.g., gemtuzumab ozogamicin,
SGN33A)
•  Bispecific T-cell engagers (BiTEs) and dual affinity
re-targeting molecules (DARTs)
•  Chimeric antigen-receptor (CAR) T cells or
genetically engineered T-cell receptor (TCR) T cells
•  Immune checkpoint inhibitors (PD-1/PD-L1,
CTLA-4)
•  Anti-KIR antibody (lirilumab)
•  Vaccines (e.g., WT1)
Therapies targeting •  CXCR4 and CXCL12 antagonists
AML environment
•  Anti-angiogenic therapies
Source: Adapted from Döhner H et al: Diagnosis and management of acute
myeloid leukemia in adults: 2017 recommendations from an international expert
panel, on behalf of the European LeukemiaNet. Blood. 129:424, 2017.
early relapse and direct initiation of reinduction therapy prior to
onset of overt relapse.
SUPPORTIVE CARE
Measures geared to supporting patients through several weeks of
neutropenia and thrombocytopenia are critical to successful AML
therapy. Patients with AML should be treated in centers expert in
providing supportive care. Multilumen central venous catheters
should be inserted as soon as newly diagnosed AML patients have
been stabilized. They should be used thereafter for administration of
intravenous medications/chemotherapy and transfusions, as well as
for blood drawing instead of venipuncture.
Adequate and prompt blood bank support is critical to ther-
apy of AML. Platelet transfusions should be given as needed to
maintain a platelet count ≥10,000/μL. The platelet count should
be kept at higher levels in febrile patients and during episodes of
active bleeding or DIC. Patients with poor posttransfusion platelet
count increments may benefit from administration of platelets from
HLA-matched donors. RBC transfusions should be administered to
keep the hemoglobin level >70–80 g/L (7–8 g/dL) in the absence
of active bleeding, DIC, or congestive heart failure, which require
higher hemoglobin levels. Blood products leukodepleted by filtra-
tion should be used to avert or delay alloimmunization as well as
febrile reactions. Blood products may also be irradiated to prevent
perirectal examination (for perirectal abscess), as well as procurement
of cultures and radiographs aimed at documenting the source of
fever. Specific antibiotic regimens should be based on institutional
antibiotic sensitivity data obtained from where the patient is being
treated. Acceptable regimens for empiric antibiotic therapy include
monotherapy with imipenem-cilastatin, meropenem, piperacillin/
tazobactam, or an extended-spectrum antipseudomonal cephalospo-
rin (cefepime or ceftazidime). The combination of an aminoglycoside
with an antipseudomonal penicillin (e.g., piperacillin) or an aminogly-
coside in combination with an extended-spectrum antipseudomonal
cephalosporin should be considered in complicated or resistant cases.
Aminoglycosides should be avoided, if possible, in patients with renal
insufficiency. Empirical vancomycin should be added in neutropenic
patients with catheter-related infections, blood cultures positive for
gram-positive bacteria before final identification and susceptibility
testing, hypotension or shock, or known colonization with penicillin/
cephalosporin-resistant pneumococci or methicillin-resistant Staphy-
lococcus aureus. In special situations where decreased susceptibility to
vancomycin, vancomycin-resistant organisms, or vancomycin toxicity
is documented, other options including linezolid, daptomycin, and
quinupristin/dalfopristin need to be considered.
Caspofungin (or a similar echinocandin), voriconazole, isavuco-
nazonium, or liposomal amphotericin B should be considered for
antifungal treatment if fever persists for 4–7 days following initi-
ation of empiric antibiotic therapy. Amphotericin B has long been
used for antifungal therapy. Although liposomal formulations have
improved the toxicity profile of this agent, its use has been limited
to situations with high risk of or documented mold infections.
Caspofungin has been approved for empiric antifungal treatment.
Voriconazole has also been shown to be equivalent in efficacy and
less toxic than amphotericin B; isavuconazonium may also be effec-
tive with fewer drug-drug interactions. Antibacterial and antifungal
antibiotics should be continued until patients are no longer neutro-
penic, regardless of whether a specific source has been found for the
fever. Unfortunately, this practice likely contributes to development
of resistance and increased incidence of nosocomial infections such
as Clostridium difficile colitis, so great care should be taken preferably
in hospital-wide antibiotic surveillance and isolation strategies to
reduce these complications. Recombinant hematopoietic growth
factors have a limited role in AML; myeloid growth factors may
be useful in the postremission setting but are not recommended in
induction or for “palliative” care for patients not in remission.
TREATMENT FOR REFRACTORY OR RELAPSED AML
In patients who relapse after achieving CR, the length of first
CR is predictive of response to salvage chemotherapy treatment;
patients with longer first CR (>12 months) generally relapse with

Harrisons_20e_Part4_p0435-p0858.indd 747 6/1/18 5:43 PM

 748 drug-sensitive disease and have a higher chance of attaining a CR,
even with the same chemotherapeutic agents used for first remis-
sion induction. Whether initial CR was achieved with one or two
courses of chemotherapy and the type of postremission therapy
may also predict achievement of second CR. Similar to patients
with refractory disease, patients with relapsed disease are rarely
cured by salvage chemotherapy treatments. Therefore, patients who
eventually achieve a second CR and are eligible for allogeneic HCT
should be transplanted. However, there is no consensus on optimal
treatment for patients who relapse after allogeneic HCT; outcomes
in this setting are very poor.
Because achievement of a second CR with routine salvage ther-
apies is relatively uncommon, especially in patients who relapse
rapidly after achievement of first CR (<12 months), these patients and
those lacking HLA-compatible donors or who are not candidates for
allogeneic HCT should be considered for innovative approaches on
clinical trials. Many new agents are in current testing (Table 100-6).
The discovery of novel gene mutations and mechanisms of leuke-
mogenesis that might represent actionable therapeutic targets has
prompted the development of many new targeting agents. In addi-
tion to kinase inhibitors for FLT3-mutated AML, other compounds
targeting the aberrant activity of mutant proteins (e.g., IDH1/2
inhibitors) and numerous other biologic mechanisms are being tested
PART 4
in clinical trials. Furthermore, approaches with antibodies targeting
markers commonly expressed on leukemia blasts (e.g., CD33) or leu-
kemia-initiating cells (e.g., CD123) are also under investigation. Once
these compounds have demonstrated safety and activity as single
agents, investigation of combinations with other molecular targeting
Oncology and Hematology
compounds and/or chemotherapy should be pursued.
TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA
APL is a highly curable AML subtype, and ~85% of these patients
achieve long-term survival with current approaches. APL has long
been shown to be responsive to cytarabine and daunorubicin, but in
the past patients who were treated with these drugs alone frequently
died from DIC induced by the release of granule components by
the chemotherapy-treated leukemia cells. However, the prognosis
of APL patients has changed dramatically with the introduction of
tretinoin (ATRA), an oral drug that induces the differentiation of
leukemic cells bearing the t(15;17), where disruption of the RARA
gene encoding a retinoid acid receptor occurs. ATRA decreases the
frequency of DIC but often produces another complication called the
APL (differentiation) syndrome. Occurring within the first 3 weeks
of treatment, it is characterized by fever, fluid retention, dyspnea,
chest pain, pulmonary infiltrates, pleural and pericardial effusions,
and hypoxemia. The syndrome is related to adhesion of differen-
tiated neoplastic cells to the pulmonary vasculature endothelium.
Glucocorticoids, chemotherapy, and/or supportive measures can
be effective for management of the APL syndrome. Temporary dis-
continuation of ATRA is necessary in cases of severe APL syndrome
(i.e., patients developing renal failure or requiring admission to the
intensive care unit due to respiratory distress). The mortality rate
of this syndrome is ~10%. APL syndrome may also occur, less com-
monly, with ATO in APL.
In low-risk APL (low leukocyte count at presentation), ATRA
(45 mg/m2/d) plus ATO (0.15 mg/kg/d) was recently compared to
ATRA plus concurrent idarubicin chemotherapy. ATRA/ATO was
superior and is the new standard of care for such patients. CR rates
in low-risk disease approach 100%, with excellent long-term sur-
vival. Notably, patients with high-risk APL (high leukocyte count)
must be uniquely treated, as they require immediate cytoreduction
with chemotherapy due to life-threatening APL syndrome often
with rapidly rising leukocyte count after initiation of ATRA. High-
risk patients are at increased risk for induction death due to this syn-
drome as well as increased frequency of hemorrhagic complications
(related to DIC).
Assessment of residual disease by RT-PCR amplification of the
t(15;17) chimeric gene product PML-RARA following the final cycle
of treatment is important. Disappearance of the signal is associated
Harrisons_20e_Part4_p0435-p0858.indd 748
with long-term disease-free survival; its persistence or reemergence
invariably predicts relapse. Sequential monitoring of RT-PCR for
PML-RARA is now considered standard for postremission monitor-
ing of APL, at least in high-risk patients.
Patients in molecular, cytogenetic, or clinical relapse should be
salvaged with ATO with or without ATRA; in patients who were
treated with ATRA plus chemotherapy in the frontline setting, ATO-
based therapy at relapse produces meaningful responses in up to
85% of patients. Though experience with relapsed APL in patients
who received ATO during initial induction is limited (given that
few relapses occur in low-risk patients, and widespread use of ATO
during first-line therapy is relatively new), ATO remains the pre-
ferred reinduction therapy for patients who relapse. Achievement of
CR2 should be followed by consolidation with autologous HCT (for
patients who achieve RT-PCR negative status). In the minority who
do not achieve negative RT-PCR or who relapse again, allogeneic
HCT may still be potentially curative.
■■FURTHER READING
Ablain J et al: Activation of a promyelocytic leukemia–tumor
protein 53 axis underlies acute promyelocytic leukemia cure. Nature
Medicine 20: 167, 2014.
Arber DA et al: Acute myeloid leukaemia (AML) with recurrent
genetic abnormalities, in World Health Organization Classification of
Tumours of Haematopoietic and Lymphoid Tissues, update to 4th ed. In
Press.
Burnett AK et al: Arsenic trioxide and all-trans retinoic acid treat-
ment for acute promyelocytic leukaemia in all risk groups (AML17):
Results of a randomised, controlled, phase 3 trial. Lancet Oncol
16:1295, 2015.
Cancer Genome Atlas Research Network: Genomic and epige-
nomic landscapes of adult de novo acute myeloid leukemia. N Engl
J Med 368:2059, 2003.
Döhner H et al: Diagnosis and management of acute myeloid leuke-
mia in adults: 2017 recommendations from an international expert
panel, on behalf of the European LeukemiaNet. Blood. 129:424, 2017.
Döhner H et al: Review article: Acute myeloid leukemia. N Engl J Med
373:1136, 2015.
Fernandez HF et al: Anthracycline dose intensification in acute mye-
loid leukemia. N Engl J Med 361:1249, 2009.
Lo-Coco F et al: Retinoic acid and arsenic trioxide for acute promyelo-
cytic leukemia. N Engl J Med 369:111, 2013.
Löwenberg B et al: Cytarabine dose for acute myeloid leukemia. N
Engl J Med 364:1027, 2011.
Papaemmanuil E et al: Genomic classification and prognosis in acute
myeloid leukemia. N Engl J Med 374:2209, 2016.
Peterson L et al: Myeloid neoplasms with germline predisposition, in
World Health Organization Classification of Tumours of Haematopoietic
and Lymphoid Tissues, update to 4th ed. In Press.
101 Chronic Myeloid Leukemia
Hagop Kantarjian, Jorge Cortes
Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell
disorder. The disease is driven by the BCR-ABL1 chimeric gene prod-
uct, that codes for a constitutively active tyrosine kinase, resulting
from a reciprocal balanced translocation between the long arms of
chromosomes 9 and 22, t(9;22)(q34.1;q11.2), known as the Philadel-
phia chromosome (Ph) (Fig. 101-1). Untreated, the course of CML is
typically biphasic or triphasic, with an early indolent or chronic phase,
followed often by an accelerated phase and a terminal blastic phase.
Before the era of selective BCR-ABL1 tyrosine kinase inhibitors (TKIs),
6/1/18 5:43 PM
 749

q11.2

q34
t(9;22)(q34.1;q11.2)
A

Chromosomes
9 5'

22 e1
Minor BCR
e1'
e2'
BCR e12
e13
Major BCR e14
e15
e16

CHAPTER 101 Chronic Myeloid Leukemia

ABL e19 5'
Micro BCR
Normal

1b

ABL
Breakpoint 1a

a2
a3 3'
e1a2 e13a2 e14a2 e19a2

Translocation (9;22)
a11
p190BCR-ABL1 p210BCR-ABL1 p230BCR-ABL1
B 3'
FIGURE 101-1  A. The Philadelphia (Ph) chromosome cytogenetic abnormality. B. Breakpoints in the long arms of chromosome 9 (ABL locus) and chromosome 22
(BCR regions) result in at least three different BCR-ABL1 oncoprotein messages, p210BCR-ABL1 (most common message in chronic myeloid leukemia [CML]), p190BCR-ABL1
(present in two-thirds of patients with Ph-positive acute lymphocytic leukemia; rare in CML), and p230BCR-ABL1 (rare in CML and associated with an indolent course). Other
rearrangements (e.g., b14a3) are less common. (© 2013 The University of Texas MD Anderson Cancer Center.)

the median survival in CML was 3–7 years, and the 10-year survival
rate was 30% or less. Introduced into standard CML therapy in 2000,
TKIs have revolutionized the treatment, natural history, and progno-
sis of CML. Today, the estimated 10-year survival rate with imatinib
mesylate, the first BCR-ABL1 TKI approved, is 85%. Allogeneic stem
cell transplantation (SCT), a curative approach but one that involves
more risks, is now more often offered as second- or third-line therapy
after failure of TKIs.
■■INCIDENCE AND EPIDEMIOLOGY
CML accounts for ∼15% of all cases of leukemia. There is a slight male
preponderance (male:female ratio 1.6:1). The median age at diagnosis is
55–65 years. It is uncommon in children; only 3% of patients with CML
are younger than 20 years although in recent years a higher proportion
of young patients seem to be diagnosed. CML incidence increases
slowly with age, with a steeper increase after the age of 40–50 years.
The annual incidence of CML is 1.5 cases per 100,000 individuals. In
the United States this translates into about 8000 new cases per year. The
incidence of CML has not changed over several decades. By extrapola-
tion, the worldwide annual incidence of CML is about 100,000–120,000
cases. With a median survival of 6 years before 2000, the disease prev-
alence in the United States was 25,000–30,000 cases. With TKI therapy,
the annual mortality has been reduced from 10–20% to about 2%.
Therefore, the prevalence of CML in the United States is expected to
continue to increase (approximately 100,000 in 2016). The worldwide
prevalence will depend on the treatment penetration of TKIs and their
effect on reduction of worldwide annual mortality. Ideally, with full
TKI treatment penetration, the worldwide prevalence should plateau
at 35 times the incidence, or around 3–4 million patients.
■■ETIOLOGY
There are no familial associations in CML. The risk of developing
CML is not increased in monozygotic twins or in relatives of patients.
No etiologic agents are incriminated, and no associations exist with
exposures to benzene or other toxins, fertilizers, insecticides, or viruses.
CML is not a frequent secondary leukemia following therapy of other
cancers with alkylating agents and/or radiation. Exposure to ionizing
radiation (e.g., nuclear accidents, radiation treatment for ankylosing
spondylitis or cervical cancer) has increased the risk of CML, which
peaks at 5–10 years after exposure and is dose-related. The median
time to development of CML among atomic bomb survivors was
6.3 years. Following the Chernobyl accident, the incidence of CML
did not increase, suggesting that larger dose exposures of radiation
are required to cause CML. Because of adequate protection, the risk of
CML is not increased in individuals working in the nuclear industry or
among radiologists in recent times.

Harrisons_20e_Part4_p0435-p0858.indd 749 6/1/18 5:43 PM

 750 ■■PATHOPHYSIOLOGY
The t(9;22)(q34.1;q11.2) is present in >90% of classical CML cases. It
results from a balanced reciprocal translocation between the long
arms of chromosomes 9 and 22. It is present in hematopoietic cells
(myeloid, erythroid, megakaryocytes, and monocytes; less often mature
B lymphocytes; rarely mature T lymphocytes, but not stromal cells), but
not in other cells in the human body. As a result of the translocation,
DNA sequences from the cellular oncogene ABL1 are translocated next
to the major breakpoint cluster region (BCR) gene on chromosome
22, generating a hybrid oncogene, BCR-ABL1. This fusion gene typ-
ically encodes for a novel oncoprotein of molecular weight 210 kDa,
referred to as p210BCR-ABL1 (Fig. 101-1B). This BCR-ABL1 oncoprotein
exhibits constitutive kinase activity that leads to excessive proliferation
and reduced apoptosis of CML cells, endowing them with a growth
advantage over their normal counterparts. Over time, normal hemato-
poiesis is suppressed, but normal stem cells can persist and reemerge
following effective therapy, for example with TKIs. In most instances
of Ph-positive acute lymphoblastic leukemia (ALL) and in rare cases
of CML, the breakpoint in BCR is more centromeric, in a region called
the minor BCR region (mBCR). As a result, a shorter sequence of BCR
is fused to ABL1, with a consequent smaller BCR-ABL1 oncoprotein,
p190BCR-ABL1. When occurring in Ph-positive CML, this translocation
may predict for a worse outcome. A third rarer breakpoint in BCR
PART 4
occurs telomeric to the major BCR region and is called micro-BCR
(μ-BCR). It juxtaposes a larger fragment of the BCR gene to ABL1 and
produces a larger p230BCR-ABL1 oncoprotein, which is associated with a
more indolent CML course. Other rearrangements, such as b14a3, occur
much less frequently.
Oncology and Hematology
The constitutive activation of BCR-ABL1 results in autophosphoryla-
tion and activation of multiple downstream pathways that affect gene
transcription, apoptosis, stromal adherence, skeletal organization, and
degradation of inhibitory proteins. These transduction pathways may
involve RAS, mitogen-activated protein (MAP) kinases, signal transduc-
ers and activators of transcription (STAT), phosphatidylinositol-3-kinase
(PI3k), MYC, and others. These interactions are mostly mediated
through tyrosine phosphorylation and require binding of BCR-ABL1
to adapter proteins such as GRB-2, CRK, CRK-like (CRK-L) protein,
and Src homology containing proteins (SHC). Most BCR-ABL1 TKIs
bind to the BCR-ABL1 ATP-binding domain, preventing the activation
of transformation pathways and inhibiting downstream signaling. As
a result, proliferation of CML cells is inhibited and apoptosis induced,
allowing the reemergence of normal hematopoiesis. A plethora of sig-
naling pathways have been implicated in BCR-ABL1-mediated cellular
transformation. The emerging picture is a complex and redundant
transformation network. An additional layer of complexity is related
to differences in signal transduction between CML-differentiated
cells and early progenitors. Beta-catenin, Wnt1, Foxo3a, transforming
growth factor β, interleukin-6, PP2A, SIRT1, and others have been
implicated in CML stem cell survival.
Experimental models have established the causal relationship
between the BCR-ABL1 rearrangement and the development of CML.
In animal models, expression of BCR-ABL1 in normal hematopoietic
cells produced CML-like disorders or lymphoid leukemia, demon-
strating the leukemogenic potential of BCR-ABL1 as a single oncogenic
abnormality. Other models however suggest the need for a “second
hit.”
The cause of the BCR-ABL1 molecular rearrangement is unknown.
Molecular techniques that detect BCR-ABL1 at a level of 1 in 108 iden-
tify this molecular abnormality in the blood of up to 25% of normal
adults and 5% of infants, but 0% of cord blood samples. This suggests
that BCR-ABL1 is not sufficient to cause overt CML in the overwhelm-
ing majority of individuals in whom it occurs. Because CML develops
in only 1.5 of 100,000 individuals annually, it is evident that additional
molecular events or poor immune recognition of the rearranged cells
are needed to cause overt CML.
CML is defined by the presence of BCR-ABL1 fusion gene in a patient
with a myeloproliferative neoplasm. In some patients with a typical
morphologic picture of CML, the Ph chromosome is not detectable by
standard G-banding karyotype, but fluorescence in situ hybridization
Harrisons_20e_Part4_p0435-p0858.indd 750
(FISH) and/or molecular studies (polymerase chain reaction [PCR])
detect BCR-ABL1. These patients have a course similar to Ph-positive
CML and respond to TKI therapy. Many of the remaining patients have
atypical morphologic or clinical features and belong to other diagnostic
groups, such as atypical CML, chronic myelomonocytic leukemia, and
myelodysplastic-myeloproliferative neoplasms (MDS-MPN). These
individuals do not respond to TKI therapy and have a poor prognosis
with a median survival of about 2–3 years. Detection of mutations in
the granulocyte colony-stimulating factor receptor (CSF3R) in chronic
neutrophilic leukemia (90% of cases) and in some cases of atypical
CML, of mutations in SETBP1 in atypical CML (25% of cases), and of
mutations in SF3B1 in MDS-MPN with ringed sideroblasts and marked
thrombocytosis (MDS-MPD-RST; 50–70% of cases, associated with
longer median survival of 7 years vs 3.3 years with wild-type SF3B1),
confirmed that they are distinct molecular and biologic entities.
The events associated with the transition of CML from a chronic to
accelerated-blastic phase are poorly understood. They are often asso-
ciated with characteristic chromosomal abnormalities such as a double
Ph, trisomy 8, isochromosome 17 or deletion of 17p (loss of TP53), 20q–,
and others. Molecular events associated with transformation include
mutations in TP53, retinoblastoma 1 (RB1), myeloid transcriptions
factors like RUNX1, and cell cycle regulators like p16. A plethora of
other mutations or functional abnormalities have been implicated in
blastic transformation, but no unifying theme has emerged other than
the fact that BCR-ABL1 itself induces genetic instability that favors the
acquisition of additional molecular events and eventually to blastic
transformation. In this frame of thinking, one critical effect of TKIs is
their ability to stabilize the CML genome, leading to a much reduced
transformation rate. In particular, the previously observed sudden
blastic transformations (i.e., abrupt transformation to blastic phase
in a patient who had been in cytogenetic response) have become
uncommon, occurring rarely in younger patients in the first 1–2 years
of TKI therapy (usually sudden lymphoid blastic transformations).
Sudden transformations beyond the third year of TKI therapy are rare
in patients who continue on TKI therapy. Moreover, initial experience
suggests that the course of CML has become significantly more indo-
lent, even without cytogenetic responses, in patients on TKI-based
therapy compared to previous experience with hydroxyurea/busulfan.
Among patients developing resistance to TKIs, several resistance
mechanisms have been observed. The most clinically relevant one is
the development of different ABL1 kinase domain mutations that may
prevent the binding of TKIs to the catalytic site (ATP-binding site) of
the kinase or maintain the kinase activity despite the presence of a TKI.
More than 100 BCR-ABL1 mutations have now been described, many
of which confer relative or absolute resistance to imatinib. This has
resulted in the development of second-generation TKIs (i.e., dasatinib,
nilotinib, bosutinib) and of a third-generation TKI (ponatinib) with sig-
nificant efficacy against T315I, a “gatekeeper” mutation that prevents
binding of and causes resistance to all other TKIs.
■■CLINICAL PRESENTATION
The presenting signs and symptoms in CML depend on the availabil-
ity of and access to health care, including physical examinations and
screening tests. In the United States, because of the wider access to
health care screening and physical examinations, 50–60% of patients
are diagnosed on routine blood tests and have minimal symptoms at
presentation, such as fatigue. In geographic locations where access to
health care is more limited, patients often present with high CML bur-
den including splenomegaly, anemia, and related symptoms (abdomi-
nal pain, weight loss, fatigue), which translate into a higher frequency
of high-risk CML. Presenting findings in patients diagnosed in the
United States are shown in Table 101-1.
Symptoms  Most patients with CML (90%) present in the indolent or
chronic phase. Depending on the timing of diagnosis, patients are often
asymptomatic (if the diagnosis is discovered during health care screen-
ing tests). Common symptoms, when present, are manifestations of
anemia and splenomegaly. These may include fatigue, malaise, weight
loss (if high leukemia burden), or early satiety and left upper quadrant
pain or masses (from splenomegaly). Less common presenting findings
6/1/18 5:43 PM
 TABLE 101-1  Presenting Signs and Symptoms of Newly Diagnosed 5% or less; when higher, they carry a worse prognosis or represent 751
Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in transformation to accelerated phase (if they are ≥15%). Increased
Chronic Phase reticulin fibrosis (by Snook’s silver stain) is common, with 30–40% of
PARAMETER PERCENTAGE patients demonstrating grade 3–4 reticulin fibrosis. This was consid-
Age ≥60 years (median) 40–50 (55–65) ered adverse in the pre-TKI era. With TKI therapy, reticulin fibrosis
Female gender 35–45 resolves in most patients and is not an indicator of poor prognosis.
Splenomegaly 30
Collagen fibrosis (Wright-Giemsa stain) is rare at diagnosis. Disease
progression with a “spent phase” of myelofibrosis (myelophthisis, or
Hepatomegaly 5–10
burnt-out marrow) was common with busulfan therapy (20–30%) but
Lymphadenopathy 5
is rare with TKI therapy.
Other extramedullary disease 2
Hemoglobin <10 g/dL 10–15 Cytogenetic and Molecular Findings  The diagnosis of CML is
Platelets   straightforward and depends on documenting the t(9;22)(q34.1;q11.2),
  >450 × 109 cells/L 30–35 which is identified by G-banding in 90% of cases. This is known as
  <100 × 109 cells/L 3–5 the Philadelphia chromosome (initially identified in Philadelphia as a
White blood cells ≥50 × 109 cells/L 35–40
minute chromosome), later identified to be chromosome 22 (Fig. 101-1).
Some patients may have complex translocations (variant Ph) involving
Marrow  
three or more chromosomes including chromosomes 9 and 22 and one
  ≥5% blasts 5
or more additional chromosomes. Others may have a “masked Ph,”
  ≥5% basophils 10–15 involving translocations between chromosome 9 and a chromosome
Peripheral blood   other than 22 (but molecularly showing the BCR-ABL1 rearrangement).
  ≥3% blasts 8–10 The prognosis of these patients and their response to TKI therapy are
  ≥7% basophils 10 similar to those in patients with Ph. About 5–10% of patients may have

CHAPTER 101 Chronic Myeloid Leukemia

Cytogenetic clonal evolution other than the 4–5
Philadelphia chromosome
Sokal risk  
 Low 60–65
 Intermediate 25–30
 High 10
include thrombotic or hyperviscosity-related events (from severe leu-
kocytosis or thrombocytosis). These include priapism, cardiovascular
complications, myocardial infarction, venous thrombosis, visual dis-
turbances, dyspnea and pulmonary insufficiency, drowsiness, loss of
coordination, confusion, or cerebrovascular accidents. Manifestations
of bleeding diatheses include retinal hemorrhages, gastrointestinal
bleeding, and others. Patients who present with, or progress to, the
accelerated or blastic phases frequently have additional symptoms
including unexplained fever, significant weight loss, severe fatigue,
bone and joint pain, bleeding and thrombotic events, and infections.
Physical Findings  Splenomegaly is the most common physical
finding, occurring in 20–70% of patients depending on health care
screening frequency. Other less common findings include hepatomeg-
aly (5–10%), lymphadenopathy (5–10%), and extramedullary disease
(skin or subcutaneous lesions). The latter indicates CML transfor-
mation if a biopsy confirms predominance of blasts. Other physical
findings are manifestations of complications of high tumor burden
described earlier (e.g., cardiovascular, cerebrovascular, bleeding). High
basophil counts may be associated with histamine overproduction
causing pruritus, diarrhea, flushing, and even gastrointestinal ulcers.
Hematologic and Marrow Findings  In untreated CML, leuko-
cytosis ranging from 10–500 × 109/L is common. The peripheral blood
differential shows left-shifted hematopoiesis with predominance of
neutrophils and the presence of bands, myelocytes, metamyelocytes,
promyelocytes, and blasts (usually ≤5%). Basophils and/or eosinophils
are frequently increased. Thrombocytosis is common, but thrombocy-
topenia is rare and, when present, suggests a worse prognosis, disease
acceleration, or an unrelated etiology. Anemia is present in one-third of
patients. Cyclic oscillations of counts are noted in 10–20% of patients
without treatment. Biochemical abnormalities include a low leukocyte
alkaline phosphatase score and high levels of vitamin B12, uric acid,
lactic dehydrogenase, and lysozyme. The presence of unexplained and
sustained leukocytosis, with or without splenomegaly, should lead to a
marrow examination and cytogenetic analysis.
The bone marrow is hypercellular with marked myeloid hyperplasia
and a high myeloid-to-erythroid ratio of 15–20:1. Marrow blasts are
additional chromosomal abnormalities in the Ph-positive cells. These
usually involve trisomy 8, a double Ph, isochromosome 17 or 17p dele-
tion, 20q–, or others. This is referred to as cytogenetic clonal evolution
and was historically a sign of adverse prognosis, particularly when
trisomy 8, double Ph, or chromosome 17 abnormalities were noted. A
less common abnormality involving chromosome 3q26.2 also carries a
poor prognosis.
Techniques such as FISH and PCR are now used to aid in the diag-
nosis of CML. They are more sensitive approaches to estimate the CML
burden in patients on TKI therapy. They can be done on peripheral
blood, and thus are more convenient to patients. Patients with CML
at diagnosis should have a FISH analysis to quantify the percentage of
Ph-positive cells, if FISH is used to replace marrow cytogenetic analysis
in monitoring response to therapy. FISH will not detect additional chro-
mosomal abnormalities (clonal evolution); thus, a cytogenetic analysis
is usually recommended at the time of diagnosis. The BCR-ABL1 rear-
rangement is usually one of two variants: e13a2 (formerly b2a2) and
e14a2 (formerly b3a2). About 2–5% of patients may have other RNA
fusion types (e.g., e1a2, e13a3, or e14a3). In these patients, the routine
real-time PCR primers may not amplify the BCR-ABL1 transcripts, thus
leading to false-negative results. Therefore, molecular studies at diag-
nosis are important to document the type and presence of BCR-ABL1
transcripts to avoid erroneously “undetectable” BCR-ABL1 transcripts
on follow-up studies, with the false impression of a complete molecular
response. The presence of the Philadelphia chromosome with “nega-
tive” PCR with standard methodology should prompt investigation of
atypical transcripts.
Both FISH and PCR studies can be falsely positive at low levels or
falsely negative because of technical issues. Therefore, a diagnosis of
CML must always rely on a marrow analysis with routine cytogenetics.
The diagnostic bone marrow confirms the presence of the Ph chromo-
some, detects clonal evolution, that is, chromosomal abnormalities in
the Ph-positive cells (which may be prognostic), and also quantifies
the percentage of marrow blasts and basophils. In 10% of patients, the
percentage of marrow blasts and basophils can be significantly higher
than in the peripheral blood, conferring poorer prognosis or even
representing disease transformation.
Monitoring patients on TKI therapy by cytogenetics, FISH, and
molecular studies has become an important standard practice to
assess response to therapy, emphasize compliance, evaluate possi-
ble treatment resistance, identify the need to change TKI therapy,
and determine the need to assess for kinase domain mutations. It is
thus important to recognize the comparability of these measures in
monitoring response. A partial cytogenetic response is defined as the
presence of 35% or less Ph-positive metaphases by routine cytogenetic
analysis. This is roughly equivalent to BCR-ABL1 transcripts by the

Harrisons_20e_Part4_p0435-p0858.indd 751 6/1/18 5:43 PM

 752 International Scale (IS) of 10% or less. A complete cytogenetic response 1.0
refers to the absence of Ph-positive metaphases (0% Ph positivity). This 92%
is approximately equivalent to BCR-ABL1 transcripts (IS) of 1% or less. 83%
A major molecular response refers to BCR-ABL1 transcripts (IS) ≤0.1%, 0.8
or roughly a 3-log or greater reduction of BCR-ABL1 transcripts from a 68%

Survival probability
standardized basline. A molecular response MR4.5 refers to BCR-ABL1
transcripts (IS) ≤0.0032%, roughly equivalent to a 4.5-log reduction or 0.6
greater of transcripts.
43%
Findings in CML Transformation  Progression of CML is usu- 0.4
ally associated with leukocytosis resistant to therapy, increasing anemia, Treatment era Total Died

fever and constitutional symptoms, and increased blasts and basophils

TKI 2001-today
(CML-related deaths) 445 17
35%
TKI 2001–today
in the peripheral blood or marrow. Criteria of accelerated-phase CML, 0.2 (all deaths) 445 39
1996–2000 581 178
historically associated with median survival of <1.5 years, include the 1991–1995 367 220 8%
1983–1990 415 308
presence of 15% or more peripheral blasts, 30% or more peripheral ≤1982 227 220
blasts plus promyelocytes, 20% or more peripheral basophils, cyto- 0.0
genetic clonal evolution (presence of chromosomal abnormalities in 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
addition to Ph), and thrombocytopenia <100 × 109/L (unrelated to ther- A Years
apy). About 5–10% of patients present with de novo accelerated phase CML Phase Referral Year Total Died Median (months)
or blastic phase. The prognosis of de novo accelerated phase with TKI 1.0 Accelerated 1980–2000 398 325 28
Accelerated 2001–2013 258 86 88
therapy has improved significantly, with an estimated 8-year survival Blastic 1980–2000 196 189 5
rate of 75%. The median survival of accelerated phase evolving from Blastic 2001–2013 175 133 7
chronic phase has also improved from a historical median survival of 0.8
p <0.001
18 months to an estimated 4-year survival rate of 70% on TKI therapy.

Survival probability
PART 4

Therefore, the criteria for accelerated-phase CML should be revisited

0.6
because most clinical criteria defining accelerated phase have lost
much of their prognostic significance. Blastic-phase CML is defined
by the presence of 30% or more peripheral or marrow blasts or the 41%
0.4
Oncology and Hematology

presence of sheets of blasts in extramedullary disease (usually skin, soft

tissues, or lytic bone lesions). Blastic-phase CML is commonly mye-
loid (60%) but can present uncommonly as erythroid, promyelocytic,
monocytic, or megakaryocytic. Lymphoid blastic phase occurs in about
25% of patients. Lymphoblasts are terminal deoxynucleotide transfer-
ase positive and peroxidase negative (although occasionally with low
positivity up to 3–5%) and express lymphoid markers (CD10, CD19,
CD20, CD22). However, they also often express myeloid markers
(50–80%), resulting in diagnostic challenges. This is important because,
unlike other morphologic blastic phases, lymphoid blastic-phase CML
is quite responsive to anti-ALL-type chemotherapy (e.g., hyper-CVAD
[cyclophosphamide, vincristine, doxorubicin, and dexamethasone])
in combination with TKIs (complete response rates 60–70%; median
survival 2–3 years).
■■PROGNOSIS AND CML COURSE
Before the imatinib era, the annual mortality in CML was 10% in the first
2 years and 15–20% thereafter. The median survival time in CML was 3–7
years (with hydroxyurea-busulfan and interferon α). Without a curative
option of allogeneic SCT, the course of CML was toward transforma-
tion to, and death from, accelerated or blastic phases for most patients
as the rate of complete cytogenetic response with interferon was low.
Even apparent disease stability was unpredictable, with some patients
demonstrating sudden transformation to a blastic phase. With imatinib
therapy, the annual mortality in CML has decreased to 2% in the first
16 years of observation. More than half of the deaths are from factors
other than CML, such as aging-related comorbidities, accidents, sui-
cides, other cancers, and other medical conditions (e.g., infections, sur-
gical procedures). The estimated 10-year survival rate is 85%, or 93% if
only CML-related deaths are considered (Fig. 101-2). The course of CML
has also become quite predictable. In the first 2 years of TKI therapy,
rare sudden transformations are still reported (1–2%), usually lymphoid
blastic transformations that respond to combinations of chemotherapy
and TKIs followed by allogeneic SCT. These may be explained by the
intrinsic mechanisms of sudden transformation already existing in the
CML clones before the start of therapy that were not amenable to TKI
inhibition, in particular imatinib. Second-generation TKIs (nilotinib,
dasatinib) used as frontline therapy have reduced the incidence of trans-
formation in the first 2–3 years from 6–8% with imatinib to 2–5% with
nilotinib or dasatinib. Disease transformation to accelerated or blastic
phase is rare with continued TKI therapy, estimated at <1% annually in
p <0.001
19%
0.2
p = 0.015 5% 2%
0.0
0 1 2 3 4 5 6 7 8 9 10
B Years
FIGURE 101-2  A. Survival in newly diagnosed chronic-phase chronic myeloid
leukemia (CML) by era of therapy (MD Anderson Cancer Center experience
from 1965 to present). Causes of non-CML deaths in 22 patients were other
cancers (n = 7), postsurgical complications (n = 3), car accident (n = 2), suicide
(n = 1), neurologic events (n = 3), cardiac (n = 3), pneumonia (n = 1), and unknown
(n = 2). B. Survival in patients with accelerated- and blastic-phase CML referred
to MD Anderson Cancer Center by era of therapy, demonstrating the significant
survival benefit in the tyrosine kinase inhibitor (TKI) era in accelerated-phase CML
but the modest benefit in blastic-phase CML. Referred cases included de novo
and post-chronic-phase transformations.
years 4–10 of follow-up on the original imatinib trials. Patients usually
develop resistance in the form of cytogenetic resistance or relapse, fol-
lowed by hematologic relapse and subsequent transformation, rather
than the previously feared sudden transformations without the warning
signals of cytogenetic-hematologic relapse.
Before the imatinib era, several pretreatment prognostic factors
predicted for worse outcome in CML and have been incorporated into
prognostic models and staging systems. These have included older
age, significant splenomegaly, anemia, thrombocytopenia or thrombo-
cytosis, high percentages of blasts and basophils (and/or eosinophils),
marrow fibrosis, deletions in the long arm of chromosome 9, clonal
evolution, and others. Different risk models and staging systems,
derived from multivariate analyses, were proposed to define different
risk groups. As with the introduction of cisplatin into testicular cancer
therapy, the introduction of TKIs into CML therapy has decreased
or, in some instances, eliminated the prognostic impact of most of
these prognostic factors and the significance of the CML models (e.g.,
Sokal, Hasford, European Treatment and Outcome Study [EUTOS]).
Treatment-related prognostic factors have emerged as the most impor-
tant prognostic factors in the era of imatinib therapy. Achievement
of complete cytogenetic response has become the major therapeutic
endpoint and is the only endpoint associated with improvement in

Harrisons_20e_Part4_p0435-p0858.indd 752 6/1/18 5:43 PM

 survival. Achievement of a major molecular response is associated
with decreased risk of events (relapse) and CML transformation, but
has not been associated with survival prolongation among patients
with complete cytogenetic response. This may be due to the efficacy
of salvage TKI therapies, which are and should be implemented at
the first evidence of cytogenetic relapse. Achievement of undetectable
BCR-ABL1 transcripts, particularly when sustained (>2–3 years), may
offer the possibility of treatment-free remission (molecular cure rather
than functional cure) in the context of investigational trials, and may
allow temporary therapy interruption in women pursuing pregnancy.
The lack of achievement of major or “complete” molecular responses
should not be considered as “failure” of a particular TKI therapy and/
or an indication to change the TKI or to consider allogeneic SCT.
Long-term updates of randomized trials suggest that second gener-
ation TKIs and imatinib are more similarly effective in lower-risk CML,
but second generation TKIs may offer a greater therapeutic advantage
for patients with high-risk CML.
TREATMENT
Chronic Myeloid Leukemia
also inhibits VEGFR which may be related to the high incidence 753
of hypertension observed with this agent (Table 101-2). The sixth
approved agent is omacetaxine (Synribo), a protein synthesis inhib-
itor with presumed more selective inhibition of the synthesis of the
BCR-ABL1 oncoprotein. It is approved for the treatment of chronic
and accelerated phase CML after failure of two or more TKIs, at 1.25
mg/m2 subcutaneously twice a day for 14 days for induction and
for 7 days for consolidation-maintenance. The main adverse event of
omacetaxine is prolonged myelosuppression: omacetaxine 5–7 days
induction and 2–5 days maintenance, perhaps combined with a TKI,
may be equally effective and less toxic (Table 101-2).
Imatinib, nilotinib, and dasatinib are all acceptable frontline ther-
apies in CML. The long-term results of imatinib are very favorable.
The 8-year follow-up results show a cumulative complete cytoge-
netic response rate (occurring at least once) of 83%, with 60–65% of
patients being in complete cytogenetic response at 5-year follow-up.
The estimated 10-year survival rate is 85%. Among patients contin-
uing on imatinib, the annual rate of transformation to accelerated
-blastic phase in years 4–8 is <1%. In two randomized studies, one
comparing nilotinib 300 mg twice daily or 400 mg twice daily with
imatinib (ENESTnd) and the other comparing dasatinib 100 mg daily
with imatinib (DASISION), the second-generation TKIs were asso-

CHAPTER 101 Chronic Myeloid Leukemia

With TKI therapy, the estimated 10-year survival in CML is 85%.
Since 2001, six agents have been approved by the U.S. Food and
Drug Administration (FDA) for the treatment of CML. These include
five oral TKIs: imatinib (Gleevec, Glivec), nilotinib (Tasigna), dasat-
inib (Sprycel), bosutinib (Bosulif), and ponatinib (Iclusig). Imatinib
400 mg orally daily, nilotinib 300 mg orally twice a day (on an empty
stomach), dasatinib 100 mg orally daily, and bosutinib 400 mg orally
daily are approved for frontline therapy of CML. All four are also
approved for salvage therapy (nilotinib 400 mg twice daily; bosu-
tinib 500 mg daily), in addition to ponatinib (45 mg daily). Because of
concerns of arterio-occlusive events with ponatinib, the dose is often
reduced to 15–30 mg daily after a response is achieved. Imatinib,
dasatinib (140 mg daily), bosutinib, and ponatinib are also approved
for the treatment of CML in transformation (accelerated and blastic
phase), whereas nilotinib is only approved for chronic and accel-
erated phase. Dasatinib, nilotinib, and bosutinib are referred to as
second-generation TKIs; ponatinib is referred to as a third-generation
TKI as it is the only currently approved TKI that has clinical activity
in the setting of T315I mutation (in addition to unmutated BCR-
ABL1 and BCR-ABL1 with other common mutations). Nilotinib is
similar in structure to imatinib but 30 times more potent. Dasatinib
and bosutinib inhibit SRC family of kinases in addition to ABL1,
with dasatinib reported to be 300 times more potent and bosutinib
30–50 times more potent than imatinib. In contrast to all other TKI,
bosutinib has no activity against c-Kit or PDGFR. Ponatinib is effec-
tive against wild-type, and mutant BCR-ABL1 clones. It is currently
the only available BCR-ABL1 TKI active against T315I, a gatekeeper
mutation resistant to the other four TKIs (Table 101-2). Ponatinib
ciated with better outcomes in early surrogate endpoints, including
higher rates of complete cytogenetic responses (85–87% vs 77–82%),
major molecular responses (5-year rates 76–77% vs 60–64%), and
MR4.5 (5-year rates 42–53% vs 31–33%), with lower rates of transfor-
mation to accelerated and blastic phase (2–5% vs 7%). However, nei-
ther study has shown a survival benefit with second-generation TKIs
(with a minimum follow-up times of 5–6 years). This may be because
the rate of complete cytogenetic response is ultimately similarly high
with either agent, and also because sequential therapy with TKIs (fol-
lowing close observation and treatment change at progression) pro-
vides highly effective therapy for most patients that allows adequate
long-term outcome despite relapse or intolerance after initial therapy.
Salvage therapy in chronic phase with dasatinib, nilotinib, bosu-
tinib, or ponatinib is associated with complete cytogenetic response
rates of 30–60%, depending on the salvage status (cytogenetic vs
hematologic relapse), prior response to other TKIs, and the muta-
tions at the time of relapse. Complete cytogenetic responses are
generally durable, particularly in the absence of clonal evolution
and mutations. Ponatinib is the only TKI active in the setting
of T315I mutation, with complete cytogenetic response rates of
50–70% among patients who have received 2 or more TKI. The esti-
mated 5-year survival rates with new TKIs as salvage are 70–75%
(compared with <50% before their availability). For example, with
dasatinib salvage after imatinib failure in chronic-phase CML, the
estimated 7-year rate of major molecular was 46%, the estimated
7-year survival rate was 65%, and progression-free survival rate
was 42%. Thus, TKIs in the salvage setting have already reduced the
annual mortality from the historical rate of 10–15% to ≤5%.

