Acute Myeloid Leukemia

104
William Blum

INCIDENCE
Acute myeloid leukemia (AML) is a neoplasm characterized by
infiltration 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 2020, the estimated number of new
AML cases in the United States was 19,940. AML is the diagnosis in
1.3% of all cancer cases and 31% of all new acute leukemias but
causes 62% of leukemic deaths. AML is the most common 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.
Use of the term premalignant to describe these lesions is not
precisely accurate; rather, these mutations represent clonal
hematopoiesis of indeterminate potential (CHIP; sometimes called
age-related clonal hematopoiesis). The genes most commonly
altered include the epigenetic regulators DNMT3A, TET2, and
ASXL1.
Study of CHIP is important because CHIP has relevance not just
to blood cancer evolution but also other medical conditions. Clonal
expansion driven by the acquisition of new mutations is associated
with a 10-fold increase in risk for developing a hematologic
malignancy (compared to matched patients without CHIP), but it is
clear that additional “hits” must occur to drive toward leukemia. We
do not yet fully understand why or how these secondary lesions
occur. Patients with CHIP also have increased risk of cardiovascular
mortality that is not fully explained. The link between these two
seemingly unrelated issues (cardiovascular and hematologic
malignancy) may lie in understanding the interactions between
circulating clonally expanded blood cells and vascular endothelium.
A “proinflammatory” state caused by clonal, infiltrating monocytes
leads to accelerated atherosclerotic plaque development and altered
cardiac remodeling. Similar phenomena may occur in the marrow
and blood—altered relationships between hematopoietic stem cells
with the marrow microenvironment along with altered immune
surveillance. Both increase the likelihood that a clone may survive,
acquire additional mutations, and then further expand eventually to
leukemia. Whether early identification of CHIP in patients will provide
therapeutic opportunities for patients remains to be seen. Certainly,
modifying cardiovascular risk in patients with CHIP seems prudent,
but development of mutation-directed therapies to eliminate
problematic clones to prevent leukemia is likely to be more elusive.

Genetic Predisposition Myeloid neoplasms typically occur

sporadically in adults; inherited predisposition is rare. Yet, it is clear
that myeloid neoplasms with germline predisposition represent an
important 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 104-1). Likewise, myeloid neoplasms with germline
predisposition are a feature of several 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., dyskeratosis
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.

TABLE 104-1 WHO 2016 Classification of Myeloid Neoplasms

with Germline Predisposition

Several genetic syndromes with somatic cell chromosome

aneuploidy, 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 diseases with defective DNA repair (e.g.,
Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia) are
also associated with AML. Each syndrome is associated with unique
clinical features and atypical toxicities 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
monosomy/aberrations in chromosomes 5 and 7. Topoisomerase II
inhibitor–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
Organization (WHO) classification (Table 104-2), which defines
biologically distinct groups based on cytogenetic and molecular
abnormalities in addition to clinical features and light microscope
morphology. Myeloid neoplasms with germline predisposition, as
introduced above, are included as a new and important feature of
this classification (Table 104-1). The WHO classification enables the
identification of subsets of disease that may be treated differently
(now or in the future) and enhances recognition of the molecular
basis of 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).

TABLE 104-2 WHO 2016 Classification of Acute Myeloid

Leukemia and Related Neoplasms
Clinical Features Even with advances in molecular biology,
recognizing 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 changes is recognized 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 are
therefore in the WHO classification.

Genetic Findings Subtypes of AML are recognized due to

the presence or absence of specific, recurrent cytogenetic, and/or

genetic abnormalities. For example, the diagnosis of acute
promyelocytic 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 three
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/or mutation of TP53) and AML with myelodysplasia-
related changes. Patients with such changes typically fare poorly
with standard treatments. However, only one abnormality is
invariably associated with specific morphologic features: t(15;17)
(q22;q12) or the molecular fusion PML-RARA with APL. Other
cytogenetic and genetic findings may be commonly, but not always,
associated with a morphologic description, highlighting the necessity
of genetic and cytogenetic testing for precise diagnosis. Several
chromosomal abnormalities often associate primarily with one
morphologic/immunophenotypic group. Examples include inv(16)
(p13.1q22) with AML with abnormal bone marrow eosinophils;
t(8;21)(q22;q22) with slender Auer rods, expression of CD19, and
increased normal eosinophils; and t(9;11)(p22;q23) and other
translocations involving 11q23 with monocytic features. Mutation of
nucleophosmin (nucleolar phosphoprotein B23, numatrin, NPM1),
especially when co-occurring with mutation of fms-related tyrosine
kinase 3 (FLT3), often presents with “cup-shaped” nuclear
morphology. 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), del(7q), and mutated TP53. Myeloid
sarcomas are associated with t(8;21); disseminated intravascular
coagulation (DIC) is associated with t(15;17). 11q23 aberrations and
monocytic leukemia are associated with extramedullary sites of
involvement at presentation, especially gingival hypertrophy. High
leukocyte count is commonly observed with NPM1 or FLT3 mutation.
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 leukemia (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. Unique clinical therapy with
retinoic acid and arsenic trioxide 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 and CBFB-
MYH11 and the so-called CBF AML subtypes noted cytogenetically
as t(8;21), inv(16), or t(16;16). Additional fusions are MLLT3-KMT2A
and DEK-NUP214, resulting from t(9;11) and t(6;9)(p23;q34),
respectively, among others.
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. For example, AML
with mutated NPM1 and AML with biallelic mutated CEBPA,
respectively, are associated with more favorable clinical outcome,
though the presence of coexisting mutation in FLT3 affects NPM1
prognostic impact. Activating mutations of FLT3 are present in ∼30%
of adult AML patients, primarily due to internal tandem duplications
(ITDs) 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 progenitor 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 it is not only useful as a
prognosticator but also may predict response to specific treatment
such as a tyrosine kinase inhibitor (TKI). Several TKIs targeting FLT3
are either approved for AML (e.g., midostaurin, only in first-line
therapy in combination with chemotherapy; gilteritinib, in relapse as
monotherapy) or currently in clinical investigation (e.g., quizartinib,
crenolanib, sorafenib, and others). The FLT3 allelic ratio (of the
number of mutated alleles to wild-type alleles) provides information
beyond the mere presence or absence of the mutation. 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 affect the ratio.
The allelic ratio affects the prognostic impact of the FLT3-ITD
mutation; patients with FLT3-ITD “low” allelic ratio (<0.5) fare better.
Accordingly, mutated NPM1 without FLT3-ITD or with FLT3-ITDlow is
viewed as favorable risk by the European LeukemiaNet (ELN) risk
stratification schema (Table 104-3). Conversely, FLT3-ITDhigh has an
adverse prognostic impact; patients with both mutated NPM1 and
FLT3-ITD with an allelic ratio >0.5 are 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 104-2).
TABLE 104-3 2017 European LeukemiaNet Risk Stratification
by Genetics for Acute Myeloid Leukemia (AML)a
Immunophenotypic Findings The immunophenotype of human
leukemia cells can be studied by multiparameter flow cytometry 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
reactions, 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. Although flow cytometry is widely used, and in some cases
essential for the diagnosis of AML, it has only a supportive role in
establishing the different subtypes of AML through the WHO
classification. Increasingly, multiparameter flow cytometry is used for
the measurement of measurable residual disease (MRD) after
remission is achieved.