TABLE 101-2  Medical Therapeutic Options in Chronic Myeloid Leukemia

AGENT (BRAND NAME)
Imatinib mesylate (Gleevec)
Dasatinib (Sprycel)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Ponatinib (Iclusig)
Omacetaxine mepesuccinate
(Synribo)
APPROVED INDICATIONS
All phases
All phases
All phases except blastic phase
All phases except frontline
Optimal TKI if T315I mutation
Failure of ≥2 tyrosine kinase
inhibitors
Failure ≥2 tyrosine kinase
inhibitors
DOSE SCHEDULE NOTABLE TOXICITIES
400 mg daily See text
First-line: 100 mg daily Myelosuppression; pleural and
Salvage: 100 mg daily in chronic phase; pericardial effusions; pulmonary
140 mg daily in transformation hypertension
First-line: 300 mg twice daily Diabetes; arterio-occlusive disease;
Salvage: 400 mg twice daily pancreatitis
500 mg daily Diarrhea, liver toxicity
45 mg daily (may consider lower starting doses Skin rashes (10–20%); pancreatitis
in the future, e.g., 30 mg daily) (5%); arterio-occlusive disease
(10–20%); systemic hypertension
(10–15%)
1.25 mg/m2 subcutaneously twice daily for Myelosuppression
14 days of induction; 7 days of maintenance
every month (may consider shorter dose schedules,
7 days of induction, 2–5 days of maintenance)

Harrisons_20e_Part4_p0435-p0858.indd 753 6/1/18 5:43 PM

 754 The goal of CML therapy is viewed differently in the context of
research versus standard practice. In current practice, functional cure,
which can be considered when the relative survival is similar to that
of the general population, is the current goal of therapy. CML is now
considered an indolent disease, which, with appropriate continuous
TKI therapy, treatment compliance, careful monitoring, and early
change to other TKIs as indicated, can be associated with close to
normal survival. Therefore, in standard practice, achievement and
maintenance of a complete cytogenetic response are the aims of ther-
apy because complete cytogenetic response is the only outcome asso-
ciated with survival prolongation. Lack of achievement of a major
molecular response (protects against events; associated with longer
event-free survival) or of negative BCR-ABL1 transcripts (offers the
potential of TKI interruption on investigational studies) should
not be considered indications to change TKI therapy or to consider
allogeneic SCT. A general practice rule is to continue the particular
TKI chosen at the most tolerable dose schedule not associated with
grade 3–4 side effects or with bothersome chronic side effects, for as
long as possible, until either cytogenetic relapse or the persistence of
unacceptable side effects. These two factors (i.e., cytogenetic relapse
and intolerable side effects as judged by the patient and treating
physician) are the indicators of “failure” of a particular TKI therapy.
A second emerging general practice rule is that patients with CML
PART 4
should always receive daily TKI therapy throughout their lifetime
(chronic, transformation), either alone (chronic) or in combinations
(possibly for those in transformation although combinations not for-
mally approved), except perhaps in situations of “molecular cure”
(elective discontinuation of TKI with close observation if BCR-ABL
Oncology and Hematology
transcripts undetectable are sustained for >2–3 years) or after alloge-
neic SCT with undetectable disease.
Because of the increasing prevalence of CML (cost of TKI therapy)
and the emerging evidence of possible organ toxicities with long-
term use (e.g., renal with imatinib, arterio-occlussive with nilotinib,
dasatinib, and ponatinib), a goal of therapy of increasing interest in
CML is to achieve eradication of the disease (molecular cure) that is
prolonged and durable, with recovery of non-neoplastic, non-clonal
hematopoiesis off TKI therapy. The first step toward this aim is
to obtain the highest rates of undetectable BCR-ABL1 transcripts
lasting for at least 2 or more years. This is currently achievable in
about 25–30% of patients treated with imatinib and in 40–45% of
patients treated with second-generation TKIs. As a result, molecular
cures (off TKI therapy) are estimated to be about 15% post-imatinib
therapy and 20–25% post–second-generation TKIs.
Recommendations provided by the National Comprehensive
Cancer Network (NCCN) and by the European LeukemiaNet
(ELN) propose optimal/expected, suboptimal/warning, and failure
response scenarios at different time points of TKI treatment dura-
tion. Unfortunately, they may have been misinterpreted in current
practice, because oncologists often report that their aim of treatment
is the achievement of major molecular response and disease eradica-
tion. Significantly, a substantial proportion of oncologists consider a
change of TKI therapy in a patient in complete cytogenetic response
if they note “loss of major molecular response” (increase of BCR-
ABL1 transcripts ([IS] from ≤0.1 to >0.1%). This perception may be
the result of confusion regarding the aims of the NCCN and ELN
guidelines, which have been updated often as a result of matur-
ing data and have multiple treatment endpoint considerations.
Although such endpoints may have been suggested as possible
criteria for failure or suboptimal response, it is important to empha-
size that no randomized study has yet shown that a change of TKI
treatment in patients with complete cytogenetic response because
of a loss of major molecular response, versus changing at the time
of cytogenetic relapse, has been shown to improve survival or other
long-term outcome. This is likely because of the high efficacy of sal-
vage TKI therapy at the time of cytogenetic relapse.
Side effects of TKIs are generally mild to moderate, although
with long-term TKI therapy, they could affect the patient’s quality
of life. Serious side effects occur in <5–10% of patients. With ima-
tinib therapy, common mild to moderate side effects include fluid
Harrisons_20e_Part4_p0435-p0858.indd 754
retention, weight gain, nausea, diarrhea, skin rashes, periorbital
edema, bone or muscle aches, fatigue, and others (rates of 10–20%).
In general, second-generation TKIs are associated with lower rates
of these bothersome adverse events. However, dasatinib 100 mg
daily is associated with higher rates of myelosuppression (20–30%),
particularly thrombocytopenia, with pleural (10–25%) or pericardial
effusions (≤5%), and with pulmonary hypertension (<5%). Nilotinib
is associated with higher rates of hyperglycemia (10–20%), pruritus
and skin rashes, hyperbilirubinemia (typically among patients with
Gilbert’s syndrome and mostly of no clinical consequences), and
headaches. Nilotinib is also associated with occasional instances
of pancreatitis (<5%). Bosutinib is associated with higher rates of
liver toxicity and of early and self-limited gastrointestinal adverse
events, particularly diarrhea (70–85%). Ponatinib is associated with
higher rates of skin rashes (10–15%), pancreatitis (10%), elevations
of amylase/lipase (10%), and systemic hypertension (50–60%; severe
in 20%). Arterio-occlusive events (cardiovascular, cerebrovascular,
and peripheral arterial) have been reported with most TKI. The
incidence appears to be highest with ponatinib, but both nilotinib
and dasatinib are associated with these events at an incidence
significantly higher than imatinib. Nilotinib and dasatinib may
cause prolongation of the QTc interval; therefore, they should be
evaluated cautiously in patients with prolonged QTc interval on
electrocardiogram (>470–480 ms), and drugs given for other medical
conditions should have relatively smaller or no effects on QTc. These
side effects can often be dose-dependent and are generally reversible
with treatment interruptions and dose reductions. Dose reductions
can be individualized. However, the lowest estimated effective
doses of TKIs (from different studies and treatment practices) are
imatinib 200–300 mg daily; nilotinib 150–200 mg twice daily; dasat-
inib 20 mg daily; bosutinib 300 mg daily; and ponatinib 15 mg daily.
With long-term follow-up, rare but clinically relevant serious
toxicities are emerging. Renal dysfunction and occasionally renal
failure (creatinine elevations >2–3 mg/dL) are observed in 2–3% of
patients, more frequently with imatinib and bosutinib than other TKI,
and usually reverse with TKI discontinuation and/or dose reduction.
Rarely, patients may develop TKI-related peripheral neuropathy or
even central neurotoxicities that are misdiagnosed as dementia or
Alzheimer’s disease; they may reverse slowly after TKI discontin-
uation. Pulmonary hypertension has been reported with dasatinib
(<1–2%) and should be considered in a patient with shortness of
breath and a normal chest x-ray (echocardiogram with emphasis on
measurement of pulmonary artery pressure). This may be reversible
with dasatinib discontinuation and occasionally the use of silden-
afil citrate. Systemic hypertension has been observed more often
with ponatinib. Hyperglycemia and occasionally diabetes have been
noted more frequently with nilotinib. Finally, mid- and small-vessel
arterio-occlusive and vasospastic events have been reported at low
but significant rates with nilotinib and ponatinib and should be con-
sidered possibly TKI-related and represent indications to interrupt or
reduce the dose of the TKI. These events include angina, coronary
artery disease, myocardial infarction, peripheral arterial occlusive
disease, transient ischemic attacks, cerebral vascular accidents,
Raynaud’s phenomenon, and accelerated atherosclerosis. Although
these events are uncommon (<5%) (10-year cumulative rates 10% with
nilotinib 300 mg BID, 16% with 400 mg BID, compared with 2.5% with
imatinib), they are clinically significant for the patient’s long-term
prognosis and occur at significantly higher rates than in the general
population. Serious arterio-occlusive and vasospastic events are more
common with ponatinib 45 mg daily (5-year rates 20%).
Discontinuation of TKIs and Treatment-Free Remissions or “Molecular
Cures”  Several studies have confirmed that TKI discontinuation
among patients who achieve undetectable BCR-ABL1 transcripts
for longer than 2–3 years can result in treatment-free remission rates
of 40–60%. Since the incidence of durable undetectable BCR-ABL1
transcripts is 20–45%, about 13–22% of all patients with CML on TKI
therapy may achieve treatment-free remission status or molecular
cure. This approach is still considered investigational, but may be
ready for community practice provided it is done under optimal
6/1/18 5:43 PM
 conditions. These include the following: patients must have low TABLE 101-3  General Suggestions Regarding the Use of Tyrosine 755
Sokal-risk CML in first chronic phase (no evidence of transforma- Kinase Inhibitors (TKIs) and Allogeneic Stem Cell Transplantation
tion), with history of quantifiable BCR-ABL1 transcripts (e13a2, (SCT) in Chronic Myeloid Leukemia (CML)
e14a2), on long-term TKI therapy (5 to 8+ years), with documented CONSIDERATION OF
undetectable BCR-ABL1 transcripts for >2–3 years (assessed every CML PHASE USE OF TKI ALLOGENEIC SCT
6 months during this timespan and with a PCR with adequate Accelerated or blastic Interim therapy to As soon as possible
sensitivity), and should be monitored at referral centers that offer achieve minimal CML (exception: de novo
rigorous testing of residual CML disease. Patients must also be burden accelerated phase)
compliant to frequent monitoring (PCR studies every 1–2 months T315I mutation Ponatinib to achieve Depends on longer term
for the first 6 months, then every 2 months until 2 years and every minimal CML burden follow-up results of
3–6 months thereafter). ponatinib efficacy
Imatinib failure in Second-line tyrosine Third-line after second-
ALLOGENEIC STEM CELL TRANSPLANT chronic phase; no clonal kinase inhibitors line TKI failures
Allogeneic SCT, a curative modality in CML, is associated with long- evolution, no mutations, long-term
term survival rates of 40–60% when implemented in the chronic good initial response;
no T315I
phase. It is associated with early (1-year) mortality rates of 5–30%.
Although the 5- to 10-year survival rates were reported to be around Clonal evolution or Interim therapy with Second-line
mutations, or no alternative second
50–60% (and considered as cure rates), about 10–15% of patients die cytogenetic response to generation TKI or
in the subsequent 1–2 decades from subtle long-term complications second-line TKI ponatinib to achieve
of the transplant (rather than from CML relapse). These are related minimal CML burden
to chronic graft-versus-host disease (GVHD), organ dysfunction, Older patients Salvage TKIs as longer- May forgo allogeneic
development of second cancers, and hazard ratios for mortality (≥65–70 years) after term therapy SCT in favor of good
higher than in the normal population. Other significant morbid- imatinib failure in quality of life and

CHAPTER 101 Chronic Myeloid Leukemia

ities include infertility, chronic immune-mediated complications,
cataracts, hip necrosis, and other morbidities affecting quality of
life. The cure and early mortality rates in chronic-phase CML are
also associated with several factors: patient age, duration of chronic
phase, whether the donor is related or unrelated, degree of match-
ing, preparative regimen, and others. In accelerated-phase CML, the
cure rates with allogeneic SCT are 20–40%, depending on the defi-
nition of accelerated disease. Patients with clonal evolution as the
only criterion have cure rates of up to 40–50%. Patients undergoing
allogeneic SCT in second chronic phase have cure rates of 40–50%.
The cure rates with allogeneic SCT in blastic phase CML are ≤15%.
Post–allogeneic SCT strategies are now implemented in the setting
of molecular or cytogenetic relapse or in hematologic relapse/trans-
formation. These include the use of TKIs for prevention or treatment
of relapse, donor lymphocyte infusions, and second allogeneic SCTs,
among others. TKIs appear to be highly successful at reinducing
cytogenetic/molecular remissions in the setting of cytogenetic or
molecular relapse after allogeneic SCT.
Choice and Timing of Allogeneic SCT  Allogeneic SCT was con-
sidered first-line CML therapy before 2000. The maturing positive
experience with TKIs has now relegated its use to after first-line
TKI failures. An important question is the optimal timing and
sequence of TKIs and allogeneic SCT (whether allogeneic SCT
should be used as second- or third-line therapy). Among patients
who present with or evolve to blastic phase, combinations of che-
motherapy and TKIs should be used to induce remission, followed
by allogeneic SCT as soon as possible. The same applies to patients
who evolve from chronic to accelerated phase. Patients with de
novo accelerated-phase CML may do well with long-term TKI
therapy (estimated 8-year survival rate 75%); the timing of alloge-
neic SCT depends on their optimal response to TKI (achievement
of complete cytogenetic response). Among patients who relapse in
chronic phase, the treatment sequence depends on several factors:
(1) patient age and availability of appropriate donors; (2) risk of
allogeneic SCT; (3) presence or absence of clonal evolution and
mutations; (4) patient’s prior history and comorbidities; and (5)
patient and physician preferences (Table 101-3). Patients with T315I
mutations at relapse should be offered ponatinib and considered
for allogeneic SCT particularly in blastic phase and perhaps also
in accelerated phase (because of the short follow-up with pona-
tinib). Patients with mutations involving Y253H, E255K/V, and
F359V/C/I respond better to dasatinib or bosutinib. Patients with
mutations involving V299L, T315A, and F317L/F/I/C respond
better to nilotinib. Comorbidities such as diabetes, hypertension,
pulmonary hypertension, chronic lung disease, cardiac conditions,
and pancreatitis may influence the choice for or against a particular
chronic phase survival in chronic phase
Imatinib failure; – Second-line: curative,
emerging nation one-time cost $20,000–
100,000 (versus
>$40,000–100,000/
year with TKI)
Note: Mutations involving Y253H, E255K/V, or F359V/C/I: prefer dasatinib or
bosutinib. Mutations involving V299L, T315A, or F317L/F/I/C: prefer nilotinib.
TKI. Patients with clonal evolution, unfavorable mutations, or lack
of major/complete cytogenetic response within 1 year of salvage TKI
therapy have short remission durations and should consider alloge-
neic SCT as more urgent in the setting of salvage. Patients without
clonal evolution or mutations at relapse and who achieve a complete
cytogenetic response with TKI salvage, have long-lasting complete
remissions and may delay the option of allogeneic SCT to third-
line therapy. Finally, older patients (age 65–70 years or older) and
those with high risk of mortality with allogeneic SCT may forgo this
curative option for several years of disease control in chronic phase
with or without cytogenetic response (Table 101-3). In emerging
nations, where generic imatinib is now available at the annual price
of $400–3000, frontline imatinib is a cost-effective therapy. However,
second-line therapy with allogeneic SCT, a one-time curative option
with a cost of $20,000–100,000, may be considered (in preference
to second-generation TKIs—annual cost above $40,000–100,000)
as a more cost-effective national health-care strategy in CML.
Table 101-3 summarizes a general guidance to the choice of TKIs
versus allogeneic SCT.
MONITORING THERAPY IN CML
Achievement of complete cytogenetic response by 12 months of ima-
tinib therapy and its persistence later, the only consistent prognostic
factor associated with survival, is now the main therapeutic end-
point in CML. Failure to achieve a complete cytogenetic response by
12 months or occurrence of later cytogenetic or hematologic relapse
are considered as treatment failure and an indication to change ther-
apy. Because salvage therapy with other TKIs re-establishes good
outcome, it is important to ensure patient compliance to continued
TKI therapy and change therapy when cytogenetic relapse is con-
firmed unless this is related to non-adherence. Patients on frontline
imatinib therapy should be closely monitored until documentation
of complete cytogenetic response, at which time they can be moni-
tored every 6 months with peripheral blood FISH and PCR studies
(to check for concordance of results), or more frequently if there
are concerns about changes in BCR-ABL1 transcripts (e.g., every
3 months). Monitoring by PCR only is reasonable in patients who

Harrisons_20e_Part4_p0435-p0858.indd 755 6/1/18 5:43 PM

 756 are in major molecular response. Cytogenetic relapse on imatinib is
an indication of treatment failure and need to change TKI therapy.
Mutational analysis in this instance helps in the selection of the
next TKI and identifies mutations in 30–50% of patients. Mutational
studies by standard Sanger sequencing (which is the technique cur-
rently available in most clinical laboratories) in patients in complete
cytogenetic response (in whom there may be concerns of increasing
BCR-ABL1 transcripts) identify mutations in ≤5% and are therefore
not indicated. Earlier response has been identified as a prognostic
factor for long-term outcome, including achievement of partial
cytogenetic response (BCR-ABL1 transcripts ≤10%) by 3–6 months of
therapy. Failure to achieve such a response has been associated with
significantly worse survival.
The use of second-generation TKIs (nilotinib, dasatinib) as front-
line therapy changed the monitoring approach slightly. Patients are
expected to achieve major cytogenetic response (or BCR-ABL1 tran-
scripts ≤10%) by 3–6 months of therapy. Failure to do so is associated
with worse event-free survival, transformation rates, and survival.
However, the 3- to 5-year estimated survival among such patients
is still high, around 80–90%, which is better than what would be
anticipated if such patients were offered allogeneic SCT at that time.
Changes of therapy for patients with “slow” response have not been
proven to be of long-term benefit compared to changes when more
PART 4
obvious signs of resistance appear. Thus, this adverse response to
therapy is considered a warning signal, but it is not known whether
changing therapy to other TKIs at that time would improve lon-
ger-term outcome.
TREATMENT OF ACCELERATED AND BLASTIC PHASES
Oncology and Hematology
Patients in accelerated or blastic phase may receive therapy with
TKIs, preferably second- or third-generation TKIs (dasatinib, nilo-
tinib, bosutinib, ponatinib), alone or in combination with chemo-
therapy, to reduce the CML burden, before undergoing allogeneic
SCT. Response rates (major hematologic) with single-agent TKIs
range from 30 to 50% in accelerated phase and from 20 to 30%
in blastic phase. Cytogenetic responses, particularly complete
cytogenetic responses, are uncommon (10–30%) and transient in
blastic phase. Studies of TKIs in combination with chemotherapy
are ongoing; the general experience suggests that combined TKI-
chemotherapy strategies increase the response rates and their durabil-
ity and improve survival. This is particularly true in CML lymphoid
blastic phase, where the combination of anti-ALL chemotherapy
with TKIs results in complete response rates of 60–70% and median
survival times of 2–3 years (compared with historical response rates
of 40–50% and median survival times of 12–18 months). This allows
many patients to undergo allogeneic SCT in a state of minimal CML
burden or second chronic phase, which are associated with higher
probability of long-term survival. In CML nonlymphoid blastic
phase, anti-AML chemotherapy combined with TKIs results in CR
rates of 30–50% and median survival times of 9–12 months (com-
pared with historical response rates of 20–30% and median survival
times of 3–5 months). In accelerated phase, response to single TKIs
is significant in conditions where “softer” accelerated phase criteria
are considered (e.g., clonal evolution alone, thrombocytosis alone,
significant splenomegaly or resistance to hydroxyurea, but without
evidence of high blast and basophil percentages). In accelerated
phase, combinations frequently include TKIs with low-intensity
chemotherapy such as low-dose cytarabine, low-dose idarubicin,
decitabine, interferon α, hydroxyurea, or others.
OTHER TREATMENTS AND SPECIAL THERAPEUTIC
CONSIDERATIONS
Interferon `  Interferon α is considered in combination with TKIs
(an investigational approach), sometimes after CML failure on TKIs,
occasionally in patients during pregnancy, or as part of investiga-
tional strategies with TKIs to eradicate residual molecular disease.
Chemotherapeutic Agents  Hydroxyurea remains a safe and effec-
tive agent (at daily doses of 0.5–10 g) to reduce initial CML bur-
den, as a temporary measure in between definitive therapies, or
Harrisons_20e_Part4_p0435-p0858.indd 756
in combination with TKIs to sustain complete hematologic or
cytogenetic responses. Busulfan is often used in allogeneic SCT
preparative regimens. Because of its side effects (delayed myelo-
suppression, Addison-like disease, pulmonary and cardiac fibrosis,
myelofibrosis), it is now only rarely used in the chronic manage-
ment of CML. Low-dose cytarabine, decitabine, anthracyclines,
6-mercaptopurine, 6-thioguanine, thiotepa, anagrelide, and other
agents are sometimes useful in different CML settings to control the
disease burden.
Others  Splenectomy is now seldom considered to alleviate symp-
toms of massive splenomegaly and/or hypersplenism. Splenic
irradiation is rarely used, if at all, because of the postirradiation
adhesions and complications. Leukapheresis is occasionally used
in patients presenting with extreme leukocytosis and leukostatic
complications. Single doses of high-dose cytarabine or high doses
of hydroxyurea, with tumor lysis management, may be as effective
and less cumbersome.
Special Considerations  Women with CML who become pregnant
should discontinue TKI therapy immediately. Among 125 babies
delivered to women with CML who discontinued imatinib ther-
apy as soon as the pregnancy was known, three babies were born
with neurologic, skeletal, and renal malformations, suggesting the
teratogenicity of imatinib known from animal studies. A similar
experience has been reported with dasatinib, the incidence of mal-
formations was reported to be higher, 10–12%. There are no or little
data with other TKIs. Control of CML during pregnancy can be
managed with leukapheresis for severe symptomatic leukocytosis
in the first trimester and with hydroxyurea subsequently until
delivery. There are case reports of successful pregnancies and deliv-
eries of normal babies with interferon α therapy and registry stud-
ies in essential thrombocytosis of its safety, but interferon α can be
antiangiogenic and may increase the risk of spontaneous abortions.
Approximately 10–15% of patients on TKI therapy may develop
chromosomal abnormalities in the Ph-negative cells. These may
involve loss of chromosome Y, trisomy 8, 20q–, chromosome 5
or 7 abnormalities, and others. Most chromosomal abnormalities
disappear spontaneously and may be indicative of the genetic insta-
bility of the hematopoietic stem cells that predisposes the patient
to develop CML in the first place. Rarely (in <1% of instances),
abnormalities involving chromosomes 5 or 7 may be truly clonal and
evolve into myelodysplastic syndrome or acute myeloid leukemia.
This is thought to be part of the natural course of patients in whom
CML was suppressed and who live long enough to develop other
hematologic malignancies.
■■GLOBAL ASPECTS OF CML
Routine physical examinations and blood tests in the United
States and advanced countries result in early detection of CML
in most patients. About 50–70% of patients with CML are diag-
nosed incidentally, and high-risk CML as defined by prognostic models
(e.g., Sokal risk groups) is found in only 10% of patients. This is not the
same situation in emerging nations where most patients are diagnosed
following evaluation for symptoms and many present with high tumor
burden, such as massive splenomegaly, and advanced phases of CML
(high-risk CML documented in 20–30%). Therefore, the prognosis of such
patients on TKI therapy may be worse than the published experience.
The high cost of TKI therapies (annual costs of $90,000–140,000 in
the United States; lower but variable in the rest of the world) makes
the general affordability of such treatments difficult. Although TKI
treatment penetration is high in nations where cost of therapy is not
an issue (e.g., Sweden, European Union), it may be less so in other
nations, even in advanced ones like the United States, where out-of-
pocket expenses may be prohibitive to a subset of patients. Based
on the sales of imatinib worldwide and charity-free drug supplies,
it is estimated that <30% of patients are treated with imatinib (or
other TKIs) consistently. Although the estimated 10-year survival in
CML is 85% in single-institution studies (e.g., MD Anderson Cancer
Center), in national studies in countries with TKI affordability (Sweden)
6/1/18 5:43 PM
 1.0
0.8
0.6
Overall survival
0.4
0.2 Chronic phase
Accelerated phase
Blast crisis
0.0
0 1 2 3 4 5
Years after diagnosis
No. at risk
CP 699 672 631 530 446
AP 32 22 21 18 14
BC 17 11 10 7 6
FIGURE 101-3  Survival in chronic (CP), accelerated (AP), and blastic crisis (BC)
phases of chronic myeloid leukemia (CML) in the population-based Swedish
national registry study. The accelerated- and blastic-phase cases are de novo
presentations. The favorable outcome with de novo blastic phase may be due
to use of 20% blasts or more to define blastic phase. (With permission from Dr.
Martin Hoglund, Swedish CML Registry, 2013.)
(Figs. 101-2 and 101-3) or in company-sponsored studies (where all
patients have access to TKIs throughout their care), the estimated
10-year survival worldwide, even 16 years after the introduction of TKI
therapies, is likely to be <50%. The Surveillance, Epidemiology, and
End Results (SEER) data from the United States report an estimated
5-year survival rate of 60% in the era of TKIs.
The current high cost of TKI therapies poses two additional consid-
erations. The first are the treatment pathways and guidelines in nations
where TKIs may not be affordable by patients or the health care system.
In these conditions, there are trends of pathways advocating allogeneic
SCT as frontline or second-line therapy (i.e., after imatinib failure; as a
one time cost of $20,000–100,000) despite the associated mortality and
morbidities. The second is the choice of frontline TKI therapy once
imatinib becomes available in generic forms, hopefully at much lower
annual prices, e.g., $2000–10,000 per year (currently $400 per year in
India). This will depend on the maturing data in randomized studies
of second-generation TKIs versus imatinib in relation to important
long-term outcome endpoints, particularly survival, but also event-free
survival, transformation-free survival, and treatment-free remission.
■■FURTHER READING
Baccarani M et al: European LeukemiaNet recommendations for the
management of chronic myeloid leukemia. Blood 122:872, 2013.
Cortes J, Kantarjian H: How I treat newly diagnosed chronic phase
CML. Blood 120:1390, 2012.
Cortes JE et al: Ponatinib in refractory Philadelphia chromosome-
positive leukemias. N Engl J Med 367:2075, 2012.
Cortes JE et al: Final 5-year study results of DASISION: The dasatinib
versus imatinib study in treatment-naïve chronic myeloid leukemia
patients trial. J Clin Oncol 34:2333, 2016.
Gambacorti-Passerini C et al: Long-term efficacy and safety of
bosutinib in patients with advanced leukemia following resistance/
intolerance to imatinib and other tyrosine kinase inhibitors. Am J
Hematol 90:755, 2015.
Hochhaus A et al: Long-term benefits and risks of frontline nolitinib
vs imatinib for chronic myeloid leukemia in chronic phase: 5-year
update of the randomized ENESTnd trial. Leukemia 30:1044, 2016.
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Hochhaus A et al: Long-term outcomes of imatinib treatment for 757
chronic myeloid leukemia. N Engl J Med 376; 917, 2017.
Kantarjian HM et al: Nilotinib is effective in patients with chronic
myeloid leukemia in chronic phase after imatinib resistance or
intolerance: 24-month follow-up results. Blood 117:1141–1145, 2013.
Rousselot P et al: Loss of major molecular response as a trigger for
restarting tyrosine kinase inhibitor therapy in patients with chronic-
phase chronic myelogenous leukemia who have stopped imatinib
after durable undetectable disease. J Clin Oncol 32:424–430, 2014.
Sasaki K et al: Conditional survival in patients with chronic myeloid
leukemia in chronic phase in the era of tyrosine kinase inhibitors.
Cancer 122:238–248, 2016.
Shah NP et al: Dasatinib in imatinib-resistant or –intolerant
chronic-phase, chronic myeloid leukemia patients: 7-year follow-up
of study CA180-034. Am J Hematol 9:869–874, 2016.
6 7 8
102 Acute Lymphoid Leukemia
365 278 212 144
10 5 4 2
CHAPTER 102 Acute Lymphoid Leukemia
5 4 4 1
Dieter Hoelzer
In acute lymphoblastic leukemia (ALL), the malignant clone arises
from hematopoietic progenitors in the bone marrow or lymphatic
system resulting in an increase of immature nonfunctioning leukemic
cells. Infiltration of bone marrow leads to anemia, granulocytopenia,
and thrombocytopenia with the clinical manifestations of fatigue,
weakness, infection, and hemorrhages. These symptoms are more often
the reason a patient first seeks medical advice rather than consequences
of tumor bulk, such as lymph node enlargement, hepatosplenomegaly
caused by leukemic infiltration, or symptoms of the central nervous
system (meningeosis leukemica).
The diagnosis of ALL is made by morphology from smears of periph-
eral blood or bone marrow. The classification includes cytochemistry,
immunological markers, cytogenetic, and molecular genetic analysis.
■■INCIDENCE AND AGE
ALL is the most frequent neoplastic disease in children with an early
peak at the age of 3–4 years. The incidence in adults ranges from 0.7 to
1.8/100,000 per year, being somewhat higher in younger adults (1–1.5
for the age group 15–24 years) and decreasing thereafter, only to increase
again in elderly people to 2.3 for age >65 years. The frequency of immu-
nological, cytogenetic, and genetic subtypes changes with age.
■■ETIOLOGY
The etiology of acute leukemias is unknown. There are, however, inter-
nal and external factors that influence the incidence of leukemia. In
ALL, inheritance of certain diseases and exposure to ionizing radiation
or to chemicals, including prior chemotherapy, are associated with an
increased risk of developing leukemia, but less than in acute myeloid
leukemia (AML).
■■CONGENITAL DISORDERS
Patients with some rare congenital chromosomal abnormalities have
a higher risk of development of acute leukemia; e.g., Klinefelter’s
syndrome, Fanconi’s anemia, Bloom’s syndrome, ataxia telangiectasia,
and neurofibromatosis. There is a twentyfold increased incidence of
leukemia in patients with Down syndrome, in whom ALL is increased
in childhood or AML at an older age. Genetic predisposition may play
a part in acute leukemia even, when not associated with another inher-
ited disease, as the identical twin of a leukemic child has a fivefold risk
of developing acute leukemia.
■■INFECTIOUS AGENTS
Human T-cell leukemia virus I (HTLV-I), endemic in Japan and
the Caribbean, is the etiological agent for adult T-cell leukemia/
6/1/18 5:43 PM
 758 lymphoma, an aggressive adult T-cell leukemia (see Chap. 196). In the in ~70% of patients. The normal hemopoietic elements are greatly
endemic African type of Burkitt’s lymphoma, the Epstein-Barr virus, reduced or absent. A biopsy of the bone marrow will further demon-
a DNA virus of the herpes family, has been implicated as a potential strate marked hypercellularity with replacement of fat spaces and
causative agent. normal elements by infiltration with leukemic cells.

■■DIAGNOSIS AND CLASSIFICATION ■■LUMBAR PUNCTURE

The diagnosis of acute leukemia is made by examination of the periph-
eral blood and bone marrow. Classification of the patient’s disease also
requires cytochemical stains, assessment of expression of immunolog-
ical markers, cytogenetic analysis, and molecular markers. The major
aim of classification is to distinguish between AML and ALL because
of the different treatment approaches and drug sensitivities. The immu-
nological markers are the major criteria to subdivide ALL into B-cell
lineage or T-cell lineage (T-ALL) leukemias. Cytogenetic and molecular
evaluation provide further identification of ALL subgroups.
■■PERIPHERAL BLOOD
Peripheral blood counts and a differential count from a Wright-Giemsa-
stained blood smear are essential at the time of presentation. The
white blood cell count in about 40% of ALL patients is reduced or
normal (Table 102-1). Thus, in the frequently used automatic blood
cell counter, the disease may not be detected. One-third of the patients
have a moderately increased initial white blood cell count, between
10 × 109 and 50 × 109/L. Leukemic blast cells (LBC) in the peripheral
PART 4
The examination of the cerebrospinal fluid is an essential routine diag-
nostic measure for ALL. There are different opinions as to when the first
lumbar puncture should be done. One procedure is to delay the exami-
nation until remission is achieved in order to avoid seeding the central
nervous system (CNS) by circulating leukemic blast cells from the
peripheral blood. On the other hand, early recognition of CNS disease
will lead to immediate CNS-specific therapy, which is required for such
patients. Thus, other clinicians prefer to perform the lumbar puncture
before treatment starts. This procedure is restricted to patients with an
adequate platelet count (>20 × 109/L), an absence of manifest clinical
hemorrhage, and without a high white blood cell count. For safety
reasons, all patients should receive intrathecal methotrexate at the first
lumbar puncture.
■■MORPHOLOGICAL SUBTYPES IN ALL
Three morphologic subgroups of acute lymphoblastic leukemia are
distinguished by the French-American-British classification. Whereas
the distinction between L1 and L2 morphology has no clinical conse-

blood are largely responsible for the rise in white blood cell count, but
it is noteworthy that in 8% of the ALL patients, no circulating leukemic
blast cells are observed.
Peripheral blood observation shows characteristic anemia, thrombo-
cytopenia, and neutropenia. The reduction in the level of hemoglobin
Oncology and Hematology
quences, the detection of L3 ALL is of clinical and prognostic relevance.
It is observed in up to 5% of adult patients and should be distinguished
as it is indicative of mature B-ALL, usually termed Burkitt’s leukemia,
with distinct treatment options. A surface marker confirmation should
be obtained.

is usually mild to moderate, but nearly one-third of the patients have

hemoglobin levels <7–8 g/dL. A platelet count below the critical num- ■■IMMUNOLOGICAL SUBTYPES OF ALL
ber of 20 × 109/L is seen in one-fifth of the ALL patients. The proportion A series of monoclonal antibodies is employed to identify antigens
of patients with granulocyte count <0.5 × 109/L usually associated with expressed on the surface of normal or leukemic cells. The main aim of
high risk of infection was only one-fifth in adult ALL series. the immunological classification is to subdivide ALLs according to the
presence or absence of B-cell or T-cell markers, or B-phenotypic/hybrid
■■BONE MARROW EXAMINATION acute leukemia. A marker is positive if >20% of the cells are stained
Bone marrow aspirates are important for immunological, cytogenetic, with the monoclonal antibody (Table 102-2).
and genomic markers. Direct smears from the bone marrow are essen-
tial to confirm the diagnosis of acute leukemia and to distinguish
B-Cell Lineage  More than 70% of adult ALLs are of B-cell origin,
and the most frequent immunological subtype, common ALL, is charac-
between AML and ALL. The bone marrow is usually heavily packed
terized by the presence of ALL antigen, a glycoprotein (gp100/CD10).
with leukemic blast cells comprising >90% of the nucleated cells
Common ALL blast cells do not carry markers of mature B cells such as
cytoplasmic immunoglobulins or surface membrane immunoglobulins.
TABLE 102-1  Laboratory Values at Diagnosis of Acute Lymphoblastic Pre-B-ALL (early B-ALL) is characterized by the expression of cytoplas-
Leukemia mic immunoglobulin, being negative in common ALL but is otherwise
    ALL identical with all other cell markers. Very rarely, the common ALL anti-
gen may be absent in this subtype. Mature B-ALL comprises about 3–4%
N   1273*
of adult ALL patients. The blast cells express surface antigens of mature
Initial white blood cell <10 41%
count B cells, including the sIgM. Common ALL antigens may also be present
10–50 31%
and also occasionally cytoplasmic immunoglobulin. Pro-B-ALL (also
(× 109/L) >50 28% termed early B-precursor ALL) is a leukemia that was formerly termed
Neutrophils <50–100 12% non-T, non-B-ALL, or null-ALL as neither T-cell nor B-cell features could
<100,000 16% be demonstrated. This subtype is Tdt (terminal) deoxynucleotidyl trans-
Platelets <20 22% ferase, and CD19 positive and forms about 11% of adult ALL.
(× 109/L) 21–40 22%
T-Cell Lineage  Approximately 25% of adult ALL belongs to the
41–100 29%
T-cell lineage. All cases express the T-cell antigen (gp40, CD7) and cyto-
>100 27% plasmatic or surface CD3. They may, according to their step of T-cell
Hemoglobin (g/dL) <7 20% differentiation, express other T-cell antigens, e.g., the E-rosette receptor
7–9 33% (CD2) and/or the cortical thymocyte antigen T6 (CD1). A minority
>9 47% of T-ALL blast cells may also express common ALL antigen together
Leukemic blasts in PB 0% 8% with other T-cell antigens. According to these markers, it is possible to
25–75% 34% distinguish a pro-T-ALL (also termed early T-precursor ALL), cortical,
>75% 36% or thymic T-ALL and a mature T-ALL expressing different stages of
Leukemic blasts in BM <50% 4% differentiation.
51–90% 25% Biphenotypic or Mixed Leukemias  Biphenotypic leukemias
>90% 71% are defined as those in which markers of lymphoid and myeloid
Source: Data from three consecutive German Multicenter Trials for Adult ALL lineages are coexpressed on the same leukemic cells without the typ-
(GMALL). ical phenotype of either ALL or AML. Bilineage leukemias are those

Harrisons_20e_Part4_p0435-p0858.indd 758 6/1/18 5:43 PM

 TABLE 102-2  Immunological, Cytogenetic, Molecular, and Clinical Characteristics of Adult ALL 759

FREQUENT FUSION
CYTOGENETIC TRANSCRIPTS AND RELAPSE KINETICS
SUBTYPES MARKER INCIDENCE ABERRATIONS MUTATIONS CLINICAL CHARACTERISTICS AND LOCALIZATION
B-lineage ALL HLA-DR+, TdT+, CD19+ 76%        
and/or
CD79a+ and/or CD22+
Pro B-ALL No additional 12% t(4;11) 70% ALL1-AF4 High WBC (>100.000/mL) Mainly BM
differentiation markers, (q21;q23) (20% Flt3 in MLL+) (26%) (>90%)
Freq. myeloid
coexpression (>50%)
Common ALL CD10 49% t(9;22)(q34;q11) 33% BCR–ABL Higher age >50 years (24%) Mainly BM
del(6q) (30–50% in c/preB) (>90%)
Prolonged relapse
kinetics (up to
5–7 years)
Pre-B-ALL CD10±, cyIg+ 11% t(9;22)(q34;q11) 4% t(1;19)/    
t(1;19)(q23;p13) PBX-E2A
Mature B-ALL CD10 ±, sIg+ 4% t(8;14)(q24;q32)   Higher age >55 years (27%) Frequent CNS (10%)
t(2;8)(p12;q24) Frequent organ involvement Short relapse
t(8;22)(q24;q11) (32%) kinetics
and CNS-involvement (13%) (up to 1–1.5 years)

CHAPTER 102 Acute Lymphoid Leukemia

T-lineage ALL cyCD3 or sCD3 24%     Younger age (90% <50 years) Frequent CNS (10%)/
Frequent mediastinal tumors extramedullary (6%)
(60%) Intermediate
Frequent CNS involvement relapse kinetics
(8%)
(up to 3–4 years)
High WBC (>50/mL) (46%)
Early Pro/Pre No additional 6% t(10;14)(q24;q11) 5% HOX11-TCR    
T-ALL differentiation t(11;14)(p13;q11) <5% LMO/TCR
markers, mostly CD2- 12% 2% SIL-TAL1
Cortical T-ALL CD1a+, sCD3± In T-ALL
sCD3+, CD1a- 6% 4% NUP213-ABL1
Mature T-ALL 33% HOX11b
5% HOX11L2b
50% Notch1b

with two populations of blast cells with either lymphoid or myeloid
antigens. They must be differentiated from AML by coexpression of
lymphoid markers and from ALL by coexpression of myeloid markers.
■■CYTOGENETIC AND MOLECULAR ANALYSIS
Cytogenetic analysis should be performed in all cases of acute leuke-
mia. The demonstration of a specific karyotype may be required for
the confirmation of the diagnosis, but chromosome abnormalities may
be also important independent prognostic variables for disease-free
survival or may lead to a specific targeted therapy.
■■DIAGNOSTICS
The diagnostic techniques are standard cytogenetics, fluorescence in
situ hybridization, and reverse transcriptase polymerase chain reaction.
These methods allow the detection of Ph+ ALL, with the chromosomal
translocation t(9;22)(q34;q11), and the detection of the corresponding
BCR-ABL1 gene rearrangement. Further ALL entities that have been
identified are t(4;11)(q21;q23)/MLL-AFA4, abn11q23/MLL, and t(1;19)
(q23;p13)/PBX-E2A.
Gene expression profiling, single nucleotide polymorphism array
analysis, array-comparative genomic hybridization, and next genera-
tion sequencing recognize newly defined ALL entities with poor prog-
nosis: Ph-like ALL and early T-precursor ALL.
■■NEW ENTITIES
involving ABL1, JAK2, PDGFRB, and several others. The frequency is 10%
in children and 25–30% in young adults, but does not increase further with
age. Treatment could be directed at the underlying genetic pattern with
BCR-ABL inhibitors (e.g., dasatinib) or JAK2 inhibitors (e.g., ruxolitinib).
Early T-Precursor ALL  (ETP-ALL) is characterized by lack of
CD1a and CD8, weak CD5 expression, at least one myeloid/stem cell
marker, a specific transcriptional profile and the possible involvement
of several critical genes. No new treatment approaches are currently
available for this subtype, and thus hematopoietic stem cell transplan-
tation in first complete remission is the preferred option.
■■MINIMAL RESIDUAL DISEASE (MRD)
MRD is the detection of residual leukemic cells, not recognizable by
light microscopy.
Methods for determining MRD are based on the detection of
leukemia-specific aberrant immunophenotypes by flow cytometry,
the evaluation of leukemia-specific rearranged immunoglobulin or
T-cell receptor sequences by real-time quantitative polymerase chain
reaction, or the detection of fusion genes associated with chromosomal
abnormalities (e.g., BCR-ABL, MLL-AF4). The detection limit with
these methods is 10–3–10–5 (0.1–0.001%). The phenotypic aberrations are
unique to each patient with ALL and can be detected in up to 95% of
individuals. Methods for MRD evaluation and standardization of MRD
quantification have been extensively described.

Ph-Like ALL,  also called BCR-ABL1-like ALL, is characterized ■■MRD RESPONSE AND TERMINOLOGY
by genetic lesions similar to Ph+ ALL, associated with IKZF1 deletion, Molecular response can be evaluated only for patients in complete
CLRF2 overexpression, and tyrosine kinase activating rearrangements cytological remission, with one marker or more for MRD analysis and

Harrisons_20e_Part4_p0435-p0858.indd 759 6/1/18 5:43 PM

 760 TABLE 102-3  Response Parameters According to MRD
TERMINOLOGY DEFINITION
Complete (hematologic) Leukemic cells not detectable by light
remission microscopy (<5% blast cells in bone marrow)
Complete molecular Patient in complete remission, MRD not
remission MRD-negativity detectable, ≤0.01% = ≤1 leukemia blast cell in
10,000
Molecular failure/ Patient in complete hematologic remission but
MRD-positivity not in molecular complete remission >0.01%
Molecular relapse/ Patient still in complete remission had prior
MRD-positivity molecular complete remission
Leukemic blast cells detectable in bone marrow
not detectable (<5%)
Hematologic relapse >5% ALL cells in bone marrow/blood
samples available at diagnosis and followed at specific time points
during the course of disease. Results are classified as presented in
Table 102-3.
■■MOLECULAR RESPONSE AFTER INDUCTION
THERAPY AND IMPACT ON OUTCOME
Achievement of molecular complete response/molecular remission is the
PART 4
most relevant independent prognostic factor for disease-free survival and
overall survival. Patients with molecular complete remission after induc-
tion therapy had significantly superior outcome in several studies, with
a disease-free survival of 54–74%, compared to 17–40% for MRD-positive
Oncology and Hematology
patients. Patients with molecular failure after induction therapy should
proceed to a targeted therapy to reduce the tumor load, to be followed by
immediate allogeneic hematopoietic stem cell transplant.
■■PROGNOSTIC FACTORS, RISK STRATIFICATION,
AND MRD
The aim of identification of prognostic parameters at diagnosis, which
include age, white blood cell count, specific immunophenotypes, and
cytogenetic and genetic aberrations, is to stratify patients into risk
groups: standard-risk patients without any poor-risk factors, with a
good chance of cure by chemotherapy, and high-risk patients with one
or more of those risk factors. High-risk patients are most often candi-
dates for a stem cell transplant in first complete remission.
■■WILL MINIMAL RISK DISEASE EVALUATION
REPLACE PRETHERAPEUTIC RISK FACTORS?
The question arises as to whether the evaluation of MRD overcomes
all of those pretherapeutic risk factors, or whether they should be com-
bined. A practical approach is to enter the conventional prognostic fac-
tors and MRD into a decision algorithm. Thereby defined standard-risk
patients who are highly likely to achieve molecular remission (about
90–95%) will remain as standard-risk patients, whereas those who
are MRD-positive will be defined accordingly as high-risk patients.
Clinically defined high-risk patients are potential candidates for a
stem cell transplant in first complete remission. However, it is not
clear how to proceed if they achieve a complete molecular remission,
since some studies suggest a lack of benefit from transplant in those
who are MRD negative. If MRD information is not available, the risk
stratification should rely on clinical risk factors evaluated at diagnosis.
Unfortunately, 20–30% of adult ALL patients who are MRD-negative
after induction will relapse. Potential reasons include loss of sensitivity,
evolution of leukemic subclones, and extramedullary origin of disease.
■■TREATMENT PRINCIPLES
The goal of induction therapy is the achievement of a complete remis-
sion, or even better, a molecular complete remission, mostly evaluated
within 6–16 weeks of starting chemotherapy. With current regimens
(see Fig. 102-1), the complete remission rate has increased to 80–90%,
being higher for standard-risk patients (≥90%), and lower for high-risk
patients (~80%). The outcome of ALL is strictly related to the age of the
patient, and treatment protocols considering the age of an individual
patient have emerged.
Harrisons_20e_Part4_p0435-p0858.indd 760
■■TREATMENT IN ADULT PATIENTS WITH ACUTE
LYMPHOBLASTIC LEUKEMIA
Pediatric-Inspired Therapies  Pediatric-inspired therapies for
adolescents and young adults provide increased drug intensity at
several stages of treatment, including larger cumulative doses of drugs
such as glucocorticoids, vincristine, L-asparaginase, and consequent
central nervous system-directed therapy, which should be strictly
adhered to, thereby reducing the role of stem cell transplant in such
cases. In a 2012 meta-analysis of 11 trials, including 2489 adolescents
and young adults, pediatric-inspired regimens were superior to con-
ventional adult chemotherapy. However, none of the trials was a ran-
domized comparison. Table 102-4 gives the outcome of recent studies
with pediatric-inspired regimens for adolescents and young adults
with a median age of 27 years. The complete remission rate was very
high with 93% (85–98%), and the overall survival rate of 70% (60–78%)
was very encouraging. Survival rates at ≥5 years were 70% (67–78%)
compared to 34–41% with the former protocols.
Adult ALL  The treatment results for adult ALL patients have
moderately improved (Table 102-4). The overall survival is 36%
with a wide variation from 27 to 60% due to differences in the
intensity of the chemotherapy regimen and the outcome of stem cell
transplantation.
In several current multicenter prospective trials, the overall survival
rate for standard-risk adult ALL patients is now 50–70% with chemo-
therapy alone. Overall survival for high-risk patients increased from
20–30% to >50% when they received an allogeneic stem cell transplant
in first complete remission.
Elderly ALL  Since palliative treatments or intensive chemother-
apy regimens have failed, with either low complete remission rates or
high early death rates, short elderly specific ALL protocols have been
initiated, with less intensive therapy (avoiding anthracyclines and
alkylating agents). With these protocols, the complete remission rate
was increased to 73%, early death could be reduced to 13% (0–36%),
and overall survival was 42%.
■■MAINTENANCE
Maintenance therapy usually consists of 6-mercaptopurine and metho-
trexate, a strategy transferred from childhood ALL. The duration of
maintenance therapy is between 2 and 2.5 years. The potential effect of
further intensification cycles of maintenance therapy remains unclear.
In a large multicenter Italian study after intensive consolidation treat-
ment, patients were randomly assigned to postconsolidation therapy
with conventional maintenance or to intensified maintenance with
additional alternating treatment courses of different intensity. There
was no difference in the survival rate at 10 years between the treat-
ment groups, which may suggest that, after adequate induction and
consolidation therapy, the intensity of the maintenance therapy has no
influence on survival.
Maintenance therapies should be adapted to immunological sub-
types of ALL. In mature B-ALL, maintenance is not required. In T-ALL
and B-Lineage ALL with relapses up to 2.5 years, maintenance therapy
is necessary. In Ph-positive ALL, maintenance should include a BCR/
ABL tyrosine kinase inhibitor (TKI), most likely the one that was used
during induction and consolidation therapy. It is now also standard to
give a TKI after allogeneic stem cell transplant in Ph-positive ALL as a
maintenance therapy. The duration of maintenance therapy with a TKI
is also 2–2.5 years and may be guided by MRD evaluation.
■■PROPHYLAXIS OF CENTRAL NERVOUS SYSTEM
LEUKEMIA
Without some form of prophylactic CNS-directed therapy, in very
early studies without any intensive systemic chemotherapy, around
30% of adults with ALL developed CNS leukemia. Prophylactic CNS
therapy in ALL is essential for several reasons: CNS leukemia is more
easily prevented than treated; once CNS leukemia has developed, it is
generally followed by systemic relapse shortly after; and effective CNS
prophylaxis also prevents systemic relapse.
6/1/18 5:43 PM
 Risk and MRD Adapted German Multicenter Study for Adult ALL—GMALL 07/2003 761
Overview Plan and Indication for SCT in CR1

Stratification according to
risk factors and MRD

Mol. CR
HD-MTX HD-MTX VM 26 CYCLO HD-MTX
ReInduction Maintenance
SR ASP ASP ARAC ARAC ASP
I II
6 MP 6 MP 6 MP

Induction Cons. I
Molecular
V Phase I Phase II SR/ Mol. relapse
CNS 24 Gy Med 24 Gy Failure
SC- SCT
collection SCT Hematol.
relapse
HR/VHR
risk
HR

i.th. Triple
i.th. MTX

CHAPTER 102 Acute Lymphoid Leukemia

prophylaxis
å å å å å å (HR/VHR) å å å å å

MRD decision

d11d26 d46 d41 wk16 wk22 wk30 wk41 wk52

1 4 5 7 9 11 13 16 19 22 25 27 30 33 36 39 41 43 46 49 51 53 weeks
1
NCT00198991
FIGURE 102-1  An example treatment schema for adult ALL. A variety of effective treatment programs are available. Each generally includes an induction phase
followed by a consolidation phase and concludes with a maintenance phase. 6-MP, 6-mercaptopurine; arac, cytosine arabinoside, or cytarabine; ASP, L-asparaginase;
cyclo, cyclophosphamide; HD-MTX, systemic high-dose methotrexate; HR, high risk; i.th. MTX, intrathecal methotrexate; SCT, stem cell transplantation; SR, standard
risk; VM26, teniposide.

Several treatment options are available for prevention of CNS
relapse: intrathecal (i.th.) therapy, cranial radiation therapy (CRT), and
systemic high-dose or intrathecal therapy is usually based on metho-
trexate as single drug, but combinations with cytosine arabinoside and/
or glucocorticoids are used in some studies. The route of application is
generally lumbar puncture. CRT (18–24 Gy in 12 fractions >16 days)
may be administered with or without parallel intrathecal therapy. Sys-
temic high-dose chemotherapy may include methotrexate or cytosine
arabinoside since both drugs reach cytotoxic drug levels in the cere-
brospinal fluid (CSF) and showed efficacy in overt CNS leukemia. A
liposomal preparation of cytosine arabinoside has been introduced for
the treatment of CNS in patients with ALL or lymphoma; this formu-
lation is more effective since it has a half-life of >2 weeks, compared to
only a few hours for the other used intrathecal drugs.
In Ph-positive ALL, tyrosine kinase inhibitors are now an essential
part of the treatment strategy. TKIs are equally effective at crossing the
blood-brain barrier; dasatinib and ponatinib do, whereas imatinib and
nilotinib do not.
In several studies with combined modalities of CNS prophylaxis, the
CNS relapse rate was ≤5%. In trials with early high-dose chemotherapy
and intrathecal therapy with or without CNS irradiation, the CNS
relapse rate was as low as 2%.
■■THERAPY OF CNS DISEASE
About 5–10% of adult patients present with manifestations of CNS
leukemia. The incidence is correlated with the immunological subtype
and is higher in mature B-ALL up to 10–15% and in T-ALL up to 10%.
For the treatment of CNS leukemia, the same treatment measures as
those used for CNS prophylaxis are employed, either intrathecal MTX
alone or in combination with cytosine arabinoside or hydrocortisone.
The intrathecal therapy is given 2–3 times per week, continued for >2
or 3 weeks until two consecutive CSF examinations show no evidence

TABLE 102-4  Outcome of Adult ALL

TREATMENT NUMBER NUMBER OVERALL*
APPROACHES TIME PERIOD STUDIES PATIENTS AGE* YEARS CR* RATE EARLY* DEATH SURVIVAL
Pediatric-inspired 2008–2015 6 832 27 93% 5% 70%
for adult ALL (15–60) (85–98%) (1–7%) (60–78%)
Adult protocols 1998–2016 20 7961 32.7 84% 7% 36%
(12–92) (74–93%) (1–10%) (27–60%)
Elderly protocols 1996–2016 62
  Palliative 4 94 60–91 43% 24% 7 months
  Intensive 12 519 60–92 56% 23% 14%
  Age-specific 11 653 55–85 73% 13% 42%
*
Weighted mean and range.

Harrisons_20e_Part4_p0435-p0858.indd 761 6/1/18 5:43 PM

 762 of leukemic infiltration. When adult ALL patients with initial CNS leu-
kemia are treated adequately, leukemia-free survival and CNS relapse
rate are not inferior to those without CNS involvement.
Relapse in the CNS is difficult to treat. Mostly it occurs synchro-
nously with bone marrow relapse, and if leukemic blasts are not seen
morphologically, MRD is positive in nearly all cases. This requires a
local as well as a systemic therapy. The outcome after CNS relapse
is still dismal, and an allogeneic stem cell transplantation is the most
promising option to achieve a remission.
■■STEM CELL TRANSPLANTATION
Hematopoietic stem cell transplantation is an essential part in the
treatment strategy of adult ALL. As a stem cell source, peripheral blood
cells are increasingly used compared to bone marrow. Also with regard
to the donors, there is a shift from sibling donors to matched unrelated
donors or haploidentical transplants from relatives. Indications for
stem cell transplantation in first remission are controversial. However,
in most studies, it is recommended for patients with persistent MRD
and all high-risk patients either defined by conventional clinical
prognostic factors or by MRD positivity. High-risk patients have a
survival rate of ≥50% if transplanted in first remission. For standard
risk patients with sustained molecular remission, allogeneic stem cell
transplantation is not recommended in first remission. Autologous
stem cell transplantation in first remission is restricted to a few disease
PART 4
entities, e.g., in Ph+ ALL, and should be done only in patients who are
MRD negative or older patients.
For all relapsed adult ALL patients, an allogeneic stem cell trans-
plant is the only curative option to date, and it is recommended
Oncology and Hematology
to all patients in second or later complete remission. The potential
advantages of stem cell transplant short treatment duration, favorable
outcome in some trials must be balanced against the disadvantages;
mortality of about 20%, morbidity, late complications, reduced quality
of life, and has to be assessed in relation to the improved outcome with
targeted therapies.
■■TARGETED THERAPIES
Substantial progress in adult acute lymphoblastic leukemia has been
made in the last decade by the introduction of targeted therapies, either
with tyrosine kinase inhibitors or by immunotherapeutic approaches
(Table 102-5).
■■TYROSINE KINASE INHIBITORS IN PHILADELPHIA
POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA
Patients with Ph+ ALL constitute ~25% of adult B-lineage ALL, with
the incidence increasing to about 50% among elderly patients. In the
“pre-Imatinib era,” complete remission rates were 60–70%, the survival
in those patients treated with chemotherapy alone was ~10%, and
after allogeneic stem cell transplant it was ~30%. The results improved
substantially when the first-generation TKI imatinib became available,
with complete remission rates of 80–90%, but particularly the rate of
molecular remissions (BCR-ABL-negativity) increased from 5 to 50% or
higher, and the 5-year survival increased to ≥50–60%.
TABLE 102-5  Targeted Therapies in Ph-Positive Adult ALL
Tyrosine Kinase Inhibitors
  Ph/BCR-ABL+ ALL
  TKIs
   Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib
  Ph-/BCR-ABL-like ALL
   ABL1, ABL2; Dasatinib, JAK2; Ruxolitinib
Immunologic Approaches (see Table 102-6)
  Antibodies directed leukemia surface antigens
  Monovalent antibodies
   Bivalent antibodies against the tumor and CD3 (e.g., blinatumomab)
  Adoptive cellular therapy
   T cells engineered to kill leukemic cells
Harrisons_20e_Part4_p0435-p0858.indd 762
TABLE 102-6  Expression of Antigens in B-Cell Lineage ALL for
Potential Antibody Therapy
SURFACE EXPRESSION
ANTIGEN ALL SUBTYPE ON LBC MONOCLONAL ANTIBODY
CD20 Burkitt 86–100% Rituximab
lymphoma/ Ofatumomab
leukemia
B-precursor 30–40%
CD22 B-precursor 93–98% Inotuzumab
Mature B-ALL ~100% Epratuzumab
Moxetumomab pasudotox
CD19 B-precursor 95–<100% T-cell-activating therapies
Mature B-ALL 94–<100% Blinatumomab
Bispecific CD3/CD19
CAR T cells
(Chimeric antigen receptor
modified T cells)
Abbreviation: LBC, leukemic blast count.
Source: D Hoelzer: Hematology Am Soc Hematol Educ Program 2011:243, 2011.
Treating adult Ph+ ALL with an allogeneic stem cell transplant in first
complete remission is still the best treatment option. However, patients
may receive only chemotherapy plus a TKI as primary treatment, not
undergoing a stem cell transplant in first remission. Thus, a Ph+ group
with lower relapse risk could probably be identified by MRD response,
absence of additional chromosomal abnormalities, or IKZF1 gene
deletion. Faster and deeper molecular responses are achieved with sec-
ond-generation TKIs (dasatinib, nilotinib), but it is not clear whether this
translates into a survival benefit. A third-generation TKI is ponatinib,
which targets the T315I and other resistant mutations either present at
diagnosis, or developing after treatment with other TKIs.
■■IMMUNOTHERAPEUTIC APPROACHES
Immunologically based treatments with monoclonal antibodies or
activated T cells are showing encouraging antitumor effects in patients
with ALL.
B-lineage blast cells express a variety of specific antigens, such as
CD19, CD20, and CD22. Monoclonal antibodies have been developed
to target these antigens.
Anti-CD20  The anti-CD20 monoclonal antibody rituximab has sub-
stantially improved the outcome of patients with de novo Burkitt leuke-
mia/lymphoma. With repeated short cycles of intensive chemotherapy
combined with rituximab, the overall survival of such patients increased
to >80% compared to earlier results of <60% without rituximab.
Anti-CD22  Monoclonal antibodies directed against CD22, linked
to cytotoxic agents, such as calicheamicin (inotuzumab ozogamicin),
or to plant or bacterial toxins (epratuzumab) are being explored in
refractory/relapsed adult ALL. In a trial of patients with relapsed/
refractory ALL treated with inotuzumab ozogamicin, the complete
response rate (including responses without blood cell count recovery)
was 66%, and of those, 78% achieved a molecular complete remis-
sion. When inotuzumab is combined with less intensive chemother-
apy (anthracyclines and alkylating agents) encouraging results were
obtained in elderly patients (>60 years) as first-line therapy.
Anti-CD19  Targeting CD19 is of great interest, as this antigen is
expressed in all B-lineage cells, most likely including early lymphoid
precursor cells. A promising approach is the bi-specific antibody
blinatumomab, which combines single chain antibodies to CD19 and
CD3, such that T cells are brought into proximity with and lyse the
CD19-bearing B cells.
This antibody was effective in patients with positive MRD, and 80%
converted to MRD-negativity; some patients had promising survival dura-
tions even without stem cell transplantation. In a trial of adult patients
with refractory/relapsed ALL treated with blinatumomab, the rate of
complete remissions was 43%, and the MRD response rate was 82%.
6/1/18 5:43 PM
 Chimeric Antigen Receptor (CAR) T cells  The adoptive
transfer of CAR-modified T cells directed against CD19 is a promising
approach to the treatment of CD19+ childhood or adult ALL. Complete
response rates in adults ranged from 67 to 91% with an MRD negativity
in 60–81% of the complete responders. The rate of allogeneic stem cell
transplantation after CAR T cells varied from about 10 to 50%. Since
patients who underwent an allogeneic stem cell transplant after CAR
T-cell therapy had a similar outcome as the nontransplanted patients,
the value of the transplant is unclear. CAR T-cell therapy can be highly
toxic. The accompanying cytokine release syndrome related to systemic
immune activation produces fever, hypotension, confusion, and delir-
ium. These effects appear in the first week of therapy and generally
abate, but severe neurotoxicity may be slow to recover. The CD19 neg-
ative relapse rate after CAR T-cell therapy is 10–20%, and those patients
have limited treatment options.
■■CONCLUSION AND FUTURE DIRECTIONS
Progress in ALL has led to the recognition of better defined ALL sub-
entities, the importance of MRD as a prognostic factor and therapeutic
target, and the value of new targeted therapies. Treatment outcome
of adult ALL has improved with about half of the patients surviving
>5 years and those surviving 5 years are most likely cured. Newer
options, such as less intensive chemotherapy, reduction of stem cell
transplantation, and incorporation of targeted therapies are promising
options to reduce toxicities and improve the life quality.
■■FURTHER READING
Bassan R, Hoelzer D: Modern therapy of acute lymphoblastic leuke-
mia. J Clin Oncol 29:532, 2011.
Campana D: Minimal residual disease in acute lymphoblastic leuke-
mia. Hematology Am Soc Hematol Educ Program 2010:7, 2010.
Coustan-Smith E et al: Early T-cell precursor leukaemia: A subtype of
very high-risk acute lymphoblastic leukaemia. Lancet Oncol 10:147,
2009.
Gökbuget N et al: Adult patients with acute lymphoblastic leukemia
and molecular failure display a poor prognosis and are candidates
for stem cell transplantation and targeted therapies. Blood 120:1868,
2012.
Hoelzer D et al: Improved outcome of adult Burkitt lymphoma/
leukemia with rituximab and chemotherapy: Report of a large pro-
spective multicenter trial. Blood 124:3870, 2014.
Iacobucci I, Mullighan C: Genetic basis of acute lymphoblastic leu-
kemia. J Clin Oncol 35:975, 2017.
Kantarjian HM: Inotuzumab ozogamicin versus standard therapy for
acute lymphoblastic leukemia. N Engl J Med 375:740, 2016.
Park JH et al: CD19-targeted CAR T-cell therapeutics for hematologic
malignancies: Interpreting clinical outcomes to date. Blood 127:3312,
2016.
Roberts KG et al: Targetable kinase-activating lesions in Ph-like acute
lymphoblastic leukemia. N Engl J Med 371:1005, 2014.
103 Chronic Lymphocytic
Leukemia
Jennifer A. Woyach, John C. Byrd
Chronic lymphocytic leukemia (CLL) is a monoclonal proliferation of
mature B lymphocytes defined by an absolute number of malignant
cells in the blood (5 × 109/mL). The presence of malignant B cells under
this count in the blood without nodal, spleen, or liver involvement and
absent cytopenias is a precursor of this disease called monoclonal B-cell
lymphocytosis (MBL) with ~1–2% chance per year of progressing to overt
CLL. CLL is a heterogeneous disease in terms of natural history, with
Harrisons_20e_Part4_p0435-p0858.indd 763
some patients presenting asymptomatically and never requiring therapy, 763
whereas others present with symptomatic disease, require multiple lines
of therapy, and eventually die of their disease. Over the past 10–15 years,
the understanding of CLL origin and biology has grown exponentially,
leading first to more refined disease definition, prognostic markers, and,
subsequently, introduction of novel therapies that have significantly
changed the natural history of this disease. In this chapter, we review
the epidemiology, biology, and management of CLL, with a focus on
new knowledge that is currently changing standards of care.
EPIDEMIOLOGY
CLL is primarily a disease of older adults, with a median age at diag-
nosis of 71 and an age-adjusted incidence of 4.5/100,000 people in
the United States. The prevalence of CLL has increased over the past
decades due to improvements in therapy for this disease and also
survival of older patients from other medical ailments. In 1980, the
5-year overall survival of patients was 69%, and this increased to 87.9%
in 2007 and is likely even higher today. The male:female ratio is 2:1;
however, as patients age, the ratio becomes more even, and over the
age of 80, the incidence is equal between men and women. The disease
is most common in Caucasians, less common in Hispanic and African
Americans, and is rare in the Asian population.
CHAPTER 103 Chronic Lymphocytic Leukemia
Unlike many other malignancies, there have been no definitive links
between CLL and exposures. Indeed, CLL is one of the only types of
leukemia not linked to radiation exposure. Agent Orange exposure
has been implicated, and CLL is thus a service-connected condition
for those who were exposed to Agent Orange in the Vietnam conflict.
CLL is one of the most familial-associated malignancies, and the
first-degree relative of a CLL patient has an 8.5-fold elevated risk
of developing CLL than the general population. MBL is also more
common in families with two first-degree relatives having CLL, fur-
ther supporting a genetic predisposition of this disease. Despite this,
specific genes conferring risk in the familial setting outside of specific
families have been difficult to identify. In genome-wide association
studies (GWAS), ~30 SNPs have been identified, which is estimated to
account for 19% of the familial risk of CLL. Genes involved in apop-
tosis, telomere function, B-cell receptor (BCR) activation, and B cell
differentiation have all been implicated in GWAS. Variants in shelterin
complex proteins involved in telomere maintenance such as POT1 have
been identified in a small number of families.
BIOLOGY AND PATHOPHYSIOLOGY
■■CELL OF ORIGIN
The cell of origin in CLL has not definitively been established. The
morphology, immunophenotype, and gene expression pattern of CLL
cells are that of a mature B cell (Fig 103-1), and so it has been presumed
that the initiating cell is a mature lymphocyte, perhaps memory B
cells. However, many facets of CLL biology do not support this idea,
FIGURE 103-1  Chronic lymphoid leukemia in the peripheral blood. (From Williams
Hematology, 7th ed, in M Lichtman et al [eds]: New York, McGraw-Hill, 2005.)
6/1/18 5:44 PM
 764 including antigen-binding characteristics of CLL cells and the presence
of stereotyped BCRs. Other possibilities include a stepwise process
including a series of transforming events at various stages of B-cell
development, potentially including de-differentiation of more mature
cells. The self-renewing, multipotent hematopoietic stem cell (HSC)
might also be the originating cell of CLL, postulated based on trans-
plant studies in mice showing clonal leukemic cell development with
same or different characteristics from donor leukemia after transplan-
tation of HSC. More work will be required to elucidate the origins of
CLL.
■■B-CELL RECEPTOR SIGNALING IN CLL
Perhaps the most important advancement in CLL biology is the under-
standing of the role of BCR signaling in the disease. CLL has distinct
BCR signaling as compared to normal B cells, which is characterized
by low-level IgM expression, variable response to antigen stimulation,
and tonic activation of antiapoptotic signaling pathways that promote
tumor survival. CLL cells by gene expression profiling share many
features with antigen-activated mature B cells, suggesting a role for
activation of BCR signaling in the disease pathogenesis. Tissue-based
microarrays have revealed upregulation of BCR pathway genes in the
lymph nodes and bone marrow compared to the peripheral blood,
suggesting a particular importance of this pathway in microenviron-
mental homing.
PART 4
with a more indolent disease course. Conversely, ~40% of patients will
have IGVH <2% mutated from germline, which is associated with
more rapid progression of disease and short survival. Unfavorable
biologic properties including enhanced telomerase activity, overex-
pression of activation-induced cytidine deaminase, increased nuclear
factor-κB (NF-κB) activity, high-risk genomic features, and clonal
evolution are also associated with IGHV unmutated disease.
Because IGHV sequencing was initially cumbersome to perform, a
number of surrogate factors have been identified; however, none yet
have been shown to be equal or superior to IGVH sequencing. The most
prevalent of these surrogate markers are Zap-70 expression, ZAP-70
methylation, and surface CD38 expression. Zap-70 protein is a normal
intracellular T-cell signaling protein that is aberrantly expressed in
most IGHV unmutated CLL cells. CD38 is a marker that is also more
highly expressed on the surface of IGHV unmutated CLL cells. Both
these prognostic factors are widely used but limited in their applicabil-
ity. Zap-70 protein status is difficult to measure by flow cytometry, and
it has low reproducibility. Measurement of methylation status of the
ZAP-70 promoter is much more precise but not widely available. CD38
expression is easier to measure by flow cytometry but not as highly
predictive of outcomes and can change during the course of disease.
■■CYTOGENETIC ABNORMALITIES
Besides IGHV mutational status, recurrent cytogenetic abnormalities

Fitting with the role of BCR signaling in CLL, one of the most influ-
ential prognostic factors identified in this disease is the mutational sta-
tus of the immunoglobulin heavy chain variable (IGHV) region. During
normal B-cell maturation, the variable regions of the immunoglobulin
Oncology and Hematology
are the most robust prognostic factor clinically available in CLL. These
abnormalities are typically identified by fluorescent in situ hybridiza-
tion (FISH) analysis; however, stimulated metaphase karyotype has a
role as well. The most well-characterized abnormalities include del(13)

heavy chain undergo somatic hypermutation. In CLL, ~60% of patients (q14.3), trisomy 12, del(11)(q22.3), and del(17)(p13.1) (Fig. 103-2). The
have IGVH that is ≥2% mutated from germline. This may indicate a presence of sole del(13)(q14.3) is associated with more indolent disease,
more mature, postgerminal center progenitor, and is typically associated prolonged survival, and good response to traditional therapies. Usually

100
17p deletion
11q deletion
12q trisomy
Normal
13q deletion as
80
sole abnormality
Patients surviving (%)

60

40

20

0
1 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
Months
No. AT Risk
17p deletion 23 18 13 8 5 4 1 0 0 0 0 0 0 0 0 0
11q deletion 56 53 47 43 33 27 20 15 10 4 2 2 1 0 0 0
12q trisomy 47 44 41 29 24 17 14 13 12 11 4 3 2 1 1 0
Normal 57 51 45 37 30 27 20 17 12 11 6 5 2 2 1 1
13q deletion as sole 117 117 106 91 80 63 45 36 24 16 12 11 3 1 1 0
abnormality
FIGURE 103-2  Outcomes among CLL patients with various cytogenetic abnormalities. (From Döhner H et al: N Engl J Med 343:1910, 2000.)

Harrisons_20e_Part4_p0435-p0858.indd 764 6/1/18 5:44 PM

 this abnormality is not seen on banded karyotype analysis, and when
present on karyotype, it indicates a larger deletion involving the retin-
oblastoma gene, which negates the favorable prognosis associated with
this marker. Trisomy 12 has a more intermediate prognosis. The del(11)
(q23.3) results in deletion of the ATM gene and is associated with bulky
lymphadenopathy and aggressive disease in young patients, with infe-
rior prognosis, more rapid progression to symptomatic disease, and
shorter survival. The del(17)(p13.1) results in loss of one allele of the
tumor suppressor TP53 and is associated with the poorest prognosis
in CLL with rapid disease progression, poor response to traditional
therapies, and shorter survival. Other abnormalities have been shown
to be important in smaller studies but are not routinely performed at
all centers. Finally, complex karyotype (three or more abnormalities)
on stimulated metaphase karyotype analysis has significant adverse
impact on time to treatment and overall survival.
Clonal evolution, or acquisition of cytogenetic or molecular abnormali-
ties, is common in CLL, especially in patients with IGHV unmutated CLL.
Because the cytogenetics of patients can change even in the absence of
therapy, it is recommended that FISH +/− cytogenetics are checked before
every line of therapy, mostly to evaluate acquisition of del(17)(p13.1).
■■GENE MUTATIONS AND MIR ALTERATIONS
Compared with many other malignancies, the genome in CLL is rel-
atively simple, with an average CLL genome carrying ~20 nonsynon-
ymous alterations and ~5 structural abnormalities. And, unlike many
other hematologic malignancies, there is no unifying genetic lesion,
and most recurrent genetic driving mutations exist at frequencies of
<5%. Whole genome and whole exome sequencing have identified the
most common mutations in CLL to be in SF3B1, NOTCH1, MYD88,
ATM, and TP53 (Table 103-1). Most of the identified mutations in these
genes are common among different malignancies, and with the excep-
tion of MYD88, they are generally subclonal drivers identified with
much higher frequency in IGHV unmutated disease.
NOTCH1 mutations are present in ~15% of CLL patients and are
commonly associated with trisomy 12. Although multiple different
mutations are seen, most are located within the PEST (proline, glutamic
acid, serine, and threonine) domain and result in constitutive NOTCH
signaling. NOTCH1 mutations have been associated with lower sen-
sitivity to CD20 antibody therapy and increased risk of transforma-
tion to aggressive diffuse large B-cell lymphoma (DLBCL; Richter’s
transformation).
SF3B1 is a component of the RNA spliceosome and is mutated
in 10–15% of CLL cases. Mutations appear to be associated with
intermediate-risk disease, and, functionally, SF3B1 may be important in
the response to DNA damage.
Mutations of the tumor suppressor TP53 are found in ~5% of CLL in
previously untreated early stage disease and up to 40% in later stages.
Seventy percent of the time these mutations coexist with del(17)(p13.1),
effectively eliminating TP53 function. As expected, and consistent with
other malignancies, TP53 mutations are associated with a poor progno-
sis and expected lack of response to DNA-damaging therapies.
TABLE 103-1  Recurrent Mutations in CLL
GENE FREQUENCY OF MUTATIONS (%)
SF3B1 8–14
TP53 5–13
NOTCH1 10–13
MYD88 4–8
ATM 8–11
BIRC3 <5
XPO1 <5
FBXW7 <5
POT1 <5
BRAF <5
EGR2 <5
IKZF3 <5
Abbreviation: CLL, chronic lymphocytic leukemia.
Harrisons_20e_Part4_p0435-p0858.indd 765
ATM mutations, which are heterogeneous and occur throughout the 765
gene, occur in 10–15% of CLL patients. ATM mutations often coexist
with del(11)(q22.3), eliminating ATM on the alternate allele. Similar to
TP53, mutations in ATM tend to result in impaired response to DNA
damage, which can reduce responsiveness to chemotherapy.
In contrast to the aforementioned mutations, those in MYD88 tend
to occur in IGHV mutated CLL and be associated with a more indolent
prognosis. This gene is involved in Toll-like receptor signaling, and the
most common mutation, L265P, results in constitutive activation and
NF-κB activity.
Along with abnormalities in coding genes, it has become apparent
that noncoding genes such as microRNAs are recurrently altered in
CLL. The most common cytogenetic abnormality, del(13)(q14.3) results
in loss of the miR15/16 cluster, which is important in the pathogenesis
of CLL. In normal cells, miR15A/miR16A inhibit antiapoptotic gene
expression (including BCL2, CCND1&3, and CDK6), and this specific
deletion allows for overexpression of these genes and thus increased
cell survival. Loss of other miR expression such as mir-181a leads
to overexpression of proteins such as the antiapoptotic gene MCL-1
and TCL1. Overexpression of miR-155, an onco-miR associated with
B-cell transformation, has also been documented in the majority of CLL
patients.
CHAPTER 103 Chronic Lymphocytic Leukemia
■■IMMUNOLOGY
CLL is characterized by dysregulation of the normal immune system in
addition to the malignant immune cells. Besides numerical abnormali-
ties due to bone marrow dysfunction, even in the early stages of disease
there are skewed ratios of immune cells and functional abnormalities.
Innate immune system defects associated with CLL include reduced
complement proteins and activity, qualitative neutrophil defects, and
functional defects of natural killer cells.
More focus has been placed on the impairments in the adaptive
immune system in this disease. Within the CD4+ T-cell compartment, a
qualitative defect is noted similar to chronic antigen stimulation induc-
ing a phenotype of T-cell exhaustion typical of what is seen in chronic
viral infections such as hepatitis. This has been demonstrated to lead
to impaired T-cell cytotoxic capacity and reduced proliferative ability.
Additionally, there are physical changes in the T-cell cytoskeleton that
causes impaired immune synapse formation with antigen presenting
cells. In addition to a lack of capacity to respond to pathogens, the
T-cell defect in CLL also likely leads to tumor cell tolerance. During
the course of the disease, the polarization of the CD4+ T cells shifts
from a Th1 (cytotoxic) phenotype to a Th2 phenotype, which leads to
expansion of immunosuppressive cytokines such as IL-10. Addition-
ally, in the later stage of disease T regulatory cells are expanded, which
contributes to an immunosuppressive phenotype.
Other components of the immune microenvironment are altered
as well to form a more supportive environment for the malignant
cells. M2 monocytes have been shown to differentiate into a type of
tumor-associated macrophage known as a nurse-like cell in CLL. These
cells promote survival by secreting chemokines and cytokines that
increase migration and activation.
The humoral immune system in CLL is also dysregulated, as is
expected for a malignancy that results in very few normal B cells.
Hypogammaglobulinemia is very common and affects all subclasses of
immunoglobulins, occurring in ~85% of patients at some time in their
disease course, and is more common as disease progresses. A correla-
tion between low IgG and IgA and infection risk has been established,
but isolated IgM reduction does not seem to be associated with excess
infection risk. Also, CLL cells can secrete monoclonal IgM in a small
number of cases, and this can correlate with disease progression.
CLINICAL PRESENTATION AND DIAGNOSIS
OF CLL
■■CLINICAL PRESENTATION AND DIAGNOSIS
The presentation of CLL most commonly occurs as an incidental
diagnosis made at the time of medical evaluation for another cause. In
this regard, CLL is most commonly diagnosed on routine blood work
6/1/18 5:44 PM
 766 TABLE 103-2  Typical Immunophenotype of CLL Compared with Other B-Cell Malignancies
  CD5 CD10 CD19
Disease      
CLL + − + + (dim)
Mantle cell lymphoma + − + + (mod/bright)
Marginal zone lymphoma −/+ − +
Follicular lymphoma − + + +
Abbreviation: CLL, chronic lymphocytic leukemia.
demonstrating an elevated lymphocyte count in asymptomatic indi-
viduals, although some patients present with symptoms and require
early therapy. When noting either an elevated total white blood cell
(WBC) count with lymphocytic predominance or a normal WBC with a
differential showing a lymphocytosis, the next step is to perform flow
cytometry on the peripheral blood. In CLL, this will reveal the typical
immunophenotype that includes the typical B-cell markers CD19,
CD20, CD22, CD23, the T-cell marker CD5 (CD5 is also expressed on
the B1 subset of B cells that typically has unmutated immunoglobulin
and responds to antigens independent of cognate T-cell help), and dim
surface immunoglobulin of either kappa or lambda type (Table 103-2).
PART 4
Atypical phenotypes can be seen as well and usually can be differenti-
ated on the basis of morphology, cytogenetics, or clinical presentation.
In cases in which the clonal B cell count based on flow cytometry is
≥5 × 109/L, no further workup is needed to confirm the diagnosis of CLL.
Some patients will present with a small clonal proliferation of CLL
Oncology and Hematology
cells in the peripheral blood but will also have lymphadenopathy or
splenomegaly. In these cases, the likely diagnosis is small lymphocytic
lymphoma (SLL), a semantic designation from CLL that denotes a
primarily tissue-based disease rather than bone marrow/blood-based
disease. The genetic and molecular features of SLL are identical to those
of CLL. The retention of the cells in tissues may be related to the expres-
sion of particular adhesion molecule. Thus, SLL patients are managed
identically to CLL, and often in the later stages of disease these patients
will often have blood and bone marrow involvement as well.
MONOCLONAL B-CELL LYMPHOCYTOSIS
Patients who do not meet the diagnostic criteria for CLL based on quan-
tification of clonal B cells in the peripheral blood and who do not have
associated signs of CLL including lymphadenopathy, organomegaly, or
cytopenias have a disorder known as monoclonal B-cell lymphocytosis
(MBL), which is now thought to precede every case of CLL. Analogous
to monoclonal gammopathy of uncertain significance (MGUS) in mye-
loma, not all MBL progresses to CLL. MBL is initially characterized by
a CLL-like immunophenotype in ~75% of cases but can also be atypical
(CD23 negative or bright CD20) or CD5 negative. More relevant for
prognosis is characterization by count, with low-count MBL defining
those patients with <0.5 × 109 clonal B cells/L, and high-count MBL
defining those with >0.5 × 109 but <5 × 109/L. Patients with low-count
MBL have a negligible rate of progression to CLL, whereas those with
high count progress to overt CLL at a rate of 1–2% per year, warranting
continued monitoring. Population-based studies have estimated the
prevalence of MBL up to ~12% in the general population, where it is
most common in elderly men. It is especially common in first-degree
relatives of CLL patients, where the frequency is ~18%.
Although the risk of MBL progression is relatively low, it has
become apparent that patients still experience complications that
suggest an immune dysfunction in MBL that is similar to that seen with
CLL. Rates of serious infections requiring hospitalization appear to be
significantly increased in MBL, similar to the rates seen in CLL. In a
case-control study, patients with MBL had a 16% chance of hospitaliza-
tion over a 4-year time period, compared with 18.4% in patients with
newly diagnosed CLL. Secondary cancers also appear to be increased
in MBL. These data suggest that monitoring for patients with MBL
should focus on vaccinations and age-appropriate cancer screening, as
the probability of complications appears to be higher than the risk of
progression in most of these patients. Follow-up for patients with MBL
Harrisons_20e_Part4_p0435-p0858.indd 766
CD20 CD23 CYCLIN D1 SURFACE IG
       
+ − + (dim)
− + + (mod/bright)
+ (mod/bright) −/+ − + (mod/bright)
+ −
can occur with the primary care physician as this does not represent a
malignancy, whereas CLL is mostly comanaged with both a primary
care physician and a hematologist.
COMPLICATIONS OF CLL
A significant amount of morbidity and mortality related to CLL is
due to complications of the disease. In general, complications besides
disease progression include infections, secondary cancers, autoim-
mune complications, and transformation to a more aggressive clonally
related lymphoma.
■■INFECTIONS
Infections are a leading cause of both disease-related morbidity and
death in patients with CLL, with ~30–50% of deaths in CLL patient
attributed to infection. Owing to the immune dysfunction associated
with the disease, patients are at risk for both typical and atypical infec-
tions. Besides this baseline risk of infections, most CLL therapies can
increase infection risk. For many nucleoside analog-based chemother-
apy regimens used in CLL, prophylaxis for Pneumocystis pneumonia is
indicated for at least 6 months following therapy to allow recovery of
functional T cells. Viral prophylaxis is also indicated for many chemo-
therapy regimens and for patients with a history of varicella zoster to
diminish reactivation and morbidity from this virus.
Because of the abnormalities in cellular and humoral immunity,
vaccine responses in CLL are limited in many patients, especially in
the later stages of disease. In one study, one dose of 13-valent pneu-
mococcal vaccine produced an adequate immune response in only 58%
of patients compared with 100% in age-matched controls. Despite the
known limitations, vaccination against influenza and pneumococcal
pneumonia is recommended in CLL. Live vaccines, such as the vari-
cella zoster vaccine, should be avoided because of the small risk of viral
reactivation with an immunocompromised host.
As discussed earlier, hypogammaglobulinemia is common in CLL
and can be associated with significant risk for infections, primarily of
mucocutaneous etiology such as sinusitis and bronchitis. In addition,
women can have frequent urinary tract infections. While administra-
tion of prophylactic intravenous immunoglobulin (IVIg) has not been
shown to improve survival, it has been shown to reduce the number of
minor or moderate bacterial infections, and thus is indicated in patients
with hypogammaglobulinemia who suffer from recurrent infections
or have pulmonary bronchiectasis. It is also our practice to adminis-
ter at least one dose immunoglobulin to CLL patients who develop
influenza with coexisting hypogammaglobulinemia to diminish risk of
post-influenza pneumococcal pneumonia. IVIg is probably indicated in
patients who have been hospitalized for a serious infection and in those
whose IgG level is <300 mg/dL.
■■SECONDARY MALIGNANCIES
Multiple population-based studies have shown that patients with CLL
are at an elevated risk to develop other cancers, with a rate up to three
times that of the general population, even in the absence of cytotoxic
chemotherapy. The most common types of cancers seen in CLL are skin
cancers, prostate, and breast cancers, although other cancers are seen as
well. Skin cancers are particularly common, with a rate of 8- to 15-fold
higher than the general population, and may behave more aggres-
sively. All CLL patients should be counseled on the use of sunscreen
while outdoors and should undergo preventative skin examinations.
6/1/18 5:44 PM
 In one single-center study, older age at CLL diagnosis, male sex,
high β2 microglobulin, high lactate dehydrogenase (LDH), and chronic
kidney disease were associated with excess risk of other cancers; other
CLL-specific risk factors have not shown association with other cancer
risk.
While cancer risk is higher, there are no specific recommendations for
increased cancer screening in CLL patients. Age- and sex-appropriate
screenings should be recommended.
Conflicting data exist regarding the risk of cancers following
CLL-specific therapy. Chemoimmunotherapy, in particular alkylator-
containing regimens, seems to be associated with an increased risk for
secondary cancers.
■■AUTOIMMUNE COMPLICATIONS
Autoimmune complications are frequent in CLL. Most commonly,
these include autoimmune cytopenias, but autoimmune complications
of other organs including glomerulonephritis, vasculitis, and neurop-
athies have also been reported. Of the autoimmune cytopenias, the
most common is autoimmune hemolytic anemia (AIHA), which is an
antibody-mediated destruction of autologous red blood cells (RBCs).
Second most common is immune thrombocytopenia (ITP), which
shares some features with AIHA and has a similar mechanism targeting
platelets. These two syndromes may occur in isolation, sequentially in
the same patient, or present in combination as Evan’s syndrome. Pure
red cell aplasia (PRCA) and autoimmune granulocytopenia (AIG) are
comparatively rare and can occur alone or in combination with other
AIC. It is difficult to tease out whether autoimmune cytopenias lead
to worse prognosis in CLL because of various complicating factors.
However, it is clear that these can lead to significant morbidity, both
due to the process itself and due to therapies required for management.
AIHA usually presents as an isolated anemia with an elevated retic-
ulocyte count and features of hemolysis including elevated bilirubin
and LDH, and low haptoglobin. Detection of a warm IgG antibody on
the surface of RBCs with a Coombs test can help solidify the diagno-
sis, although Coombs-negative cases can occur. Immediate therapy is
almost always necessary, and consists of transfusion and immunosup-
pression. Glucocorticoids are often used for initial therapy, although in
most cases additional treatment is needed due to either poor response
or recurrence with taper of steroid dosing. Rituximab can be successful,
and therapy directed toward the underlying CLL is often effective in
more resistant cases. Transfusion of blood in cases of robust AIHA must
be initiated with caution as transfusion reactions can be seen due to
poorly matched blood.
ITP can be more difficult to diagnose, as it may be difficult to differ-
entiate from progression of disease due to the lack of laboratory tests
that identify platelet destruction from this mechanism. Signs that point
toward ITP include isolated thrombocytopenia and rapid decline in
platelet levels in the absence of an alternative etiology. A bone marrow
biopsy showing normal or increased megakaryocytes can be used to
confirm the diagnosis but is often not necessary. In CLL, treatment for
ITP is usually instituted when platelet levels drop to 20–30,000 or if
there is evidence of bleeding complications or need for invasive proce-
dures. Like AIHA, initial therapy consists of glucocorticoids and IVIG,
with rituximab also being an effective method to induce long-term
remissions. Also, the thrombopoietin receptor agonists romiplostim
and eltrombopag are effective in secondary ITP. In many cases, ITP
can be successfully treated without treating the underlying CLL. In
cases in which anemia or thrombocytopenia appear, it is important to
investigate the mechanism as the approach to therapy of autoimmune
cytopenias in CLL differs from cytopenias due to marrow replacement.
■■RICHTER’S TRANSFORMATION
One of the most devastating complications of CLL is Richter’s trans-
formation, transformation of CLL to an aggressive lymphoma, most
commonly DLBCL. The World Health Organization also recognizes
Hodgkin’s lymphoma (HL) as a variant of Richter’s transforma-
tion; other aggressive lymphomas are rarely identified. Some older
series have included prolymphocytic transformation in this category,
although this has much less prognostic impact on long-term outcome.
Harrisons_20e_Part4_p0435-p0858.indd 767
The prevalence of Richter’s transformation is difficult to estimate based 767
on previous studies, but one prospective observational study estimated
a rate of 0.5% per year for DLBCL and 0.05% per year for HL. Risk
factors for development include bulky lymphadenopathy, NOTCH1
mutations, del(17)(p13.1), and a specific stereotyped IGVH usage.
Lymphomas arising in the setting of CLL can either be clonally related
or unrelated to the initial CLL, with prognosis significantly better for
clonally unrelated lymphomas. In addition, patients with Hodgkin’s
transformation have improved outcome, particularly in the absence of
prior fludarabine treatment.
Clinical signs of Richter’s transformation include rapid progression
in adenopathy, often in a specific area, and constitutional symptoms
including fatigue, night sweats, fever, and weight loss. LDH is usually
high. In suspected cases, the first step is 18FDG-PET/CT (fluorodeox-
yglucose–positron emission tomography combined with computed
tomography) scan to localize an area for biopsy. Standardized uptake
values (SUV) <5 is consistent with CLL and can rule out Richter’s trans-
formation in many cases. SUV >5 are suspicious for Richter’s transfor-
mation, with SUV ≥10 very concerning. Excisional biopsy is diagnostic.
Needle biopsy should be discouraged.
Therapy for DLBCL Richter’s transformation usually involves
combination chemoimmunotherapy. Outcomes are poor with median
CHAPTER 103 Chronic Lymphocytic Leukemia
survivals of 6–16 months in most series for clonally related Richter’s
versus ~5 years for clonally unrelated. This highlights an area of unmet
need in CLL therapy and an area of active investigation. For fit patients
who achieve a response with therapy, stem cell transplantation has the
possibility to induce long-term remissions and should be explored.
Patients with Hodgkin’s disease can be treated according to the
algorithm for this disease, with many individuals being cured.
WORKUP OF CLL AND APPROACH TO
THERAPY
■■WORKUP AND STAGING
Workup of a patient with new diagnosis of CLL based on typical
immunophenotyping includes a detailed history of infectious history;
family history of CLL; and careful physical examination with attention
to the lymph nodes, spleen, and liver. In patients desiring to know the
expected natural history of their CLL, prognostic testing using FISH
and stimulated karyotype as well as IGHV sequencing can be per-
formed. Imaging with CT scan is usually not necessary unless there are
symptoms and concern for intra-abdominal nodes out of proportion to
peripheral nodes. Bone marrow biopsy is not undertaken until therapy
is initiated except in cases of unexplained cytopenias.
■■STAGING
There are two widely used staging systems in CLL: The Rai staging
system is used more commonly in the United States, whereas the Binet
system is more commonly used in Europe. Both characterize CLL on
the basis of disease bulk and marrow failure (Table 103-3). Both rely
on physical examination and laboratory studies and do not require
imaging or bone marrow analysis. While the initial staging systems
could reliably predict survival in CLL, with the changes in therapy
TABLE 103-3  Staging of CLL
Rai Staging System
Low risk (stage 0) Lymphocytosis only
Intermediate risk Lymphocytosis with lymphadenopathy, with
(stage I/II) or without splenomegaly or hepatomegaly
High risk (stage III/IV) Lymphocytosis with anemia or thrombocytopenia
due to bone marrow involvement
Binet Staging System
A <3 areas of lymphadenopathy
B ≥3 areas of lymphadenopathy
C Hemoglobin ≤10 g/dL and/or platelets
<100,000/μL
Abbreviation: CLL, chronic lymphocytic leukemia.
6/1/18 5:44 PM
 768 TABLE 103-4  Criteria for the Initiation of Therapy combination of FCR improved survival over the combination chemo-
Symptoms Indicating Need for Therapy in CLL
therapy regimen FC. Alone, this antibody has shown modest activity,
but activity is improved with higher doses and increased frequency of
Evidence of progressive marrow failure (worsening of anemia or
administration. Both ofatumumab and obinutuzumab are effective as
thrombocytopenia not due to autoimmune destruction)
single agents, but it is likely that monoclonal antibodies will be most
Massive (≥6 cm below costal margin), progressive, or symptomatic
splenomegaly
widely used in combination. Current trials are focused on combining
anti-CD20 antibodies with therapies that target BCR signaling or
Massive (≥10 cm), progressive, or symptomatic lymphadenopathy
antiapoptotic proteins. Antibodies against other targets are also being
Autoimmune anemia or thrombocytopenia not responsive to standard therapy
developed, including CD19, BAFF receptor, and CD37.
Constitutional symptoms (one or more of the following: unintentional weight
loss ≥10% over 6 months, significant fatigue, fevers ≥100.5°C for 2+ weeks B-Cell Receptor Signaling Inhibitors  Three specific targets
without infection, night sweats for >1 month without infection)  were the first identified: spleen tyrosine kinase, phosphoinositide-
Abbreviation: CLL, chronic lymphocytic leukemia. 3-kinase (PI3K), and Bruton’s tyrosine kinase (BTK). Therapeutics
directed at the latter two targets have moved forward through clinical
trials and are now utilized in clinical practice.
Idelalisib is a reversible, p110 delta isoform-specific PI3K inhibitor.
since the original description of the stages, the impact of initial stage Because the delta isoform is specific for B lymphocytes, this agent has
on survival is not as clear. Cytogenetic and genomic testing can help selective effects on the CLL cells with relative sparing of other hemato-
refine outcome of these staging tests. An international collaboration poietic cells. The definitive phase III study of the idelalisib plus rituxi-
integrated both clinical and genomic staging to better predict outcome mab regimen assessed this combination versus placebo plus rituximab
at diagnosis and time of initial treatment. in 220 patients and showed an ORR of 77% (vs 15% with rituximab plus
placebo) with improved progression-free and overall survival. Toxicity
■■CRITERIA FOR THE INITIATION OF THERAPY specific to idelalisib included elevated alanine transaminase (ALT) and
Currently, a watchful waiting strategy is used for most patients with aspartate transaminase (AST) in the first 3 months of therapy and diar-
PART 4

CLL, with therapy reserved for patients with symptomatic disease. rhea, colitis, pneumonitis, and rash later (9+ months) into treatment.
This recommendation is based on multiple trials showing no survival These side effects appear to be more common in younger patients given
advantage with earlier therapy, although this question is currently idelalisib earlier in the course of their disease.
being revisited with novel targeted therapies. Ibrutinib is a relatively selective, irreversible inhibitor of BTK.
With the exception of patients participating on early intervention This target is attractive because, unlike other kinases in the BCR
Oncology and Hematology

studies in CLL, disease-related symptoms that require the initiation pathway, BTK does not have natural redundancy and is selective for
of therapy are outlined in Table 103-4. Except for the rare patient who B cells, so inhibition leads to a B-cell–specific phenotype. As initial
presents with disease requiring urgent therapy, most times these symp- therapy, ibrutinib was compared with chlorambucil, and there was
toms can be monitored over short periods to determine relatedness to an 84% lower risk of progression or death with ibrutinib, with 90%
CLL and need for therapy. of ibrutinib-treated patients alive and progression-free at 18 months.
In the relapsed phase III study, ibrutinib was compared to the CD20
■■INITIAL THERAPY FOR CLL monoclonal antibody ofatumumab, and there was a 78% reduction in
Chemoimmunotherapy and Monoclonal Antibody Therapy  the risk of progression or death with ibrutinib. Side effects distinct to
Chemotherapy and chemoimmunotherapy are the standard therapies ibrutinib include rash, diarrhea, dyspepsia, increased risk of bleeding
for CLL. For patients who are young (≤65 years), the gold standard for (particularly when on anticoagulation therapy or with surgery), and
therapy is a combination of the nucleoside analogue fludarabine, the atrial fibrillation. Second-generation BTK inhibitors with more speci-
alkylator cyclophosphamide, and the anti-CD20 monoclonal antibody ficity such as acalabrutinib are in clinical trials and may diminish these
rituximab (FCR). In phase III study, this combination produced an side effects. Although direct comparison of agents targeting p110 delta
overall response rate (ORR) of 93% with a complete response (CR) rate PI3 kinase and BTK has not occurred, BTK inhibitors appear to induce
of 44%. Median progression-free survival (PFS) is almost 5 years. Substi- more durable remissions.
tution of bendamustine for fludarabine and cyclophosphamide or addi- The success of ibrutinib and idelalisib has generated significant
tion of other chemotherapy-based treatments to FCR have not improved interest in other molecules targeting PI3K, BTK, and other members of
outcome. A subset of patients treated with the FCR regimen has durable the BCR signaling pathway. One issue with most drugs targeting this
responses over 10 years. This group is primarily composed of those pathway in CLL is that while durable responses are common, CRs are
patients with mutated IGVH and good cytogenetic risk. However, not, which leads to the recommendation for indefinite therapy with
despite the efficacy of this regimen, short- and long-term toxicities limit these molecules. Combination clinical trials are currently underway to
its adaptability to many patients with IGHV-mutated disease. Short- determine whether combinations with other active agents might allow
term toxicities are mostly related to myelosuppression and include discontinuation of drug in some settings.
neutropenia and infection. Long-term cytopenias are less common, but Antiapoptotic Therapies  BCL2 is another promising target in
they do occur. Also, there is about a 3–5% risk of therapy-related mye- CLL. Venetoclax is an orally bioavailable, selective BCL2 inhibitor.
loid neoplasm with this regimen that is almost always fatal. Trials in It is currently Food and Drug Administration (FDA) approved for
the future will need to focus on the superiority of FCR versus targeted marketing in patients with relapsed or refractory CLL who have the
regimens for patients who may be cured by chemoimmunotherapy. del(17)(p13.1). In a phase I study, the ORR with this agent in relapsed/
For older patients or those with multiple comorbidities, FCR is not refractory CLL was 79%, with 69% of patients on the recommended
an appropriate option due to toxicities. For these patients, the alkylator phase II dose being progression-free at 15 months. Unlike the BCR
chlorambucil in combination with the anti-CD20 antibody obinutuzumab signaling antagonists, venetoclax is able to induce very deep responses
or bendamustine with rituximab are appropriate options. While neither including CRs with minimal residual disease negativity in a subset of
produces remissions as durable as FCR, both can induce CRs and remis- patients. Distinct toxicities associated with venetoclax include neu-
sions of 2–3 years in many patients. Toxicities with these regimens mostly tropenia, diarrhea, and acute tumor lysis syndrome. Tumor lysis syn-
relate to myelosuppression, but neither is as immunosuppressive as FCR. drome risk can be mitigated with stepped-up dosing at the beginning
Monoclonal antibodies given alone or in combination with of treatment.
chemotherapy were the first targeted therapies to be successful in
CLL. Anti-CD20 monoclonal antibodies including rituximab, ofatu- Immune Therapies  Current immune therapies include allogenic
mumab, and obinutuzumab are all used in this disease. Rituximab stem cell transplantation, chimeric antigen receptor (CAR) T-cell
was the first agent to show a survival advantage in CLL, where the therapy, and oral immunomodulatory agents such as lenalidomide.