■ PROGNOSTIC FACTORS
Several factors predict outcome of AML patients treated with
chemotherapy; they should be used for risk stratification and
treatment guidance.
Chromosome and molecular investigations performed at
diagnosis currently provide the most important prognostic
information. WHO has categorized patients as having favorable,
intermediate, or adverse risk based on the presence of structural
and/or numerical chromosomal or genetic aberrations. Patients with
t(15;17) have a very good prognosis (∼85% cured), and those with
t(8;21) and inv(16) have a good prognosis (∼55% cured), whereas
those with no cytogenetic abnormality have an intermediate outcome
risk (∼40% cured). Patients with a TP53 mutation, complex
karyotype, t(6;9), inv(3), or –7 have a very poor prognosis. Another
cytogenetic subgroup, the monosomal karyotype, has been
suggested to adversely influence the outcome of AML patients other
than those with t(15;17), t(8;21), or inv(16) or t(16;16). The
monosomal karyotype subgroup is defined by the presence of at
least two autosomal monosomies (loss of chromosomes other than
Y or X) or a single autosomal monosomy with additional structural
abnormalities.
For patients lacking prognostic cytogenetic abnormalities, i.e.,
those with CN-AML, testing for several mutated genes can help to
risk-stratify. In addition to NPM1 mutation and FLT3-ITD as
described above, biallelic CEBPA mutations have prognostic value.
Such mutations predict favorable outcome. Given the proven
prognostic 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 cytogenetic and molecular abnormalities and
is used for comparing clinical features/treatment response among
subsets of patients reported across different clinical studies (Table
104-3). These genetic groups should be used for risk stratification
and treatment guidance.
In addition to NPM1, CEBPA, FLT3, and TP53 mutations,
molecular aberrations in other genes may be routinely used for
prognostication (Table 104-4). Among these mutated genes are
those encoding receptor tyrosine kinases (KIT), transcription factors
(RUNX1 and WT1), and epigenetic modifiers (ASXL1, DNMT3A,
isocitrate dehydrogenase 1 [IDH1], IDH2, KMT2A [also known as
MLL], and 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.
Mutations of ASXL1 and RUNX1 are associated with adverse
outcome, independent of other prognostic factors. However, for
some of these mutations, 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 (especially FLT3, IDH1, and IDH2)
have been remarkably effective in subsets of disease, leading to
U.S. Food and Drug Administration approvals (see section on
treatment of AML).

TABLE 104-4 Molecular Prognostic Markers in AMLa

 In addition to gene mutations, deregulation of the expression
levels of coding genes and of short noncoding RNAs (microRNAs)
also provides prognostic information (Table 104-4). Overexpression
of genes such as BAALC, ERG, MN1, and MDS1 and EVI1 complex
locus (MECOM; also known as EVI1) predict poor outcome,
especially in CN-AML. Similarly, deregulated expression levels of
microRNAs, naturally occurring noncoding RNAs that regulate 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
posttranslational histone modification) and microRNAs are often
involved in deregulation of genes involved in hematopoiesis,
contribute to leukemogenesis, and may associate with the previously
discussed prognostic gene mutations. These changes have been
shown to provide biologic insights into leukemogenic mechanisms
and provide independent prognostic information. Therapeutic
progress based on advances in understanding the role of epigenetic
changes in AML is currently unfolding. For example, in patients with
mutations of IDH1 or IDH2, novel active enzymes produced from
these respective mutations hijack the citric acid cycle, leading to
production of a novel “oncometabolite,” 2-hydroxyglutarate, which
disrupts a myriad of epigenetic processes. Pharmacologic inhibition
of these aberrant enzymes can reverse these leukemogenic
activities.
In addition to cytogenetic 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 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, TP53)
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
bleeding and pulmonary leukostasis contribute to poor outcomes.
Following administration of therapy, achievement of CR is
associated with better outcome and longer survival. CR is defined
after examination of both blood and bone marrow and essentially
represents 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
considered 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. Extramedullary 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 thrombocytopenia. 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, lymphadenopathy, nonspecific cough, headache, or
diaphoresis may also occur.
Rarely, patients may present with symptoms from a myeloid
sarcoma (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 involvement by AML. Patients who present
with isolated myeloid sarcoma typically develop blood and/or marrow
involvement quickly thereafter 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,
lymphadenopathy, 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 feature 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 hemorrhages are detected in 15% of patients.
Infiltration of the gingiva, skin, soft tissues, or meninges with
leukemic blasts at diagnosis is characteristic of the monocytic
subtypes and those with 11q23 chromosomal abnormalities.