Harrisons_20e_Part4_p0435-p0858.indd 768 6/1/18 5:44 PM

 TABLE 103-5  Response Criteria in CLL
  LYMPHOCYTE COUNT LYMPH NODES a
SPLEEN/LIVER SIZE
CR <4000/μL None >1.5 cm Not palpable
PR Decrease ≥50% from Decrease ≥50% Decrease ≥50% from
baseline from baseline baseline
Stable Not meeting CR/PR/PD Not meeting Not meeting CR/PR/PD Not meeting CR/PR/
disease criteria CR/PR/PD criteria criteria
PD Increase ≥50% Increase ≥50% Increase ≥50%
Refers to sum of the products of multiple lymph nodes evaluated by CT scan. bBased on physical examination. cBone marrow only required to confirm CR.
a
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; PD, progressive disease; PR, partial response.
Stem cell transplantation is currently considered the only stan-
dard curative approach to CLL. Because most CLL patients are older
and many have significant comorbidities, myeloablative transplants
incur extensive morbidity and mortality, making them prohibitive in
many individuals. Reduced intensity conditioning (RIC) allogeneic
transplants have been successfully incorporated into the treatment
of patients up to ~75 years in age but still have a ≥50% frequency of
chronic graft-versus-host disease.
■■ASSESSING RESPONSE TO THERAPY AND MINIMAL
RESIDUAL DISEASE IN CLL
Following the completion of therapy or during therapy for indefinite
targeted agents, response is initially assessed using physical exami-
nation and laboratory studies (Table 103-5). If residual disease is
not detected using these methodologies, CT scans are used to assess
response. Bone marrow biopsies with flow cytometry are indicated if
no disease is detected to confirm CR.
It has been established in various malignancies that complete tumor
eradication is associated with longer survival. In CLL, if no malignant
cells can be detected in the bone marrow down to a level of 1 CLL cell
in 104 leukocytes (0.01%), the patient is said to be negative for minimal
residual disease (MRD). Following combination chemoimmunother-
apy, eradication of MRD correlates with long-term survival and poten-
tially cure in a subset of patients receiving FCR chemoimmunotherapy.
It has yet to be established whether MRD negativity in the setting of
targeted therapies is a meaningful endpoint.
■■CONCLUSION
CLL is treated only when it becomes symptomatic. At the time of
therapy chemoimmunotherapy in a small subset of patients is poten-
tially curative. In the majority of remaining individuals with symptom-
atic CLL, targeted therapy directed at BTK greatly improves survival
and also reverses the immune deficiency associated with the disease.
■■FURTHER READING
Burger JA et al: Ibrutinib as initial therapy for patients with chronic
lymphocytic leukemia. N Engl J Med 373:2425, 2015.
Byrd JC et al: Targeting BTK with ibrutinib in relapsed chronic lympho-
cytic leukemia. N Engl J Med 369:32, 2013.
Hallek M et al: Guidelines for the diagnosis and treatment of chronic
lymphocytic leukemia: A report from the International Workshop
on Chronic Lymphocytic Leukemia updating the National Cancer
Institute-Working Group 1996 guidelines. Blood 111:5446, 2008.
Landau DA et al: Evolution and impact of subclonal mutations in
chronic lymphocytic leukemia. Cell 152:714-26, 2013.
Oakes CC et al: DNA methylation dynamics during B cell maturation
underlie a continuum of disease phenotypes in chronic lymphocytic
leukemia. Nat Genet 48:253, 2106.
Puente XS et al: Whole-genome sequencing identifies recurrent
mutations in chronic lymphocytic leukaemia. Nature 475:101, 2011.
Harrisons_20e_Part4_p0435-p0858.indd 769
769
b
BONE MARROW c
PERIPHERAL BLOOD COUNTS
Normocellular, <30% •  Platelet count >100,000/μL
lymphocytes, no B •  Hemoglobin >11 g/dL
lymphoid nodules
•  Neutrophils >1500/μL
Infiltrate ≤50% of One of the following:
baseline •  Platelet count >100,000/μL or ≥50% from
baseline
•  Hemoglobin >11 g/dL or ≥50% from baseline
•  Neutrophils >1500/μL or ≥50% from baseline
Not meeting CR/PR/PD criteria
PD criteria
  •  Platelet count ≤50% of baseline due to CLL
•  Hemoglobin decrease >2 g/dL due to CLL
Roberts AW et al: Targeting BCL2 with venetoclax in relapsed and
refractory CLL. N Engl J Med 374:311, 2016.
Thompson PA et al: Fludarabine, cyclophosphamide, and rituximab
CHAPTER 104 Non-Hodgkin’s Lymphoma
treatment achieves long-term disease-free survival in IGHV-mutated
chronic lymphocytic leukemia. Blood 127:303, 2016.
Woyach JA et al: Resistance mechanisms for the Bruton’s tyrosine
kinase inhibitor ibrutinib. N Engl J Med 370:2286, 2014.
104 Non-Hodgkin’s Lymphoma
Caron A. Jacobson, Dan L. Longo
Non-Hodgkin’s lymphomas (NHL) are cancers of mature B, T, and NK
cells. They were distinguished from Hodgkin lymphoma (HL) upon
recognition of the Reed-Sternberg (RS) cell, and differ from HL with
respect to their biologic and clinical characteristics. Whereas ~80–85%
of patients with HL will be cured of their lymphoma by chemother-
apy with or without radiotherapy, the prognosis and natural history
of NHL tends to be more variable. NHL can be classified as either a
mature B-NHL, or a mature T/NK-NHL depending on whether the
cancerous lymphocyte is a B, T, or NK-cell, respectively. Within each
category are lymphomas that grow quickly and behave aggressively, as
well as lymphomas that are more indolent, or slow growing in nature.
For a list of the World Health Organization (WHO) classification of
lymphoid neoplasms, see Table 104-1.
■■EPIDEMIOLOGY AND ETIOLOGY
In 2017 over 72,000 new cases of NHL were diagnosed in the United
States, about 4% of all new cancers in both males and females making
it the eighth and ninth most common cause of cancer-related death
in women and men, respectively. The incidence is nearly 10 times the
incidence of Hodgkin’s lymphoma. There is a slight male-to-female
predominance and a higher incidence for Caucasians than for African
Americans. The incidence rises steadily with age, especially after age
40, but lymphomas are also among the most common malignancies in
adolescent and young adult patients. The incidence of NHL has nearly
doubled over the last 20–40 years, and continues to rise by 1.5–2% each
year. Patients with both primary and secondary immunodeficiency
states are predisposed to developing non-NHL. These include patients
with HIV infection; patients who have undergone organ transplanta-
tion; and patients with inherited immune deficiencies and autoimmune
conditions. The 5-year survival rates for NHL is 72% for Caucasians
and 63% for African Americans.
6/1/18 5:44 PM
 770 TABLE 104-1  WHO Classification of Lymphoid Malignancies
B CELL
Mature (peripheral) B-cell neoplasms
 Lymphoplasmacytic lymphoma
(Waldenstrom’s macroglobulinemia)
  Hairy cell leukemia
 Splenic marginal zone B-cell
lymphoma
 Extranodal marginal zone B-cell
lymphoma of MALT type
 Nodal marginal zone B-cell
lymphoma
  Follicular lymphoma
  Mantle cell lymphoma
 Diffuse large B-cell lymphoma
(including subtypes)    Peripheral T-cell lymphoma, NOS
 High grade B-cell lymphoma with
MYC and BCL2 and/or BCL6
rearrangements
  High grade B-cell lymphoma NOS
 Burkitt’s lymphoma/Burkitt’s cell
leukemia
 Primary mediastinal large B-cell
PART 4
T CELL
Mature (peripheral) T-cell neoplasms
  T-cell granular lymphocytic leukemia
 Adult T-cell leukemia/lymphoma
(HTLV-1+)
 Extranodal NK/T-cell lymphoma,
nasal type
 Enteropathy-associated T-cell
lymphoma
  Hepatosplenic T-cell lymphoma
 Subcutaneous panniculitis-like T-cell
lymphoma
  Mycosis fungoides
  Sezary syndrome
 Angioimmunoblastic T-cell
lymphoma
 Anaplastic large cell lymphoma,
ALK+
 Anaplastic large cell lymphoma,
ALK-
(FL) are more common in Western countries. A specific subtype of non-
Hodgkin’s lymphoma known as the angiocentric nasal T/natural killer-
(NK-) cell lymphoma has a striking geographic occurrence, being most
frequent in Southern Asia and parts of Latin America. Another subtype
of non-Hodgkin’s lymphoma associated with infection by human T-cell
lymphotropic virus (HTLV) 1 is seen particularly in southern Japan and
the Caribbean. Likewise, there are differences in the age-dependent
incidence of NHL by histologic subtype, with aggressive lymphomas
like diffuse large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma
(BL) being the most common entities in children, and DLBCL and indo-
lent lymphomas including FL being the most common forms in adults.
The relative frequencies of the various types of lymphoid malignancies,
including Hodgkin’s lymphoma, plasma cell disorders, and lymphoid
leukemias is shown in Fig. 104-1.
A number of environmental factors have been implicated in the
occurrence of non-Hodgkin’s lymphoma, including infectious agents,
chemical exposures, and medical treatments. Several studies have
demonstrated an association between exposure to agricultural chemi-
cals and an increased incidence of non-Hodgkin’s lymphoma. Patients
treated for Hodgkin’s lymphoma can develop non-Hodgkin’s lym-
phoma; it is unclear whether this is a consequence of the Hodgkin’s
lymphoma or its treatment, especially radiation.
Several NHL are associated with infectious agents (Table 104-2).

lymphoma Epstein-Barr Virus (EBV) is associated with the development of

  Plasmablastic lymphoma Burkitt’s lymphoma in Central Africa and the occurrence of aggressive
NHL in immunosuppressed patients in Western countries. The major-
  Primary effusion lymphoma
ity of primary central nervous system (CNS) lymphomas are associated
  HHV8+ DLBCL NOS
with EBV. EBV infection is strongly associated with the occurrence of
Oncology and Hematology

  Intravascular large B-cell lymphoma
  ALK+ large B-cell lymphoma
Abbreviations: HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated
lymphoid tissue; NK, natural killer; WHO, World Health Organization.
Source: Adapted from SH Swerdlow et al: WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues, 5th ed. IARC, 2016.
The incidence of NHL and the patterns of expression of the various
subtypes differ geographically and across age groups. T-cell lym-
phomas are more common in Asia than in Western countries, while
certain subtypes of B-cell lymphomas such as follicular lymphoma
extranodal nasal NK/T-cell lymphomas in Asia and South America.
HTLV-1 infects T cells and leads directly to the development of adult
T-cell lymphoma (ATL) in a small percentage of patients infected
as babies through ingestion of breast milk of infected mothers. The
median age of patients with ATL is ~56 years; thus, HTLV-1 demon-
strates a long latency from infection to oncogenesis (Chap. 196). Infec-
tion with HIV predisposes to the development of aggressive, B-cell
non-Hodgkin’s lymphoma. This may be through overexpression of
interleukin 6 by infected macrophages. Infection of the stomach by the
bacterium Helicobacter pylori induces the development of gastric MALT
(mucosa-associated lymphoid tissue) lymphomas. This association is

Non-Hodgkin’s
lymphoma
subtypes

31% Diffuse large B-cell lymphoma

Plasma cell
disorders
16%

CLL 22% Follicular lymphoma

9%

Non-Hodgkin’s
Hodgkin’s lymphoma
62.4% 7.6% MALT lymphoma
disease
8.2%
7.6% Mature T-cell lymphoma

ALL 6.7% Small lymphocytic lymphoma

3.8%
6% Mantle cell lymphoma
2.4% Mediastinal large B-cell lymphoma
2.4% Anaplastic large cell lymphoma
2.4% Burkitt’s lymphoma
1.8% Nodal marginal zone lymphoma
1.7% Precursor T lymphoblastic lymphoma
1.2% Lymphoplasmacytic lymphoma
7.4% Others
FIGURE 104-1  Relative frequency of lymphoid malignancies. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; MALT, mucosa-associated lymphoid
tissue.

Harrisons_20e_Part4_p0435-p0858.indd 770 6/1/18 5:44 PM

 TABLE 104-2  Infectious Agents Associated with the Development of Wiskott-Aldrich syndrome, Chédiak-Higashi syndrome, ataxia telang- 771
Lymphoid Malignancies iectasia, and common variable immunodeficiency syndrome are com-
INFECTIOUS AGENT LYMPHOID MALIGNANCY plicated by highly aggressive lymphomas. The elevated incidence of
Epstein-Barr virus Burkitt’s lymphoma lymphoma in iatrogenic immunosuppression, AIDS, and autoimmune
disease argues strongly for immune dysregulation contributing in the
  Post–organ transplant lymphoma
pathogenesis of some lymphomas. An increased risk of NHL has been
  Primary CNS diffuse large B-cell lymphoma
observed in first-degree relatives with NHL, Hodgkin’s lymphoma or
  Hodgkin’s lymphoma chronic lymphocytic leukemia (CLL). In large databases studies, about
  Extranodal NK/T-cell lymphoma, nasal type 9% of patients with lymphoma or CLL have a first-degree relative with
HTLV-1 Adult T-cell leukemia/lymphoma a lymphoproliferative disorder.
HIV Diffuse large B-cell lymphoma
  Burkitt’s lymphoma ■■IMMUNOLOGY
Hepatitis C virus Lymphoplasmacytic lymphoma All lymphoid cells are derived from a common hematopoietic progen-
Helicobacter pylori Gastric MALT lymphoma itor that gives rise to lymphoid, myeloid, erythroid, monocyte, and
Human herpesvirus 8 Primary effusion lymphoma megakaryocyte lineages. Through the ordered and sequential activa-
  Multicentric Castleman’s disease tion of a series of transcription factors, the cell first becomes committed
to the lymphoid lineage and then gives rise to B and T cells.
Abbreviations: CNS, central nervous system; HIV, human immunodeficiency virus; About 90% of all lymphomas are of B-cell origin. A cell becomes
HTLV, human T cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue;
NK, natural killer. committed to B-cell development when it expresses the master B lin-
eage transcription factor PAX5, which ultimately results in a transcrip-
tional program that leads to the rearrangement of its immunoglobulin
supported by evidence that patients treated with antibiotics to eradi- genes, which involves chromosomal recombination as well as somatic

CHAPTER 104 Non-Hodgkin’s Lymphoma

cate H. pylori have regression of their MALT lymphoma. The bacterium
does not transform lymphocytes to produce the lymphoma; instead, a
vigorous immune response is made to the bacterium, and the chronic
antigenic stimulation leads to the neoplasia. MALT lymphomas of the
skin may be related to Borrelia sp. infections in Europe, those of the eyes
to Chlamydophila psittaci, and those of the small intestine to Campylobacter
jejuni. Chronic hepatitis C virus infection has been associated with the
development of lymphoplasmacytic lymphoma and splenic marginal
zone lymphoma (MZL). Human herpesvirus 8 is associated with pri-
mary effusion lymphoma in HIV-infected persons and multicentric
Castleman’s disease, a diffuse lymphadenopathy associated with sys-
temic symptoms of fever, malaise, and weight loss.
In addition to infectious agents, a number of other diseases or expo-
sures may predispose to developing lymphoma (Table 104-3). Diseases
of inherited and acquired immunodeficiency as well as autoimmune
diseases are associated with an increased incidence of lymphoma. The
association between immunosuppression and induction of NHLs is
compelling since if the immunosuppression can be reversed, a percent-
age of these lymphomas regress spontaneously. The incidence of NHL
is nearly hundredfold increased for patients undergoing organ trans-
plantation necessitating chronic immunosuppression, and is greatest in
the first year post-transplant. About 30% of these arise as a polyclonal
B-cell proliferation that evolves into a clonal B-cell malignancy. The
NHLs that occur in the context of immunosuppression or immunode-
ficiency, including HIV infection, are frequently associated with EBV.
Histologically, DLBCLs are most frequently associated with immuno-
suppression and autoimmune diseases, although almost all histologies
can be seen, especially MALT lymphomas in the context of autoimmune
diseases like Sjogren’s and Hashimoto’s thyroiditis. The rare inherited
immunodeficiency diseases X-linked lymphoproliferative syndrome,
TABLE 104-3  Diseases or Exposures Associated with Increased Risk
of Development of Malignant Lymphoma
Inherited immunodeficiency disease Autoimmune disease
  Klinefelter’s syndrome   Sjögren’s syndrome
  Chédiak-Higashi syndrome   Celiac sprue
  Ataxia-telangiectasia syndrome  Rheumatoid arthritis and systemic
  Wiskott-Aldrich syndrome lupus erythematosus  malignancies, it is presumed that they exist. As previously discussed,
 Common variable immunodeficiency Chemical or drug exposures
disease  Phenytoin
Acquired immunodeficiency diseases   Dioxin, phenoxy herbicides
  Iatrogenic immunosuppression  Radiation
  HIV-1 infection  Prior chemotherapy and radiation
  Acquired hypogammaglobulinemia therapy  phomas contain balanced chromosomal translocations involving the
hypermutation to create an immunoglobulin gene that is unique to
that B cell. The sequence of cellular changes, including changes in cell-
surface phenotype that characterizes normal B-cell development is
shown in Fig. 104-2. Most B-cell lymphomas arise following the process
of immunoglobulin gene recombination and somatic hypermutation,
which leads to class switching and affinity maturation of the mature
immunoglobulin, respectively, suggesting that it is the error-prone
nature of these genetic events that contributes to oncogenesis. Certainly
the frequency of chromosomal translocations that result in the activa-
tion of an oncogene or the inactivation of a tumor suppressor gene in
B-cell NHL may be the result of these normal cellular processes gone
awry (see below). In addition, the key roles of the transcription factors
MYC and BCL6 and the anti-apoptotic protein BCL2 in the process of
B-cell development explain why the genes encoding these proteins are
commonly mutated in B-cell lymphomas.
A cell becomes committed to T-cell differentiation upon migration
to the thymus and rearrangement of T-cell receptor (TCR) genes. This
requires the expression of the T-cell master regulatory transcription
factor, NOTCH-1. As in B cells, the development of the mature TCR
involves the rearrangement and recombination of the TCR loci, which
is error-prone and potentially oncogenic. The sequence of the events
that characterize T-cell development is depicted in Fig. 104-3.
Although lymphoid malignancies often retain the cell-surface phe-
notype of lymphoid cells at particular stages of differentiation, this
information is of little clinical or prognostic consequence. The so-called
stage of differentiation of a malignant lymphoma does not predict its
natural history. The antigen footprint, or immunophenotype, of the
cell, however, is valuable diagnostically as it allows for the distinguish-
ing of specific NHL subtypes. It can be detected by flow cytometry of
single cell suspension from blood, bone marrow, body fluid or disag-
gregated tissue using fluorescently labeled antibodies against these
antigens, or by immunohistochemical staining of paraffin-embedded
tissue sections with enzyme-linked antibodies against these antigens
followed by a colorimetric reaction.
As already mentioned, malignancies of lymphoid cells are asso-
ciated with recurring genetic abnormalities including chromosomal
translocations and genetic mutations that may in part be the result of
aberrant immunoglobulin or TCR development. While specific genetic
abnormalities have not been identified for all subtypes of lymphoid
B cells are even more susceptible to acquiring mutations during their
maturation in germinal centers; the generation of antibody of higher
affinity requires the introduction of mutations into the variable region
genes in the germinal centers. Given this, other nonimmunoglobulin
genes, e.g., bcl-6, may acquire mutations as well. Likewise, many lym-
antigen receptor genes; immunoglobulin genes on chromosomes 2, 14,

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 772 Follicular/diffuse
lymphomas IgM±IgG
or
IgG

Bone marrow Lymphoid follicle

Unclassified Pre–B ALL Burkitt’s
ALL HLA–DR+
IgM IgM IgM CD19+/−
+
IgD IgG CD20
TdT CD22+/−
TdT
TdT HCR HCR CD21+/−
HCR κR or D λR or D
H H Follicular center B cells
Multiple
HLA–DR+ HLA–DR+ HLA–DR+ HLA–DR+ HLA–DR+ HLA–DR+
CD19+ CD19+ CD19+ CD19+ CD19+ CD19+ Waldenström’s myeloma
CD10+ CD10+ CD20+ CD20+ CD20+ IgM
CD20+ CD22+ CD22+ CD22+
CD22+ CD21+ CD21+ CD21+
Lymphoid Mature
stem cell Early B cells Intermediate B cells B cells
Mantle cell CLL CD19+/− CD38+
lymphoma SL CD20+ PCA–1+
IgM IgM±IgD CD38+
IgD
Secretory B cells
PART 4

HLA–DR+ HLA–DR+
CD19+ CD19+
Oncology and Hematology

CD10+/− CD20+
CD20+ CD22+/−
CD22+ CD21+
CD21+ CD5+
CD5+
Mantle zone B cells

Antigen-independent differentiation Antigen-driven differentiation

FIGURE 104-2  Pathway of normal B-cell differentiation and relationship to B-cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell
markers used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light
chain gene rearrangement or deletion (κR or D, λR or D) occur early in B-cell development. The approximate normal stage of differentiation associated with particular
lymphomas is shown. ALL, acute lymphoid leukemia; CLL, chronic lymphoid leukemia; SL, small lymphocytic lymphoma.

and 22 in B cells; and T-cell antigen receptor genes on chromosomes
7 and 14 in T cells. The rearrangement of chromosome segments to
generate mature antigen receptors must create a site of vulnerability
to aberrant recombination. Examples of this type of event include the
(8;14)(q24;q32) translocation in BL, involving the MYC proto-oncogene
and the IgH gene; the (14;18)(q32;q32) translocation in FL, involving
the BCL2 proto-oncogene and the IgH gene; and the (11;14) (q13;q32)
translocation in mantle cell lymphoma (MCL), involving the gene
encoding cyclin D1 (CCDN1) and the IgH gene. Less commonly, chro-
mosomal translocations produce fusion genes that encode chimeric
oncogenic proteins. Examples of this include the (2;5)(p23;q35) translo-
cation involving the ALK and NPM1 genes in anaplastic large cell
lymphoma (ALCL) and the t(11;18)(q21;q21) translocation involving
the API2 and MLT genes in MALT lymphoma. Table 104-4 presents
the most common translocations and associated oncogenes for various
subtypes of lymphoid malignancies.
Gene profiling using array technology allows the simultaneous
assessment of the expression of thousands of genes. This technology
provides the possibility to identify new genes with pathologic impor-
tance in lymphomas, the identification of patterns of gene expression
with diagnostic and/or prognostic significance, and the identification
of new therapeutic targets. Recognition of patterns of gene expression is
complicated and requires sophisticated mathematical techniques. Early
successes using this technology in lymphoma include the identification
of previously unrecognized subtypes of DLBCL whose gene expres-
sion patterns resemble either those of follicular, or germinal center B
(GCB) cells or activated peripheral blood B cells (ABC). Patients whose
lymphomas have a GCB-like pattern of gene expression have a consid-
erably better prognosis than those whose lymphomas have a pattern
resembling ABCs. This improved prognosis is independent of other
known prognostic factors. Similar information is being generated in
FL and MCL. The challenge remains to provide information from such
techniques in a clinically useful time frame.
APPROACH TO THE PATIENT
Regardless of the type of lymphoid malignancy, the initial evalua-
tion of the patient should include performance of a careful history
and physical examination. These will help confirm the diagnosis,
identify those manifestations of the disease that might require
prompt attention, and aid in the selection of further studies to
optimally characterize the patient’s status to allow the best choice
of therapy. It is difficult to overemphasize the importance of a care-
fully done history and physical examination. They might provide
observations that lead to reconsidering the diagnosis, provide hints
at etiology, clarify the stage, and allow the physician to establish
rapport with the patient that will make it possible to develop and
carry out a therapeutic plan.
The duration of symptoms and pace of symptomatic progression
are important in distinguishing aggressive from more indolent lym-
phomas, as are the presence or absence of “B” symptoms, such as

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 T-CELL T-CELL 773
DIFFERENTIATION THYMUS MALIGNANCIES fevers, night sweats, or unexplained weight loss. Patients should be
asked about localizing symptoms that may point towards lympho-
matous involvement of specific sites, such as the chest, abdomen, or
Stage I Majority of
Prothymocyte T cell ALL CNS. Comorbid diagnoses that may impact therapy or monitoring
on therapy should be reviewed and acknowledged, including a
CD: 2, 7, 38, 71 history of diabetes or congestive heart failure. A physical exami-
nation should pay close attention to all the peripherally accessible
Stage II
sites of lymph nodes, the liver and spleen size, Waldeyer’s ring,
Thymocyte Minority of T-ALL whether there is a pleural or pericardial effusion or abdominal
Majority of T-LL ascites, whether there is an abdominal, testicular or breast mass, and
CD: 1, 2, 4, 7, 8, 38 whether there is cutaneous involvement as all of these findings may
influence further evaluation and disease management.
Laboratory studies should include a complete blood count,
Stage III routine chemistries, liver function tests, and serum protein elec-
Thymocyte Minority of T-LL
CD: 2, 3, 4/8, 5, 6, 7; TCR
Rare T-ALL trophoresis to document the presence of circulating monoclonal
paraproteins. The serum b-2 microglobulin level and serum lactate
PERIPHERAL BLOOD AND NODES dehydrogenase (LDH) are important independent prognostic factors
Majority of in NHL. Staging of certain diseases may involve a bone marrow
Mature T Helper T-CLL, CTCL, biopsy; results of other laboratory and staging studies may also
Cell Sezary Cell, NHL
warrant a marrow evaluation. A lumbar puncture for evaluation
CD: 2, 3, 4, 5, 6, 7; TCR of lymphomatous involvement may be indicated in the setting of
concerning neurologic signs or symptoms, or diseases that are high

CHAPTER 104 Non-Hodgkin’s Lymphoma

Mature T Cytotoxic/ Minority of
risk for CNS involvement. The latter may include disease involving
Suppressor Cell T-CLL, NHL the paranasal sinuses, testes, breast, kidneys, adrenal glands, and
epidural space, as well as highly aggressive histologies like BL. Since
CD: 2, 3, 4, 5, 6, 7; TCR HIV and hepatitis B and C infection can be risk factors for devel-
FIGURE 104-3  Pathway of normal T-cell differentiation and relationship to oping NHL, and since treatment for some NHL can result in the
T-cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and potentially life threatening reactivation of hepatitis B, patients with
CD71 are cell markers used to distinguish stages of development. T-cell antigen a new diagnosis of NHL should be screened for these viruses as well.
receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes Lymphoma histology and clinical presentation dictates which
and peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T-cell ALL; T-LL,
T-cell lymphoblastic lymphoma; T-CLL, T-cell chronic lymphoid leukemia; CTCL, imaging studies should be ordered. Chest, abdominal, and pelvic
cutaneous T-cell lymphoma; NHL, non-Hodgkin’s lymphoma. computed tomography (CT) scans are essential for accurate stag-
ing to assess lymphadenopathy for indolent lymphomas, whereas
positron emission tomography (PET) using 18F-fluorodeoxyglucose
(FDG PET) is useful for aggressive lymphomas, including BL,
DLBCL, plasmablastic lymphoma, and the aggressive T-cell NHLs.
TABLE 104-4  Genetic Features of B- and T-Cell Lymphomas It is highly sensitive for detecting both nodal and extranodal sites
GENETIC FEATURE GENES LYMPHOMA involved by NHL. The intensity of FDG avidity, or SUV, correlates
t(8;14) MYC/IgH Burkitt’s lymphoma with histologic aggressiveness, and may be useful in cases when
t(2;8) MYC/Igκ disease transformation of an indolent lymphoma to a diffuse aggres-
t(8;22) MYC/Igλ sive lymphoma is suspected. PET scanning can also differentiate
t(11;14) BCL1 (CCND1)/IgH Mantle cell lymphoma; between treated disease and active disease at the end of therapy
multiple myeloma in patients with residual masses on CT scans. Consensus recom-
t(14;18) BCL2/IgH Follicular lymphoma, diffuse mendations regarding PET scanning were published as a result of
t(3;14) BCL6/IgH large B-cell lymphoma an International Harmonization Project, and state that PET should
(DLBCL) only be used for DLBCL and Hodgkin’s lymphoma, that scanning
t(11;18) API2/MALT1 MALT lymphoma during therapy should only be done as part of clinical trials, and
t(1;14) BCL10/IgH that the end-of-treatment scan should not be done before 3 weeks
t(14;18) MALT1/IgH but preferably 6–8 weeks after chemotherapy and 8–12 weeks after
t(3;14) FOXP1/IgH radiation or chemoradiotherapy. There is no evidence that long-term
Trisomy 3 Unknown Splenic marginal zone follow-up should include PET scanning. More recently, though, PET
7q21 deletion CDK6 lymphoma scan results at the end of therapy for FL have been associated with
t(9;14) PAX5/IgH Lymphoplasmacytic prognosis, with patients with residual PET avid disease at the end
6q21 deletion Unknown lymphoma of treatment having a poorer prognosis than those who are PET
negative, and so it may be used for this prognostic purpose. Finally,
inv(14) TCRa/TCL1 Peripheral T-cell lymphoma,
NOS; T-PLL magnetic resonance imaging (MRI) is useful in detecting bone, bone
t(14;14)
marrow and CNS disease in the brain and spinal cord. The staging
t(2;5) NPM1/ALK Anaplastic large cell evaluation is outlined in Table 104-5.
t(1;2) TPM3/ALK lymphoma (ALCL)
The Ann Arbor staging system developed in 1971 for HL was
t(2;3) TFG/ALK adapted for staging NHLs (Table 104-6). This staging system focuses
t(2;17) CTLC/ALK on the number of tumor sites (nodal and extranodal), location, and
inv(2) ATIC/ALK the presence or absence of systemic, or B, symptoms. Table 104-6
Trisomy 3 Unknown Angioimmunoblastic summarizes the essential features of the Ann Arbor system.
Trisomy 5 Unknown T-cell lymphoma This anatomic based system is less useful in NHL, which dis-
Isochromosome 7q Unknown Hepatosplenic T-cell seminates widely, not in an ordered stepwise fashion. A majority of
lymphoma patients with NHL have advanced stage disease at diagnosis. Apart
Abbreviation: MALT, mucosa-associated lymphoid tissue.
from early-stage disease limited to a radiation field where local

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 774 TABLE 104-5  Staging Evaluation for Non-Hodgkin’s Lymphoma
Physical examination
Documentation of B symptoms
Laboratory evaluation
  Complete blood counts
  Liver function tests
  Uric acid
 Calcium
  Serum protein electrophoresis
 Serum β2-microglobulin
Chest radiograph
CT scan of abdomen, pelvis, and usually chest
Bone marrow biopsy
Lumbar puncture in lymphoblastic, Burkitt’s, and diffuse large B-cell lymphoma
with positive marrow biopsy
Gallium scan (SPECT) or PET scan in large cell lymphoma
Abbreviations: CT, computed tomography; PET, positron emission tomography;
SPECT, single-photon emission computed tomography.
therapy with radiation is an option, all other disease is treated the same
regardless of stage. Histology and clinical parameters at presentation
PART 4
are more important than stage with respect to prognosis. The Interna-
tional Prognostic Index (IPI) is perhaps the best predictor of outcome
(Table 104-7). The IPI was developed based on the analysis of over
2000 patients with aggressive NHLs treated with an anthracycline
Oncology and Hematology
containing regimen. Age (≤60 vs >60); serum LDH (≤normal vs
>normal); performance status (0 or 1 vs 2–4); stage (I or II vs III or
IV); and extranodal involvement (<1 site vs >1 site) were identified
as independently prognostic for overall survival (OS). A point is
awarded for each risk factor and then summed, defining four risk
groups: low-risk (0 or 1); low-intermediate (2); high-intermediate (3);
and high (4–5). The 5-year OS rates for patients with scores of 0 to 1,
2, 3, and 4–5 were 73, 51, 43, and 26%, respectively. The age-adjusted
IPI separates patients ≤60 from patients >60. For the age adjusted IPI,
only stage, LDH, and performance status were important. Younger
patients with 0, 1, 2, or 3 risk factors had 5-year survival rates of 83%,
69%, 46%, and 32%, compared to 56%, 44%, 37%, and 21% for older
patients. When factoring in the introduction and clinical benefit of
rituximab, the 4-year progression-free survival is 94%, 80%, and 53%
for 0 and 1, 2, or 3 or more risk factors, respectively.
The follicular lymphoma prognostic index (FLIPI) is a similar pre-
dictive model for FL, derived from the analysis of over 4000 patients.
Age >60, stage III/IV disease, the presence of >4 nodal sites, an
elevated serum LDH concentration and a hemoglobin <12 were
identified as independent prognostic variables, and summation
of each variable identified three risk groups. The median 10-year
survival rates for patients with zero to one (low-risk), two (interme-
diate-risk), or three or more (high-risk) of these adverse factors were
TABLE 104-6  Ann Arbor Staging for Lymphoma*
STAGE DESCRIPTION
I Involvement of a single lymph node region (I) or single extra-
nodal site (IE)
II Involvement of two or more lymph node regions or lymphatic
structures on the same side of the diaphragm alone (II) or with
involvement of limited, contiguous, extralymphatic organ or
tissue (IIE)
III Involvement of lymph node regions on both sides of the
diaphragm (III), which may include the spleen (IIIS), or limited,
contiguous, extralymphatic organ or tissue (IIIE), or both (IIIES)
IV Diffuse or disseminated foci of involvement of one or more
extralymphatic organs or tissues, with or without associated
lymphatic involvement
*
All stages are further subdivided according to the absence (A) or presence (B) of
systemic B symptoms including fevers, night sweats, and/or weight loss (>10% of
body weight over 6 months prior to diagnosis).
Harrisons_20e_Part4_p0435-p0858.indd 774
TABLE 104-7  International Prognostic Index for NHL
Five Clinical Risk Factors
Age ≥60 years
Serum lactate dehydrogenase levels elevated
Performance status ≥2 (ECOG) or ≤70 (Karnofsky)
Ann Arbor stage III or IV
>1 site of extranodal involvement
For Diffuse Large B-cell Lymphoma
0, 1 factor = low risk 35% of cases; 5-year survival, 73%
2 factors = low-intermediate risk 27% of cases; 5-year survival, 51%
3 factors = high-intermediate risk 22% of cases; 5-year survival, 43%
4, 5 factors = high risk 16% of cases; 5-year survival, 26%
For Diffuse Large B-cell Lymphoma Treated With R-CHOP
0 factor = good 10% of cases; 4-year survival, 94%
1, 2 factors = intermediate 45% of cases; 4-year survival, 80%
3, 4, 5 factors = poor 45% of cases; 4-year survival, 53%
Abbreviations: ECOG, Eastern Cooperative Oncology Group; R-CHOP, rituximab,
cyclophosphamide, doxorubicin, vincristine, prednisone.
71, 51, and 36%, respectively. Similar disease-specific IPIs have been
developed for MCL and peripheral T-cell lymphoma (PTCL) as well.
These prognostic indices take into account the proliferative index
and cell surface markers, respectively.
Finally, as mentioned previously, gene expression profiling has
identified DLBCLs with differential prognoses: GCB and ABC,
where GCB-like DLBCL is associated with a significantly better
OS. A more readily accessible immunohistochemical algorithm has
been developed, based on the presence of absence of CD10, BCL6,
and MUM1 that correlates closely with gene expression profiles and
can differentiate the majority of GCB from non-GCB-like DLBCL.
These profiles have prognostic importance but to date do not alter
treatment recommendations for the primary treatment of DLBCL.
Current clinical trials do stratify by DLBCL subtype, and it appears
that agents like the Bruton’s tyrosine kinase (BTK) inhibitor ibru-
tinib and lenalidomide are most active in non-GCB DLBCL in the
relapsed setting. Treatment may then be differentiated by these
subtypes in the future.
CLINICAL FEATURES, TREATMENT, AND
PROGNOSIS OF SPECIFIC NHL
■■MATURE B-CELL NEOPLASMS
B-cell NHLs can be characterized into two broad groups—those that
behave aggressively, require immediate or urgent treatment with com-
bination chemotherapy regimens, and are potentially curable, and those
that are more indolent in nature, can be observed and treated only
when they cause symptoms or signs of organ function impairment, are
very responsive to therapy, but are not ultimately curable in the vast
majority of cases. Among the aggressive diseases, the most common
are NHL and DLBCL; and the most rapidly prolific are NHL and BL.
FL is the second most common NHL and the most common indolent
NHL. Other indolent NHLs include MZL, lymphoplasmacytic lym-
phoma (LPL), and hairy cell leukemia (HCL). MCL is an intermediate
grade lymphoma that shares some characteristics with the aggressive
lymphomas (fairly urgent need for treatment and aggressive upfront
combination chemotherapy regimens), but like the indolent lympho-
mas, it is not readily curable with conventional dose therapies.
Burkitt’s Lymphoma  Burkitt’s lymphoma/leukemia is a rare dis-
ease in adults in the United States, making up <1% of NHL, but it makes
up ~30% of childhood non-Hodgkin’s lymphoma. It is one of the fastest
growing neoplasms, with a doubling time of <24 h. In general it is a
pediatric tumor that has three major clinical presentations. The endemic
(African) form presents as a jaw or facial bone tumor that spreads to
extranodal sites including ovary, testis, kidney, breast, and especially
to the bone marrow and meninges. The non-endemic form has an
6/1/18 5:44 PM

FIGURE 104-4  Burkitt’s lymphoma. The neoplastic cells are homogeneous,
medium-sized B cells with frequent mitotic figures, a morphologic correlate of
high growth fraction. Reactive macrophages are scattered through the tumor, and
their pale cytoplasm in a background of blue-staining tumor cells gives the tumor
a so-called starry sky appearance.
abdominal presentation with massive disease, ascites, and renal, testis,
and/or ovarian involvement, and, like the endemic form, also spreads
to the bone marrow and CNS. Immunodeficiency-related cases more
often involve lymph nodes and may present as acute leukemia. BL has
a male predominance and is typically seen in patients <35 years of age.
On biopsy, there is a monotonous infiltration of medium-sized cells
with round nuclei, multiple nucleoli, and basophilic cytoplasm with
vacuoles. The proliferation rate is ~100%, and tingible body macro-
phages give rise to the classic “starry sky” appearance of this tumor
(Fig. 104-4). Tumor cells are positive for B-cell antigens CD19, CD20,
and surface immunoglobulin. They are also uniformly positive for
CD10 and BCL6 but negative for BCL2. Endemic BLs are EBV positive,
whereas the majority of non-endemic BLs are EBV negative. BL is
associated with a translocation involving MYC on chromosome 8q24
in >95% of the cases. The most common partners are chromosomes 14,
2, or 22, rearrangements that produce fusions of MYC with either the
IgH (80%), kappa (15%), or lambda (5%) light chain genes, respectively.
While exquisitely chemosensitive, it is imperative that treatment for
BL be initiated quickly given the rapid doubling time and high mor-
bidity of this disease. There are several effective intensive combination
chemotherapy regimens, all of which incorporate high doses of cyclo-
phosphamide. Prophylactic therapy to the CNS is mandatory. Cure can
be expected in 70–80% of patients when treated promptly and correctly.
Salvage therapy has been generally ineffective in patients whose dis-
ease progresses after upfront therapy, emphasizing the importance of
the initial treatment approach and referral to a tertiary cancer center
with experience treating this disease.
Diffuse Large B-Cell Lymphoma  Diffuse large B-cell lym-
phoma (DLBCL) is the most common histologic subtype of NHL
diagnosed, representing about one-third of all cases. Previously felt to
be “one disease” it is now recognized as a heterogeneous collection of
multiple entities. It is slightly more common in Caucasians and men,
and the median age at diagnosis is 64. The relative risk of DLBCL is
higher amongst people with affected first-degree relatives (RR 3.5-fold),
and patients with congenital or acquired immunodeficiency, patients
on immunosuppression, and patients with autoimmune disorders also
have a higher risk of developing DLBCL, often EBV-related. The major-
ity of patients present with advanced stage disease, with only 30–40%
of patients having stage I or II disease; about 40% of patients will have
“B” symptoms, and 50% of patients will have an elevated LDH. Up
to 40% of patients will have involvement of non-lymph node sites
including bone marrow, CNS, GI track, thyroid, liver, and skin. Patients
with extensive bone marrow involvement, or involvement of the testes,
breast, kidney, adrenal gland, paranasal sinus, or epidural space are at
increased risk of CNS dissemination.
Harrisons_20e_Part4_p0435-p0858.indd 775
775
FIGURE 104-5  Diffuse large B-cell lymphoma. The neoplastic cells are
heterogeneous but predominantly large cells with vesicular chromatin and
prominent nucleoli.
The tumor consists of a diffuse proliferation of large, atypical lym-
CHAPTER 104 Non-Hodgkin’s Lymphoma
phocytes with a high proliferative index (Fig. 104-5). These cells typi-
cally express the B-cell antigens CD19, CD20, and CD79a. Expression
of CD10 and BCL6 is consistent with the tumor cell being of germinal
center origin (GCB), while the expression of MUM1 corresponds with
the non-GC or activated B cell (ABC) subtype. BCL2 is overexpressed
in anywhere from 25 to 80% of DLBCL, whereas BCL6 is positive in
more than two-thirds of cases, either as the result of translocations,
gain of copy number, or promoter mutations. MYC is rearranged in
10% of DLBCLs, and ~20% of MYC-rearranged cases have concurrent
BCL2 or BCL6 rearrangements, a combination referred to as “double-
hit lymphoma.” These double-hit lymphomas are associated with an
extremely poor prognosis with a median OS of only 12–18 months.
Amplification and/or overexpression of MYC independent of rear-
rangements or amplification has also been described and is also associ-
ated with a poor, albeit better, prognosis.
Combination chemotherapy offers potentially curative therapy for
DLBCL, regardless of the stage. The addition of the anti-CD20 antibody
rituximab to cyclophosphamide, doxorubicin, vincristine, and predni-
sone (R-CHOP) improved survival beyond CHOP alone and is the stan-
dard first-line chemotherapy for this disease. For patients with early
stage disease localized to a radiation field, treatment options include
full course chemotherapy with R-CHOP every 3 weeks for 6 cycles, or
abbreviated chemotherapy for 3–4 cycles followed by involved field
radiotherapy. For advanced stage DLBCL, therapy is with a full course
of chemotherapy. On average, about 60–65% of patients with DLBCL
can be expected to be cured with this approach, and the likelihood of
cure is predicted by the IPI, gene expression profile cell of origin, and/
or MYC cytogenetics and expression. Several studies have investigated
alternative anthracycline-containing chemotherapy regimens and/or
consolidation autologous stem cell transplantation in first remission
for higher-risk disease without improvement over R-CHOP alone.
Dose adjusted R-EPOCH (rituximab, infusional etoposide/vincristine/
adriamycin, cyclophosphamide, prednisone) is one such regimen.
Although this regimen is no better than R-CHOP for DLBCL in general,
it is often used to treat primary mediastinal large B-cell lymphoma and
double-hit DLBCL based on results from phase 2 and retrospective
studies, respectively. CNS prophylaxis with either intrathecal chemo-
therapy or high-dose systemic methotrexate and leucovorin rescue
should be considered for patients with high risk of CNS dissemination.
This includes patients with primary testicular involvement and breast
involvement, as well as patients with several IPI risk factors and diffuse
bone marrow involvement, renal involvement, or adrenal involvement.
The use of CNS prophylaxis for disease involving the paranasal sinuses
or the epidural space is less clear but may be considered.
Over one-third of patients will either have primary refractory
disease or disease that relapses after first-line chemotherapy. These
patients may still be cured with salvage chemotherapy regimens
6/1/18 5:44 PM
 776 followed by autologous stem cell transplantation. Patients with a poor
performance status or advanced age that are not candidates for such
an approach, however, are often managed with palliative intentions.
Radiation to symptomatic areas of disease can be transiently helpful.
Less intensive chemotherapy with drugs like gemcitabine, cytarabine,
or bendamusine can help control disease and symptoms for a limited
period of time. These patients should be referred for clinical trials when
applicable. For patients in whom more aggressive therapy is an option,
treatment is with combination chemotherapy using various combina-
tions of drugs primarily in order to identify patients with chemosen-
sitive disease. Patients with chemosensitive disease have the greatest
likelihood of benefiting from high-dose chemotherapy and autologous
stem cell transplant, which improves response duration and survival
over salvage chemotherapy alone and leads to long-term disease free
survival in about 40–50% of patients. For patients with chemorefractory
disease, clinical trials or palliative therapy or clinical trials should be
considered, with a goal of achieving a disease response sufficient for
allogeneic stem cell transplant. Several new agents have shown some
promise in patients with relapsed DLBCL, including ibrutinib, particu-
larly in the ABC cell of origin subtype, lenalidomide, and everolimus.
Chimeric antigen receptor T cells (CAR-T cells) are an investiga-
tional immunotherapy approach for treating malignancies that have
had early success in CLL and B-cell acute lymphoblastic leukemia, as
PART 4
well as B-cell NHL. This strategy uses T cells collected from a patient
that are genetically modified to express a receptor that will bind to a
surface antigen expressed on the patient’s own tumor cells. In the case
of B-cell malignancies, CD19 has been targeted most commonly. After
infusion, autologous CAR-T cells home to sites of disease and also per-
Oncology and Hematology
sist over time. The CARs consist of an extracellular antigen recognition
domain (typically a single chain Fv variable fragment from a monoclo-
nal antibody) linked via a transmembrane domain to an intracellular
signaling domain (usually the CD3ζ endodomain), resulting in the
redirection of T-cell specificity toward target antigen-positive cells, and
one or more costimulatory domains including CD28, 4-1BB, or OX40
to enhance cytokine secretion and effector cell expansion, and prevent
activation-induced apoptosis and immune suppression by tumor-
related metabolites. Anti-CD19 CAR-T cells have been approved for the
treatment of relapsed/refractory DLBCL following two prior systemic
therapies. This would include patients with chemoinsensitive disease
following second-line salvage chemotherapy for whom autologous
stem cell transplant is not an option, or for patients who relapse after
autologous stem cell transplant. In this setting, the response rate of
CAR-T cells is over 80%, with over 50% of patients achieving a com-
plete response. These responses appear to be durable, with 70% of
complete responders still in remission past 1 year of therapy.
Other large B-cell lymphomas include intravascular large B-cell
lymphoma, T-cell/histiocyte–rich large B-cell lymphoma, EBV-
positive DLBCL of the elderly, and ALK-positive large B-cell lym-
phoma. Patients with the latter two diseases tend to have a poor
prognosis, whereas the addition of rituximab to CHOP chemotherapy
has dramatically improved outcomes with intravascular large B-cell
lymphoma, and the outcomes in T-cell/histiocyte-rich large B-cell lym-
phoma are similar to DLBCL. R-CHOP remains the treatment of choice
for each of these lymphomas.
Follicular Lymphoma  FLs are the second leading NHL diag-
nosis in the United States and Europe and makes up 22% of NHL
worldwide and at least 30% of NHL diagnosed in the United States.
This type of lymphoma can be diagnosed accurately on morphologic
findings alone and has been the diagnosis in the majority of patients in
therapeutic trials for “low-grade” lymphoma in the past.
Evaluation of an adequate biopsy by an expert hematopathologist is
sufficient to make a diagnosis of FL. The tumor is composed of small
cleaved and large cells in varying proportions organized in a follicular
pattern of growth (Fig. 104-6). Confirmation of B-cell immunopheno-
type (monoclonal immunoglobulin light chain, CD19, CD20, CD10
and BCL6 positive, and CD5 and CD23 negative) and the existence
of the t(14;18) and abnormal expression of BCL-2 protein are confir-
matory. While >85% of FL will harbor a t(14;18) and overexpress the
Harrisons_20e_Part4_p0435-p0858.indd 776
FIGURE 104-6  Follicular lymphoma. The normal nodal architecture is effaced by
nodular expansions of tumor cells. Nodules vary in size and contain predominantly
small lymphocytes with cleaved nuclei along with variable numbers of larger cells
with vesicular chromatin and prominent nucleoli.
antiapoptotic protein BCL2, this genetic event is necessary but not suf-
ficient for malignant transformation of the B lymphocytes and multiple
genetic events are required for the development of FL. Studies have
identified the most common recurrent genetic events in FL, and they
included mutations in several epigenetic modifying genes, including
MLL2, EZH2, CREBBP, and EP300. The major differential diagnosis
is between lymphoma and reactive follicular hyperplasia. The coex-
istence of DLBCL must be considered. Patients with FL are often sub-
classified, or graded, into those with predominantly small cells, those
with a mixture of small and large cells, and those with predominantly
large cells. The WHO Classification adopted grading from 1 to 3 based
on the number of centroblasts, or large cells, counted per high power
field (hpf): grade I, from 0 to 5 centroblasts/hpf; grade II, from 6 to
15 centroblasts/hpf; and grade III, >15 centroblasts/hpf. Grade III has
been subdivided into grade IIIa, in which centrocytes predominate,
and grade IIIb, in which there are sheets of centroblasts. While this
distinction cannot be made simply or very reproducibly, these subdivi-
sions do have prognostic significance. Patients with FL with predom-
inantly large cells have a higher proliferative fraction, progress more
rapidly, and have a shorter OS with simple chemotherapy regimens.
Grade IIIb FL is an aggressive disease and considered most similar to
DLBCL and treated as such with curative intent.
The most common presentation for FL is with new, painless lymph-
adenopathy. Multiple sites of lymphoid involvement are typical, and
unusual sites such as epitrochlear nodes are sometimes seen. However,
essentially any organ can be involved, and extranodal presentations
do occur. Most patients do not have an elevated LDH or fevers, night
sweats, or weight loss, although histologic transformation to DLBCL
does occur at a rate of ~3% per year and can be associated with these
signs/symptoms. As discussed previously, prognosis is best predicted
by the FLIPI. Staging is typically done with CT scans of the chest,
abdomen and pelvis, as well as the neck if neck disease is suspected,
although PET/CT scans can be helpful in cases where disease trans-
formation is suspected, as transformed disease will be more FDG avid
than indolent disease, or for confirmation of early-stage disease, where
definitive local therapy with radiation may be considered.
Although FL is highly sensitive to chemotherapy and radiotherapy,
these therapies are usually not ultimately curative, except in the setting
of early-stage disease. If the disease can be encompassed in a radiation
field, involved field radiotherapy at a dose of 24–30 Gy may be cura-
tive, with 5-, 10-, and 15-year freedom from treatment failure of 72%,
46%, and 39%, and an overall 5-, 10-, and 15-year survival rates of 93%,
75%, and 62%, respectively. If radiation therapy would not be tolerated,
or if a patient prefers not to receive radiation, observation is a reason-
able alternative with a median time to treatment not reached at 7 years
of follow-up in one study. Many of these patients are diagnosed inci-
dentally or at a time when their lymphoma is not causing symptoms
6/1/18 5:44 PM
 or signs of organ function impairment. Numerous studies have shown
that treating patients with asymptomatic disease does not improve
survival compared with a program of close observation with treatment
reserved for symptomatic disease progression or organ dysfunction.
Thus, asymptomtic patients should be observed. When treatment is
indicated, there are a variety of treatment options, ranging from the
use of the monoclonal antibody against CD20, rituximab, alone or its
use in combination with chemotherapy. Treatment decisions are often
determined by the indication for treatment and/or by the volume of
disease being treated. For patients requiring therapy for inflamma-
tory or autoimmune phenomenon thought to be driven by FL, or for
patients with low volume disease, single-agent rituximab is associated
with a response rate of ~70% and a median response duration of
>2 years. This response duration is improved with the addition of
maintenance rituximab following a favorable response to rituximab
induction therapy. For patients with a larger volume of disease at the
time of treatment initiation, the addition of rituximab to chemother-
apy like cyclophosphamide, doxorubicin, vincristine and prednisone
(CHOP) or cyclophosphamide, vincristine, and prednisone (CVP) has
improved survival in this disease. The combination of bendamustine
and rituximab (BR) has been compared to R-CHOP and results in
longer response duration and less toxicity. BR then has become the
standard of care for the first-line therapy of medium to high-volume
FL. Similarly, the addition of maintenance rituximab following a good
response to R-CHOP or R-CVP improves response duration when used
in newly treated FL patients.
In patients with FL, the disease nearly always recurs following ther-
apy, after which retreatment is again reserved for symptomatic disease
or disease interfering with organ function. Single agent rituximab
or alternative chemotherapy regimens can again be employed. Both
autologous and allogeneic hematopoietic stem cell transplantation yield
high complete response rates in patients with relapsed FL, and long-
term remissions can occur in 40 and 60% of patients, respectively. The
latter is associated with considerable treatment-related morbidity and
mortality and so is usually reserved for patients with multiply relapsed
FL that is no longer responsive to chemotherapy. More targeted oral
therapies like lenalidomide and the PI3 kinase inhibitor idelalisib are
active in both untreated and relapsed FL. On average, most patients
will live with FL for 15–20 years, a number that is increasing given our
improved understanding of the genetics and microenvironment of FL,
and the increasing number of drugs and therapies being tested in this
disease. However, in addition to a high risk FLIPI, patients who do not
have a complete metabolic response by PET/CT scanning to their pri-
mary therapy, and patients who relapse within 2 years of the completion
of their primary chemotherapy tend to do poorly with chemotherapy.
Patients with FL have a high rate of histologic transformation to
DLBCL (~3% per year). This is recognized ~40% of the time during
the course of the illness by repeat biopsy and is present in almost all
patients at autopsy. This transformation is usually heralded by rapid
growth of lymph nodes—often localized—and the development of
systemic symptoms such as fevers, sweats, and weight loss. When this
happens in patients who have had previously untreated FL, treatment
with R-CHOP chemotherapy, as for DLBCL, can be curative for the
aggressive component while the FL may eventually recur. In patients
with previously treated FL that transforms to DLBCL, prognosis is
poor, and successful therapy with an aggressive combination chemo-
therapy regimen should be consolidated with an autologous stem cell
transplant. Finally, as discussed previously, grade 3B FL is more similar
to DLBCL than it is to FL and should be treated as such.
Marginal Zone Lymphoma  The second most common indolent
B-cell NHL is MZL. There are three main types: splenic MZL, extran-
odal MZL of MALT, and nodal MZL.
Nodal MZL most closely resembles FL clinically, and much of the
way we manage and treat it is based on studies done in FL. Tumor
biopsies in this disease show parafollicular and perivascular infil-
tration by monocytoid-appearing atypical lymphocytes with folded
nuclear contours that are positive for CD19, CD20, and CD79a but
negative for CD10 and largely negative for CD5. Some cases can have
plasmacytoid differentiation and can be associated with a monoclonal
Harrisons_20e_Part4_p0435-p0858.indd 777
expression of kappa or lambda light chains and with small monoclonal 777
immunoglobulin spikes.
Splenic MZL is largely a disease of older Caucasian patients; infec-
tion with hepatitis C is a risk factor for this disease and treatment of
hepatitis C can result in regression of the lymphoma. Patients present
with a lymphocytosis with or without cytopenias and splenomegaly.
Bone marrow involvement is common. Diagnosis can be made by
flow cytometry of the peripheral blood; malignant lymphocytes will
be positive for surface immunoglobulin, CD19, and CD20 and will
generally lack CD5 and CD10. On peripheral smear they have small
nuclei and abundant cytoplasm with “shaggy” or villous projections. It
can be differentiated from hairy cell leukemia by the absence of CD25,
CD103, and annexin A1. Recurrent cytogenetic abnormalities include
trisomy 3 and abnormalities of chromosome 7q. Therapy is indicated
for symptomatic disease or significant cytopenias. Splenectomy is
reasonable for selected patients with excellent relief of symptoms and
cytopenias. Splenectomy is associated with an overall response rate of
85% and an estimated progression-free and OS at 5 years of 58 and 77%,
respectively. Single-agent rituximab can improve splenomegaly and
cytopenias in >90% of patients. In a study of induction with weekly
rituximab followed by maintenance, the response rate was 95%, with
overall and progression-free survival at 5 years of 92 and 73%, respec-
CHAPTER 104 Non-Hodgkin’s Lymphoma
tively. Other options for therapy at relapse are similar to those used
for FL and include retreatment with rituximab, alkylating agents, and
purine analogues in combination with rituximab. The survival rate of
patients is in excess of 70% at 10 years.
MALT lymphoma is an MZL lymphoma of extranodal tissue, most
commonly the stomach but other common sites include the skin,
salivary glands, lung, small bowel, ocular adnexa, breasts, bladder,
thyroid, dura, and synovium. It is associated with states of chronic
inflammation either due to autoimmune diseases like Sjogren’s syn-
drome or Hashimoto’s thyroiditis, or chronic infections with organisms
like Helicobacter pylori (gastric), Borrelia burgdorferi (skin), Chlamydia
psittaci (conjunctiva), Campylobacter jejuni (intestines), and hepatitis
C virus. The essential pathologic feature of MALT lymphoma is the
presence of lymphepithelial lesions, which result from invasion of
mucosal glands and crypts by the neoplastic lymphocytes. These cells
are positive for CD19, CD20, and CD79a and negative for CD5 and
CD10. Recurrent cytogentic abnormalities include t(11;18), t(14;18),
t(1;14), t(3;14), and trisomy 8. The t(11;18) is most common, occurring in
up to 50% of MALT lymphomas. It results in the fusion of the apoptosis
inhibitor 2 (API2) gene and the MALT1 gene, resulting in activation
of nuclear factor κB (NFκB). Unlike other indolent B-cell lymphomas,
MALT lymphomas present most commonly with stage I or II dis-
ease. In these cases, radiation therapy may be curative. Alternatively,
patients may respond to antibiotics for the associated underlying infec-
tion. Treatment of symptomatic or organ impairing relapsed, refractory,
or advanced stage disease is similar to approaches used in FL with
chemotherapy, immunotherapy, or chemoimmunotherapy.
Lymphoplasmacytic Lymphoma  About 1% of all NHLs will
be lymphoplasmacytic lymphomas, which are indolent B-cell NHLs
with lymphoplasmacytic differentiation, most commonly associated
with a monoclonal IgM paraprotein. Nearly all patients will have stage
IV disease at diagnosis with bone marrow involvement. Patients with
high levels of circulating IgM paraproteins constitute a specific entity
known as Waldenstrom macroglobulinemia and can have symptoms
due to hyperviscosity as a result of the circulating IgM. Activating
mutations in MYD88, an adaptor protein that is involved in signaling
downstream of the Ig receptor leading to NFκB activation, is present
in >90% of cases. Tumor biopsies are notable for proliferation of small
lymphocytes, lymphoplasmacytic cells, and plasma cells, and malig-
nant lymphocytes are positive for CD19, CD20, and surface IgM but
generally negative for CD5 and CD10. Like the other indolent NHLs,
treatment is indicated for disease that causes symptoms or interferes
with organ function; hyperviscosity related to elevated serum IgM
and paraneoplastic neuropathy are additional indications for therapy.
Single-agent rituximab may be useful for low-volume disease, but can
be associated with a transient rise in serum IgM concentrations that
6/1/18 5:44 PM
 778 can cause or exacerbate hyperviscosity. Chemoimmunotherapy with
regimens like BR and rituximab, cyclophosphamide, and dexametha-
sone are active, as are myeloma therapies such as bortezomib. Given
that 85% of IgM remains intravascular, acute relief of hyperviscosity
symptoms can be obtained by plasmapheresis. For recurrent disease,
one can often utilize agents that were previously used. For patients
with more refractory LPL, the mTOR inhibitor everolimus and the oral
BTK ibrutinib are active. Selected patients with relapsed disease are
considered for high-dose therapy with ASCT or alloSCT. The results
seen are similar to that of other indolent lymphomas.
Mantle Cell Lymphoma  MCL comprises about 6% of NHLs. It
is an intermediate grade lymphoma that like the indolent B-cell NHLs
is not curable with conventional therapies, but like the aggressive
lymphomas often requires more aggressive chemoimmunotherapy
regimens with or without an autologous stem cell transplant to achieve
a reasonable response duration. This therapy is not curative, however,
and median survival with this disease is on the order of 5–10 years. An
exception to this is a more indolent, SOX11 variant that often presents
with circulating disease with splenomegaly but without significant
lymphadenopathy and with a low Ki67 (<10%). This subset behaves
more like the indolent B-cell NHLs and can be observed until treatment
is indicated by symptoms or organ function impairment. Similarly,
there is a blastic variant with a high Ki67 index that is associated with a
PART 4
poor prognosis and a median OS of only 18 months. For other patients,
prognosis is best predicted by the biologic mantle cell prognostic index
(MIPI), which factors in age, performance status, LDH, white blood
cell count, and Ki67 expression to determine a risk group. This disease
is more common in men, and the average age of diagnosis is 63. Over
Oncology and Hematology
two-thirds of patients will have stage IV disease, mostly with bone
marrow and peripheral blood involvement, at the time of diagnosis.
Other common extranodal sites of involvement include the GI tract
where diffuse lymphomatous polyposis may be seen.
The pathognomonic cytogentic finding in MCL is t(11;14), which
brings the gene for the cell cycle control protein cyclin D1 under the
control of the immunoglobulin heavy chain gene promoter on chromo-
some 14. This translocation is present in >90% of cases. The remaining
cases usually overexpress cyclin D2, cyclin D3, or cyclin E. Tumor cells
also are positive for B-cell markers CD19 and CD20, as well as CD5.
They usually lack CD10 and CD23.
Therapies for MCL are evolving. Patients with localized disease
might be treated with combination chemotherapy followed by radio-
therapy; however, these patients are exceedingly rare. Similarly,
patients with the indolent variant can be observed until disease pro-
gresses to cause symptoms or signs of organ function impairment. For
the usual presentation with disseminated disease, standard lymphoma
treatments like R-CHOP have been unsatisfactory, with the minority
of patients achieving complete remission. The addition of high dose
cytarabine to an R-CHOP-like backbone with or without consolidation
autologous stem cell transplantation in first remission has improved
progression-free survival, but it has not elicited cures in this disease.
These include the Nordic regimens and R-HyperCVAD (rituximab,
cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytara-
bine, and methotrexate). BR has activity in this disease and is more
effective and better tolerated than R-CHOP. Newer studies with short
follow-up suggest that strategies that combine BR with cytarabine
with or without autologous stem cell transplant may be effective and
well tolerated. Maintenance rituximab, following a good response to
induction chemotherapy or after autologous stem cell transplant, also
improves outcomes over observation alone. For relapsed disease, the
BTK inhibitor ibrutinib has single-agent activity with a response rate
of almost 70% but a response duration of only 18 months. Drugs like
lenalidomide, bortezomib, and temsirolimus can similarly induce tran-
sient partial responses. Appropriate patients who respond to salvage
therapy should be considered for allogeneic stem cell transplant, which
can lead to long-term disease-free survival in 30–50% of patients.
■■MATURE (PERIPHERAL) T-CELL DISORDERS
Mature T-cell disorders include cutaneous lymphomas, like mycosis
fungoides, and the PTCLs, some of which are distinguished based on
Harrisons_20e_Part4_p0435-p0858.indd 778
specific clinical presentations or contexts or by molecular or biologic
features, but many of which fall into the category of PTCL not other-
wise specified (NOS). T-cell NHLs are significantly more rare than the
B-cell NHLs, and as such, our understanding of their biology is less
advanced, and our therapies are less well developed. While some T-cell
lymphomas, like mycosis fungoides, can behave indolently and some,
like ALK-positive ALCL, can be cured with chemotherapy, the majority
are associated with a poor prognosis. The advent of genomic technol-
ogies is enhancing our ability to understand the genetic and biologic
basis of these neoplasms.
Mycosis Fungoides  Mycosis fungoides is also known as cutane-
ous T-cell lymphoma. This lymphoma is more often seen by dermatol-
ogists than internists. The median age of onset is in the mid-fifties, and
the disease is more common in males and in blacks.
Mycosis fungoides is an indolent lymphoma with patients often
having several years of eczematous or dermatitic skin lesions before
the diagnosis is finally established. The skin lesions progress from
patch stage to plaque stage to cutaneous tumors. Early in the disease,
biopsies are often difficult to interpret, and the diagnosis may only
become apparent by observing the patient over time. Adenopathy may
reflect involvement with mycosis fungoides or be read as dermatopathic
change. In advanced stages, the lymphoma can spread to lymph nodes
and visceral organs. Patients with this lymphoma may develop general-
ized erythroderma and circulating tumor cells, called Sézary’s syndrome.
Rare patients with localized early-stage mycosis fungoides can be
cured with radiotherapy, often total-skin electron beam irradiation.
More advanced disease has been treated with topical glucocorticoids,
topical nitrogen mustard, phototherapy, psoralen with ultraviolet A
(PUVA), extracorporeal photopheresis, retinoids (bexarotene), electron
beam radiation, interferon, antibodies, fusion toxins, histone deacet-
ylase inhibitors, and systemic cytotoxic therapy. Unfortunately, these
treatments are palliative.
Peripheral T-Cell Lymphoma, Not Otherwise Specified 
PTCLs include a number of entities, which constitute 15% of all NHLs
in adults. PTCL, NOS, comprising 6% of all NHLs, is the term used
for cases that are not other entities defined in the WHO classification.
Named varieties include ALCL, angioimmunoblastic T-cell lymphoma
(AITL), hepatosplenic T-cell lymphoma, enteropathy-associated T-cell
lymphoma, and subcutaneous panniculitis T-cell lymphoma. PTCL
NOS is a disease of older individuals, with a median age at presentation
of 65, and the majority of patients will have advanced-stage disease at
diagnosis, with involvement of the bone marrow, liver, spleen, and
skin being common. Associated “B” symptoms and pruritis are also
common. These lymphomas can be associated with a reactive eosino-
philia as well as hemophagocytic syndrome. The IPI has been applied
to PTCL NOS and provides some assessment of outcomes, but even the
low-risk group has a median OS of just >2 years.
This diagnostic category is a collection of heterogeneous lymphomas
that vary widely and lack typical findings of other specific PTCL sub-
groups. Because of this heterogeneity, histology, immunophenotype,
and genetics are variable. Often lymph nodes are effaced by atypical
lymphoid cells of various sizes, sometimes associated with vascular
proliferation or an infiltrate of eosinophils and/or macrophages. As
most of these lymphomas behave aggressively, note is often made of
mitotic and apoptotic figures as well as geographic necrosis. The cells
often are positive for CD3, and the majority of PTCL NOS is positive for
CD4 rather than CD8, but some are negative for both markers. There
can be loss of more mature T-cell markers like CD5 and CD7, and this
is associated with a more aggressive course. There are some recurrent
translocations, including t(7;14), t(11;14), inv(14), and t(14;14), all of
which involve the TCR genes.
The most common primary therapy for PTCL NOS involves a
CHOP-like chemotherapy backbone—either CHOP alone or CHOP in
combination with etoposide, or CHOEP. The latter may provide the
most benefit to younger patients and patients with more favorable
disease risk factors. Autologous stem cell transplant has been inves-
tigated for patients in their first remission and does seem to improve
PFS in certain contexts. Drugs like gemcitabine, bendamustine, and
6/1/18 5:44 PM
 pralatrexate have activity in relapsed disease, as do the histone deacet-
ylase inhibitors romidepsin and belinostat. All of these agents are
associated with transient responses in a minority of patients. Patients
should be considered for clinical trials. For patients who do achieve
remission, reduced intensity allogeneic stem cell transplantation can
yield long-term non-relapse survival on the order of 40–50%.
Angioimmunoblastic T-Cell Lymphoma  AITL constitutes
about 20% of T-cell NHL and about 4% of all NHL diagnosed. Patients
present with a variety of signs and symptoms, most often including
lymphadenopathy, hepatosplenomegaly, B symptoms, rash, polyarthri-
tis, and hemolytic anemia. Over 80% of patients have advanced stage
disease at diagnosis, and bone marrow involvement is common. Poly-
clonal hypergammaglobulinemia is common, as are elevated LDH,
eosinophilia, a positive Coombs test, and opportunistic infections.
On biopsy, lymph nodes are effaced by a polymorphous infiltrate
of lymphoctyes, ranging in size and shape, and of immunoblasts. The
neoplastic lymphocytes are positive for CD3 as well as CXCL13, PD-1,
CD10, and BCL6, most closely resembling CD4-positive follicular
helper T cells. There is an expanded follicular dendritic cell network
surrounding tumor cells. Scattered immunoblasts are often EBV pos-
itive and may give rise to secondary EBV-positive B-cell lymphomas
at a later time. Genetic analysis of this disease has revealed recurrent
Other PTCL Subtypes  Enteropathy-associated T-cell lymphoma, 779
hepatosplenic T-cell lymphoma, and subcutaneous panniculitis-like
T-cell lymphoma are other less common PTCL subtypes. Enteropathy-
type intestinal T-cell lymphoma is a rare disorder. Type I occurs in
patients with a history of gluten-sensitive enteropathy and is associated
with HLADQA1*0501, DQB1*0201; a gluten-free diet can prevent the
development of this lymphoma. Type II is not associated with celiac
disease and may be a separate disease entity. Patients are frequently
cachectic and sometimes present with intestinal perforation. The prog-
nosis is poor with a median survival of 10 months. Therapy is often
with combination chemotherapy, including high-dose methotrexate, and
autologous stem cell transplant in first remission. Hepatosplenic γδ T-cell
lymphoma is a systemic illness that presents with sinusoidal infiltration of
the liver, spleen, and bone marrow by malignant T cells. Tumor masses
generally do not occur. The disease is associated with systemic symp-
toms and is often difficult to diagnose. Recurrent genetic events include
isochromosome 7q and trisomy 8. Treatment outcome is poor, but regi-
mens that include ifosphamide, like ifosphamide, carboplatin, etoposide
(ICE) or ifosphamide, etoposide, cytarabine (IVAC), are associated with
better outcomes in small series of patients. Responding patients should
be considered for allogeneic stem cell transplantation. Subcutaneous
panniculitis-like T-cell lymphoma is a rare disorder that is often confused

CHAPTER 104 Non-Hodgkin’s Lymphoma

with panniculitis. Patients present with multiple subcutaneous nodules,
mutations in TET2 (76%), DNMT3 (33%), and IDH2 (20%). which progress and can ulcerate. There is a more indolent form that
There is a subset of AITL that can remit with immunosuppression tends to express a/b TCRs and can be managed with immune suppres-
with agents like glucocorticoids or methotrexate. Most patients, how- sion, whereas lymphomas that express g/d TCRs are more aggressive and
ever, will need combination chemotherapy with regimens like those are associated with a worse prognosis and coincident hemophagocytic
used in PTCL NOS. Median response duration is short, median OS is syndrome. This is a disease of young men in their fifth and sixth decades
only 15–36 months. Treatment of relapsed disease is similar to that of of life. Patients with aggressive disease are managed with multiagent
relapsed PTCL NOS. chemotherapy, and responding patients should be considered for alloge-
Anaplastic Large Cell Lymphoma  ALCL is the next most neic stem cell transplantation.
common T-cell lymphoma after AITL but is more common in children,
Adult T-Cell Leukemia/Lymphoma  Adult T-cell leukemia/
accounting for up to 10% of pediatric lymphomas. Approximately
lymphoma (ATLL) is a disease that is most prevalent in Japan and the
40–60% of cases with harbor t(2;5) which fuses a portion of the nucle-
Caribbean basin. It is a neoplasm that is driven by HTLV-1, often con-
olar protein nucleophosmin-1 (NPMI) gene to a part of the anaplastic
tracted through the breast milk of infected mothers. The average age at
lymphoma kinase (ALK) gene, the product of which has constitutive
diagnosis is 60, so there is a long latency between viral infection and
tyrosine kinase activity. These patients have a much more favorable
viral transformation, and only 4% of infected patients will develop the
prognosis compared to ALK-negative ALCL, akin to that of DLBCL.
disease. This suggests that HTLV-1 may not be sufficient to cause the
There is an additional, more indolent and favorable subtype that
malignant phenotype. There are four disease variants: acute (60% of
occurs in the breast tissue of patients with breast implants, and there is
patients), lymphomatous (20% of patients), chronic (15% of patients),
a cutaneous variant. In general, this is a disease that is more common
and smoldering (5% of patients). Prognosis varies across these groups
in men. ALK-positive disease is a disease of younger patients with a
with with median survivals of 6 months, 10 months, 24 months, and
median age at diagnosis of 34 years, whereas the median age at diagno-
not yet reached, respectively. Presentation depends on the subtype,
sis of ALK negative patients is 58. With the exception of the cutaneous
but most commonly patients present with circulating disease and bone
variant and the variant associated with breast implants, most patients
marrow involvement, hypercalcemia, lytic bone lesions, lymphadenop-
present with rapidly growing lymphadenopathy with or without extra-
athy, heptosplenomegaly, skin lesions, and opportunistic infections.
nodal involvement; B symptoms are common.
The pathognomonic finding is the malignant “flower cell” that is
Most cases of ALCL involve large atypical lymphocytes with a
positive for CD4 and CD25, as well as CD2, CD3, and CD5 but lack-
horseshoe-shaped nuclei with prominent nucleoli (“hallmark” cells).
ing CD7 (Fig. 104-7). Combination chemotherapy is generally used,
Tumor cells tend to be localized within the lymph node sinuses, and
almost all are positive for CD30 but negative for CD15. A majority will
also express CD3, CD25, CD43, and CD4. ALK rearranged ALCL can be
diagnosed by FISH cytogenetics for t(2;5) or by immunohistochemical
staining for ALK.
ALCL is generally treated with CHOP, although like PTCL NOS,
CHOEP may benefit younger patients, particularly with ALK+ disease.
Overall, ALCL has a better prognosis than PTCL, and this is particu-
larly true for ALK-positive disease, which has an 8-year OS of 82 versus
49% for ALK-negative disease. Relapsed ALK-positive ALCL is treated
similarly to relapsed DLBCL, with salvage combination chemotherapy
to identify chemotherapy sensitivity followed by autologous stem cell
transplant. For patients with chemoinsensitive diseaese or for ALK-
negative disease, the conjugated anti-CD30 antibody to monomethyl
aurostatin E (MMAE) brentuximab is highly active with a response
rate of 86% and a complete response rate of 57%. It is currently being
investigated in combination with cyclophosphamide, adriamycin, and
prednisone for the primary treatment of disease. The ALK inhibitors,
including crizotinib, are active in refractory ALK-positive ALCL with FIGURE 104-7  Adult T-cell leukemia/lymphoma. Peripheral blood smear showing
excellent outcomes. leukemia cells with typical “flower-shaped” nucleus.

Harrisons_20e_Part4_p0435-p0858.indd 779 6/1/18 5:44 PM

 780 but for patients fortunate enough to respond, response durations
are very short. Other active agents in this disease include the anti-
retroviral agent zidovudine, interferon α, and arsenic. In any patients
who do respond to therapy, allogeneic stem cell transplant should be
considered.
Extranodal NK/T-Cell Lymphoma, Nasal Type  Extranodal
NK/T-cell lymphoma, nasal type, is a lymphoma that is associated
with EBV infection in nearly all cases and more common in Asia
and native populations in Peru. It usually presents with a mass and
obstructive symptoms in the upper aerodigestive tract with occasional
extranodal sites, but over two-thirds of patients will have localized
disease. It is more common in men, and the median age at diagnosis is
60. This disease has its own prognostic score, which takes into account
the presence or absence of B symptoms, disease stage, whether LDH
is elevated, and whether there is lymph node involvement. EBV viral
load at diagnosis and end of therapy is also predictive.
Treatment for early stage disease is usually with combined modal-
ity therapy of chemotherapy (commonly using etoposide, ifosfamide,
cisplating, and dexamethasone) and intensity-modulated radiation
therapy (50–55 Gy), and patients with localized disease involving the
nasal passages do quite well, with 3-year OS of ~85%. Patients with
more advanced stage disease do poorly with disseminated extranodal
relapse occurring frequently, and median OS is only 4.3 months. The
PART 4
most commonly used regimen for the regimens is the SMILE regi-
men (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and
etoposide).
■■FURTHER READING
Oncology and Hematology
Al-Zahrani M, Savage KJ: Peripheral T-cell lymphoma, not otherwise
specified: A review of current disease understanding and therapeutic
approaches. Hematol Oncol Clin North Am 31:189, 2017.
Bachy E, Salles G: Treatment approach to newly diagnosed diffuse
large B-cell lymphoma. Semin Hematol 52:107, 2015.
Broccoli A, Zinzani PL: Angioimmunoblastic T-cell lymphoma.
Hematol Oncol Clin North Am 31:223, 2017.
Cheah CY et al: Mantle cell lymphoma. J Clin Oncol 34:1256, 2016.
Du MQ: MALT lymphoma: Genetic abnormalities, immunological
stimulation and molecular mechanism. Best Pract Res Clin Haematol
30:13, 2017.
Dunleavy K et al: Update on Burkitt lymphoma. Hematol Oncol Clin
North Am 30:1333, 2016.
Jacobson CA, Freedman AS: Is there a best initial treatment for a new
patients with low grade follicular lymphoma? Curr Hematol Malig
Rep 11:218, 2016.
Sesques P, Johnson NA: Approach to the diagnosis and treatment of
high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6
rearrangements. Blood 129:280, 2017.
Zucca E, Bertoni F: The spectrum of MALT lymphoma at different
sites: Biological and therapeutic relevance. Blood 127:2082, 2016.
105 Hodgkin’s Lymphoma
Caron A. Jacobson, Dan L. Longo
Hodgkin’s lymphoma (HL) is a malignancy of mature B lymphocytes.
It represents ~10% of all lymphomas diagnosed each year. The majority
of HL diagnoses are classical HL (cHL), but there is a second subtype
of HL, nodular lymphocyte predominant HL (NLPHL). While this
diagnosis does resemble cHL morphologically in certain respects, there
is some evidence that it is more related to the indolent B-cell NHLs bio-
logically than it is to cHL. The majority of this chapter will be specific
to cHL, with a discussion of NLPHL at the end.
Harrisons_20e_Part4_p0435-p0858.indd 780
Classical HL is one of the success stories of modern oncology. Until
the advent of extended-field radiotherapy in the mid-twentieth cen-
tury, it was a highly fatal disease of young people. Radiation therapy
cured some patients with early stage disease, and the introduction of
multi-agent chemotherapy in the 1970s resulted in further improved
cure rates, both for patients with early and advanced stage disease.
Cure rates now are >85%. The new challenge in the treatment of HL is
late therapy-related toxicity, including a high rate of secondary malig-
nancies and cardiovascular disease. Current clinical trials are aimed at
minimizing this risk while preserving efficacy.
■■EPIDEMIOLOGY AND ETIOLOGY
HL is of B-cell origin. The incidence of HL appears fairly stable, with
8260 new cases diagnosed in 2017 in the United States. HL is more
common in whites than in blacks and more common in males than in
females. A bimodal distribution of age at diagnosis has been observed,
with one peak incidence occurring in patients in their twenties and
the other in those in their eighties. Some of the late age peak may be
attributed to confusion among entities with similar appearance such
as anaplastic large cell lymphoma and T-cell/histiocyte–rich B-cell
lymphoma. There are four distinct subtypes of classical Hodgkin’s
lymphoma (cHL) that are differentiated based on their histopathologic
features (Table 105-1): nodular sclerosis, mixed cellularity, lympho-
cyte-rich, and lymphocyte-depleted. Patients in the younger age groups
diagnosed in the United States largely have the nodular sclerosing sub-
type of HL. Elderly patients, patients infected with HIV, and patients
in Third World countries more commonly have mixed-cellularity HL
or lymphocyte-depleted HL. Together, nodular sclerosis and mixed
cellularity types account for nearly 95% of cases. Infection by HIV is
a risk factor for developing HL. In addition, an association between
infection by Epstein-Barr virus (EBV) and HL has been suggested. A
monoclonal or oligoclonal proliferation of EBV-infected cells in 20–40%
of the patients with HL has led to proposals for this virus having an eti-
ologic role in HL. However, the matter is not settled definitively. Viral
oncogenesis appears to play a greater role in HIV-related cHL: EBV
can be detected in nearly all cases of HIV-associated cHL, compared
to only one-third of cases of non-HIV-associated cHL. Reed-Sternberg
(HRS) cells are the malignant cells in HL. HRS cells in HIV-associated
cHL express the EBV-transforming protein latent membrane protein 1
(LMP-1), and the EBV genomes from multiple disease sites in the same
HIV-associated cHL patient are episomal and clonal, suggesting that
EBV is directly involved in early lymphomagenesis.
Histologically, the HRS cell is diagnostic of cHL (Fig. 105-1). These
cells are large cells with abundant cytoplasm with bilobed and/or mul-
tiple nuclei. By immunohistochemistry they are often PAX-5 positive
but have low to no expression of other B-cell antigens like CD19 and
CD20. They express CD15 and CD30 in 85 and 100% of cases, respec-
tively. These cells, though, comprise <1% of the tumor cellularity, with
the majority of the tumor made up of a surrounding inflammatory
infiltrate of polyclonal lymphocytes, eosinophils, neutrophils, macro-
phages, plasma cells, fibroblasts, and collagen. The HRS cell interacts
with its microenvironment via cell-cell contact and elaboration of
growth factors and cytokines, which results in a surrounding cellular
milieu that protects it from host immune attack. The surrounding
environmental cells likewise support the HRS cells via cell-cell sig-
naling and cytokine production which provides signals that promote
proliferation and survival of the HRS cell itself. Interestingly, 97% of
HRS cells in cHL harbor genetic aberrations in the PD-L1 locus on chro-
mosome 9p24.1, resulting in overexpression of PD-L1, the ligand for
TABLE 105-1  WHO Classification of Hodgkin’s Lymphoma
Nodular lymphocyte predominant Hodgkin’s lymphoma
Classical Hodgkin’s lymphoma
  Nodular sclerosis
 Lymphocyte-rich
  Mixed cellularity
 Lymphocyte-depleted
6/1/18 5:44 PM

FIGURE 105-1.  Hodgkin’s disease: A classic Reed-Sternberg (RS) cell is present
near the center of the field. RS cells are large cells with a bilobed nucleus and
prominent nucleoli surrounded by a pleiomorphic cellular infiltrate.
the inhibitory PD-1 receptor on immune cells. This is one mechanism
whereby the HRS cell may be able to avoid immune destruction in its
inflammatory microenvironment and may contribute to the general-
ized immune suppression in HL patients.
APPROACH TO THE PATIENT
Classic Hodgkin’s Lymphoma
Most patients with cHL present with palpable lymphadenopathy
that is nontender; in most patients, these lymph nodes are in
the neck, supraclavicular area, and axilla. More than half of the
patients will have mediastinal adenopathy at diagnosis, and this
is sometimes the initial manifestation. Subdiaphragmatic presen-
tation of cHL is unusual and more common in older males. One-
third of patients present with fevers, night sweats, and/or weight
loss, or “B” symptoms. Occasionally, HL can present as a fever of
unknown origin. This is more common in older patients who are
found to have mixed-cellularity HL in an abdominal site. Rarely,
the fevers persist for days to weeks, followed by afebrile intervals
and then recurrence of the fever. This pattern is known as Pel-
Ebstein fever. HL can occasionally present with unusual manifes-
tations. These include severe and unexplained itching, cutaneous
disorders such as erythema nodosum and ichthyosiform atrophy,
paraneoplastic cerebellar degeneration and other distant effects
on the CNS, nephrotic syndrome, immune hemolytic anemia and
thrombocytopenia, hypercalcemia, and pain in lymph nodes on
alcohol ingestion.
Evaluation of patients with HL will typically begin with a careful
history and physical examination. Patients should be asked about
the presence or absence of “B” symptoms. Comorbid diagnoses
that may impact therapy should be reviewed, including a history
of pulmonary disease and congestive heart failure given the use
of chemotherapy drugs that can cause both lung and heart tox-
icity. A physical examination should pay attention to the periph-
erally accessible sites of lymph nodes and to the liver and spleen
size. Laboratory evaluation should include a complete blood count
with differential; erythrocyte sedimentation rate; chemistry studies
reflecting major organ function including serum albumin; and HIV
and hepatitis virus testing. A PET/CT scan is used for staging, and
is more accurate than a bone marrow biopsy for evaluation of bone
marrow involvement as the bone marrow involvement in cHL tends
to be patchy and therefore potentially missed on a unilateral bone
marrow biopsy. The initial evaluation of a patient with HL or NHL is
similar. In both situations, the determination of an accurate anatomic
stage is an important part of the evaluation. Staging is done using
the Ann Arbor staging system (Table 105-2).
Harrisons_20e_Part4_p0435-p0858.indd 781
TABLE 105-2  The Ann Arbor Staging System for Hodgkin’s 781
Lymphoma
STAGE DEFINITION
I Involvement of a single lymph node region or lymphoid
structure (e.g., spleen, thymus, Waldeyer’s ring)
II Involvement of two or more lymph node regions on
the same side of the diaphragm (the mediastinum is
a single site; hilar lymph nodes should be considered
“lateralized” and, when involved on both sides,
constitute stage II disease)
III Involvement of lymph node regions or lymphoid
structures on both sides of the diaphragm
 III1  Subdiaphragmatic involvement limited to spleen,
splenic hilar nodes, celiac nodes, or portal nodes
 III2  Subdiaphragmatic involvement includes paraaortic,
iliac, or mesenteric nodes plus structures in III1
IV Involvement of extranodal site(s) beyond that
designated as “E”
    More than one extranodal deposit at any location
    Any involvement of liver or bone marrow
A No symptoms
B Unexplained weight loss of >10% of the body weight
CHAPTER 105 Hodgkin’s Lymphoma
during the 6 months before staging investigation
  Unexplained, persistent, or recurrent fever with
temperatures >38°C during the previous month
  Recurrent drenching night sweats during the previous
month
E Localized, solitary involvement of extralymphatic tissue,
excluding liver and bone marrow
The diagnosis of HL is established by review of an adequate
biopsy specimen by an expert hematopathologist. HL is a tumor
characterized by rare neoplastic cells of B-cell origin (immunoglob-
ulin genes are rearranged but not expressed) in a tumor mass that
is largely polyclonal inflammatory infiltrate, probably a reaction to
cytokines produced by the tumor cells. The differential diagnosis
of a lymph node biopsy suspicious for HL includes inflammatory
processes, mononucleosis, NHL, phenytoin-induced adenopathy,
and nonlymphomatous malignancies.
Staging for cHL is anatomically based given the propensity of
the disease to march from one lymph node group to the next group,
often contiguous to the first. Staging is important for selecting ther-
apy of appropriate intensity, but the outcome of optimal therapy for
all the stages is excellent. Patients are stratified based on whether
they have early stage, stage I or II, or advanced stage, stage III or
IV, disease. Patients with early stage disease have a better prognosis
overall but are further classified as favorable or unfavorable based
on a variety of factors. These factors vary from study to study but
include bulky disease, number of lymph node areas involved, an
elevated ESR (>30 if B symptoms are present; >50 if B symptoms
are absent), and age. Prognosis in advanced stage disease is best
predicted by the International Prognostic Score (IPS), which ascribes
a point for male sex, older age (>45 years), stage IV disease, serum
albumin <4 g/dL, hemoglobin <10.5 g/dL, white blood cell count
≥15,000/μL, and a lymphocyte count <600/μL and/or <8% of white
blood cell count. Five-year progression-free survival ranges from
88% for patients with no risk factors, to 62% for patients with four
or more factors, but very few patients have multiple risk factors.
TREATMENT
Classic Hodgkin’s Lymphoma
The overwhelming majority of patients with HL will be cured with
either chemotherapy alone, or a combination of chemotherapy and
radiation therapy. It has long been appreciated that patients with
advanced stage disease do not benefit from the addition of radiation
6/1/18 5:44 PM
 782 therapy to chemotherapy and are thus treated with chemotherapy
alone. For early stage disease, however, treatment with combined
modality therapy has been associated with a small decrease in risk of
relapse but with an increased risk of late toxicity including secondary
malignancies, thyroid disease, and premature cardiovascular disease
and stroke resulting in minimal or no improvement in long-term sur-
vival. Much of this risk can be attributed to radiation therapy. Thus,
investigation into the treatment of early stage HL at present is aimed
at trying to maximize treatment outcome without using radiother-
apy. This is an area of controversy in the treatment of HL.
EARLY STAGE DISEASE
The most common chemotherapy regimen used to treat HL in the
United States is ABVD (adriamycin, bleomycin, vinblastine, and
dacarbazine). This regimen is given every other week, with each
cycle including two treatments. In patients with low-risk, or favor-
able disease, the use of 4–6 cycles of ABVD alone, without radiation
therapy, results in progression-free and overall survivals of 88–92%
and 97–100% at 5–7 years. This may be associated with a slightly
increased risk of relapse when compared with abbreviated che-
motherapy (ABVD x4 cycles) followed by involved field radiation
therapy (30 Gy), but with no difference in overall survival owing
to the excellent salvage strategies used for relapsed HL and to the
late toxicities seen following radiation therapy to the chest. German
PART 4
studies have examined a very abbreviated chemotherapy regimen
(ABVD x2 cycles) and low-dose radiation (20 Gy) for particularly
good risk disease with two or fewer lymph node areas involved
and found that this was equally effective to standard combined
Oncology and Hematology
modality therapy of ABVD x4 cycles and 30 Gy of radiation, though
long-term follow-up is not yet available to assess the impact of the
lower radiotherapy dose on late toxicities. Finally, the use of an early
interim PET/CT scan can aid decisions on the duration and extent
of therapy. In one study, a negative PET/CT scan after 3 cycles of
ABVD predicted for excellent outcomes with no additional therapy;
in another, a negative PET/CT scan after 2 cycles of ABVD predicted
for good outcomes with 2 additional cycles of ABVD alone, without
radiation therapy.
For unfavorable risk disease, the omission of radiation ther-
apy following chemotherapy is associated with a more significant
increased risk of relapse compared to favorable risk disease, but
again with no change in overall survival. For these patients, treat-
ment options would include ABVD x4 cycles followed by involved
field radiation therapy or ABVD alone for 6 cycles. Treatment deci-
sions are often based on the extent of the radiation field and the
unfavorable risk factor, with patients with non-bulky disease being
candidates for chemotherapy alone if radiation would be contraindi-
cated for another reason. Combined modality therapy has typically
been used for patients with bulky disease, although patients with
bulky disease who have a negative PET/CT scan after chemother-
apy may not benefit from additional radiation therapy.
Alternative chemotherapy regimens to ABVD have been devel-
oped and include the Stanford V regimen and escalated BEACOPP.
Neither of these regimens has resulted in improved outcomes in
patients with early stage disease.
ADVANCED STAGE DISEASE
Patients with advanced stage disease do not benefit from the addi-
tion of radiation therapy after a complete response to chemotherapy
alone and should be treated with chemotherapy alone. The most
common regimen used in the United States is ABVD x6 cycles.
Again, Stanford V and escalated BEACOPP have been evaluated in
advanced stage disease and are not associated with an improvement
in overall survival but are associated with increased toxicity. The
small fraction of patients who do not achieve complete remission
with chemotherapy alone (partial responders with persistent PET
scan positivity account for <10% of patients) may benefit from the
addition of involved field radiotherapy.
Newer drugs have been developed for the treatment of relapsed
HL (see “Relapsed Disease,” below). These include the antibody
Harrisons_20e_Part4_p0435-p0858.indd 782
drug conjugate brentuximab, which is an antibody against CD30
conjugated to the microtubule inhibitor MMAE. This drug has been
combined with adriamycin, bleomycin, and dacarbazine in early
phase studies for advanced stage HL with favorable efficacy com-
pared to historical controls. We await the data from the randomized
trial of AVD+brentuximab compared to ABVD. Drugs that target the
PD-1/PD-L1 axis have been developed in an attempt to boost the
host immune recognition of tumors. This was particularly attractive
in HL given the overexpression of PD-L1 on the HRS cell surface.
In the setting of relapsed disease, these drugs, which include pem-
brolizumab and nivolumab, have very high response rates and are
associated with durable responses. These are now being tested in
conjunction with chemotherapy both as salvage therapy for relapsed
disease and in previously untreated patients.
RELAPSED DISEASE
Patients who relapse after primary therapy of Hodgkin’s lym-
phoma can frequently still be cured. Patients who relapse after
an effective chemotherapy regimen are usually not curable with
subsequent chemotherapy administered at standard doses. Alter-
native salvage chemotherapy administered at standard doses,
then, is given in order to document sensitivity to chemotherapy
and to achieve maximum reduction of tumor mass. For patients
who respond completely or nearly so, autologous bone marrow
transplantation can cure over half of patients. Standard salvage
chemotherapy regimens include ICE (ifosfamide, carboplatin,
etoposide) or GND (gemcitabine, navelbine, doxil). For patients
with early stage disease who do not respond sufficiently to salvage
chemotherapy, radiation therapy can be very effective to achieve a
remission; whether to consolidate such a remission with an autol-
ogous stem cell transplant is debated. For patients with advanced
stage disease in whom salvage chemotherapy fails, the antibody
drug conjugate brentuximab vedotin, a CD30-directed antibody
linked to the microtubule toxin MMAE, is active and can be tried
as a bridge to allogeneic transplant. This immunotoxin is also
being combined with chemotherapy for use in both the first-line
salvage setting and for the upfront treatment of both early- and
advanced-stage disease. The anti-PD-1 immune checkpoint inhibi-
tors, nivolumab and pembrolizumab, have efficacy in relapsed HL,
and many responses are durable.
SURVIVORSHIP
Because of the very high cure rate in patients with HL, long-term
complications have become a major focus for clinical research.
In fact, in some series of patients with early-stage disease, more
patients died from late complications of therapy than from HL itself.
This is particularly true in patients with localized disease. The most
serious late side effects include second malignancies and cardiac
injury. Patients are at risk for the development of acute leukemia in
the first 10 years after treatment with combination chemotherapy
regimens that contain alkylating agents plus radiation therapy. The
risk for development of acute leukemia is greater after MOPP-like
and BEACOPP-like regimens than with ABVD. The risk of devel-
opment of acute leukemia after treatment for HL is also related
to the number of exposures to potentially leukemogenic agents
(i.e., multiple treatments after relapse) and the age of the patient
being treated, with those aged >60 years at particularly high risk.
The development of carcinomas as a complication of treatment for
HL is a major problem. These tumors usually occur ≥10 years after
treatment and are associated with use of radiotherapy. For this
reason, young women treated with thoracic radiotherapy for HL
should institute screening mammograms 5–10 years after treatment,
and all patients who receive thoracic radiotherapy for HL should
be discouraged from smoking. Mediastinal radiation also acceler-
ates coronary artery disease, and patients should be encouraged to
minimize risk factors for coronary artery disease such as smoking
and elevated cholesterol levels. Cervical radiation therapy increases
the risk of carotid atherosclerosis and stroke and thyroid disease,
including cancer.
6/1/18 5:44 PM
 A number of other late side effects from the treatment of HL are Radford J et al: Results of a trial of PET-directed therapy for 783
well known. Patients who receive thoracic radiotherapy are at very early-stage Hodgkin’s lymphoma. N Engl J Med 372:1598, 2015.
high risk for the eventual development of hypothyroidism and Rashidi A et al: Allogeneic hematopoietic stem cell transplantation
should be observed for this complication; intermittent measurement in Hodgkin lymphoma: A systemic review and meta-analysis. Bone
of thyrotropin should be made to identify the condition before it Marrow Transplant 51:521, 2016.
becomes symptomatic. Lhermitte’s syndrome occurs in ~15% of
patients who receive thoracic radiotherapy. This syndrome is mani-
fested by an “electric shock” sensation into the lower extremities on
flexion of the neck. Because of the young age at which HL is often
diagnosed, infertility is a concern for patients undergoing treat-
ment for HL. Chemotherapy regimens containing alkylating agents