Hematologic Findings Anemia is usually present at diagnosis,

although 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)
survival 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
characteristic of immature cells. Abnormal rod-shaped granules
called Auer rods are not uniformly present, but when they are, AML
is virtually certain (Fig. 104-1).
FIGURE 104-1 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.

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 suspected,

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 104-5). Factors that have prognostic significance,
either for achieving CR or for CR duration, should also be assessed
before initiating treatment including cytogenetics and molecular
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. During the ongoing
global pandemic, testing for the presence of the novel coronavirus,
SARS-COV2, is recommended before initiation of chemotherapy.

TABLE 104-5 Initial Diagnostic Evaluation and Management of

Adult Patients with AML
 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 presence 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 serious 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 dysfunction 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. 104-2). 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 cytarabine and anthracycline 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 treatment and new therapies are being pursued. Additional
options for therapy have emerged for older AML patients such as
the addition of the BCL2 antagonist venetoclax to one of several
low-intensity chemotherapies. Likewise, novel oral drugs targeting
IDH1 or IDH2, alone or in combination with low-intensity
chemotherapy, may be considered as initial therapy for older
patients who have mutations in those respective pathways.
FIGURE 104-2 Algorithm for the therapy of newly diagnosed acute myeloid
leukemia (AML). aRisk stratification according to the European LeukemiaNet
(see Table 104-3). bYounger patients (<60–65 years) should routinely be offered
investigational therapy on a backbone of standard chemotherapy for induction
and consolidation. cOlder patients, especially those >65 years or with adverse
risk disease, or those who are unfit for intensive anthracycline + cytarabine
regimens, may be considered for investigational therapy alone or in combination
with lower intensity chemotherapy (azacitidine, decitabine, cytarabine), or lower
intensity chemotherapy in combination with venetoclax. 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).
Allogeneic hematopoietic cell transplantation (HCT) is a consideration for all
eligible patients in first complete remission (CR) with non–favorable-risk disease
and highly recommended for older patients (60–75 years) and those with adverse
risk.
For all forms of AML in fit patients, 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) can 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 CR undergo
postremission consolidation therapy, including sequential courses of intermediate-
dose cytarabine, allogeneic HCT, autologous HCT, or novel therapies, based on
their predicted risk of relapse (i.e., risk-stratified therapy). Patients receiving
induction of lower intensity chemotherapy with venetoclax (or investigational
therapy) typically receive repetitive cycles of same on an attenuated schedule, if
necessary due to myelotoxicity, after achieving remission. 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. HLA, human leukocyte antigen; IDAC, intermediate-dose cytarabine.

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 inhibition
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.,
gemtuzumab ozogamicin) 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 induction are offered reinduction with the same (or slightly
modified) therapy. The CD33-targeting immunoconjugate
gemtuzumab ozogamicin may be added to induction therapy for
subsets of patients, especially those with CBF AML.
In older patients (age ≥60–65 years), the outcome with
conventional intensive therapy 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 myeloproliferative neoplasms),
therapy-related AML, or cytogenetic and genetic abnormalities that
adversely influence clinical outcome. Patients still fare far better
with treatment than with supportive care only. Conventional therapy
for fit older patients is similar to that for younger patients: the 7 and
3 regimen with standard-dose cytarabine and idarubicin (12 mg/m2),
or daunorubicin (60 mg/m2). For patients aged >65 years, high-dose
daunorubicin (90 mg/m2) has increased toxicity and is not
recommended. A novel liposomal preparation of cytarabine and
daunorubicin in a fixed molar ratio may instead be administered to
fit patients with AML with myelodysplasia-related changes or arising
from MDS. Older patients and those unable to receive intensive
therapy due to medical comorbidity may receive repetitive cycles of
lower intensity therapy with a hypomethylating agent (HMA;
decitabine or azacitidine) or low-dose cytarabine, in combination
with daily venetoclax. As noted, targeted IDH1- or IDH2-directed
therapy is another consideration. All patients should be considered
for clinical trials. Investigational therapy remains the best option for
many older patients but especially those with adverse-risk features.
(Table 104-6).

TABLE 104-6 Novel Therapies in Clinical Development in

Acute Myeloid Leukemia (AML)
 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. Response rates around
60% have been similarly reported with the combination of HMA plus
venetoclax in older or infirm patient groups. Of patients who do not
achieve CR, most have drug-resistant leukemia. Induction death is
more frequent with advancing age and medical comorbidity.
Patients with refractory disease after induction should be
considered for salvage treatments, preferably on clinical trials.
Planning for the possibility of allogeneic hematopoietic stem cell
transplantation (HCT) for all eligible patients under age 75 years is
part of optimal initial AML care. Typically, allogeneic HCT is
performed for patients in CR but at risk for relapse, but fit younger
patients with primary refractory disease (not in remission after initial
induction) have ∼15–20% cure rates with allogeneic HCT (after
myeloablative conditioning). For this reason, early planning for
possible future allogeneic HCT (including human leukocyte antigen
[HLA] typing, donor search, etc.) should be part of the initial
approach for most AML patients.