106 Less Common Hematologic

induce permanent infertility in nearly all men. The risk of perma-
nent infertility in women treated with alkylating agent-containing
chemotherapy is age-related, with younger women more likely to Malignancies
recover fertility. Infertility is very rare after treatment with ABVD.
NODULAR LYMPHOCYTE-PREDOMINANT Ayalew Tefferi, Dan L. Longo
HODGKIN LYMPHOMA
NLPHL is now recognized as an entity distinct from cHL. Previous The most common lymphoid malignancies are discussed in Chaps.
classification systems recognized that biopsies from a small subset 102, 103, 104, 105 and 107, myeloid leukemias in Chaps. 100 and 101,
of patients diagnosed as having HL contained a predominance of myelodysplastic syndromes (MDS) in Chap. 98, and myeloproliferative
small lymphocytes and rare Reed-Sternberg-like cells; tumors have a syndromes in Chap. 99. This chapter will focus on the more unusual
nodular growth pattern and a clinical course that varied from that of

CHAPTER 106 Less Common Hematologic Malignancies

forms of hematologic malignancy. The diseases discussed here are
patients with cHL. This is an unusual clinical entity and represents listed in Table 106-1. Each of these entities accounts for <1% of hema-
<5% of cases of HL and defines NLPHL. tologic neoplasms.
NLPHL has a number of characteristics that suggest its relation-
ship to NHL, rather than cHL, however. The HRS-like cell, or L&H
(lymphocyte and histiocyte) or “popcorn” cell, is a clonal prolifer-
TABLE 106-1  Unusual Lymphoid and Myeloid Malignancies
ation of B cells that are positive for B cell markers CD45, CD79a,
CD20, CD19, and BCL2. They do not express two markers normally Lymphoid
found on HRS cells, CD30 and CD15. This lymphoma tends to have Mature B-cell neoplasms
a chronic, relapsing course and sometimes transforms to diffuse   B-cell prolymphocytic leukemia
large B-cell lymphoma, including a specific subtype of diffuse large   Splenic marginal zone lymphoma
B-cell lymphoma known as T cell/histiocyte-rich B-cell lymphoma,   Hairy cell leukemia
which shares an immunophenotype with the L&H cell. This natural   Nodal marginal zone B-cell lymphoma
history most closely resembles that of the indolent B cell NHLs out-   Mediastinal large B-cell lymphoma
lined in Chaps. 104 and 106..
  Intravascular large B-cell lymphoma
Patients with NLPHL are more commonly male (75%). Like cHL,
  Primary effusion lymphoma
the age distribution of patients with this disease has two peaks,
but unlike cHL these peaks include children and adults ages 30–   Lymphomatoid granulomatosis
40 years, respectively. The majority of patients diagnosed have stage Mature T-cell and natural killer (NK) cell neoplasms
I or II disease (75%), with a minority having advanced stage disease   T-cell prolymphocytic leukemia
at diagnosis. B symptoms are uncommon.   T-cell large granular lymphocytic leukemia
Patients with early stage disease at diagnosis should be treated   Aggressive NK cell leukemia
with definitive radiotherapy. This is associated with a 15-year   Extranodal NK/T-cell lymphoma, nasal type
non-relapse survival of 82%. The treatment of patients with   Enteropathy-type T-cell lymphoma
advanced stage NLPHL is controversial. Some clinicians favor no   Hepatosplenic T-cell lymphoma
treatment of asymptomatic disease and merely close follow-up, akin   Subcutaneous panniculitis-like T-cell lymphoma
to the indolent B cell NHLs. For patients who need therapy due to
  Blastic NK cell lymphoma
symptoms or signs of organ function impairment, both cHL regi-
  Primary cutaneous CD30+ T-cell lymphoma
mens and B-cell NHL regimens have been used, including ABVD
and R-CHOP. A single institution experience with R-CHOP resulted   Angioimmunoblastic T-cell lymphoma
in a 100% response rate in a small group of patients without a single Myeloid
relapse with 42 months follow-up. Although this is short follow-up Chronic neutrophilic leukemia
for an indolent disease, some believe R-CHOP may be curative in Chronic eosinophilic leukemia/hypereosinophilic syndrome
this disease and advocate treating with advanced stage disease at Histiocytic and Dendritic Cell Neoplasms
diagnosis, regardless of symptoms or organ function.
Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
■■FURTHER READING
Interdigitating dendritic cell sarcoma
Alperovich A, Younes A: Targeting CD30 using brentuximab vedotin
in the treatment of Hodgkin lymphoma. Cancer J 22:23, 2016. Follicular dendritic cell sarcoma
Ansell SM: Hodgkin lymphoma: 2016 update on diagnosis, risk- Mast Cells
stratification, and management. Am J Hematol 91:434, 2016. Mastocytosis
Armand P et al: Programmed death-1 blockade with pembrolizumab Cutaneous mastocytosis
in patinets with classical Hodgkin lymphoma after brentuximab Systemic mastocytosis
vedotin failure. J Clin Oncol 34:3733, 2016. Mast cell sarcoma
Ng AK, van Leeuwen FE: Hodgkin lymphoma: Late effects of treat- Extracutaneous mastocytoma
ment and guidelines for surveillance. Semin Hematol 53:209, 2016.

Harrisons_20e_Part4_p0435-p0858.indd 783 6/1/18 5:44 PM

 784 RARE LYMPHOID MALIGNANCIES
All the lymphoid tumors discussed here are mature B-cell or T-cell
natural killer (NK) cell neoplasms.
■■MATURE B-CELL NEOPLASMS
B-Cell Prolymphocytic Leukemia (B-PLL)  This is a malig-
nancy of medium-sized (about twice the size of a normal small lym-
phocyte), round lymphocytes with a prominent nucleolus and light
blue cytoplasm on Wright’s stain. It dominantly affects the blood, bone
marrow (BM), and spleen and usually does not cause adenopathy. The
median age of affected patients is 70 years, and men are more often
affected than women (male-to-female ratio is 1.6). This entity is distinct
from chronic lymphoid leukemia (CLL) and does not develop as a con-
sequence of that disease.
Clinical presentation is generally from symptoms of splenomegaly
or incidental detection of an elevated white blood cell (WBC) count.
The clinical course can be rapid. The cells express surface IgM (with or
without IgD) and typical B-cell markers (CD19, CD20, CD22). CD23 is
absent, and about one-third of cases express CD5. The CD5 expression
along with the presence of the t(11;14) translocation in 20% of cases
leads to confusion in distinguishing B-PLL from the leukemic form
of mantle cell lymphoma. No reliable criteria for the distinction have
emerged and gene expression studies suggest a close relationship
PART 4
center, and ongoing mutations suggest that the mutation machinery
has remained active. About 40% of patients have either deletions or
translocations involving 7q21, the site of the FLNC gene (filamin Cγ,
involved in cross-linking actin filaments in the cytoplasm). NOTCH2
mutations are seen in 25% of patients. Chromosome 8p deletions may
also be noted. The genetic lesions typically found in extranodal mar-
ginal zone lymphomas (e.g., trisomy 3 and t[11;18]) are uncommon in
SMZL.
The clinical course of disease is generally indolent with median sur-
vivals exceeding 10 years. Patients with elevated lactate dehydrogenase
(LDH) levels, anemia, and hypoalbuminemia generally have a poorer
prognosis. Long remissions can be seen after splenectomy. Rituximab is
also active. A small fraction of patients undergo histologic progression
to diffuse large B-cell lymphoma with a concomitant change to a more
aggressive natural history. Experience with combination chemotherapy
in SMZL is limited.
Hairy Cell Leukemia  Hairy cell leukemia is a tumor of small
lymphocytes with oval nuclei, abundant cytoplasm, and distinctive
membrane projections (hairy cells). Patients have splenomegaly and
diffuse BM involvement. While some circulating cells are noted, the
clinical picture is dominated by symptoms from the enlarged spleen
and pancytopenia. The mechanism of the pancytopenia is not com-
pletely clear and may be mediated by both inhibitory cytokines and

between mantle cell lymphoma and B-PLL and significant differences
with CLL. About half of patients have mutation or loss of p53, and
deletions have been noted in 11q23 and 13q14. Nucleoside analogues
like fludarabine and cladribine and combination chemotherapy (cyclo-
phosphamide, doxorubicin, vincristine, and prednisone [CHOP]) have
Oncology and Hematology
marrow replacement. The marrow has an increased level of reticulin
fibers; indeed, hairy cell leukemia is a common cause of inability to
aspirate BM or so-called “dry tap” (Table 106-3). Monocytopenia is
profound and may explain a predisposition to atypical mycobacte-

rial infection that is observed clinically. The tumor cells have strong
produced responses. CHOP plus rituximab may be more effective than expression of CD22, CD25, and CD103; soluble CD25 level in serum
CHOP alone, but the disease is sufficiently rare that large series have is an excellent tumor marker for disease activity. The cells also express
not been reported. Splenectomy can produce palliation of symptoms tartrate-resistant acid phosphatase. The immunoglobulin genes are
but appears to have little or no impact on the course of the disease. BM rearranged and mutated, indicating the influence of a germinal center.
transplantation may be curative. Imatinib may also have activity. No specific cytogenetic abnormality has been found, but most cases
contain the activating BRAF mutation V600E.
Splenic Marginal Zone Lymphoma (SMZL)  This tumor of
The median age of affected patients is mid-fifties, and the male-to-
mainly small lymphocytes originates in the marginal zone of the spleen
female ratio is 5:1. Treatment options are numerous. Splenectomy is often
white pulp, grows to efface the germinal centers and mantle, and
associated with prolonged remission. Nucleosides including cladribine
invades the red pulp. Splenic hilar nodes, BM, and peripheral blood
and deoxycoformycin are highly active but are also associated with
(PB) may be involved. The circulating tumor cells have short surface
further immunosuppression and can increase the risk of certain oppor-
villi and are called villous lymphocytes. Table 106-2 shows differences
tunistic infections. However, after brief courses of these agents, patients
in tumor cells of a number of neoplasms of small lymphocytes that aid
usually obtain very durable remissions during which immune function
in the differential diagnosis. SMZL cells express surface immunoglobu-
spontaneously recovers. Interferon α is also an effective therapy but is
lin and CD20, but are negative for CD5, CD10, CD43, and CD103. Lack
not as effective as nucleosides. Chemotherapy-refractory patients have
of CD5 distinguishes SMZL from CLL, and lack of CD103 separates
responded to vemurafenib, a BRAF inhibitor. It is not yet clear if vemu-
SMZL from hairy cell leukemia.
rafenib can induce long-term remissions without continuous treatment.
The median age of patients with SMZL is mid-fifties, and men and
women are equally represented. Patients present with incidental or Nodal Marginal Zone B-Cell Lymphoma  This rare node-
symptomatic splenomegaly or incidental detection of lymphocytosis based disease bears an uncertain relationship with extranodal marginal
in the PB with villous lymphocytes. Autoimmune anemia or throm- zone lymphomas, which are often mucosa-associated and are called
bocytopenia may be present. The immunoglobulin produced by these mucosa-associated lymphoid tissue (MALT) lymphomas, and SMZLs.
cells contains somatic mutations that reflect transit through a germinal Patients may have localized or generalized adenopathy. The neoplastic
cell is a marginal zone B cell with monocytoid features and has been
called monocytoid B-cell lymphoma in the past. Up to one-third of the
TABLE 106-2  Immunophenotype of Tumors of Small Lymphocytes patients may have extranodal involvement, and involvement of the
CD5 CD20 CD43 CD10 CD103 sIg CyclinD1 lymph nodes can be secondary to the spread of a mucosal primary
Follicular neg pos pos pos neg pos neg lesion. In authentic nodal primaries, the cytogenetic abnormalities
lymphoma
Chronic lymphoid pos pos pos neg neg pos neg
leukemia TABLE 106-3  Differential Diagnosis of “Dry Tap”—Inability to
B-cell pos pos pos neg neg pos pos
Aspirate Bone Marrow
prolymphocytic Dry taps occur in about 4% of attempts and are associated with:
leukemia   Metastatic carcinoma infiltration 17%
Mantle cell pos pos pos neg neg pos pos   Chronic myeloid leukemia 15%
lymphoma  Myelofibrosis 14%
Splenic marginal neg pos neg neg neg pos neg   Hairy cell leukemia 10%
zone lymphoma
  Acute leukemia 10%
Hairy cell neg pos ? neg pos pos neg
leukemia   Lymphomas, Hodgkin’s disease 9%
  Normal marrow Rare
Abbreviations: neg, negative; pos, positive.

Harrisons_20e_Part4_p0435-p0858.indd 784 6/1/18 5:44 PM

 associated with MALT lymphomas (trisomy 3 and t[11;18]) are very
rare. The clinical course is indolent. Patients often respond to combi-
nation chemotherapy, although remissions have not been durable. Few
patients have received CHOP plus rituximab, which is likely to be an
effective approach to management.
Mediastinal (Thymic) Large B-Cell Lymphoma  This entity
was originally considered a subset of diffuse large B-cell lymphoma;
however, additional study has identified it as a distinct entity with its
own characteristic clinical, genetic, and immunophenotypic features.
This is a disease that can be bulky in size but usually remains confined
to the mediastinum. It can be locally aggressive, including progressing
to produce a superior vena cava obstruction syndrome or pericardial
effusion. About one-third of patients develop pleural effusions, and
5–10% can disseminate widely to kidney, adrenal, liver, skin, and even
brain. The disease affects women more often than men (male-to-female
ratio is 1:2–3), and the median age is 35–40 years.
The tumor is composed of sheets of large cells with abundant
cytoplasm accompanied by variable, but often abundant, fibrosis. It is
distinguished from nodular sclerosing Hodgkin’s disease by the pau-
city of normal lymphoid cells and the absence of lacunar variants of
Reed-Sternberg cells. However, more than one-third of the genes that
are expressed to a greater extent in primary mediastinal large B-cell
lymphoma than in usual diffuse large B-cell lymphoma are also over-
expressed in Hodgkin’s disease, suggesting a possible pathogenetic
relationship between the two entities that affect the same anatomic
site. Tumor cells may overexpress MAL. The genome of tumor cells is
characterized by frequent chromosomal gains and losses. The tumor
cells in mediastinal large B-cell lymphoma express CD20, but surface
immunoglobulin and HLA class I and class II molecules may be absent
or incompletely expressed. Expression of lower levels of class II HLA
identifies a subset with poorer prognosis. The cells are CD5 and CD10
negative but may show light staining with anti-CD30. The cells are
CD45 positive, unlike cells of classical Hodgkin’s disease.
Methotrexate, leucovorin, doxorubicin, cyclophosphamide, vin-
cristine, prednisone, and bleomycin (MACOP-B) and rituximab plus
CHOP are effective treatments, achieving 5-year survival of 75–87%.
Dose-adjusted therapy with prednisone, etoposide, vincristine, cyclo-
phosphamide, and doxorubicin (EPOCH) plus rituximab has produced
5-year survival of 97%. A role for mediastinal radiation therapy has
not been definitively demonstrated, but it is frequently used, espe-
cially in patients whose mediastinal area remains positron emission
tomography–avid after 4–6 cycles of chemotherapy.
Intravascular Large B-Cell Lymphoma  This is an extremely
rare form of diffuse large B-cell lymphoma characterized by the
presence of lymphoma in the lumen of small vessels, particularly
capillaries. It is also known as malignant angioendotheliomatosis or
angiotropic large cell lymphoma. It is sufficiently rare that no con-
sistent picture has emerged to define a clinical syndrome or its epi-
demiologic and genetic features. It is thought to remain inside vessels
because of a defect in adhesion molecules and homing mechanisms,
an idea supported by scant data suggesting absence of expression of
β-1 integrin and ICAM-1. Patients commonly present with symptoms
of small-vessel occlusion, skin lesions, or neurologic symptoms. The
tumor cell clusters can promote thrombus formation. In general, the
clinical course is aggressive and the disease is poorly responsive to
therapy. Often a diagnosis is not made until very late in the course of
the disease.
Primary Effusion Lymphoma  This entity is another variant of
diffuse large B-cell lymphoma that presents with pleural effusions,
usually without apparent tumor mass lesions. It is most common
in the setting of immune deficiency disease, especially AIDS, and is
caused by human herpes virus 8 (HHV-8)/Kaposi’s sarcoma herpes
virus (KSHV). It is also known as body cavity–based lymphoma. Some
patients have been previously diagnosed with Kaposi’s sarcoma. It
can also occur in the absence of immunodeficiency in elderly men
of Mediterranean heritage, similar to Kaposi’s sarcoma but even less
common.
Harrisons_20e_Part4_p0435-p0858.indd 785
The malignant effusions contain cells positive for HHV-8/KSHV, 785
and many are also co-infected with Epstein-Barr virus. The cells
are large with large nuclei and prominent nucleoli that can be con-
fused with Reed-Sternberg cells. The cells express CD20 and CD79a
(immunoglobulin-signaling molecule), although they often do not
express immunoglobulin. Some cases aberrantly express T-cell mark-
ers such as CD3 or rearranged T-cell receptor genes. No characteristic
genetic lesions have been reported, but gains in chromosome 12 and
X material has been seen, similar to other HIV-associated lymphomas.
The clinical course is generally characterized by rapid progression and
death within 6 months. CHOP plus lenalidomide or bortezomib may
produce responses. HAART therapy for HIV should be maintained
during treatment.
Lymphomatoid Granulomatosis  This is an angiocentric,
angiodestructive lymphoproliferative disease comprised by neoplastic
Epstein-Barr virus–infected monoclonal B cells accompanied and out-
numbered by a polyclonal reactive T-cell infiltrate. The disease is graded
based on histologic features such as cell number and atypia in the B
cells. It is most often confused with extranodal NK/T-cell lymphoma,
nasal type, which can also be angiodestructive and is Epstein-Barr
virus–related. The disease usually presents in adults (males > females)
as a pulmonary infiltrate. Involvement is often entirely extranodal and
CHAPTER 106 Less Common Hematologic Malignancies
can include kidney (32%), liver (29%), skin (25%), and brain (25%). The
disease often but not always occurs in the setting of immune deficiency.
The disease can be remitting and relapsing in nature or can be
rapidly progressive. The course is usually predicted by the histologic
grade. The disease is highly responsive to combination chemotherapy
and is curable in most cases. Some investigators have claimed that low-
grade disease (grade I and II) can be treated with interferon α.
■■MATURE T-CELL AND NK CELL NEOPLASMS
T-Cell Prolymphocytic Leukemia  This is an aggressive leu-
kemia of medium-sized prolymphocytes involving the blood, mar-
row, nodes, liver, spleen, and skin. It accounts for 1–2% of all small
lymphocytic leukemias. Most patients present with elevated WBC
count (often >100,000/μL), hepatosplenomegaly, and adenopathy. Skin
involvement occurs in 20%. The diagnosis is made from PB smear,
which shows cells about 25% larger than those in small lymphocytes,
with cytoplasmic blebs and nuclei that may be indented. The cells
express T-cell markers like CD2, CD3, and CD7; two-thirds of patients
have cells that are CD4+ and CD8–, and 25% have cells that are CD4+
and CD8+. T-cell receptor β chains are clonally rearranged. In 80% of
patients, inversion of chromosome 14 occurs between q11 and q32.
Ten percent have t(14;14) translocations that bring the T-cell receptor
alpha/beta gene locus into juxtaposition with oncogenes TCL1 and
TCL1b at 14q32.1. Chromosome 8 abnormalities are also common.
Deletions in the ATM gene are also noted. Activating JAK3 mutations
have also been reported.
The course of the disease is generally rapid, with median survival
of about 12 months. Responses have been seen with the anti-CD52
antibody, alemtuzumab, nucleoside analogs, and CHOP chemotherapy.
Histone deacetylase inhibitors like vorinostat and romidepsin may also
have activity. Small numbers of patients with T-cell prolymphocytic
leukemia have also been treated with high-dose therapy and allogeneic
BM transplantation after remission has been achieved with conven-
tional-dose therapy.
T-Cell Large Granular Lymphocytic Leukemia  T-cell large
granular lymphocytic leukemia (LGL leukemia) is characterized by
increases in the number of LGLs in the PB (2000–20,000/μL) often
accompanied by severe neutropenia, with or without concomitant
anemia. Patients may have splenomegaly and frequently have evi-
dence of systemic autoimmune disease, including rheumatoid arthritis,
hypergammaglobulinemia, autoantibodies, and circulating immune
complexes. BM involvement is mainly interstitial in pattern, with fewer
than 50% lymphocytes on differential count. Usually the cells express
CD3, T-cell receptors, and CD8; NK-like variants may be CD3–. The
leukemic cells often express Fas and Fas ligand.
6/1/18 5:44 PM
 786 The course of the disease is generally indolent and dominated by
the neutropenia. Paradoxically, immunosuppressive therapy with
cyclosporine, methotrexate, or cyclophosphamide plus glucocorticoids
can produce an increase in granulocyte counts. Nucleosides have been
used anecdotally. Occasionally the disease can accelerate to a more
aggressive clinical course.
Aggressive NK Cell Leukemia  NK neoplasms are very rare,
and they may follow a range of clinical courses from very indolent
to highly aggressive. They are more common in Asians than whites,
and the cells frequently harbor a clonal Epstein-Barr virus episome.
The PB white count is usually not greatly elevated, but abnormal large
lymphoid cells with granular cytoplasm are noted. The aggressive form
is characterized by symptoms of fever and laboratory abnormalities of
pancytopenia. Hepatosplenomegaly is common; node involvement is
less common. Patients may have hemophagocytosis, coagulopathy, or
multiorgan failure. Serum levels of Fas ligand are elevated.
The cells express CD2 and CD56 and do not have rearranged T-cell
receptor genes. Deletions involving chromosome 6 are common. The
disease can be rapidly progressive. Some forms of NK neoplasms
are more indolent. They tend to be discovered incidentally with LGL
lymphocytosis and do not manifest the fever and hepatosplenomegaly
characteristic of the aggressive leukemia. The cells are also CD2 and
CD56 positive, but they do not contain clonal forms of Epstein-Barr
PART 4
virus and are not accompanied by pancytopenia or autoimmune
disease.
Extranodal NK/T-Cell Lymphoma, Nasal Type  Like lym-
phomatoid granulomatosis, extranodal NK/T-cell lymphoma tends
Oncology and Hematology
to be an angiocentric and angiodestructive lesion, but the malignant
cells are not B cells. In most cases, they are CD56+ Epstein-Barr virus–
infected cells; occasionally they are CD56–Epstein-Barr virus–infected
cytotoxic T cells. They are most commonly found in the nasal cavity.
Historically, this illness was called lethal midline granuloma, poly-
morphic reticulosis, and angiocentric immunoproliferative lesion.
This form of lymphoma is prevalent in Asia, Mexico, and Central and
South America; it affects males more commonly than females. When it
spreads beyond the nasal cavity, it may affect soft tissue, the gastroin-
testinal tract, or the testis. In some cases, hemophagocytic syndrome
(HPS) may influence the clinical picture. Patients may have B symp-
toms. Many of the systemic manifestations of disease are related to the
production of cytokines by the tumor cells and the cells responding to
their signals. Deletions and inversions of chromosome 6 are common.
Many patients with extranodal NK/T-cell lymphoma, nasal type
have excellent antitumor responses with combination chemotherapy
regimens, particularly those with localized disease. Radiation therapy
is often used after completion of chemotherapy. Four risk factors have
been defined, including B symptoms, advanced stage, elevated LDH,
and regional lymph node involvement. Patient survival is linked to the
number of risk factors: 5-year survival is 81% for zero risk factors, 64%
for one risk factor, 32% for two risk factors, and 7% for three or four
risk factors. Combination regimens without anthracyclines have been
touted as superior to CHOP, but data are sparse. High-dose therapy
with stem cell transplantation has been used, but its role is unclear.
Enteropathy-Type T-Cell Lymphoma  Enteropathy-type T-cell
lymphoma is a rare complication of longstanding celiac disease. It most
commonly occurs in the jejunum or the ileum. In adults, the lymphoma
may be diagnosed at the same time as celiac disease, but the suspicion
is that the celiac disease was a longstanding precursor to the develop-
ment of lymphoma. The tumor usually presents as multiple ulcerating
mucosal masses, but may also produce a dominant exophytic mass or
multiple ulcerations. The tumor expresses CD3 and CD7 nearly always
and may or may not express CD8. The normal-appearing lymphocytes
in the adjacent mucosa often have a similar phenotype to the tumor.
Most patients have the HLA genotype associated with celiac disease,
HLA DQA1*0501 or DQB1*0201.
The prognosis of this form of lymphoma is typically (median
survival is 7 months) poor, but some patients have a good response
to CHOP chemotherapy. Patients who respond can develop bowel
Harrisons_20e_Part4_p0435-p0858.indd 786
perforation from responding tumor. If the tumor responds to treatment,
recurrence may develop elsewhere in the celiac disease–affected small
bowel.
Hepatosplenic T-Cell Lymphoma  Hepatosplenic T-cell lym-
phoma is a malignancy derived from T cells expressing the gamma/
delta T-cell antigen receptor that affects mainly the liver and fills
the sinusoids with medium-size lymphoid cells. When the spleen is
involved, dominantly the red pulp is infiltrated. It is a disease of young
people, especially young people with an underlying immunodeficiency
or with an autoimmune disease that demands immunosuppressive
therapy. The use of thiopurine and infliximab is particularly common
in the history of patients with this disease. The cells are CD3+ and
usually CD4– and CD8–. The cells may contain isochromosome 7q,
often together with trisomy 8. The lymphoma has an aggressive natural
history. Combination chemotherapy may induce remissions, but most
patients relapse. Median survival is about 2 years. The tumor does not
appear to respond to reversal of immunosuppressive therapy.
Subcutaneous Panniculitis-Like T-Cell Lymphoma  Sub-
cutaneous panniculitis-like T-cell lymphoma involves multiple sub-
cutaneous collections of neoplastic T cells that are usually cytotoxic
cells in phenotype (i.e., contain perforin and granzyme B and express
CD3 and CD8). The rearranged T-cell receptor is usually alpha/beta-
derived, but occasionally the gamma/delta receptors are involved, par-
ticularly in the setting of immunosuppression. The cells are negative
for Epstein-Barr virus. Patients may have a HPS in addition to the skin
infiltration; fever and hepatosplenomegaly may also be present. Nodes
are generally not involved. Patients frequently respond to combination
chemotherapy, including CHOP. When the disease is progressive, the
HPS can be a component of a fulminant downhill course. Effective
therapy can reverse the HPS.
Blastic NK Cell Lymphoma  The neoplastic cells express NK
cell markers, especially CD56, and are CD3 negative. They are large
blastic-appearing cells and may produce a leukemia picture, but the
dominant site of involvement is the skin. Morphologically, the cells are
similar to the neoplastic cells in acute lymphoid and myeloid leukemia.
No characteristic chromosomal abnormalities have been described.
The clinical course is rapid, and the disease is largely unresponsive to
typical lymphoma treatments.
Primary Cutaneous CD30+ T-Cell Lymphoma  This tumor
involves the skin and is composed of cells that appear similar to the
cells of anaplastic T-cell lymphoma. Among cutaneous T-cell tumors,
about 25% are CD30+ anaplastic lymphomas. If dissemination to
lymph nodes occurs, it is difficult to distinguish between the cutaneous
and systemic forms of the disease. The tumor cells are often CD4+, and
the cells contain granules that are positive for granzyme B and perfo-
rin in 70% of cases. The typical t(2;5) of anaplastic T-cell lymphoma is
absent; indeed, its presence should prompt a closer look for systemic
involvement and a switch to a diagnosis of anaplastic T-cell lymphoma.
This form of lymphoma has sporadically been noted as a rare complica-
tion of silicone on saline breast implants. The natural history of breast
implant associated lymphoma is generally indolent. Cutaneous CD30+
T-cell lymphoma often responds to therapy. The anti-CD30 immuno-
toxin conjugate, brentuximab vedotin, is active. Radiation therapy can
be effective, and surgery can also produce long-term disease control.
Five-year survival exceeds 90%.
Angioimmunoblastic T-Cell Lymphoma  Angioimmunoblas-
tic T-cell lymphoma is a systemic disease that accounts for about 15%
of all T-cell lymphomas. Patients frequently have fever, advanced
stage, diffuse adenopathy, hepatosplenomegaly, skin rash, polyclonal
hypergammaglobulinemia, and a wide range of autoantibodies includ-
ing cold agglutinins, rheumatoid factor, and circulating immune com-
plexes. Patients may have edema, arthritis, pleural effusions, and
ascites. The nodes contain a polymorphous infiltrate of neoplastic T
cells and nonneoplastic inflammatory cells together with proliferation
of high endothelial venules and follicular dendritic cells (FDCs). The
most common chromosomal abnormalities are trisomy 3, trisomy 5, and
6/1/18 5:44 PM
 an extra X chromosome. Aggressive combination chemotherapy can
induce regressions. The underlying immune defects make conventional
lymphoma treatments more likely to produce infectious complications.
■■RARE MYELOID MALIGNANCIES
The World Health Organization (WHO) system uses PB counts and
smear analysis, BM morphology, cytogenetic and molecular genetic
tests in order to classify myeloid malignancies into several major cat-
egories (Table 106-4). Amongst them, acute myeloid leukemia (AML)
is discussed in Chap. 100, MDS in Chap. 98, chronic myeloid leukemia
(CML) in Chap. 101, and JAK2 mutation-enriched myeloprolifera-
tive neoplasms (MPN) in Chap. 99. In this chapter, we focus on the
rest (listed in Table 106-4) including chronic neutrophilic leukemia
(CNL), “atypical CML, BCR-ABL1 negative (aCML),” chronic mye-
lomonocytic leukemia (CMML), juvenile myelomonocytic leukemia
(JMML), “chronic eosinophilic leukemia, not otherwise specified
(CEL-NOS),” mastocytosis, “MPN, unclassifiable (MPN-U),” MDS/
MPN, unclassifiable (MDS/MPN-U), “MDS/MPN with ring siderob-
lasts and thrombocytosis (MDS/MPN-RS-T),” and “myeloid/lymphoid
neoplasms with eosinophilia and rearrangements of PDGFRA, PDGFRB,
FGFR1 or with PCM1-JAK2.” This chapter also includes histiocytic and
DC neoplasms, transient myeloproliferative disorders (TMD) as well
as a broader discussion on primary eosinophilic disorders including
hypereosinophilic syndrome (HES).
■■CHRONIC NEUTROPHILIC LEUKEMIA
CNL is a clonal proliferation of mature neutrophils with few or no
circulating immature granulocytes. In 2013, CNL was associated with
TABLE 106-4  World Health Organization Classification of Myeloid
Malignancies
1.  Acute myeloid leukemia (AML) and related precursor neoplasms
2.  Myeloproliferative neoplasms (MPN)
2.1.  Chronic myeloid leukemia (CML), BCR-ABL1 positive
2.2.  JAK2 mutation-enriched MPN
2.2.1.  Polycythemia vera
2.2.2.  Primary myelofibrosis
2.2.3.  Essential thrombocythemia
2.3.  Chronic neutrophilic leukemia (CNL)
2.4.  Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS)
2.5.  Myeloproliferative neoplasm, unclassifiable (MPN-U)
3.  Myelodysplastic syndromes (MDS)
3.1.  MDS with single lineage dysplasia
3.2.  MDS with ring sideroblasts (MDS-RS)
3.3.  MDS with multilineage dysplasia
3.4.  MDS with excess blasts
3.5.  MDS with isolated del(5q)
3.6.  MDS, unclassifiable (MDS-U)
3.7.  Provisional entity: Refractory cytopenia of childhood
4.  MDS/MPN overlap
4.1.  Chronic myelomonocytic leukemia (CMML)
4.2.  Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative
4.3.  Juvenile myelomonocytic leukemia (JMML)
4.4. MDS/MPN with ring sideroblasts and thrombocytosis (MDS/
MPN-RS-T)
4.5.  MDS/MPN, unclassifiable (MDS/MPN-U)
5.  Mastocytosis
6. Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of
PDGFRA, PDGFRB, FGFR1 or with PCM1-JAK2
6.1.  Myeloid/lymphoid neoplasms with PDGFRA rearrangement
6.2.  Myeloid/lymphoid neoplasms with PDGFRB rearrangement
6.3.  Myeloid/lymphoid neoplasms with FGFR1 rearrangement
6.4. Provisional entity: Myeloid/lymphoid neoplasms with PCM1-JAK2
translocation
Myeloid neoplasms with germline predisposition
Harrisons_20e_Part4_p0435-p0858.indd 787
activating mutations of the gene (CSF3R) encoding for the receptor for 787
granulocyte colony-stimulating factor (G-CSF), also known as colony
stimulating factor 3 (CSF3). Patients with CNL might be asymptomatic
at presentation but also display constitutional symptoms, splenomeg-
aly, anemia, and thrombocytopenia. Median survival is ∼2 years and
causes of death include leukemic transformation, progressive disease
associated with severe cytopenias, and marked treatment-refractory
leukocytosis. CNL is rare with <200 reported cases. Median age at diag-
nosis is ∼67 years, and the disease is equally prevalent in both genders.
Pathogenesis  CSF3 is the main growth factor for granulocyte pro-
liferation and differentiation. Accordingly, recombinant CSF3 is used
for the treatment of severe neutropenia, including severe congenital
neutropenia (SCN). Some patients with SCN acquire CSF3R mutations
and the frequency of such mutations is significantly higher (∼ 80%) in
those patients who experience leukemic transformation. SCN-associated
CSF3R mutations occur in the region of the gene coding for the cytoplas-
mic domain of CSF3R, and result in truncation of the C-terminal-negative
regulatory domain. In 2013, Maxson et al. described a different class
of CSF3R mutations in ∼ 90% of patients with CNL; these were mostly
membrane proximal, the most frequent being a C-to-T substitution at
nucleotide 1853 (T618I). In a subsequent confirmatory study, CSF3R
CHAPTER 106 Less Common Hematologic Malignancies
mutations were found to be specific to WHO-defined CNL. About 40% of
the T618I-mutated cases also harbored SETBP1 mutations. CSF3RT618I
has been shown to induce lethal myeloproliferative disorder in a mouse
model and in vitro sensitivity to JAK inhibition.
Diagnosis  Diagnosis of CNL requires exclusion of the more com-
mon causes of neutrophilia including infections and inflammatory pro-
cesses. In addition, one should be mindful of the association between
some forms of metastatic cancer or plasma cell neoplasms with second-
ary neutrophilia. Neoplastic neutrophilia also occurs in other myeloid
malignancies including aCML and CMML. Accordingly, the WHO
diagnostic criteria for CNL are designed to exclude the possibilities
of both secondary/reactive neutrophilia and leukocytosis associated
with myeloid malignancies other than CNL (Table 106-2): leukocytosis
(≥25 × 109/L), ≥80% segmented/band neutrophils, <10% immature
myeloid cells, <1% circulating blasts and absence of dysgranulopoiesis
or monocytosis (monocyte count <1 × 109/L). BM in CNL is hypercellu-
lar and displays increased number and percentage of neutrophils with
very high myeloid to erythroid ratio and minimal left shift, myeloid
dysplasia or reticulin fibrosis.
The recent discovery of CSF3R mutations (see above) and their
almost invariable association with WHO-defined CNL has allowed its
incorporation in the WHO diagnostic criteria (Table 106-5). In practi-
cal terms, the presence of a membrane proximal CSF3R mutation in
a patient with predominantly neutrophilic granulocytosis should be
sufficient for the diagnosis of CNL, regardless of the degree of leuko-
cytosis. Unfortunately, several exclusionary criteria still need to be met
for diagnosing CNL in the absence of CSF3R mutations (Table 106-5).
Treatment  Current treatment in CNL is largely palliative and
suboptimal in its efficacy. Several drugs alone or in combination
have been tried and none have shown remarkable efficacy. As such,
allogeneic stem cell transplant (ASCT) is reasonable to consider in the
presence of symptomatic disease, especially in younger patients. Oth-
erwise, cytoreductive therapy with hydroxyurea is probably as good
as anything, and a more intensive combination chemotherapy may
not have additional value. However, response to hydroxyurea therapy
is often transient, and some have successfully used interferon a as an
alternative drug. Response to treatment with ruxolitinib (a JAK1 and
JAK2 inhibitor) has been reported in several case reports but, as is the
case with hydroxyurea treatment, the response is often incomplete and
temporary.
■■ATYPICAL CHRONIC MYELOID LEUKEMIA
“Atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML)”
is formally classified under the MDS/MPN category of myeloid
malignancies and is characterized by left shifted granulocytosis and
6/1/18 5:44 PM
 788 TABLE 106-5  2016 World Health Organization (WHO) Diagnostic Criteria for Chronic Neutrophilic Leukemia (CNL), Atypical Chronic Myeloid
Leukemia, BCR-ABL1-negative (aCML), and Chronic Myelomonocytic Leukemia (CMML)
CHRONIC NEUTROPHILIC ATYPICAL CHRONIC
VARIABLES LEUKEMIA MYELOID LEUKEMIA CHRONIC MYELOMONOCYTIC LEUKEMIA
PB leukocyte count ≥25 × 109/L Granulocytosis
PB segmented neutrophils/bands ≥80%
PB immature granulocytesa <10% ≥10%
PB blast count <1% <20% <20%
PB monocyte count <1 x 10(9)/L No or minimal monocytosis ≥1 × 109/L
Persistent and lasting for at least 3 months
Dysgranulopoiesis No Yes
PB basophil percentage <2%
PB monocyte percentage <10% ≥10%
Bone marrow Hypercellular Hypercellular Dysplasia in ≥1 myeloid lineages
↑Neutrophils, number and % ↑Granulocyte proliferation or
<5% blasts Granulocytic dysplasia clonal cytogenetic/molecular abnormality
Normal neutrophilic maturation ±erythroid/megakaryocyte <20% blasts or promonocytes
Dysplasia
<20% blasts
BCR-ABL1 No No No
PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 No No No
rearrangement
PART 4

CSF3R T618I or other activating CSF3R mutation Yes

or persistent neutrophilia, splenomegaly, and no
identifiable cause of reactive neutrophilia
PB and BM blasts/promonocytes <20% <20%
Oncology and Hematology

Evidence for other MPN: CML, PV, ET, or PMF No No No

Evidence for reactive No No
Leukocytosisb or monocytosis
a
Immature granulocytes include myeloblasts, promyelocytes, myelocytes, and metamyelocytes. bCauses of reactive neutrophilia include plasma cell neoplasms, solid
tumor, infections, and inflammatory processes.
Abbreviations: BM, bone marrow; CML, chronic myeloid leukemia; ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PB, peripheral blood; PMF, primary
myelofibrosis; PV, polycythemia vera.

dysgranulopoiesis. The differential diagnosis of aCML includes CML,
which is distinguished by the presence of BCR-ABL1; CNL, which is
distinguished by the absence of dysgranulopoiesis and presence of
CSF3R mutations; and CMML, which is distinguished by the presence
of monocytosis (absolute monocyte count ≥1 × 109/L). The WHO diag-
nostic criteria for aCML are listed in Table 106-5 and include granulocy-
tosis, dysgranulopoiesis, ≥10% immature granulocytes, <20% PB or BM
myeloblasts, <10% PB monocytes, <2% basophils, absence of otherwise
specific mutations such as BCR-ABL1, PDGFRA, PDGFRB, FGFR1, or
PCM1-JAK2 and not meeting WHO criteria for CML, PMF, PV, or ET.
The BM in aCML is hypercellular with granulocyte proliferation and
dysplasia with or without erythroid or megakaryocytic dysplasia.
The molecular pathogenesis of aCML is incompletely understood;
about a fourth of the patients express SETBP1 mutations, which are,
however, also found in several other myeloid malignancies, including
CNL and CMML. SETBP1 mutations in aCML were prognostically
detrimental and mostly located between codons 858 and 871; similar
mutations are seen with Schinzel-Giedion syndrome (a congenital dis-
ease with severe developmental delay and various physical stigmata
including midface retraction, large forehead, and macroglossia). A
somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S)
was described in 9% of patients with aCML but was also seen in 14%
of patients with CMML, 6% of patients with mastocytosis (especially in
association with eosinophilia), and rarely in other MPN.
In a series of 55 patients with WHO-defined aCML, median age at
diagnosis was 62 years with female preponderance (57%), splenomeg-
aly was reported in 54% of the patients, red cell transfusion requirement
in 65%, abnormal karyotype in 20% (20q- and trisomy 8 being the most
frequent) and leukemic transformation in 40%. Median survival was
25 months. Outcome was worse in patients with marked leukocyto-
sis, transfusion requirement, and increased immature cells in the PB.
Conventional chemotherapy is largely ineffective in the treatment of
aCML. However, a favorable experience with ASCT was reported in
nine patients; after a median follow-up of 55 months, the majority of
the patients remained in complete remission.
■■CHRONIC MYELOMONOCYTIC LEUKEMIA
CMML is classified under the WHO category of MDS/MPN and is
defined by an absolute monocyte count (AMC) of ≥1 × 109/L in the
PB and accounting for ≥10% of the leukocyte count. Median age at
diagnosis ranges between 65 and 75 years and there is a 2:1 male pre-
dominance. Clinical presentation is variable and depends on whether
the disease presents with MDS-like or MPN-like phenotype; the former
is associated with cytopenias and the latter with splenomegaly and fea-
tures of myeloproliferation such as fatigue, night sweats, weight loss,
and cachexia. About 20% of patients with CMML experience serositis
involving the joints (arthritis), pericardium (pericarditis and pericardial
effusion), pleura (pleural effusion), or peritoneum (ascites).
Pathogenesis  Clonal cytogenetic abnormalities are seen in about
a third of patients with CMML and include trisomy 8 and abnormali-
ties of chromosome 7. Almost all patients with CMML harbor somatic
mutations involving epigenetic regulator genes (e.g., ASXL1, TET2),
spliceosome pathway genes (e.g., SRSF2), DNA damage response
genes (e.g., TP53), and tyrosine kinases/transcription factors (e.g.,
KRAS, NRAS, CBL, and RUNX1). However, none of these mutations
are specific to CMML, and their precise pathogenetic contribution is
unclear.
Diagnosis  Reactive monocytosis is uncommon but has been
reported in association with certain infections and inflammatory con-
ditions. Clonal (i.e., neoplastic) monocytosis defines CMML but is also
seen with JMML and AML with monocytic differentiation. The WHO
diagnostic criteria for CMML are listed in Table 106-5 and include (1)
persistent PB monocyte count of ≥1 × 109/L with monocyte percentage

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 of ≥10%, (2) absence of BCR-ABL1, PDGFRA, PDGFRB, FGFR1, or
PCM1-JAK2 rearrangements, (3) not meeting WHO criteria for CML, PV,
ET, or PMF, (4) <20% blasts and promonocytes in the PB and BM, and
(5) dysplasia involving one or more myeloid lineages or, in the absence
of dysplasia, presence of an acquired clonal cytogenetic or molecular
genetic abnormality or non-reactive monocytosis lasting for at least
3 months.
The BM in CMML is hypercellular with granulocytic and monocytic
proliferation. Dysplasia is often present and may involve one, two,
or all myeloid lineages. On immunophenotyping the abnormal cells
often express myelomonocytic antigens such as CD13 and CD33, with
variable expression of CD14, CD68, CD64, and CD163. Monocytic-
derived cells are almost always positive for the cytochemical non-
specific esterases (e.g., butyrate esterase), while normal granulocytic
precursors are positive for lysozyme and chloroacetate esterase. In
CMML, it is common to have a hybrid cytochemical staining pattern
with cells expressing both chloroacetate and butyrate esterases simul-
taneously (dual esterase staining).
Prognosis  A recent meta-analysis showed median survival of
1.5 years in CMML. Numerous prognostic systems have attempted to
better define and stratify the natural history of CMML. One of these,
the Mayo prognostic model, assigns one point each to the following
four independent prognostic variables: AMC >10 × 109/L, presence of
circulating immature cells, hemoglobin <10 gm/dL and platelet count
<100,000/mL. This model stratified patients into three risk groups: low
(0 points), intermediate (1 point), and high (≥2 points), translating to
median survival of 32, 18, and 10 months, respectively.
A French study incorporated ASXL1 mutational status in 312 CMML
patients. In a multivariable model, independent predictors of poor
survival were WBC >15 × 109/L (3 points), ASXL1 mutations (2 points),
age >65 years (2 points), platelet count <100,000/mL (2 points), and
hemoglobin <10 gm/dL in females and <11 gm/dL in males (2 points).
This model stratified patients into three groups: low (0–4 points), inter-
mediate (5–7 points), and high risk (8–12 points), with median survival
of “not reached,” 38.5 and 14.4 months, respectively.27 ASXL1 and
DNMT3A mutations also have an adverse effect on CMML.
Treatment  Current treatment in CMML consists of hydroxyurea
and supportive care, including red cell transfusions and use of ery-
thropoiesis-stimulating agents (ESA). The value of hydroxyurea was
reinforced by a randomized trial against oral etoposide. No other
single or combination chemotherapy has been shown to be superior
to hydroxyurea. ASCT is a viable treatment option for transplant-
eligible patients with poor prognostic features. Given the MDS/MPN
overlap phenotype and the presence of MDS-like genetic/methylation
abnormalities in CMML, hypomethylating agents such as 5-azacitidine
and decitabine have been used with limited efficacy; in a study using
decitabine in CMML, overall response rate was 48% with 17% complete
remissions and median survival of 17 months. The experience with
5-azacytidine was somewhat similar.
■■JUVENILE MYELOMONOCYTIC LEUKEMIA
JMML is primarily a disease of early childhood and is included, along
with CMML, in the “MDS/MPN” WHO category. Both CMML and
JMML feature leukocytosis, monocytosis, and hepatosplenomegaly.
Additional characteristic features in JMML include thrombocytopenia
and elevated fetal hemoglobin. Myeloid progenitors in JMML display
GM-CSF hypersensitivity that has been attributed to dysregulated
RAS/MAPK signaling. The latter is believed to result from mutually
exclusive mutations involving RAS, PTPN11, and NF1. A third of
patients with JMML that is not associated with Noonan syndrome
carry PTPN11 mutations while the incidence of NF1 in patients with-
out neurofibromatosis, type 1 and RAS mutations are ∼15% each. In
general, in about 85% of JMML cases, one of the classical RAS path-
way mutations (PTPN11, NRAS, KRAS, NF1, and CBL) is present; in
addition, a myrof other mutations, such as ASXL1, RUNX1, SETBP1,
JAK3, CUX1, and others have been reported. Drug therapy is relatively
ineffective in JMML, and the treatment of choice is ASCT, which results
in a 5-year survival of ∼50%.
Harrisons_20e_Part4_p0435-p0858.indd 789
The 2016 revised WHO diagnostic criteria for JMML requires the 789
presence of PB monocyte count ≥1 × 109/L, <20% blasts in blood or BM,
splenomegaly, and absence of BCR-ABL1. Diagnosis also requires the
presence of one of the following: somatic mutation of PTPN11, KRAS,
or NRAS; clinical diagnosis of NF1 or NF1 mutation; germline mutation
of CBL and loss of heterozygosity. Diagnosis of JMML can still be con-
sidered without the aforementioned genetic features, in the presence of
monosomy 7 or any other cytogenetic abnormality or in the presence
of two of the following: increased hemoglobin F, presence of myeloid
or erythroid precursors in the PB, GM-CSF hypersensitivity in colony
assay, and hyperphosphorylation of STAT5.
■■MDS/MPN, UNCLASSIFIABLE (MDS/MPN-U)
The WHO classifies patients with morphologic and laboratory features
that resemble both MDS and MPN as “MDS/MPN overlap.” This cat-
egory includes CMML, aCML, and JMML, which have been described
above. In addition, MDS/MPN includes a fourth category referred
to as MDS/MPN, unclassifiable (MDS/MPN-U). Diagnosis of MDS/
MPN-U requires the presence of both MDS and MPN features that are
not adequate to classify patients as CMML, aCML, or JMML. MDS/
MPN also includes the provisional category of refractory anemia with
ring sideroblasts and thrombocytosis (RARS-T); the 2016 revision of
CHAPTER 106 Less Common Hematologic Malignancies
the WHO classification document has changed the term RARS-T into
“MDS/MPN-RS-T.”
In a study of 85 patients with MDS/MPN-U, median age was
70 years and 72% were males. Splenomegaly at presentation was
present in 33%, thrombocytosis in 13%, leukocytosis in 18%, JAK2
mutations in 30%, and abnormal karyotype 51%; the most frequent
cytogenetic abnormality was trisomy 8. Median survival was 12.4
months and favorably affected by thrombocytosis. Treatment with
hypomethylating agents, immunomodulators, or ASCT did not appear
to favorably affect survival.
■■MDS/MPN WITH RING SIDEROBLASTS AND
THROMBOCYTOSIS (MDS/MPN-RS-T)
MDS/MPN-RS-T is classified in the MDS/MPN category because it
shares dysplastic features with MDS-RS and myeloproliferative features
with ET. The 2016 revised WHO diagnostic criteria for MDS/MPN-
RS-T includes anemia associated with erythroid lineage dysplasia,
presence of ≥15% ring sideroblasts, blast count of <5% in BM and <1%
in the PB, platelet count of ≥450 × 109/L, and absence of BCR-ABL1,
PDGFRA, PDGFRB, FGFR1, PCM1-JAK2 mutations or t(3;3)(q21;q26),
inv(3)(q21q26), or del(5q). These diagnostic criteria also require the
absence of history of MPN, MDS, or other type of MDS/MPN and
also either the presence of SF3B1 mutation or absence of exposure to
cytotoxic or other treatment that could be blamed for the morphologic
abnormalities.
One hundred eleven patients with MDS/MPN-RS-T were compared
with 33 patients with RARS. The frequency of SF3B1 mutations in MDS/
MPN-RS-T-T (87%) was similar to that in MDS-RS (85%). JAK2 V617F
mutation was detected in 49% of MDS/MPN-RS-T patients (including
48% of those mutated for SF3B1), but none of those with MDS-RS. In
MDS/MPN-RS-T, SF3B1 mutations were more frequent in females
(95%) than in males (77%), and mean ring sideroblast counts were
higher in SF3B1-mutated patients. Median overall survival was 6.9 years
in SF3B1-mutated vs 3.3 years in unmutated cases. Six-year survival was
67% in JAK2-mutated vs 32% in unmutated cases. Multivariable analysis
identified younger age, JAK2 and SF3B1 mutations as favorable factors.
Predictors of poor survival in MDS/MPN-RS-T include anemia, abnor-
mal karyotype, and presence of ASXL1 or SETBP1 mutations. Interest-
ingly, the presence of SF3B1 mutations in MDS/MPN-RS-T is associated
with increased risk of thrombosis. Several case reports have suggested
that treatment with lenalidomide might induce red cell transfusion
independence and complete remissions in MDS/MPN-RS-T.
■■MYELOPROLIFERATIVE NEOPLASM,
UNCLASSIFIABLE (MPN-U)
The category of MPN-U includes MPN-like neoplasms that cannot
be clearly classified as one of the other seven subcategories of MPN
6/1/18 5:44 PM
 790 (Table 106-4). Examples include patients presenting with unusual
thrombosis or unexplained organomegaly with normal blood counts
but found to carry MPN-characteristic mutations such as JAK2 and
CALR or display BM morphology that is consistent with MPN. It is
possible that some cases of MPN-U represent earlier disease stages in
PV or ET, which however fail to meet the threshold hemoglobin levels
or platelet counts that are required per WHO diagnostic criteria. Spe-
cific treatment interventions might not be necessary in asymptomatic
patients with MPN-U, whereas patients with arterial thrombotic com-
plications might require cytoreductive and aspirin therapy, and those
with venous thrombosis might require systemic anticoagulation.
■■MYELOID NEOPLASMS WITH GERM LINE
PREDISPOSITION
The 2016 WHO revision on the classification of myeloid neoplasms
adds a section referred to as “myeloid neoplasms with germ line pre-
disposition” and includes cases of AML, MDS, and MDS/MPN that
arise in the setting of a germ line predisposition mutation, such as
CEBPA, DDX41, RUNX1, ANKRD26, ETV6, or GATA2. This particular
category of diseases also includes myeloid neoplasms that arise in the
background of BM failure syndromes, Down syndrome, Noonan syn-
drome, neurofibromatosis, and telomeropathies.
■■TRANSIENT MYELOPROLIFERATIVE DISORDER
PART 4
with infections, especially those related to tissue-invasive helminths,
allergic/vasculitic diseases, drugs, and metastatic cancer. Primary eos-
inophilia is the focus of this chapter and is considered when a cause for
secondary eosinophilia is not readily apparent.
Primary eosinophilia is classified as clonal or idiopathic. Diagnosis
of clonal eosinophilia requires morphologic, cytogenetic, or molecular
evidence of a myeloid neoplasm. Idiopathic eosinophilia is considered
when both secondary and clonal eosinophilias have been ruled out as
a possibility. HES is a subcategory of idiopathic eosinophilia with per-
sistent AEC of ≥1.5 × 109/L and associated with eosinophil-mediated
organ damage (Table 106-6). An HES-like disorder that is associated
with clonal or phenotypically abnormal T cells is referred to as “lym-
phocytic variant hypereosinophilia” (Table 106-6).
Clonal Eosinophilia  Examples of clonal eosinophilia include
eosinophilia associated with AML, MDS, CML, mastocytosis, and
MDS/MPN overlap. Myeloid neoplasm-associated eosinophilia also
includes the WHO MPN subcategory of chronic eosinophilic leukemia,
not otherwise specified (CEL-NOS) and the WHO myeloid malignancy
subcategory referred to as “myeloid/lymphoid neoplasms with eosin-
ophilia and rearrangement of platelet-derived growth factor receptor
(PDGFR) α/β or fibroblast growth factor receptor 1 (FGFR1)” or with
PCM1-JAK2 (Table 106-4).
The diagnostic workup for clonal eosinophilia that is not associated

TMD, also referred to as transient abnormal myelopoiesis (TAM),
constitutes an often but not always transient phenomenon of abnor-
mal megakaryoblast proliferation, which occurs in ∼10% of infants
with Down syndrome. TMD is usually recognized at birth and either
undergoes spontaneous regression (75% of the cases) or progress into
Oncology and Hematology
with morphologically overt myeloid malignancy should start with
PB mutation screening for FIP1L1-PDGFRA and PDGFRB mutations
using fluorescence in situ hybridization (FISH) or reverse transcription-
polymerase chain reaction. This is crucial since such eosinophilia is

easily treated with imatinib. If mutation screening is negative, a BM

acute megakaryoblastic leukemia (AMKL) (25% of the cases). Almost
all patients with TMD and TMD-derived AMKL display somatic
GATA1 mutations. TMD-associated GATA1 mutations constitute exon
2 insertions, deletions, or missense mutations, affecting the N-terminal
transactivation domain of GATA-1 and result in loss of full-length
(50-kD) GATA-1 and its replacement with a shorter isoform (40-kD)
that retains friend of GATA-1 (FOG-1) binding. In contrast, inherited
forms of exon 2 GATA1 mutations produce a phenotype with anemia
whereas exon 4 mutations that affect the N-terminal, FOG-1-interactive
domain, produce familial dyserythropoietic anemia with thrombocy-
topenia51 or X-linked macrothrombocytopenia.
■■PRIMARY EOSINOPHILIA
Eosinophilia refers to a PB absolute eosinophil count (AEC) that
is above the upper normal limit of the reference range. The term
“hypereosinophilia” is used when the AEC is above 1500 × 109/L. Eos-
inophilia is operationally classified into secondary (non-neoplastic pro-
liferation of eosinophils) and primary (proliferation of eosinophils that
is either neoplastic or otherwise unexplained). Secondary eosinophilia
is by far the most frequent cause of eosinophilia and is often associated
examination with cytogenetic studies is indicated. In this regard, one
must first pay attention to the presence or absence of 5q33, 4q12, 8p11.2,
or t(8;9)(p22;p24.1) translocations, which, if present, would suggest
PDGFRB, PDGFRA, or FGFR1-rearranged or PCM1-JAK2-associated
clonal eosinophilia, respectively. The presence of 5q33 or 4q12 translo-
cations predicts favorable response to treatment with imatinib mesylate
and that of t(8;9)(p22;p24.1), a transient response to ruxolutinib while
8p11.2 translocations are associated with aggressive myeloid malignan-
cies that are refractory to current drug therapy.
Chronic Eosinophilic Leukemia, Not Otherwise Specified
(CEL-NOS)  CEL-NOS is a subset of clonal eosinophilia that is
neither molecularly defined nor classified as an alternative clinico-
pathologically assigned myeloid malignancy. We prefer to use the term
strictly in patients with an “HES” phenotype who also display either a
clonal cytogenetic/molecular abnormality or excess blasts in the BM or
PB. The WHO defines CEL-NOS in the presence of ≥1.5 × 109/L AEC
that is accompanied by either the presence of myeloblast excess (either
>2% in the PB or 5–19% in the BM) or evidence of myeloid clonality.
Cytogenetic abnormalities in CEL, other than those that are associated

TABLE 106-6  Primary Eosinophilia Classification

EOSINOPHILIA ASSOCIATED WITH
PDGFRA, PDGFRB, FGFR1 CHRONIC EOSINOPHILIA
OR NOT OTHERWISE SPECIFIED LYMPHOCYTIC VARIANT HYPEREOSINOPHILIC
VARIABLES PCM1-JAK2 ABNORMALITY (CEL-NOS) HYPEREOSINOPHILIA SYNDROME
Absolute eosinophil count >600 × 109/L >1500 × 109/L >1500 × 109/L >1500 × 109/L
Peripheral blood blast >2% Yes or no Yes or no No No
Bone marrow blast >5% Yes or no Yes or No No No
Abnormal karyotype Yes or no Yes or no No No
PDGFRA, PDGFRB, FGFR1 or Yes No No No
PCM1-JAK2 abnormality
BCR-ABL1 No No No No
Abnormal T lymphocyte No No Yes No
phenotype or clonal T cell
clones
Eosinophil-mediated tissue Yes or no Yes or no Yes or no Yes
damage

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 with molecularly defined eosinophilic disorders, include trisomy 8 (the
most frequent), t(10;11)(p14;q21), and t(7;12)(q11;p11). CEL-NOS does
not respond to imatinib, and treatment strategies are often not different
from those utilized in other similar MPNs; ASCT for transplant-eligible
patients with poor risk factors and participation in experimental treat-
ment protocols otherwise.
PDGFR Mutated Eosinophilia  Both platelet-derived growth fac-
tor receptors α (PDGFRA located on chromosome 4q12) and β (PDGFRB
located on chromosome 5q31-q32) are involved in MPN-relevant
activating mutations. Clinical phenotype in both instances includes
prominent blood eosinophilia and excellent response to imatinib
therapy. In regards to PDGFRA mutations, the most popular is FIP1L1-
PDGFRA, a karyotypically occult del(4)(q12), that was described in
2003 as an imatinib-sensitive activating mutation. Functional stud-
ies have demonstrated transforming properties in cell lines and the
induction of MPN in mice. Cloning of the FIP1L1-PDGFRA fusion
gene identified a novel molecular mechanism for generating this con-
stitutively active fusion tyrosine kinase, wherein a ~800kb interstitial
deletion within 4q12 fuses the 5’ portion of FIP1L1 to the 3’ portion of
PDGFRA.57 FIP1L1-PDGFRA occurs in a very small subset of patients
who present with the phenotypic features of either SM or HES, but the
presence of the mutation reliably predicts complete hematologic and
molecular response to imatinib therapy.
The association between eosinophilic myeloid malignancies and
PDGFRB rearrangement was first characterized and published in 1994
where fusion of the tyrosine kinase encoding region of PDGFRB to
the ets- like gene, ETV6 (ETV6-PDGFRB, t(5;12)(q33;p13) was demon-
strated. The fusion protein was transforming to cell lines and resulted
in constitutive activation of PDGFRB signaling. Since then, several
other PDGFRB fusion transcripts with similar disease phenotypes
have been described, cell line transformation and MPD-induction in
mice has been demonstrated, and imatinib therapy was effective when
employed.
FGFR1 Mutated Eosinophilia  The 8p11 myeloprolifera-
tive syndrome (EMS) (also known as human stem cell leukemic/
lymphoma syndrome) constitutes a clinical phenotype with features of
both lymphoma and eosinophilic MPN and characterized by a fusion
mutation that involves the gene for fibroblast growth factor receptor-1
(FGFR1), which is located on chromosome 8p11. In EMS, both myeloid
and lymphoid lineage cells exhibit the 8p11 translocation, thus demon-
strating the stem cell origin of the disease. The disease features several
8p11-linked chromosome translocations and some of the corresponding
fusion FGFR1 mutants have been shown to transform cell lines and
induce EMS- or CML-like disease in mice depending on the specific
FGFR1 partner gene, ZNF 198 or BCR, respectively. Consistent with
this laboratory observation, some patients with BCR-FGFR1 mutation
manifest a more indolent CML-like disease. The mechanism of FGFR1
activation in EMS is similar to that seen with PDGFRB-associated MPD;
the tyrosine kinase domain of FGFR1 is juxtaposed to a dimerization
domain from the partner gene. EMS is aggressive and requires combi-
nation chemotherapy followed by ASCT.
PCM1-JAK2 Associated Myeloid/Lymphoid Neoplasm
with Eosinophilia  The 2016 revised WHO document includes a
provisional entity under myeloid/lymphoid neoplasms with eosino-
philia referred to as “myeloid/lymphoid neoplasms with PCM1-JAK2.”
The entity is characterized by the t(8;9)(p22;p24.1) cytogenetic abnor-
mality and a phenotype that displays marked male predominance,
organomegaly, eosinophilia, and hetereogenous morphologic features
similar to MPN, MDS, or MDS/MPN. Current drug therapy for PCM1-
JAK2-associated disease is suboptimal, although some affected patients
have displayed transient responses to ruxolutinib therapy.
Hypereosinophilic Syndrome Blood eosinophilia that
is neither secondary nor clonal is operationally labeled as being
“idiopathic.” HES is a sub-category of idiopathic eosinophilia with per-
sistent increase of the AEC to ≥1.5 × 109/L and presence of eosinophil-
mediated organ damage, including cardiomyopathy, gastroenteritis,
cutaneous lesions, sinusitis, pneumonitis, neuritis, and vasculitis. In
Harrisons_20e_Part4_p0435-p0858.indd 791
addition, some patients manifest thromboembolic complications, hepa- 791
tosplenomegaly, and either cytopenia or cytosis.
BM histological and cytogenetic/molecular studies should be exam-
ined before a working diagnosis of HES is made. Additional blood
studies that are currently recommended during the evaluation of
“HES” include serum tryptase (an increased level suggests mastocyto-
sis and warrants molecular studies to detect FIP1L1-PDGFRA), T-cell
immunophenotyping, as well as T-cell receptor antigen gene rear-
rangement analysis (a positive test suggests an underlying clonal or
phenotypically abnormal T-cell disorder). In addition, initial evaluation
in HES should include echocardiogram and measurement of serum
troponin levels to screen for myocardial involvement by the disease.
Initial evaluation of the patient with eosinophilia should include
tests that facilitate assessment of target organ damage: complete
blood count, chest x-ray, echocardiogram, and serum troponin level.
Increased level of serum cardiac troponin has been shown to correlate
with the presence of cardiomyopathy in HES. Typical echocardio-
graphic findings in HES include ventricular apical thrombus, posterior
mitral leaflet or tricuspid valve abnormality, endocardial thickening,
dilated left ventricle, and pericardial effusion.
In a Mayo Clinic study of 98 consecutive patients with idiopathic
eosinophilia, including HES, median age was 53 years (55% males),
CHAPTER 106 Less Common Hematologic Malignancies
and overt organ involvement was seen >80% of the cases including
54% involving organs other than the skin. The frequencies of car-
diac involvement, hepatosplenomegaly, increased serum tryptase and
interleukin-5 levels were 8, 4, 24, and 31%, respectively. The study also
revealed that 11% of the affected patients harbored pathogenetic muta-
tions including TET2, ASXL1, and KIT; the presence of such mutations
did not appear to influence phenotype and the number of informative
cases was too small to assess prognostic relevance. Instead, the study
identified anemia and presence of cardiac involvement or hepatosple-
nomegaly as risk factors for survival.
Glucocorticoids are the cornerstone of therapy in HES. Treatment
with oral prednisone is usually started at 1mg/kg/d and continued
for 1 to 2 weeks before the dose is tapered slowly over the ensuing 2 to
3 months. If symptoms recur at a prednisone dose level of >10 mg/d,
either hydroxyurea or interferon α is used as steroid-sparing agent. In
patients who do not respond to usual therapy as outlined above, mepo-
lizumab or alemtuzumab might be considered. Mepolizumab targets
IL-5, a well-recognized survival factor for eosinophils. Alemtuzumab
targets the CD52 antigen, which has been shown to be expressed by
eosinophils but not by neutrophils.
■■MASTOCYTOSIS
Mast cell disease (MCD) is defined as tissue infiltration by morpholog-
ically as well as immunophenotypically abnormal mast cells. MCD is
classified into two broad categories; cutaneous and systemic mastocy-
tosis (SM). MCD in adults is usually systemic and the clinical course
can be either indolent or aggressive, depending on the respective
absence or presence of impaired organ function. Symptoms and signs
of MCD include urticaria pigmentosa, mast cell mediator release symp-
toms (e.g., headache, flushing, lightheadedness, syncope, anaphylaxis,
pruritus, urticaria, angioedema, nausea, diarrhea, abdominal cramps),
and organ damage (lytic bone lesions, osteoporosis, hepatosplenomeg-
aly, cytopenia). Aggressive SM can be associated with another myeloid
malignancy, including MPN, MDS, MDS/MPN overlap (e.g., CMML),
or present as overt mast cell leukemia (MCL). In general, life expec-
tancy is near normal in indolent SM but significantly shortened in
aggressive SM.
Diagnosis of SM is based on BM examination that shows clusters
of morphologically abnormal, spindle-shaped mast cells that are best
evaluated by the use of immunohistochemical stains that are specific to
mast cells (tryptase, CD117). In addition, mast cell immunophenotyp-
ing reveals aberrant CD25 expression by neoplastic mast cells. Other
laboratory findings in SM include increased levels of serum tryptase,
histamine and urine histamine metabolites and prostaglandins. SM is
associated with KIT mutations, usually KITD816V, in the majority of
patients. Accordingly, mutation screening for KITD816V is diagnosti-
cally useful. However, the ability to detect KITD816V depends on assay
6/1/18 5:44 PM
 792 sensitivity and mast cell content of the test sample. The 2016 WHO clas-
sification of mastocytosis includes (1) cutaneous mastocytosis (CM),
(2) SM, and (3) mast cell sarcoma (MCS). SM is further classified into
(a) indolent SM (ISM), (b) smoldering SM (SSM), (c) SM with an asso-
ciated hematological neoplasm (SM-AHN), (d) aggressive SM (ASM),
and (e) MCL.
Both indolent and aggressive SM patients might experience mast cell
mediator release symptoms, which are usually managed by both H-1
and H-2 histamine receptor blockers as well as cromolyn sodium. In
addition, patients with propensity to vasodilatory shock should wear
a medical alert bracelet as well as carry an Epi-Pen self-injector for
self-administration of subcutaneous epinephrine. Urticaria pigmentosa
shows variable response to both topical and systemic corticosteroid
therapy. Cytoreductive therapy is not recommended for indolent SM. In
aggressive SM, either interferon α or cladribine is considered first-line
therapy and benefits the majority of patients. In contrast, imatinib is
ineffective in the treatment of PDGFR-unmutated SM. A controlled study
of patients with ISM or SSM demonstrated marginal value of masitinib
(oral tyrosine kinase inhibitor that inhibits KIT and LYN) with reported
cumulative symptomatic response rate of 18.7% vs 7.4% for placebo.
Treatment responses were more impressive in another study that used
the multikinase inhibitor midostaurin in patients with the more aggres-
sive forms of SM, with 45% of the patients achieving major response.
PART 4
■■DENDRITIC AND HISTIOCYTIC NEOPLASMS
DC and histiocyte/macrophage neoplasms are extremely rare. DCs
are antigen-presenting cells, whereas histiocyte/macrophages are
antigen-processing. BM myeloid stem cells (CD34+) give rise to mono-
Oncology and Hematology
cyte (CD14+, CD68+, CD11c+, CD1a–) and DC (CD14-, CD11c+/–,
CD1a+/c) precursors. Monocyte precursors, in turn, give rise to macro-
phages (CD14+, CD68+, CD11c+, CD163+, lysozyme+) and interstitial
DCs (CD68+, CD1a–). DC precursors give rise to Langerhans cell DCs
(Birbeck granules, CD1a+, S100+, langerin+) and plasmacytoid DCs
(CD68+, CD123+). Follicular DCs (CD21+, CD23+, CD35+) originate
from mesenchymal stem cells. Dendritic and histiocytic neoplasms are
operationally classified into macrophage/histiocyte-related and DC-
related. The former includes histiocytic sarcoma/malignant histiocyto-
sis (MH) and the latter Langerhans cell (LC) histiocytosis, LC sarcoma,
interdigitating DC sarcoma, and follicular DC sarcoma.
Histiocytic Sarcoma/Malignant Histiocytosis  Histiocytic
sarcoma represents malignant proliferation of mature tissue histiocytes
and is often localized. Median age at diagnosis is estimated at 46 years
with slight male predilection. Some patients might have history of lym-
phoma, MDS, or germ cell tumors at time of disease presentation. The
three typical disease sites are lymph nodes, skin, and the gastrointesti-
nal system. Patients may or may not have systemic symptoms including
fever and weight loss, and other symptoms include hepatosplenomeg-
aly, lytic bone lesions, and pancytopenia. Immunophenotype includes
presence of histiocytic markers (CD68, lysozyme, CD11c, CD14) and
absence of myeloid or lymphoid markers. Prognosis is poor and treat-
ment often ineffective. The term MH refers to a disseminated disease
and systemic symptoms. Lymphoma-like treatment induces complete
remissions in some patients and median survival is estimated at 2 years.
Langerhans Cell Histiocytosis  LCs are specialized DCs that
reside in mucocutaneous tissue and upon activation become special-
ized for antigen presentation to T cells. LC histiocytosis (LCH; also
known as histiocytosis X) represents neoplastic proliferation of LCs
(S-100+, CD1a+, and Birbeck granules on electron microscopy). LCH
incidence is estimated at 5 per million and the disease typically
affects children with a male predilection. Presentation can be either
uni- (eosinophilic granuloma) or multi-focal. The former usually
affects bones and less frequently lymph nodes, skin, and lung, while
the latter is more disseminated. Unifocal disease often affects older
children and adults while multisystem disease affects infants. LCH
of the lung in adults is characterized by bilateral nodules. Prognosis
depends on organs involved. Only 10% of patients progress from
unifocal to multiorgan disease. LCH of the lung might improve upon
cessation of smoking. Approximately 55% of patients with LCH harbor
Harrisons_20e_Part4_p0435-p0858.indd 792
BRAFV600E gain-of-function mutations, which indicates high-risk
disease and resistance to first-line therapy, while responses to targeted
therapy with vemurafenib have been reported.
Langerhans Cell Sarcoma  Langerhans cell sarcoma (LCS) also
represents neoplastic proliferation of LCs with overtly malignant mor-
phology. The disease can present de novo or progress from antecedent
LCH. There is a female predilection and median age at diagnosis is
estimated at 41 years. Immunophenotype is similar to that seen in LCH
and liver, spleen, lung, and bone are the usual sites of disease. Progno-
sis is poor and treatment generally ineffective.
Interdigitating Dendritic Cell Sarcoma  Interdigitating DC
sarcoma (IDCS), also known as reticulum cell sarcoma, represents
neoplastic proliferation of IDCs. The disease is extremely rare and
affects elderly adults with no sex predilection. Typical presentation is
asymptomatic solitary lymphadenopathy. Immunophenotype includes
S-100+ and negative for vimentin and CD1a. Prognosis ranges from
benign local disease to widespread lethal disease.
Follicular Dendritic Cell Sarcoma  FDC reside in B-cell folli-
cles and present antigen to B cells. FDC neoplasms (FDCN) are usually
localized and often affect adults. FDCN might be associated with
Castleman’s disease in 10–20% of cases and increased incidence in
schizophrenia has been reported. Cervical lymph nodes are the most
frequent site of involvement in FDCN and other sites include max-
illary, mediastinal, and retroperitoneal lymph nodes, oral cavity, the
gastrointestinal system, skin, and breast. Sites of metastasis include
lung and liver. Immunophenotype includes CD21, CD35, and CD23.
Clinical course is typically indolent, and treatment includes surgical
excision followed by regional radiotherapy and sometimes systemic
chemotherapy.
Hemophagocytic Syndromes  HPS represents non-neoplastic
proliferation and activation of macrophages that induces cytokine-
mediated BM suppression and features of intense phagocytosis in
BM and liver. HPS may result from genetic or acquired disorders
of macrophages. The former entail genetically determined inability
to regulate macrophage proliferation and activation. Acquired HPS
is often precipitated by viral infections, most notably Epstein-Barr
virus. HPS might also accompany certain malignancies such as T-cell
lymphoma. It is characterized by pancytopenia and elevated ferritin
levels. Interferon g is thought to play a role. Clinical course is often
fulminant and fatal.
■■FURTHER READING
Arber DA et al: The 2016 revision to the World Health Organization
classification of myeloid neoplasms and acute leukemia. Blood
127:2391, 2016.
Haroche J et al: Dramatic efficacy of vemurafenib in both multisys-
temic and refractory Erdheim-Chester disease and Langerhans cell
histiocytosis harboring the BRAF V600E mutation. Blood 121:1495,
2013.
Lortholary O et al: Masitinib for treatment of severely symptomatic
indolent systemic mastocytosis: a randomised, placebo-controlled,
phase 3 study. Lancet 389:612, 2017.
Maxson JE et al: Oncogenic CSF3R mutations in chronic neutrophilic
leukemia and atypical CML. N Engl J Med 368:1781, 2013.
Pardanani A et al: Predictors of survival in WHO-defined hypereo-
sinophilic syndrome and idiopathic hypereosinophilia and the role of
next-generation sequencing. Leukemia 30:1924, 2016.
Patnaik MM et al: Mayo prognostic model for WHO-defined chronic
myelomonocytic leukemia: ASXL1 and spliceosome component
mutations and outcomes. Leukemia 27:1504, 2013.
Swerdlow SH et al: The 2016 revision of the World Health Organiza-
tion classification of lymphoid neoplasms. Blood 127(20):2375, 2016.
Taylor J et al: Diagnosis and classification of hematologic malignancies
on the basis of genetics. Blood 130:410, 2017.
Thompson PA, Ravandi F: How I manage hairy cell leukemia. Br J
Haematol 177:543, 2017.
6/1/18 5:44 PM

107 Plasma Cell Disorders
Nikhil C. Munshi, Dan L. Longo,
Kenneth C. Anderson
The plasma cell disorders are monoclonal neoplasms related to each
other by virtue of their development from common progenitors in the
late B-lymphocyte lineage. Multiple myeloma (MM), Waldenström’s
macroglobulinemia, primary amyloidosis (Chap. 108), and the heavy
chain diseases comprise this group and may be designated by a vari-
ety of synonyms such as monoclonal gammopathies, paraproteinemias,
plasma cell dyscrasias, and dysproteinemias. Mature B lymphocytes des-
tined to produce IgG bear surface immunoglobulin molecules of both
μ and γ heavy chain isotypes with both isotypes having identical idi-
otypes (variable regions). Under normal circumstances, maturation to
antibody-secreting plasma cells and their proliferation is stimulated
by exposure to the antigen for which the surface immunoglobulin is
specific; however, in the plasma cell disorders, the control over this
process is lost. The clinical manifestations of all the plasma cell disor-
ders relate to the expansion of the neoplastic cells, to the secretion of
cell products (immunoglobulin molecules or subunits, lymphokines),
and to some extent to the host’s response to the tumor. Normal devel-
opment of B lymphocytes is discussed in Chap. 342 and depicted in
Fig. 104-2.
Three categories of structural variation are present among immu-
noglobulin molecules that form antigenic determinants, and these are
used to classify immunoglobulins. Isotypes are those determinants that
distinguish among the main classes of antibodies of a given species
and are the same in all normal individuals of that species. Therefore,
isotypic determinants are, by definition, recognized by antibodies from
a distinct species (heterologous sera) but not by antibodies from the
same species (homologous sera). There are five heavy chain isotypes
(M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are distinct
determinants that reflect regular small differences between individuals
of the same species in the amino acid sequences of otherwise similar
immunoglobulins. These differences are determined by allelic genes;
by definition, they are detected by antibodies made in the same spe-
cies. Idiotypes are the third category of antigenic determinants. They
are unique to the molecules produced by a given clone of antibody-
producing cells. Idiotypes are formed by the unique structure of the
antigen-binding portion of the molecule.
Antibody molecules (Fig. 107-1) are composed of two heavy chains
(~50,000 mol wt) and two light chains (~25,000 mol wt). Each chain
has a constant portion (limited amino acid sequence variability) and
a variable region (extensive sequence variability). The light and heavy
chains are linked by disulfide bonds and are aligned so that their vari-
able regions are adjacent to one another. This variable region forms the
antigen recognition site of the antibody molecule; its unique structural
features form idiotypes that are reliable markers for a particular clone
of cells because each antibody is formed and secreted by a single clone.
Because of the mechanics of the gene rearrangements necessary to
specify the immunoglobulin variable regions (VDJ joining for the heavy
chain, VJ joining for the light chain), a particular clone rearranges only
one of the two chromosomes to produce an immunoglobulin molecule
of only one light chain isotype and only one allotype (allelic exclusion)
(Fig. 107-1). After exposure to antigen, the variable region may become
associated with a new heavy chain isotype (class switch). Each clone
of cells performs these sequential gene arrangements in a unique way.
This results in each clone producing a unique immunoglobulin mole-
cule. In most plasma cells, light chains are synthesized in slight excess,
secreted as free light chains, and cleared by the kidney, but <10 mg of
such light chains is excreted per day.
Electrophoretic analysis permits separation of components of the
serum proteins (Fig. 107-2). The immunoglobulins move heteroge-
neously in an electric field and form a broad peak in the gamma region,
which is usually increased in the sera of patients with plasma cell
Harrisons_20e_Part4_p0435-p0858.indd 793
tumors. There is a sharp spike in this region called an M component (M 793
for monoclonal). Less commonly, the M component may appear in the
β2 or α2 globulin region. The monoclonal antibody must be present at a
concentration of at least 5 g/L (0.5 g/dL) to be accurately quantitated
by this method. This corresponds to ~109 cells producing the antibody.
Confirmation of the type of immunoglobulin and that it is truly mono-
clonal is determined by immunoelectrophoresis that reveals a single
heavy and/or light chain type. Hence immunoelectrophoresis and
electrophoresis provide qualitative and quantitative assessment of the
M component, respectively. Once the presence of an M component has
been confirmed, the amount of M component in the serum is a reliable
measure of the tumor burden, making M component an excellent tumor
marker to manage therapy, yet it is not specific enough to be used to
screen asymptomatic patients. In addition to the plasma cell disorders,
M components may be detected in other lymphoid neoplasms such as
chronic lymphocytic leukemia (CLL) and lymphomas of B- or T-cell
origin; nonlymphoid neoplasms such as chronic myeloid leukemia,
breast cancer, and colon cancer; a variety of nonneoplastic conditions
such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease, and
pyoderma gangrenosum; and a number of autoimmune conditions,
including rheumatoid arthritis, myasthenia gravis, and cold agglutinin
disease. Monoclonal proteins are also observed in immunosuppressed
CHAPTER 107 Plasma Cell Disorders
patients after organ transplant and, rarely, allogeneic transplant.
At least two very rare skin diseases—lichen myxedematosus (also
known as papular mucinosis) and necrobiotic xanthogranuloma—are
associated with a monoclonal gammopathy. In papular mucinosis,
highly cationic IgG is deposited in the dermis of patients. This organ
specificity may reflect the specificity of the antibody for some antigenic
component of the dermis. Necrobiotic xanthogranuloma is a histiocytic
infiltration of the skin, usually of the face, that produces red or yellow
nodules that can enlarge to plaques. Approximately 10% progress to
myeloma. Five percent of patients with sensory motor neuropathy also
have a monoclonal paraprotein.
The nature of the M component is variable in plasma cell disorders.
It may be an intact antibody molecule of any heavy chain subclass, or it
may be an altered antibody or fragment. Isolated light or heavy chains
may be produced. In some plasma cell tumors such as extramedullary
or solitary bone plasmacytomas, less than one-third of patients will
have an M component. In ~20% of myelomas, only light chains are
produced and, in most cases, are secreted in the urine as Bence Jones
proteins. The frequency of myelomas of a particular heavy chain class
is roughly proportional to the serum concentration, and therefore, IgG
myelomas are more common than IgA and IgD myelomas. In ∼1% of
patients with myeloma, biclonal or triclonal gammopathy is observed.
MULTIPLE MYELOMA
■■DEFINITION
MM represents a malignant proliferation of plasma cells derived from a
single clone. The tumor, its products, and the host response to it result
in a number of organ dysfunctions and symptoms, including bone pain
or fracture, renal failure, susceptibility to infection, anemia, hypercal-
cemia, and occasionally clotting abnormalities, neurologic symptoms,
and manifestations of hyperviscosity.
■■ETIOLOGY
The cause of myeloma is not known. Myeloma occurred with
increased frequency in those exposed to the radiation of nuclear
warheads in World War II after a 20-year latency. Myeloma has been
seen more commonly than expected among farmers, wood workers,
leather workers, and those exposed to petroleum products. A variety
of chromosomal alterations have been found in patients with mye-
loma: hyperdiploidy, 13q14 deletions, translocations t(11;14)(q13;q32),
t(4;14)(p16;q32), and t(14;16), 1q amplification or 1p deletion, and
17p13 deletions. Evidence is strong that errors in switch recombi-
nation—the genetic mechanism to change antibody heavy chain
isotype—participate in the early transformation process. However,
no single common molecular pathogenetic pathway has yet emerged.
Genome sequencing studies have failed to identify any recurrent
6/1/18 5:44 PM
 794
λ Light-chain locus
L1 Vλ1 L2 Vλ2 L Vλ–30 Jλ1 Cλ1 Jλ2 C λ2 Jλ4 Cλ4

κ Light-chain locus
L1 Vκ1 L2 Vκ 2 L3 Vκ3 L Vκ–36 Jκ1–5 Cκ

Heavy-chain locus
L1 VH1 L2 VH2 L3 VH3 LH VH–40 DH1–23 JH 1–6 Cµ

Light chain Heavy chain

C
L V J C L V D J

Germline DNA
PART 4

Somatic
recombination C
L V DJ
DNA

D–J rearranged
DNA joined
Oncology and Hematology

Somatic
recombination C
L V J C L V DJ
V–J or V–DJ joined
rearranged DNA

Transcription C
L V J C L V DJ
Primary AAA
AAA
transcript RNA
RNA

Splicing
C
L V J C L V DJ
mRNA AAA
AAA

Translation
CH3
VL CL
CH2

Polypeptide chain
Protein

VH CH1

FIGURE 107-1  Immunoglobulin genetics and the relationship of gene segments to the antibody protein. The top portion of the figure is a schematic of the organization
of the immunoglobulin genes, λ on chromosome 22, κ on chromosome 2, and the heavy chain locus on chromosome 14. The heavy chain locus is >2 megabases,
and some of the D region gene segments are only a few bases long, so the figure depicts the schematic relationship among the segments, not their actual size. The
bottom portion of the figure outlines the steps in going from the noncontiguous germline gene segments to an intact antibody molecule. Two recombination events
juxtapose the V-D-J (or V-J for light chains) segments. The rearranged gene is transcribed, and RNA splicing cuts out intervening sequences to produce an mRNA, which
is then translated into an antibody light or heavy chain. The sites on the antibody that bind to antigen (the so-called CDR3 regions) are encoded by D and J segments
for heavy chains and the J segments for light chains. (From K Murphy: Janeway’s Immunobiology, 8th ed. Garland Science, 2011.)

mutation with frequency >20%; N-ras, K-ras, and B-raf mutations are
most common and combined occur in >40% of patients. Evidence of
complex clusters of subclonal variants is present at diagnosis, acquires
additional mutations over time, indicative of genomic evolution that
may drive disease progression. Interleukin (IL) 6 may play a role in
driving myeloma cell proliferation. It remains difficult to distinguish
benign from malignant plasma cells based on morphologic criteria in
all but a few cases (Fig. 107-3).
■■INCIDENCE AND PREVALENCE
An estimated 30,280 new cases of myeloma were diagnosed in 2017,
and 12,590 people died from the disease in the United States. Mye-
loma increases in incidence with age. The median age at diagnosis is
69 years; it is uncommon under age 40. Males are more commonly
affected than females, and blacks have nearly twice the incidence of
whites. Myeloma accounts for 1.3% of all malignancies in whites and 2%
in blacks, and 13% of all hematologic cancers in whites and 33% in blacks.

Harrisons_20e_Part4_p0435-p0858.indd 794 6/1/18 5:44 PM

 795

SP G A M Κ λ SP G A M Κ λ SP G A M Κ λ

CHAPTER 107 Plasma Cell Disorders

Normal Polyclonal increase Monoclonal IgG lambda

FIGURE 107-2  Representative patterns of serum electrophoresis and immunofixation. The upper panels represent agarose gel, middle panels are the densitometric
tracing of the gel, and lower panels are immunofixation patterns. Panel on the left illustrates the normal pattern of serum protein on electrophoresis. Because there
are many different immunoglobulins in the serum, their differing mobilities in an electric field produce a broad peak. In conditions associated with increases in
polyclonal immunoglobulin, the broad peak is more prominent (middle panel). In monoclonal gammopathies, the predominance of a product of a single cell produces
a “church spire” sharp peak, usually in the γ globulin region (right panel). The immunofixation (lower panel) identifies the type of immunoglobulin. For example, normal
and polyclonal increase in immunoglobulins produce no distinct bands; however, the right panel shows distinct bands in IgG and lambda protein lanes, confirming the
presence of IgG lambda monoclonal protein. (Courtesy of Dr. Neal I. Lindeman; with permission.)