POSTREMISSION THERAPY
Induction of a durable first CR (CR1) is critical to long-term survival
in AML. However, without further therapy, virtually all CR patients
will eventually relapse. Thus, postremission therapy is designed to
eradicate residual (typically undetectable) leukemic cells to prevent
relapse and prolong survival. As with induction, the type of
postremission therapy in AML is selected for each individual patient
based on age, fitness, and cytogenetic/molecular risk.
The choice between consolidation with chemotherapy or with
transplantation is complex and based on age, risk, and practical
considerations. In younger patients receiving chemotherapy,
postremission therapy with intermediate- or high-dose cytarabine for
two to four cycles is standard practice. Higher doses of cytarabine
during postremission therapy appear more effective than standard
doses (such as are used in induction) 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 postremission chemotherapy approach for favorable- and
intermediate-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 <1 g/m2 are used. In contrast to favorable-risk patients,
intermediate- or adverse-risk patients should proceed with
allogeneic HCT in CR1 when feasible (see transplant discussion
below). Because older patients have increased toxicities with higher
doses of cytarabine, ELN recommends relatively attenuated
cytarabine doses (0.5–1 g/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 investigational
postremission therapy is recommended. Indeed, postremission
therapy is an appropriate setting for introduction of new agents in
both older and younger patients (Table 104-6).
For patients treated initially with lower intensity regimens that
include venetoclax, the current practice is to continue repetitive
cycles of the same combination of agents after remission until
disease progression. Therapy often must be abbreviated over time
due to cumulative myelotoxicity.
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
potentially 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 (e.g., before relapse ever occurs) is a favored strategy. We
have often explained to patients that transplant can effectively
“eliminate the needle in a haystack, but not a stack of needles.”
Transplant is recommended for patients age <75 years who do not
have favorable-risk disease and who have an HLA-matched donor
(related or unrelated). We also recommend allogeneic HCT in CR1
for patients with intermediate-risk disease (Table 104-3). 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, allogeneic HCT is
generally recommended as soon as possible after CR1 is achieved
unless the patient is in a favorable-risk group. Increasingly, 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. More effective and safe
methods of in vivo T-cell depletion (i.e., posttransplant
cyclophosphamide following mismatched transplantation) 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 chemotherapy for
older patients are dismal; transplantation for such patients is
expanding. Even for older patients, nonrandomized data
demonstrate curative potential for older patients in CR1 treated with
reduced-intensity conditioning regimens and allogeneic HCT.
Trials comparing allogeneic HCT with intensive chemotherapy or
autologous HCT have shown improved duration of remission with
allogeneic HCT. However, the relapse risk reduction observed with
allogeneic HCT is partially offset by the increase in fatal 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
postremission approach in non–adverse-risk subsets. Autologous
HCT patients receive their own stem cells (collected during
remission and cryopreserved), following administration of
myeloablative chemotherapy. 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 intermediate-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 availability 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 CR1 for patients without favorable cytogenetics or genotype.
Patients with adverse-risk disease should proceed to allogeneic
HCT at CR1 if possible. The decision for allogeneic HCT for
younger intermediate-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 remission; emerging data demonstrate survival benefit
from incorporation of the FLT3 inhibitor midostaurin, for example,
into induction and postremission therapies for patients with FLT3-
mutated AML. Allogeneic transplantation in CR1 is still
recommended 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
karyotype (in spite of morphologic CR) is clearly associated with
poor clinical outcomes. Immunophenotyping to detect minute
populations of blasts or sensitive molecular assays (e.g., reverse
transcriptase polymerase chain reaction [RT-PCR]) to detect AML-
associated molecular abnormalities (e.g., NPM1, RUNX1/RUNX1T1
and CBFB/MYH11 transcripts, PML/RARA) can be performed to
assess whether MRD is present at sequential time points during or
after treatment. Whether emerging 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, although it is increasingly employed in
clinical practice. 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 therapy) can effectively eradicate
disease in such patients is not yet clear. However, in the subset of
patients with APL, serial RT-PCR (for the PML/RARA transcript) is a
very useful and reliable tool to detect early relapse and to direct
initiation of reinduction therapy prior to onset of overt relapse.
Critical in the general understanding of MRD in all disease subsets
is the recognition that even patients with undetectable levels of
MRD remain at risk for leukemic 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. Multi-lumen 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 during prolonged periods
of myelosuppression.
Adequate and prompt blood bank support is critical to therapy 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 ABO-matched
platelets or platelets from HLA-matched donors. RBC transfusions
should be considered 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 filtration should be used to avert or delay
alloimmunization as well as febrile reactions. Blood products may
also be irradiated to prevent transfusion-associated GVHD.
Cytomegalovirus (CMV)-negative blood products should be used for
CMV-seronegative patients who are potential candidates for
allogeneic HCT; fortunately, white blood cell filtration is quite
effective at reducing CMV exposure as well.
Neutropenia (neutrophils <500/μL or <1000/μL and predicted to
decline to <500/μL over the next 48 h) can be part of the initial
presentation and/or a side effect of the chemotherapy treatment in
AML patients. Thus, infectious complications remain the major
cause of morbidity and death during induction and postremission
chemotherapy for AML. Antibacterial (i.e., quinolones) and
antifungal (i.e., posaconazole) prophylaxis, especially in conjunction
with regimens that cause mucositis, is beneficial. For patients who
are herpes simplex virus or varicella-zoster seropositive, antiviral
prophylaxis should be initiated (e.g., acyclovir, valacyclovir).
Fever develops in most patients with AML, but infections are
documented in only half of febrile patients. Early initiation of
empirical broad-spectrum antibacterial and antifungal antibiotics has
significantly reduced the number of patients dying of infectious
complications (Chap. 74). An antibiotic regimen adequate to treat
gram-negative organisms should be instituted at the onset of fever
in a neutropenic patient after clinical evaluation, including a detailed
physical examination with inspection of the indwelling catheter exit
site and a 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
cephalosporin (cefepime or ceftazidime). The combination of an
aminoglycoside with an antipseudomonal penicillin (e.g.,
piperacillin) or an aminoglycoside 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 Staphylococcus aureus. In
special situations where decreased susceptibility to vancomycin,
vancomycin-resistant organisms, or vancomycin toxicity is
documented, other options including linezolid and daptomycin need
to be considered.
Caspofungin (or a similar echinocandin), voriconazole,
isavuconazonium, or liposomal amphotericin B should be
considered for antifungal treatment if fever persists for 4–7 days
following initiation of empiric antibiotic therapy. Although liposomal
formulations of amphotericin B have improved the toxicity profile of
this agent, use has been limited to situations with high risk of or
documented mold infections, especially in those in whom an azole
fails. 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 effective with fewer drug-drug interactions. Antibacterial and
antifungal antibiotics should be continued until patients are no
longer neutropenic, 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 drug-
sensitive disease and have a higher chance of attaining a CR, even
with the same chemotherapeutic agents used for first remission
induction. Patients with short prior CR duration are at high risk for
treatment failure. Similar to patients with refractory disease, patients
with relapsed disease are rarely cured by salvage chemotherapy
treatments alone. Therefore, patients who eventually achieve a
second CR and are eligible for allogeneic HCT should be
transplanted. For patients who relapse after allogeneic HCT, no
consensus for best therapy exists; outcomes in this setting are very
poor.
Because achievement of a second CR with routine salvage
therapies 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 104-6). The discovery of novel gene mutations and
mechanisms of leukemogenesis that might represent actionable
therapeutic targets has prompted the development of many new
targeting agents. In addition 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 in clinical trials. Inhibitors of FLT3
(gilteritinib), IDH1 (ivosidenib), or IDH2 (enasidenib) are
monotherapies for relapsed AML patients who have targetable
mutations. Furthermore, approaches with antibodies targeting
markers commonly expressed on leukemia blasts (e.g., CD33) or
leukemia-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 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 (all-trans-retinoic acid [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 differentiated
neoplastic cells to the pulmonary vasculature endothelium.
Glucocorticoids, chemotherapy for cytoreduction, and/or supportive
measures can be effective for management of the APL syndrome.
Temporary discontinuation 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 commonly, with arsenic trioxide (ATO) in APL.
In adults with 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 survival. Notably, patients with high-risk APL
(defined as leukocyte count >10,000/μL) must be uniquely treated,
as they require immediate cytoreduction with chemotherapy due to
life-threatening APL syndrome and rapidly rising leukocyte count
after initiation of ATRA. High-risk patients are at increased risk for
induction death due to this syndrome 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
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
monitoring 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 front-line setting, ATO-
based therapy at relapse produces meaningful responses in up to
85% of patients. Although 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
preferred reinduction therapy for patients who relapse, although the
duration of prior remission should be a factor in this choice.
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.