■■GLOBAL CONSIDERATIONS ■■PATHOGENESIS AND CLINICAL MANIFESTATIONS

The incidence of myeloma is highest in African Americans and
Pacific Islanders; intermediate in Europeans and North Amer-
ican whites; and lowest in people from developing countries
including Asia. The higher incidence in more developed countries may
result from the combination of a longer life expectancy and more fre-
quent medical surveillance. Incidence of MM in other ethnic groups
including native Hawaiians, female Hispanics, American Indians from
New Mexico, and Alaskan natives is higher relative to U.S. whites in
the same geographic area. Chinese and Japanese populations have a
lower incidence than whites. Immunoproliferative small-intestinal dis-
ease (IPSID) with alpha heavy chain disease is most prevalent in the
Mediterranean area. Despite these differences in prevalence, the char-
acteristics, response to therapy, and prognosis of myeloma are similar
worldwide.
FIGURE 107-3  Multiple myeloma (marrow). The cells bear characteristic
morphologic features of plasma cells, round or oval cells with an eccentric nucleus
composed of coarsely clumped chromatin, a densely basophilic cytoplasm,
and a perinuclear clear zone containing the Golgi apparatus. Binucleate and
multinucleate malignant plasma cells can be seen.
MM cells bind via cell-surface adhesion molecules to bone marrow
stromal cells (BMSCs) and extracellular matrix (ECM), which triggers
MM cell growth, survival, drug resistance, and migration in the bone
marrow milieu (Fig. 107-4). These effects are due both to direct MM
cell–BMSC binding via adhesion molecules and to induction of vari-
ous cytokines, including IL-6, insulin-like growth factor type I (IGF-I),
vascular endothelial growth factor (VEGF), and stromal cell–derived
growth factor (SDF)-1α. Growth, drug resistance, and migration are
mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt,
and protein kinase C signaling cascades, respectively.
Bone pain is the most common symptom in myeloma, affecting nearly
70% of patients. Persistent localized pain usually signifies a pathologic
fracture. The bone lesions of myeloma are caused by the proliferation
of tumor cells, activation of osteoclasts that destroy bone, and suppres-
sion of osteoblasts that form new bone. The increased osteoclast activ-
ity is mediated by osteoclast activating factors (OAFs) produced by the
myeloma cells (mediated by several cytokines, including IL-1, lympho-
toxin, VEGF, receptor activator of NF-κB [RANK] ligand, macrophage
inhibitory factor [MIP]-1α, and tumor necrosis factor [TNF]). The bone
lesions are lytic in nature (Fig. 107-5) and are rarely associated with
osteoblastic new bone formation due to their suppression by dickhoff-1
(DKK-1) produced by myeloma cells. Therefore, radioisotopic bone
scanning is less useful in diagnosis than is plain radiography. The bony
lysis results in substantial mobilization of calcium from bone, and seri-
ous acute and chronic complications of hypercalcemia may dominate
the clinical picture (see below). Localized bone lesions may cause the
collapse of vertebrae leading to spinal cord compression. The next most
common clinical problem in patients with myeloma is susceptibility to
bacterial infections. The most common infections are pneumonias and
pyelonephritis, and the most frequent pathogens are Streptococcus pneu-
moniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and
Escherichia coli and other gram-negative organisms in the urinary tract.
In ~25% of patients, recurrent infections are the presenting features,
and >75% of patients will have a serious infection at some time in their
course. The susceptibility to infection has several contributing causes.
First, patients with myeloma have diffuse hypogammaglobulinemia if

Harrisons_20e_Part4_p0435-p0858.indd 795 6/1/18 5:44 PM

 796
MM cell
Cytokine-mediated
signaling
Adhesion-mediated
signaling
Cytokines Adhesion
IL-6 molecules
VEGF
interactions
IGF-1
SDF-1α
NF-κB
BMSC
PART 4
FIGURE 107-4  Pathogenesis of multiple myeloma. Multiple myeloma (MM) cells interact with bone marrow stromal cells (BMSCs) and extracellular matrix proteins via
Oncology and Hematology
adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival,
and antiapoptotic effects as well as development of drug resistance.
the M component is excluded. The hypogammaglobulinemia is related
to both decreased production and increased destruction of normal
antibodies. The large M component results in fractional catabolic rates
of 8–16% instead of the normal 2%. Moreover, some patients generate a
population of circulating regulatory cells in response to their myeloma
that can suppress normal antibody synthesis. These patients have very
poor antibody responses, especially to polysaccharide antigens such as
those on bacterial cell walls. Various abnormalities in T-cell function are
also observed including decreased Th1 response, increase in Th17 cells
producing proinflammatory cytokines, and aberrant Treg cell function.
Granulocyte lysozyme content is low, and granulocyte migration is not
as rapid as normal in patients with myeloma, probably the result of a
tumor product. There are also a variety of abnormalities in comple-
ment functions in myeloma patients. All these factors contribute to the
immune deficiency in these patients. Some commonly used therapeutic
agents, e.g., dexamethasone, suppress immune responses and increase
susceptibility to bacterial and fungal infection, and bortezomib predis-
poses to herpesvirus reactivation.
Renal failure occurs in nearly 25% of myeloma patients, and some
renal pathology is noted in >50%. Of many contributing factors,
hypercalcemia is the most common cause of renal failure. Glomerular
deposits of amyloid, hyperuricemia, recurrent infections, frequent use
of nonsteroidal anti-inflammatory agents for pain control, use of iodi-
nated contrast dye for imaging, bisphosphonate use, and occasional
infiltration of the kidney by myeloma cells all may contribute to renal
dysfunction. However, tubular damage associated with the excretion
of light chains is almost always present. Normally, light chains are
filtered, reabsorbed in the tubules, and catabolized. With the increase
in the amount of light chains presented to the tubule, the tubular cells
become overloaded with these proteins, and tubular damage results
either directly from light chain toxic effects or indirectly from the
release of intracellular lysosomal enzymes. The earliest manifestation
of this tubular damage is the adult Fanconi’s syndrome (a type 2 prox-
imal renal tubular acidosis), with loss of glucose and amino acids, as
well as defects in the ability of the kidney to acidify and concentrate
the urine. The proteinuria is not accompanied by hypertension, and
the protein is nearly all light chains. Generally, very little albumin is
Harrisons_20e_Part4_p0435-p0858.indd 796
Raf MEK p42/44 MAPK Proliferation
BCl-xL
JAK STAT3
Mcl-1 Drug
resistance
anti
apoptosis
Bad
PI3-K Akt NF-κB Cyclin D
Cell cycle
FKHR p21
PKC Migration
in the urine because glomerular function is usually normal. When
the glomeruli are involved, nonselective proteinuria is also observed.
Patients with myeloma also have a decreased anion gap [i.e., Na+ –
(Cl− + HCO3−)] because the M component is cationic, resulting in reten-
tion of chloride. This is often accompanied by hyponatremia that is felt
to be artificial (pseudohyponatremia) because each volume of serum
has less water as a result of the increased protein. Renal dysfunction
due to light chain deposition disease, light chain cast nephropathy,
and amyloidosis is partially reversible with effective therapy. Myeloma
patients are susceptible to developing acute renal failure if they become
dehydrated.
Normocytic and normochromic anemia occurs in ~80% of myeloma
patients. It is usually related to the replacement of normal marrow by
expanding tumor cells, to the inhibition of hematopoiesis by factors
made by the tumor, to reduced production of erythropoietin by the
kidney, and to the effects of long-term therapy. In addition, mild hemo-
lysis may contribute to the anemia. A larger than expected fraction of
patients may have megaloblastic anemia due to either folate or vitamin
B12 deficiency. Granulocytopenia and thrombocytopenia are rare except
when therapy-induced. Clotting abnormalities may be seen due to the
failure of antibody-coated platelets to function properly; the interaction
of the M component with clotting factors I, II, V, VII, or VIII; antibody
to clotting factors; or amyloid damage of endothelium. Deep venous
thrombosis is also observed with use of thalidomide, lenalidomide,
or pomalidomide in combination with dexamethasone. Raynaud’s
phenomenon and impaired circulation may result if the M component
forms cryoglobulins, and hyperviscosity syndromes may develop
depending on the physical properties of the M component (most com-
mon with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined
based on the relative viscosity of serum as compared with water.
Normal relative serum viscosity is 1.8 (i.e., serum is normally almost
twice as viscous as water). Symptoms of hyperviscosity occur at a level
greater than 4 centipoise (cP), which is usually reached at paraprotein
concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3,
and 70 g/L (7 g/dL) for IgA; however, depending on chemical and
physical properties of the paraprotein molecule, it can occasionally be
observed at lower levels.
6/1/18 5:44 PM

A loma, occurring in 1% of the population aged >50 years and in up to 10%
B especially sensitive for identifying low concentrations of M compo-
FIGURE 107-5  Bony lesions in multiple myeloma (MM). A. The skull demonstrates
the typical “punched out” lesions characteristic of MM. The lesion represents a
purely osteolytic lesion with little or no osteoblastic activity (above). B. PET/CT
showing multiple fluorodeoxyglucose (FDG)-avid lesions in skeleton (left panel)
with their resolution on achieving complete response (CR) (right panel). (Part A
courtesy of Dr. Geraldine Schechter; with permission. Part B courtesy of Dr. Sundar
Jagannath; with permission.)
Although neurologic symptoms occur in a minority of patients, they
may have many causes. Hypercalcemia may produce lethargy, weak-
ness, depression, and confusion. Hyperviscosity may lead to headache,
fatigue, shortness of breath, exacerbation or precipitation of heart fail-
ure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, and
coma. Bony damage and collapse may lead to cord compression, radic-
ular pain, and loss of bowel and bladder control. Infiltration of periph-
eral nerves by amyloid can be a cause of carpal tunnel syndrome and
other sensorimotor mono- and polyneuropathies. Neuropathy asso-
ciated with monoclonal gammopathy of undetermined significance
(MGUS) and myeloma is more frequently sensory than motor neur-
opathy and is associated with IgM more than other isotypes. In >50%
Harrisons_20e_Part4_p0435-p0858.indd 797
of patients with neuropathy, the IgM monoclonal protein is directed 797
against myelin-associated globulin (MAG). Sensory neuropathy is also
a side effect of therapy, specifically thalidomide and bortezomib.
Many of the clinical features of myeloma, e.g., cord compression,
pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can
present as medical emergencies. Despite the widespread distribution of
plasma cells in the body, tumor expansion is dominantly within bone
and bone marrow and, for reasons unknown, rarely causes enlarge-
ment of spleen, lymph nodes, or gut-associated lymphatic tissue.
■■DIAGNOSIS AND STAGING
The diagnosis of myeloma requires marrow plasmacytosis (>10%), a
serum and/or urine M component, and at least one of the myeloma
defining events detailed in Table 107-1. Bone marrow plasma cells are
CD138+ and either monoclonal kappa or lambda light chain positive.
The most important differential diagnosis in patients with myeloma
involves their separation from individuals with MGUS or smoldering
multiple myeloma (SMM). MGUS is vastly more common than mye-
of individuals aged >75 years. The diagnostic criteria for MGUS, SMM,
and myeloma are described in Table 107-1. Although ~1% of patients per
year with MGUS go on to develop myeloma, all cases of myeloma are
CHAPTER 107 Plasma Cell Disorders
preceded by MGUS. Non-IgG subtype, abnormal kappa/lambda free
light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated
with higher incidence of progression of MGUS to myeloma. Absence of
all three features predicts a 5% chance of progression, whereas higher
risk MGUS with the presence of all three features predicts a 60% chance
of progression >20 years. The features responsible for higher risk of
progression from SMM to MM are bone marrow plasmacytosis >10%,
abnormal kappa/lambda free light chain ratio, and serum M protein
>30 g/L (3 g/dL). Patients with only one of these three features have
a 25% chance of progression to MM in 5 years, whereas patients with
high-risk SMM with all three features have a 76% chance of progres-
sion. There are two important variants of myeloma—solitary bone plas-
macytoma and solitary extramedullary plasmacytoma. These lesions
are associated with an M component in <30% of the cases, they may
affect younger individuals, and both are associated with median sur-
vivals of ≥10 years. Solitary bone plasmacytoma is a single lytic bone
lesion without marrow plasmacytosis. Extramedullary plasmacytomas
usually involve the submucosal lymphoid tissue of the nasopharynx
or paranasal sinuses without marrow plasmacytosis. Both tumors are
highly responsive to local radiation therapy. If an M component is pres-
ent, it should disappear after treatment. Solitary bone plasmacytomas
may recur in other bony sites or evolve into myeloma. Extramedullary
plasmacytomas rarely recur or progress.
Serum protein electrophoresis and measurement of serum immu-
noglobulins and free light chains are useful for detecting and charac-
terizing M spikes, supplemented by immunoelectrophoresis, which is
nents not detectable by protein electrophoresis. A 24-h urine specimen
is necessary to quantitate Bence Jones protein excretion. Serum alkaline
phosphatase is usually normal even with extensive bone involvement
because of the absence of osteoblastic activity. It is also important to
quantitate serum β2-microglobulin and albumin (see below).
The serum M component will be IgG in 53% of patients, IgA in 25%,
and IgD in 1%; 20% of patients will have only light chains in serum and
urine. Dipsticks for detecting proteinuria are not reliable at identifying
light chains, and the heat test for detecting Bence Jones protein is falsely
negative in ~50% of patients with light chain myeloma. Fewer than 1%
of patients have no identifiable M component; these patients usually
have light chain myeloma in which renal catabolism has made the light
chains undetectable in the urine. In most of these patients, light chains
can now be detected by serum free light chain assay. IgD myeloma
may also present with light chain disease. About two-thirds of patients
with serum M components also have urinary light chains. The light
chain isotype may have an impact on disease behavior. Whether this is
due to some genetically important determinant of cell proliferation or
because lambda light chains are more likely to cause renal damage and
form amyloid than are kappa light chains is unclear. The heavy chain
6/1/18 5:44 PM
 798 TABLE 107-1  Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined Significance
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Serum monoclonal protein (non-IgM type) <30 g/L
Clonal bone marrow plasma cells <10%*
Absence of myeloma defining events or amyloidosis that can be attributed to the plasma cell proliferative disorder
Smoldering Multiple Myeloma (Asymptomatic Myeloma)
Both criteria must be met:
•  Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%
•  Absence of myeloma defining events or amyloidosis
Symptomatic Multiple Myeloma
Clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytomaa and any one or more of the following myeloma defining events:
•  Evidence of one or more end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
•  Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
•  Renal insufficiency: creatinine clearance <40 mL per minb or serum creatinine >177 μmol/L (>2 mg/dL)
•  Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L
•  Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc
•  Any one or more of the following biomarkers of malignancy:
•  Clonal bone marrow plasma cell percentagea ≥60%
•  Involved: uninvolved serum free light chain ratiod ≥100
•  >1 focal lesions on MRI studiese
Nonsecretory Myeloma
PART 4

No M protein in serum and/or urine with immunofixationf

Bone marrow clonal plasmacytosis ≥10% or plasmacytomaa
Myeloma-related organ or tissue impairment (end-organ damage, as described above)
Solitary Plasmacytoma
Oncology and Hematology

Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Normal bone marrow with no evidence of clonal plasma cellsa
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell
proliferative disorder
POEMS Syndrome
All of the following four criteria must be met:
1. Polyneuropathy
2.  Monoclonal plasma cell proliferative disorder
3.  Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease; (c) elevated levels of vascular endothelial growth factor (VEGF)
4. Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or
ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiag
PET-CT=18F-fluorodeoxyglucose PET with CT. aClonality should be established by showing κ/λ-light-chain restriction on flow cytometry, immunohistochemistry, or
immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate
and core biopsy, the highest value should be used. bMeasured or estimated by validated equations. CIf bone marrow has less than 10% clonal plasma cells, more than
one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement. dThese values are based on the serum Freelite assay (The
Binding Site Group, Birmingham, UK). The involved free light chain must be ≥100 mg/L. eEach focal lesion must be 5 mm or more in size. fA small M component may
sometimes be present. gThese features should have no attributable other causes and have temporal relation with each other.
Abbreviation: POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes.

isotype may have an impact on patient management as well. About
half of patients with IgM paraproteins develop hyperviscosity com-
pared with only 2–4% of patients with IgA and IgG M components.
Among IgG myelomas, it is the IgG3 subclass that has the highest
tendency to form both concentration- and temperature-dependent
aggregates, leading to hyperviscosity and cold agglutination at lower
serum concentrations. A standard workup directed at detecting mono-
clonal plasma cells and myeloma-defining events as well as prognosis
is detailed in Table 107-2. A complete blood count with differential
may reveal anemia. Erythrocyte sedimentation rate is elevated. Rare
patients (~1%) may have plasma cell leukemia with >2000 plasma
cells/μL. This may be seen in disproportionate frequency in IgD (12%)
and IgE (25%) myelomas. Serum calcium, urea nitrogen, creatinine, and
uric acid levels may be elevated.
The clinical evaluation of patients with myeloma includes a care-
ful physical examination searching for tender bones and masses.
Chest and bone radiographs may reveal lytic lesions or diffuse oste-
openia. Magnetic resonance imaging (MRI) offers a sensitive means
to document extent of bone marrow infiltration and cord or root
compression in patients with pain syndromes. 18F-fluorodeoxyglucose
(18F-FDG) PET/CT is a valuable tool to assess bone damage and
detect extramedullary sites of the disease (Fig. 107-5). The use of
18
F-FDG PET/CT is recommended to distinguish between smolder-
ing and active MM and to confirm a suspected diagnosis of solitary
plasmacytoma. It is also a valuable tool to evaluate response in
patients with oligo- or nonsecretory myeloma.
■■PROGNOSIS
Serum β2-microglobulin is the single most powerful predictor of sur-
vival and can substitute for staging. β2-Microglobulin is the light chain
of the class I major histocompatibility antigens (HLA-A, -B, -C) on
the surface of every cell. Combination of serum β2-microglobulin and
albumin levels forms the basis for a three-stage International Staging
System (ISS) (Table 107-3) that predicts survival. With the use of high-
dose therapy and the newer agents, the Durie-Salmon staging system
is unable to predict outcome and thus is no longer used. High labeling

Harrisons_20e_Part4_p0435-p0858.indd 798 6/1/18 5:44 PM

 TABLE 107-2  Standard Investigative Workup in MM TABLE 107-3  Risk Stratification in Myeloma 799

Investigations to Evaluate for Clonal Plasma Cells CHROMOSOMAL ABNORMALITIES

Bone marrow aspirate and biopsy (fine needle aspiration of plasmacytoma if STANDARD RISK (80%) HIGH RISK (20%)
indicated) (EXPECTED SURVIVAL (EXPECTED SURVIVAL
- Histology METHOD 6–7+ YEARS) 2–3 YEARS)
- Clonality by kappa/lambda immunostaining by flow cytometry or Karyotype No chromosomal aberration Any abnormality on
immunohistochemistry conventional karyotype
Investigations to Evaluate Clonal Paraprotein FISH t(11;14) Del(17p)
t(6:14) t(4:14)
Serum protein electrophoresis and immunofixation
Del(13) t(14:16)
Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
t(14;20)
24-h Urine protein electrophoresis and immunofixation
amp 1q34
Serum free light chain and ratio
Immunofixation for IgD or IgE in select cases INTERNATIONAL STAGING SYSTEM
Investigation to Evaluate End-Organ Damage MEDIAN SURVIVAL,
STAGE MONTHS
Hemogram to assess for anemia
β2M <3.5, alb ≥3.5 I (28%)a 62
Chemistry panel for renal function and calcium
β2M <3.5, alb <3.5 or II (39%) 44
Skeletal survey to evaluate bone lesions
β2M = 3.5–5.5
- PET/CT or MRI if SMM or solitary plasmacytoma with no other MDE or
β2M >5.5 III (33%) 29
extramedullary disease
Other features suggesting high-risk disease:
Investigation for Risk Stratification
  De novo plasma cell leukemia

CHAPTER 107 Plasma Cell Disorders

- b-2 microglobulin and serum albumin for ISS stage
- Fluorescent in situ hybridization for hyperdipoidy, del17p, t(4;14); t(14;16),
amp1q34, and del 13 on bone marrow sample
- LDH
Specialized Investigation in Selected Cases
Abdominal fat pad for amyloid
Serum viscosity if IgM component or high IgA levels or serum M-component
>7 g/dL
Abbreviations: ISS, International Staging System; LDH, lactate dehydrogenase;
MRI, magnetic resonance imaging; PET/CT, positron emission tomography/
computerized tomography.
index, circulating plasma cells, performance status, and high levels of
lactate dehydrogenase are also associated with poor prognosis.
Other factors that may influence prognosis are the presence of
cytogenetic abnormalities and hypodiploidy by karyotype, fluorescent
in situ hybridization (FISH)–identified chromosome 17p deletion,
and translocations t(4;14), (14;16), and t(14;20) and 1q34 amplifica-
tion. Chromosome 13q deletion, previously thought to predict poor
outcome, is not a predictor following the use of newer agents. The
ISS system, along with cytogenetic changes, is the most widely used
method for assessing prognosis (Table 107-3). Microarray profiling has
formed the basis for RNA-based prognostic staging systems. Genome
sequencing efforts have allowed for characterization of critical genes,
pathways, and clonal heterogeneity in myeloma. The median number
of mutations per transcribed genome in myeloma is around 58. A very
heterogeneous mutational landscape with no unifying mutation has
been observed. The most frequently mutated genes are KRAS and
NRAS (about 20% each), followed by TP53, DIS3, FAM46C, and BRAF,
all mutated in 5–10% of the patients. All other mutations were observed
in <5% of the patients. These results are now being applied to develop
new targeted personalized therapies in myeloma.
TREATMENT
Multiple Myeloma
No specific intervention is indicated for patients with MGUS.
Follow-up once a year or less frequently is adequate except in higher
risk MGUS, where serum protein electrophoresis, complete blood
count, creatinine, and calcium should be repeated every 6 months.
A patient with MGUS and severe polyneuropathy is considered for
therapeutic intervention if a causal relationship can be assumed,
especially in the absence of any other potential causes for neuropa-
thy. Therapy can include plasmapheresis and occasionally rituximab
in patients with IgM MGUS or myeloma-like therapy in those with
  Extramedullary disease
  Elevated lactate dehydrogenate (LDH)
  High-risk gene expression profile
a
Percentage of patients presenting at each stage.
Abbreviations: β2M, serum β2-microglobulin in mg/L; alb, serum albumin in g/dL;
FISH, fluorescent in situ hybridization.
IgG or IgA disease. About 10% of patients have smoldering MM
(SMM) and will have an indolent course demonstrating only slow
progression of disease over many years. For patients with SMM,
no specific therapeutic intervention is indicated, although early
intervention with lenalidomide and dexamethasone may prevent
progression from high-risk SMM to active MM. At present, patients
with SMM only require antitumor therapy when myeloma-defining
events are identified. Patients with solitary bone plasmacytomas
and extramedullary plasmacytomas may be expected to enjoy pro-
longed disease-free survival after local radiation therapy at a dose
of around 40 Gy. Occult marrow involvement may occur at low inci-
dence in patients with solitary bone plasmacytoma. Such patients
are usually identified because their serum M component falls slowly
or disappears initially after local therapy, only to return after a few
months. These patients respond well to systemic therapy.
Patients with symptomatic and/or progressive myeloma require
therapeutic intervention. In general, such therapy has two purposes:
(1) systemic therapy to control myeloma; and (2) supportive care
to control symptoms of the disease, its complications, and adverse
effects of therapy. Therapy can significantly prolong survival and
improve the quality of life for myeloma patients.
The therapy of myeloma includes an initial induction regimen
followed by consolidation and/or maintenance therapy and, on
subsequent progression, management of relapsed disease. A num-
ber of agents available for use at various stages of the therapy and
their doses, schedules, and combinations are detailed in Table 107-4.
Therapy is partly dictated by the patient’s age and comorbidities,
which may affect a patient’s ability to undergo high-dose therapy
and transplantation (Fig. 107-6).
Thalidomide, when combined with dexamethasone, achieved
responses in two-thirds of newly diagnosed MM patients. Subse-
quently, lenalidomide, an immunomodulatory derivative of tha-
lidomide, and bortezomib, a proteasome inhibitor, have each been
combined with dexamethasone with high response rates (>80%) in
newly diagnosed patients with MM. Importantly, their lower toxicity
profile with improved efficacy has made them the preferred agents
for induction therapy. Efforts to improve the depth of response and
the fraction of patients responding have involved using three-drug

Harrisons_20e_Part4_p0435-p0858.indd 799 6/1/18 5:44 PM

 800 TABLE 107-4  Standard Therapeutic Agents in Myeloma
CLASS AGENT STANDARD DOSAGE AND ADMINISTRATION COMBINATION MYELOMA INDICATION
Immunomodulatory Thalidomide (T) Oral 50–200 mg qd TD, VTD Newly diagnosed and relapsed
agents
Lenalidomide (R) Oral 5–25 mg daily × 21 days q 4 week RD, RVD, DaRD, ERD, KRD, IRD Relapsed
Pomalidomide (P) Oral 2–4 mg daily × 21 days q 4 week PD Relapsed
Proteasome inhibitor Bortezomib (V) IV or SC 1.3 mg/m2 days 1, 4, 8, 11 OR 1, 8, VD, VTD, VRD, DaVD, VCD Newly diagnosed and relapsed
15
Carfilzomib (K) IV 20–56 mg/m2 days 1, 2, 8, 9, 15, 16 q 4 KD, KRD Relapsed
weeks
Ixazomib (I) Oral 4 mg days 1,8,15 IRD Relapsed
Antibodies Daratumumab (Da) IV 16 mg/kg/week for 8 weeks then every Dara, DaRD, DaVD Relapsed
2 weeks for 16 weeks and then every 4 weeks
thereafter
Elotuzumab (E) IV 10 mg/kg days 1, 8, 15, and 22 for first two EloRD Relapsed
cycles then on days 1 and 15. Along with RD
Histone deacetylase Panobinostat (Pa) PaVD Relapsed
inhibitor
Alkylating agents Melphalan (M) Oral melphalan, 0.25 mg/kg per day for 4 days MP, MPT, MPR, MPV, high-dose Newly diagnosed and relapsed
(with Pred) every 4–6 weeks M conditioning
Cyclophosphamide (C) IV—300–500 mg/m2 weekly × 2 q 4 weeks VCD Newly diagnosed and relapsed
Oral—50 mg qd × 21 days
Bendamustine (B) IV 70–90 mg days 1, 2 or days 1, 8 q 4 weeks BD or BVD Relapsed
PART 4

Steroid Dexamethasone (D) Oral 10–40 mg q week All stages

Prednisone (P) Oral 1 mg/kg
Oncology and Hematology

regimens. The combination of lenalidomide, bortezomib, and dex-
amethasone achieves close to a 100% response rate and 30% com-
plete response (CR) rate, making it one of the preferred induction
regimens in transplant-eligible patients. Other similar three-drug
combinations (bortezomib, thalidomide, and dexamethasone or
bortezomib, cyclophosphamide, and dexamethasone) also achieve
>90% response rate. Herpes zoster prophylaxis is indicated if borte-
zomib is used, and neuropathy attendant to bortezomib can be
decreased both by its subcutaneous administration and administra-
tion on a weekly schedule. Lenalidomide use requires prophylaxis
for deep-vein thrombosis (DVT) with either aspirin or if patients are
at a greater risk of DVT, warfarin or low-molecular-weight heparin.
In patients receiving lenalidomide, stem cells should be collected
within 6 months, because the continued use of lenalidomide may
compromise the ability to collect adequate numbers of stem cells.
Initial therapy is continued until maximal cytoreduction. In patients
who are transplant candidates, alkylating agents such as melpha-
lan should be avoided because they damage stem cells, leading to
decreased ability to collect stem cells for autologous transplant.
In patients who are not transplant candidates due to physi-
ologic age >70 years, significant cardiopulmonary problems, or
other comorbid illnesses, the same two- or three-drug combina-
tions described above are considered standard of care as induction
therapy. Previously, therapy consisting of intermittent pulses of

Newly diagnosed Smoldering myeloma

No therapy except on clinical study
No Regular follow-up
Myeloma defining events

Yes If appearance of MDE

Transplant eligible Transplant ineligible*

Induction therapy Induction therapy

RVD, VCD, VD or LD No response RVD-lite, VCD, VD, RD
till maximum effect VMP till maximum effect
Alternate
Response Response
regimen
HDT with ASCT/
consolidation
No
response
Maintenance Maintenance

Treatment of relapsed disease

alternate regimen
* Due to age or co-morbidities.

FIGURE 107-6  Treatment algorithm for multiple myeloma. C, cyclophosphamide; D, dexamethasone; M, melphalan; P, prednisone; R, lenalidomide; RVD-lite, weekly
regimen; V, bortezomib. Alternate regimen-combinations including daratumumab; elotuzumab; panobinostat; carfilzomib; ixazomib, pomalidomide or agents; ASCT,
autologous stem cell transplantation; HDT, high-dose therapy; MDE, myeloma defining events.

Harrisons_20e_Part4_p0435-p0858.indd 800 6/1/18 5:44 PM

 melphalan, an alkylating agent, with prednisone (MP) was used.
However, a number of studies have combined novel agents with
MP and reported superior response and survival outcomes. In
patients >65 years old, combining thalidomide with MP (MPT)
obtains higher response rates and overall survival compared with
MP alone. Similarly, significantly improved response (71 vs 35%)
and overall survival (3-year survival 72 vs 59%) were observed with
the combination of bortezomib and MP compared with MP alone.
Lenalidomide added to MP followed by lenalidomide maintenance
also prolonged progression-free survival compared with MP alone.
These combinations of novel agents with MP also achieve high CR
rates (MPT, ~15%; MP plus bortezomib, ~30%; MP plus lenalido-
mide, ~20%; and MP, ~2–4%). Continuous use of the lenalidomide
and dexamethasone combination appears to be superior to the
MPT regimen, making it a standard of care for older adults with
myeloma.
High-dose therapy (HDT) and consolidation/maintenance are
standard practice in the majority of eligible patients. Randomized
studies comparing standard-dose therapy to high-dose melphalan
therapy with hematopoietic stem cell support have shown that
HDT can achieve high overall response rates, with up to 25–40%
additional CRs and prolonged progression-free and overall survival;
however, few, if any, patients are cured. Although two successive
HDTs (tandem transplantations) are more effective than single
HDT, the benefit is only observed in the subset of patients who do
not achieve a complete or very good partial response to the first
transplantation, which is rare. Moreover, a randomized study failed
to show any significant difference in overall survival between early
transplantation after induction therapy versus delayed transplanta-
tion at relapse. These data allow an option to delay transplantation,
especially with the availability of more agents and combinations.
Allogeneic transplantations may also produce high response rates,
but with significant toxicities. Nonmyeloablative allogeneic trans-
plantation can reduce toxicity but is recommended only under
the auspices of a clinical trial to exploit an immune graft-versus-
myeloma effect while avoiding attendant toxicity.
Maintenance therapy prolongs remissions following standard-
dose regimens as well as HDT. Two phase 3 studies have demon-
strated improved progression-free survival, and one study showed
prolonged overall survival in patients receiving lenalidomide com-
pared to placebo as maintenance therapy after HDT. In nontransplant
candidates, two phase 3 studies showed prolonged progression-free
survival with lenalidomide maintenance after MP plus lenalidomide
or lenalidomide with dexamethasone induction therapy. Although
concern arises regarding an increased incidence of second primary
malignancies in patients receiving lenalidomide maintenance, its
benefits in reducing the risk of progressive disease and death from
myeloma far outweigh the small increased risk of second cancers. In
patients with high-risk cytogenetics, lenalidomide and bortezomib
have been combined and show promise as maintenance therapy
after transplantation.
Relapsed myeloma can be treated with a number of agents
including lenalidomide and/or bortezomib, if previously not used.
These agents in combination with dexamethasone can achieve a
partial response rate of up to 60% and a 10–15% CR rate in patients
with relapsed disease. The combination of bortezomib and liposo-
mal doxorubicin is active in relapsed myeloma. Thalidomide, if
not used as initial therapy, can achieve responses in refractory
cases. The second-generation proteasome inhibitor carfilzomib and
immunomodulatory agent pomalidomide have shown efficacy in
relapsed and refractory MM, even MM refractory to lenalidomide
and bortezomib. An oral proteasome inhibitor, ixazomib has also
been approved in combination with lenalidomide and dexametha-
sone as an all-oral regimen for relapsed MM. Two antibodies are
approved for treatment of relapsed MM. Daratumumab targeting
CD38 achieves high response rates and improved progression-free
survival as a single agent with further improvement in response
and survival when added to bortezomib and dexamethasone, or
lenalidomide and dexamethasone. Elotuzumab targeting SLAMF7
Harrisons_20e_Part4_p0435-p0858.indd 801
has shown significant activity in combination with lenalidomide 801
and dexamethasone in relapsed/refractory myeloma but not as a
single agent. Panobinostat, a histone deacetylase inhibitor, in com-
bination with bortezomib and dexamethasone has been approved
for treatment of relapsed refractory myeloma based on superior
response and progression-free survival compared to bortezomib
and dexamethasone alone. Incorporation of the large number of
active agents at various stages of therapies including in the newly
diagnosed patients is improving survival as well as quality of life.
Improvement in the serum M component may lag behind the
symptomatic improvement due to longer half-life (~3 weeks) of the
immunoglobulin. The fall in M component depends on the rate of
tumor kill and the fractional catabolic rate of immunoglobulin. Light
chain excretion, with a functional half-life of ~6 h, may fall within
the first week of treatment. Because urine light chain levels may
relate to renal tubular function, they are not a reliable measure of
tumor cell kill in patients with renal dysfunction; however, improve-
ments in serum free light chain measurement are often seen sooner.
Sequencing- and multicolor flow cytometry-based methods are now
used to assess minimal residual disease (MRD) in bone marrow.
Absence of MRD predicts longer survival. Although patients may
not achieve complete remission, clinical responses may last for long
CHAPTER 107 Plasma Cell Disorders
periods of time.
The median overall survival of patients with myeloma is
8+ years, with subsets of younger patients surviving >10 years. The
major causes of death are progressive myeloma, renal failure, sepsis,
or therapy-related myelodysplasia. Nearly a quarter of patients die
of myocardial infarction, chronic lung disease, diabetes, or stroke—
all intercurrent illnesses related more to the age of the patient group
than to the tumor.
Supportive care directed at the anticipated complications of the
disease may be as important as primary antitumor therapy. Hyper-
calcemia generally responds well to bisphosphonates, glucocorticoid
therapy, hydration, and natriuresis, and rarely requires calcitonin as
well. Bisphosphonates (e.g., pamidronate 90 mg or zoledronate 4 mg
initially once a month and later less frequently) reduce osteoclastic
bone resorption and preserve performance status and quality of life,
decrease bone-related complications, and may also have antitumor
effects. Osteonecrosis of the jaw and renal dysfunction can occur in
a minority of patients receiving bisphosphonate therapy. Treatments
aimed at strengthening the skeleton such as fluorides, calcium, and
vitamin D, with or without androgens, have been suggested, but
are not of proven efficacy. Kyphoplasty or vertebroplasty should be
considered in patients with painful collapsed vertebra. Iatrogenic
worsening of renal function may be prevented by maintaining a
high fluid intake to prevent dehydration and enhance excretion of
light chains and calcium. In the event of acute renal failure, plasma-
pheresis is ~10 times more effective at clearing light chains than peri-
toneal dialysis; however, its role in reversing renal failure remains
controversial. Importantly, reducing the protein load by effective
antitumor therapy with agents such as bortezomib may result in
improvement in renal function in over half of the patients. Use of
lenalidomide in renal failure is possible but requires dose modifi-
cation, as it is renally excreted. Urinary tract infections should be
watched for and treated early. Plasmapheresis may be the treatment
of choice for hyperviscosity syndromes. Although the pneumo-
coccus is a dreaded pathogen in myeloma patients, pneumococcal
polysaccharide vaccines may not elicit an antibody response. The
pneumococcal conjugate vaccines may be more protective. Prophy-
lactic administration of intravenous γ globulin preparations is used
in the setting of recurrent serious infections. Chronic oral antibi-
otic prophylaxis is not warranted. Patients developing neurologic
symptoms in the lower extremities, severe localized back pain, or
problems with bowel and bladder control may need emergency MRI
and local radiation therapy and glucocorticoids if cord compression
is identified. In patients in whom neurologic deficit is increasing
or substantial, emergent surgical decompression may be necessary.
Most bone lesions respond to analgesics and systemic therapy, but
certain painful lesions may respond most promptly to localized
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 802 radiation. The anemia associated with myeloma may respond to
erythropoietin along with hematinics (iron, folate, cobalamin). The
pathogenesis of the anemia should be established and specific ther-
apy instituted, whenever possible.
WALDENSTRÖM’S MACROGLOBULINEMIA
In 1948, Waldenström described a malignancy of lymphoplasmacy-
toid cells that secreted IgM. In contrast to myeloma, the disease was
associated with lymphadenopathy and hepatosplenomegaly, but the
major clinical manifestation was hyperviscosity syndrome. The dis-
ease resembles the related diseases CLL, myeloma, and lymphocytic
lymphoma. It originates from a postgerminal center B cell that has
undergone somatic mutations and antigenic selection in the lymphoid
follicle and has the characteristics of an IgM-bearing memory B cell.
Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a
similar clinical course, but therapeutic options are different. The diag-
nosis of IgM myeloma is usually reserved for patients with lytic bone
lesions and predominant infiltration with CD138+ plasma cells in the
bone marrow. Such patients are at greater risk of pathologic fractures
than patients with WM.
A familial occurrence is common in WM, but its molecular bases
are yet unclear. A distinct MYD88 L265P somatic mutation is present
PART 4
in >90% of patients with WM and the majority of IgM MGUS. Other
commonly occurring mutations include CXCR4 (30–40%), ARID1A
(17%), and CD79B (8–15%). Presence of MYD88 mutation status is
now used as a diagnostic test to discriminate WM from marginal
zone lymphomas (MZLs), IgM-secreting myeloma, and CLL with
Oncology and Hematology
plasmacytic differentiation. This mutation also explains the molecular
pathogenesis of the disease, with involvement of Toll-like receptor
(TLR) and interleukin 1 receptor (IL-1R) signaling leading to activation
of IL-1R–associated kinase (IRAK) 4 and IRAK1 followed by nuclear
factor-κB (NF-κB) activation. MYD88 mutation also triggers Burton’s
tyrosine kinase (BTK), hemopoietic cell kinase (HCK) growth, and sur-
vival signaling, which are now important therapeutic targets in WM.
CXCR4 mutations induce AKT and extracellular regulated kinase-1/2
(ERK 1/2) signaling. This pathway can lead to development of drug
resistance in the presence of its ligand CXCL12.
The disease is similar to myeloma in being slightly more common
in men and occurring with increased incidence with increasing age
(median 64 years). The IgM in some patients with macroglobulinemia
may have specificity for myelin-associated glycoprotein (MAG), a pro-
tein that has been associated with demyelinating disease of the periph-
eral nervous system and may be lost earlier and to a greater extent than
the better known myelin basic protein in patients with multiple sclero-
sis. Sometimes patients with macroglobulinemia develop a peripheral
neuropathy, and half of these patients are positive for anti-MAG anti-
body. The neuropathy may precede the appearance of the neoplasm.
The whole process may begin with a viral infection that may elicit an
antibody response that cross-reacts with a normal tissue component.
Like myeloma, the disease involves the bone marrow, but unlike
myeloma, it does not cause bone lesions or hypercalcemia. Bone marrow
shows >10% infiltration with lymphoplasmacytic cells (surface IgM+,
CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and CD23−) with
an increase in number of mast cells. Like myeloma, an M component is
present in the serum in excess of 30 g/L (3 g/dL), but unlike myeloma,
the size of the IgM paraprotein results in little renal excretion, and only
~20% of patients excrete light chains. Therefore, renal disease is not
common. The light chain isotype is kappa in 80% of the cases. Patients
present with weakness, fatigue, and recurrent infections similar to
myeloma patients, but epistaxis, visual disturbances, and neurologic
symptoms such as peripheral neuropathy, dizziness, headache, and
transient paresis are much more common in macroglobulinemia. Pres-
ence of MYD88 and CXCR4 mutations also affects disease presentation.
Presence of CXCR4 mutations is associated with higher bone marrow
disease burden and higher incidence of hyperviscosity. Patients with
wild-type MYD88 show lower bone marrow disease burden.
Physical examination reveals adenopathy and hepatosplenomegaly,
and ophthalmoscopic examination may reveal vascular segmentation
Harrisons_20e_Part4_p0435-p0858.indd 802
and dilation of the retinal veins characteristic of hyperviscosity states.
Patients may have a normocytic, normochromic anemia, but rouleaux
formation and a positive Coombs’ test are much more common than in
myeloma. Malignant lymphocytes are usually present in the peripheral
blood. About 10% of macroglobulins are cryoglobulins. These are pure
M components and are not the mixed cryoglobulins seen in rheuma-
toid arthritis and other autoimmune diseases. Mixed cryoglobulins
are composed of IgM or IgA complexed with IgG, for which they are
specific. In both cases, Raynaud’s phenomenon and serious vascular
symptoms precipitated by the cold may occur, but mixed cryoglobu-
lins are not commonly associated with malignancy. Patients suspected
of having a cryoglobulin based on history and physical examination
should have their blood drawn into a warm syringe and delivered to
the laboratory in a container of warm water to avoid errors in quanti-
tating the cryoglobulin.
TREATMENT
Waldenström’s Macroglobulinemia
Control of serious hyperviscosity symptoms such as an altered state
of consciousness or paresis can be achieved acutely by plasma-
pheresis because 80% of the IgM paraprotein is intravascular. The
median survival of affected individuals is ~50 months. However,
many patients with WM have indolent disease that does not require
therapy. Pretreatment parameters including older age, male sex,
general symptoms, and cytopenias define a high-risk population.
Treatment is usually not initiated unless the disease is symptomatic
or increasing anemia, hyperviscosity, lymphadenopathy, or hepato-
splenomegaly is present. Ibrutinib is approved by the U.S. Food and
Drug Administration (FDA) and the European Medicines Agency
(EMA) for use in patients with symptomatic WM. It targets the con-
stitutively activated BTK. In patients with one prior line of therapy,
the overall response to ibrutinib was 91%. Best responses to ibruti-
nib are observed in patients with mutated MYD88 and wild-type
CXCR4 status, while delayed and lower response rates to ibrutinib
are observed in patients with mutated CXCR4. The other first line
treatments include rituximab (anti-CD20) alone or combined with
alkylators (bendamustine and cyclophosphamide), or proteasome
inhibitors (bortezomib). Rituximab can produce IgM flare, so either
plasmapheresis should be used before rituximab or its use should
be initially withheld in patients with high IgM levels. Fludara-
bine (25 mg/m2 per day for 5 days every 4 weeks) and cladribine
(0.1 mg/kg per day for 7 days every 4 weeks) are also highly effec-
tive single agents. With identification of the MYD88 mutation, inhib-
itors targeting IRAK1/4 and BCL2 are being evaluated. Although
high-dose therapy plus autologous transplantation is an option, its
use has declined due to the availability of other effective agents.
POEMS SYNDROME
The features of this syndrome are polyneuropathy, organomegaly, endo-
crinopathy, M-protein, and skin changes (POEMS). Diagnostic criteria
are described in Table 107-1. Patients usually have a severe, progressive
sensorimotor polyneuropathy associated with sclerotic bone lesions
from myeloma. Polyneuropathy occurs in ~1.4% of myelomas, but the
POEMS syndrome is only a rare subset of that group. Unlike typical
myeloma, hepatomegaly and lymphadenopathy occur in about two-
thirds of patients, and splenomegaly is seen in one-third. The lymph-
adenopathy frequently resembles Castleman’s disease histologically, a
condition that has been linked to IL-6 overproduction. The endocrine
manifestations include amenorrhea in women and impotence and
gynecomastia in men. Hyperprolactinemia due to loss of normal inhib-
itory control by the hypothalamus may be associated with other central
nervous system manifestations such as papilledema and elevated cere-
brospinal fluid pressure and protein. Type 2 diabetes mellitus occurs in
about one-third of patients. Hypothyroidism and adrenal insufficiency
are occasionally noted. Skin changes are diverse: hyperpigmentation,
hypertrichosis, skin thickening, and digital clubbing. Other manifes-
tations include peripheral edema, ascites, pleural effusions, fever, and
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 thrombocytosis. Not all the components of POEMS syndrome may be
present initially.
The pathogenesis of the disease is unclear, but high circulating levels
of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have been
documented, and levels of the inhibitory cytokine transforming growth
factor β are lower than expected. Treatment of the myeloma may result
in an improvement in the other disease manifestations.
Patients are often treated similarly to those with myeloma. Plasma-
pheresis does not appear to be of benefit in POEMS syndrome. Patients
presenting with isolated sclerotic lesions may have resolution of neuro-
pathic symptoms after local therapy for plasmacytoma with radiother-
apy. Similar to MM, novel agents and high-dose therapy with autologous
stem cell transplantation have been pursued in selected patients and
have been associated with prolonged progression-free survival.
HEAVY CHAIN DISEASES
The heavy chain diseases are rare lymphoplasmacytic malignancies.
Their clinical manifestations vary with the heavy chain isotype.
Patients have absence of light chain and secrete a defective heavy chain
that usually has an intact Fc fragment and a deletion in the Fd region.
Gamma, alpha, and mu heavy chain diseases have been described,
but no reports of delta or epsilon heavy chain diseases have appeared.
Molecular biologic analysis of these tumors has revealed structural
genetic defects that may account for the aberrant chain secreted.
■■GAMMA HEAVY CHAIN DISEASE (FRANKLIN’S
DISEASE)
This disease affects individuals of widely different age groups and coun-
tries of origin. It is characterized by lymphadenopathy, fever, anemia,
malaise, hepatosplenomegaly, and weakness. It is frequently associated
with autoimmune diseases, especially rheumatoid arthritis. Its most
distinctive symptom is palatal edema, resulting from involvement of
nodes in Waldeyer’s ring, and this may progress to produce respiratory
compromise. The diagnosis depends on the demonstration of an anom-
alous serum M component (often <20 g/L [<2 g/dL]) that reacts with
anti-IgG but not antilight chain reagents. The M component is typically
present in both serum and urine. Most of the paraproteins have been of
the γ1 subclass, but other subclasses have been seen. The patients may
have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow
that may show increased numbers of lymphocytes or plasma cells that
do not stain for light chain. Patients usually have a rapid downhill
course and die of infection; however, some patients have survived
5 years with chemotherapy. Therapy is indicated when symptomatic and
involves chemotherapeutic combinations used in low-grade lymphoma.
Rituximab has also been reported to show efficacy.
■■ALPHA HEAVY CHAIN DISEASE (SELIGMANN’S
DISEASE)
This is the most common of the heavy chain diseases. It is closely related
to a malignancy known as Mediterranean lymphoma, a disease that
affects young persons in parts of the world where intestinal parasites
are common, such as the Mediterranean, Asia, and South America. The
disease is characterized by an infiltration of the lamina propria of the
small intestine with lymphoplasmacytoid cells that secrete truncated
alpha chains. Demonstrating alpha heavy chains is difficult because
the alpha chains tend to polymerize and appear as a smear instead of
a sharp peak on electrophoretic profiles. Despite the polymerization,
hyperviscosity is not a common problem in alpha heavy chain disease.
Without J chain–facilitated dimerization, viscosity does not increase
dramatically. Light chains are absent from serum and urine. The
patients present with chronic diarrhea, weight loss, and malabsorption
and have extensive mesenteric and paraaortic adenopathy. Respiratory
tract involvement occurs rarely. Patients may vary widely in their clin-
ical course. Some may develop diffuse aggressive histologies of malig-
nant lymphoma. Chemotherapy may produce long-term remissions.
Rare patients appear to have responded to antibiotic therapy, raising
the question of the etiologic role of antigenic stimulation, perhaps by
some chronic intestinal infection. Chemotherapy plus antibiotics may
be more effective than chemotherapy alone. IPSID is recognized as an
infectious pathogen–associated human lymphoma that has association
Harrisons_20e_Part4_p0435-p0858.indd 803
with Campylobacter jejuni. It involves mainly the proximal small intes- 803
tine resulting in malabsorption, diarrhea, and abdominal pain. IPSID
is associated with excessive plasma cell differentiation and produces
truncated alpha heavy chain proteins lacking the light chains as well
as the first constant domain. Early-stage IPSID responds to antibiotics
(30–70% complete remission). Most untreated IPSID patients progress
to lymphoplasmacytic and immunoblastic lymphoma. Patients not
responding to antibiotic therapy are considered for treatment with
combination chemotherapy used to treat low-grade lymphoma.
■■MU HEAVY CHAIN DISEASE
The secretion of isolated mu heavy chains into the serum appears to
occur in a very rare subset of patients with CLL. The only features that
may distinguish patients with mu heavy chain disease are the presence
of vacuoles in the malignant lymphocytes and the excretion of kappa
light chains in the urine. The diagnosis requires ultracentrifugation or
gel filtration to confirm the nonreactivity of the paraprotein with the
light chain reagents because some intact macroglobulins fail to interact
with these serums. The tumor cells seem to have a defect in the assem-
bly of light and heavy chains because they appear to contain both in
their cytoplasm. Such patients are not treated differently from other
patients with CLL (Chap. 104).
CHAPTER 108 Amyloidosis
■■FURTHER READING
Attal M et al: IFM 2009 study. Lenalidomide, bortezomib, and
dexamethasone with transplantation for myeloma. N Engl J Med
376:1311, 2017.
Avet-Loiseau H et al: Long-term analysis of the IFM 99 trials for mye-
loma: Cytogenetic abnormalities [t(4;14), del(17p), 1q gains] play a
major role in defining long-term survival. J Clin Oncol 30:1949, 2012.
Chng WJ et al: International Myeloma Working Group. IMWG consen-
sus on risk stratification in multiple myeloma. Leukemia 28:269, 2014.
Dimopoulos MA et al: Daratumumab, lenalidomide, and dexametha-
sone for multiple myeloma. N Engl J Med 375:1319, 2016.
Hunter ZR et al: Genomics, signaling, and treatment of Waldenstrom
macroglobulinemia. J Clin Oncol 35:994, 2017.
Landgren O et al: Monoclonal gammopathy of undetermined signif-
icance (MGUS) consistently precedes multiple myeloma: A prospec-
tive study. Blood 113:5412, 2009.
Palumbo A et al: Revised International Staging System for multiple
myeloma: A report from International Myeloma Working Group.
J Clin Oncol 33:2863, 2015.
Raje N, Roodman GD: Advances in the biology and treatment of bone
disease in multiple myeloma. Clin Cancer Res 17:1278, 2011.
Rajkumar SV et al: International Myeloma Working Group updated
criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538,
2014.
Robiou du Pont S et al: Genomics of multiple myeloma. J Clin Oncol
35:963, 2017.
108 Amyloidosis
John L. Berk, Vaishali Sanchorawala
■■GENERAL PRINCIPLES
Amyloidosis is the term for a group of protein misfolding disorders
characterized by the extracellular deposition of insoluble polymeric
protein fibrils in tissues and organs. A robust cellular machinery exists
to chaperone proteins during the process of synthesis and secretion, to
ensure that they achieve correct tertiary conformation and function,
and to eliminate proteins that misfold. However, genetic mutation,
incorrect processing, and other factors may favor misfolding, with
consequent loss of normal protein function and intracellular or extra-
cellular aggregation. Many diseases, ranging from cystic fibrosis to
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