ACKNOWLEDGEMENT
Clara Bloomfield, an important contributor to the field and to this
chapter in past editions, passed away since the publication of the
20th edition. Material from prior versions of this chapter on which she
was an author have been retained here.

■ FURTHER READING
ARBER DA et al: Acute myeloid leukaemia (AML) with recurrent
genetic abnormalities, in World Health Organization Classification
of Tumours of Haematopoietic and Lymphoid Tissues, 4th revised
ed. Geneva, Switzerland: World Health Organization; 2016.
DINARDO CD et al: Venetoclax combined with decitabine or
azacitidine in treatment-naive, elderly patients with acute myeloid
leukemia. Blood 133:7, 2019.
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.
JAISWAL S, EBERT BL: Clonal hematopoiesis in human aging and
disease. Science 366:eaan4673, 2019.
JONGEN-LAVRENIC M et al: Molecular minimal residual disease in
acute myeloid leukemia. N Engl J Med 378:1189, 2018.
LO-COCO F et al: Retinoic acid and arsenic trioxide for acute
promyelocytic leukemia. N Engl J Med 369:111, 2013.
PAPAEMMANUIL E et al: Genomic classification and prognosis in acute
myeloid leukemia. N Engl J Med 374:2209, 2016.
PERL AE et al: Gilteritinib or chemotherapy for relapsed or refractory
FLT3-mutated AML. N Engl J Med 381:1728, 2019.
POLLYEA DA et al: Enasidenib, an inhibitor of mutant IDH2 proteins,
induces durable remissions in older patients with newly
diagnosed acute myeloid leukemia. Leukemia 33:2575, 2019.
ROBOZ GJ et al: Ivosidenib induces deep durable remissions in
patients with newly diagnosed IDH1-mutant acute myeloid
leukemia. Blood 135:463, 2020.
STONE RM et al: Midostaurin plus chemotherapy for acute myeloid
leukemia with a FLT3 mutation. N Engl J Med 377:454, 2017.
 Chronic Myeloid Leukemia
105
Hagop Kantarjian, Elias Jabbour, Jorge Cortes

Chronic myeloid leukemia (CML) is a clonal hematopoietic

myeloproliferative stem cell neoplasm. The disease is driven by the
BCR/ABL1 chimeric gene 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 Philadelphia chromosome (Ph) (Fig.
105-1). 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
BCR-ABL1 tyrosine kinase inhibitors (TKIs), 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 prognosis of CML.
Today, the estimated 10-year survival rate with imatinib mesylate, the
first BCR-ABL1 TKI approved, is greater than 85% and approaches
that of the general population. Allogeneic stem cell transplantation
(SCT), a curative approach but one that involves more risks, is now
offered as second- or third-line therapy after failure of TKIs.
FIGURE 105-1 A. The Philadelphia (Ph) chromosome cytogenetic abnormality. B.
Breakpoints in the long arms of chromosome 9 (ABL1 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
lymphoblastic leukemia; rare in CML), and p230BCR-ABL1 (rare in CML and
associated with an indolent course). Other rearrangements (e.g., e14a3, e14a3)
are less common. (© 2013 The University of Texas MD Anderson Cancer Center.)

■ INCIDENCE AND EPIDEMIOLOGY

CML accounts for ∼15% of all cases of leukemia. There is a slight
male predominance (male-to-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 are diagnosed. The
incidence of CML increases gradually with age, with a steeper
increase after the age of 40–50 years. The annual incidence of CML
is 1.6 cases per 100,000 individuals. In the United States, this
translates into about 8500–9000 new cases per year. The incidence
of CML has not changed over several decades. By extrapolation, the
worldwide annual incidence of CML is about 200,000 cases. With a
median survival of 3–6 years before 2000, the disease prevalence in
the United States was ∼30,000 cases. With TKI therapy, the annual
mortality has been reduced from 10–20% to about 2%. Therefore,
the prevalence of CML is expected to continue to increase. Based on
an estimated annual mortality of 2% and an incidence of 8500 cases
per year, the plateau prevalence of CML is estimated to be reached
at ∼425,000 in the United Stated (8500 × 100/2) by about 2040, with
full TKI optimal treatment penetration. 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 ∼9–10 million patients. These estimates
are all based on extrapolations from the incidence and prevalence of
CML in the United States, as well as an estimated annual mortality of
2% with modern TKI therapy; they could vary considerably if the
estimates were to change.

■ ETIOLOGY
There are no familial associations in CML. The risk of developing
CML is not increased in monozygotic twins or in relatives of patients
with CML. 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, no increase in the incidence of CML was reported,
suggesting that larger dose exposures of radiation are required to
cause CML. Because of adequate protection, the risk of CML has
not increased among individuals working in the nuclear industry or
among radiologists.

■ 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
genetic translocation, DNA sequences from the cellular oncogene
ABL1 are juxtaposed to the major breakpoint cluster region (BCR)
gene on chromosome 22, generating a hybrid oncogene, BCR/ABL1.
Depending on the breakpoint site in the major BCR region on
chromosome 22 (e13 or e14), two main messenger RNA transcripts
occur, e13a2 (previously b2a2) and e14a2 (previously b3a2). Both of
them encode for a novel oncoprotein of molecular weight 210 kDa,
referred to as p210BCR-ABL1 (Fig. 105-1B). This 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
hematopoiesis 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 e1a2
transcript and a smaller BCR-ABL1 oncoprotein, p190BCR-ABL1.
When occurring in Ph-positive CML, this translocation is associated
with a worse outcome. A rarer breakpoint in BCR occurs telomeric to
the major BCR region in the micro-BCR (μ-BCR) region. It
juxtaposes a larger fragment of the BCR gene to ABL1 and produces
an e19a2 transcript and a larger p230BCR-ABL1 oncoprotein
(associated with a more indolent CML course). Other
rearrangements (based on different breakpoints in the ABL region),
such as e13a3 or e14a3 (also resulting in a p210BCR-ABL1
oncoprotein), occur much less frequently. These are not readily
identifiable nor quantifiable with the routine polymerase chain
reaction (PCR) probes, thus producing falsely negative PCR levels
on follow-up studies if not tested at diagnosis.
The constitutive activation of BCR/ABL1 results in
autophosphorylation and activation of multiple downstream pathways
that affect gene transcription, apoptosis, stromal adherence, skeletal
organization, and degradation of inhibitory proteins. These
transduction pathways involve RAS, mitogen-activated protein
(MAP) kinases, signal transducers 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, inhibiting its kinase activity,
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. 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. ABL1 also has a myristoyl site
that functions as a negative regulator of its kinase activity. This site
and its negative regulatory activity are lost upon fusion with BCR.
Novel ABL1 inhibitors (e.g., asciminib) bind this myristoyl site and
restore the lost inhibitory activity. Mutations in other cancer-
associated genes may also occur at diagnosis, most frequently in
ASXL1, IKZF1, and RUNX1; their presence is associated with worse
response to therapy and a higher risk of transformation to blastic
phase.
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, demonstrating 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 rearrangement is unknown.
Molecular techniques that detect BCR/ABL1 at a level of 1 in 108
cells identify 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
overwhelming majority of individuals in whom it occurs. Because
CML develops in only 1.6 of 100,000 individuals annually, additional
molecular events or poor immune recognition of the rearranged cells
may contribute to overt CML.
CML is defined by the presence of the 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 (FISH) and/or molecular studies (PCR) detect
BCR/ABL1. These patients have a course similar to patients with Ph-
positive CML and respond to TKI therapy. Many of the remaining
patients have atypical morphologic or clinical features and have
other diseases, such as atypical CML, chronic myelomonocytic
leukemia, and myelodysplastic/myeloproliferative neoplasms
(MDS/MPN). These individuals do not respond to TKI therapy and
usually 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 (80% of
cases) and in some cases of atypical CML (5–10% of cases),
mutations in SETBP1 in atypical CML (25% of cases), and mutations
in SF3B1 in MDS/MPN with ringed sideroblasts and marked
thrombocytosis (MDS/MPN-RS-T; 50–70% of cases, associated with
longer median survival of 7 years vs 3.3 years with wild-type SF3B1)
supports the notion that these are distinct molecular and biologic
entities. Patients with chronic neutrophilic leukemia or atypical CML
whose disease is associated with CSF3R mutation may respond well
to ruxolitinib (a JAK2 inhibitor) therapy (complete response in 50–
60% of such patients).
The events associated with the transition of CML from a chronic
to accelerated-blastic phase are poorly understood. Characteristic
chromosomal abnormalities such as a double Ph, trisomy 8,
isochromosome 17 or deletion of 17p (loss of TP53), 20q–,
translocations involving 3q26, and others may be seen with disease
acceleration. 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 defects
and eventually results in blastic transformation. One critical effect of
TKIs is to stabilize the CML genome, leading to a 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, the course
of CML is now frequently more indolent in patients treated with TKI,
even without cytogenetic response, compared to previous
experience with hydroxyurea/busulfan, suggesting a definite clinical
benefit of continued inhibition of the kinase activity.
Among patients developing resistance to TKIs, several resistance
mechanisms have been observed. The most clinically relevant one is
the development of 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 ABL1 kinase domain mutations have now been
described, many of which confer relative or absolute resistance to
imatinib. Consequently, second-generation (i.e., dasatinib, nilotinib,
bosutinib) and third-generation (ponatinib) TKIs were developed, the
latter with significant efficacy against T315I, a “gatekeeper” mutation
that prevents binding of and causes resistance to all other currently
available TKIs. Asciminib, olverembatinib (HQP1351) and other
novel TKIs under development are also active against the T315I
mutation.

■ CLINICAL PRESENTATION
The presenting signs and symptoms in CML depend on the
availability 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 burden including splenomegaly,
anemia, and related symptoms (abdominal pain, weight loss,
fatigue), associated with a higher frequency of high-risk CML.
Presenting findings in patients diagnosed in the United States are
shown in Table 105-1.

TABLE 105-1 Presenting Signs and Symptoms of Newly

Diagnosed Philadelphia Chromosome–Positive Chronic
Myeloid Leukemia in Chronic Phase
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
screening 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 include thrombotic or
hyperviscosity-related events from severe leukocytosis or
thrombocytosis. These include priapism, cardiovascular
complications, myocardial infarction, venous thrombosis, visual
disturbances, 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
hepatomegaly (5–10%), lymphadenopathy (5–10%), and
extramedullary disease (skin or subcutaneous lesions). The latter
indicates CML transformation 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, leukocytosis

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 thrombocytopenia 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 typically 5% or less; when higher, they carry a worse
prognosis or represent transformation to accelerated phase (if they
are ≥15%). Increased reticulin fibrosis (detected with silver stain) is
common, with 30–40% of patients demonstrating grade 3–4 reticulin
fibrosis. This was considered adverse in the pre-TKI era. With TKI
therapy, reticulin fibrosis resolves in most patients and is not an
indicator of poor prognosis. Collagen fibrosis (Wright-Giemsa stain)
is rare at diagnosis. Disease progression with a “spent phase” of
myelofibrosis (myelophthisis, or burnt-out marrow) was a relatively
common end-stage CML condition with busulfan therapy (20–30%);
it is extremely rare now with TKI therapy.

Cytogenetic and Molecular Findings The diagnosis of CML is

straightforward and depends on documenting the t(9;22)
(q34.1;q11.2), which is identified by G-banding in 90% of cases. This
is known as the Philadelphia chromosome (initially identified in
Philadelphia as a minute chromosome, later identified to be
chromosome 22) (Fig. 105-1). Some patients (∼10%) may have
complex translocations (complex variant Ph) involving three or more
chromosomes including chromosomes 9 and 22 and one or more
additional chromosomes. Others may have a “masked Ph,” involving
translocations between chromosome 9 and a chromosome other
than 22 (but molecularly showing the BCR/ABL1 rearrangement;
known as simple variant Ph). The prognosis of these patients and
their response to TKI therapy are similar to those in patients with Ph.
About 5–10% of patients may have additional chromosomal
abnormalities (ACAs) in the Ph-positive cells at diagnosis. These
usually involve trisomy 8, a double Ph, isochromosome 17 or 17p
deletion, 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 occurs with disease progression and carries a
poor prognosis.
 Techniques such as FISH and PCR are now used to aid in the
diagnosis of CML. They are more sensitive 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 chromosomal abnormalities (clonal evolution); thus, a
cytogenetic analysis is recommended at the time of diagnosis. In
addition, 10–15% of patients may develop chromosomal
abnormalities in Ph-negative metaphases after responding to TKIs.
These abnormalities may carry a worse prognosis but are not
detected by FISH unless already identified and FISH is used to
follow them. Molecular studies at diagnosis are important to
document the type and presence of BCR-ABL1 transcripts to avoid
spurious “undetectable” BCR-ABL1 transcripts on follow-up studies,
with the false impression of a complete molecular response. The
presence of the Philadelphia chromosome with “negative” 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 chromosome, detects clonal evolution, and 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
PCR has become an important standard practice to assess response
to therapy, emphasize compliance, evaluate possible treatment
resistance, identify the need to change TKI therapy, and determine
the need to assess for kinase domain mutations. Because of the
decreasing reliance of bone marrow aspirations to monitor response,
equivalence has been established to correlate cytogenetic results
with PCR values. These are not absolute correlations but provide
adequate guidance. 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 International Scale (IS) of 10% or less. A complete
cytogenetic response refers to the absence of Ph-positive
metaphases (0% Ph positivity). This is approximately equivalent to
BCR-ABL1 transcripts (IS) of 1% or less. A major molecular
response (MMR or MR3) refers to BCR-ABL1 transcripts (IS) ≤0.1%,
or roughly a 3-log or greater reduction of BCR-ABL1 transcripts from
a standardized baseline. MR4 refers to BCR-ABL1 transcripts (IS)
≤0.01%, and MR4.5 (deep molecular response) refers to BCR-ABL1
transcripts (IS) ≤0.0032%, roughly equivalent to a 4.5-log reduction
or greater of transcripts.

Findings in CML Transformation Progression of CML is usually

associated with leukocytosis resistant to therapy, increasing anemia,
fever and constitutional symptoms, and increased blasts and
basophils in the peripheral blood or marrow. Criteria of accelerated-
phase CML, historically associated with median survival of <1.5
years, include the presence of 15% or more peripheral blasts, 30%
or more peripheral blasts plus promyelocytes, 20% or more
peripheral basophils, cytogenetic clonal evolution (presence of
chromosomal abnormalities in addition to Ph), and thrombocytopenia
<100 × 109/L (unrelated to therapy). About 5–10% of patients
present with de novo accelerated phase or blastic phase. The
prognosis of de novo accelerated phase with TKI therapy has
improved significantly, with an estimated 8-year survival rate of 75%.
The median survival of accelerated phase evolving from chronic
phase has also improved from a historical median survival of 18
months to an estimated 4-year survival rate of 70% on TKI therapy.
Therefore, the criteria for accelerated-phase CML should be revisited
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
presence of sheets of blasts in extramedullary disease (usually skin,
soft tissues, or lytic bone lesions). Blastic-phase CML is commonly
myeloid (60%) but can present uncommonly as erythroid,
promyelocytic, monocytic, or megakaryocytic. Lymphoid blastic
phase occurs in about 25% of patients. Lymphoblasts are terminal
deoxynucleotide transferase 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. Proper immunophenotypic diagnosis is important
because 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 rate 70%; median survival 3 years; high
rates of bridging to allogeneic SCT and possible cure).

■ 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 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
transformation 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 1–2% in the first 20 years of
observation. More than half of the deaths are from conditions other
than CML, such as old age, comorbidities, accidents, suicides, other
cancers, and other medical conditions (e.g., infections, surgical
procedures). The estimated 10-year survival rate is 86%, or 92% if
only CML-related deaths are considered (Fig. 105-2). 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, bosutinib)
used as frontline therapy have reduced the incidence of
transformation in the first 2–3 years from 6–8% with imatinib to 2–5%
with second-generation TKIs. Disease transformation to accelerated
or blastic phase is rare with continued TKI therapy, estimated at <1%
annually in years 4–10 of follow-up on the original imatinib trials.
Patients usually develop resistance in the form of cytogenetic
resistance or relapse, followed by hematologic relapse and
subsequent transformation, rather than the previously feared sudden
transformations without the warning signals of cytogenetic-
hematologic relapse.
FIGURE 105-2 A. Survival in newly diagnosed chronic-phase chronic myeloid
leukemia (CML) by era of therapy (MD Anderson Cancer Center experience from
1965 to present). Top blue curve is survival with tyrosine kinase inhibitors (TKIs),
accounting for only CML-related deaths. The orange curve (second from top)
accounts for deaths related to CML or CML treatment complications (e.g., deaths
following allogeneic stem cell transplant [SCT]). The red curve (third from top) is
survival including all deaths regardless of causality (old age, car accidents,
suicide, gun shots, second cancers, complications of unrelated surgeries,
infections, others). The difference in the denominators, 613 minus 597 cases, is
because 16 deaths were from unknown/undocumented causes (outside MD
Anderson and no good tracking for cause of death). 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 TKI era in
accelerated-phase CML but the modest benefit in blastic-phase CML. Referred
cases included de novo and post-chronic-phase transformations.

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
thrombocytosis, high percentages of blasts and basophils (and/or
eosinophils), marrow fibrosis, interstitial 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 important 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 survival.
Achievement of MMR or MR3 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 survival benefit
conferred by the achievement of complete cytogenetic response,
which approximates normal life expectancy, and 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 (complete molecular response [CMR]) or
deep molecular response (DMR; defined as MR4 or MR4.5),
particularly when sustained (>2–5 years), may offer the possibility of
treatment-free remission and may allow temporary therapy
interruption in women pursuing pregnancy. The lack of achievement
of MMR or DMR 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-
generation TKIs and imatinib are similarly effective in lower-risk
CML; second-generation TKIs may offer a therapeutic advantage
among patients with high-risk CML.

TREATMENT
Chronic Myeloid Leukemia
Since 2001, six drugs 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),
dasatinib (Sprycel), bosutinib (Bosulif), and ponatinib (Iclusig).
Dasatinib, nilotinib, and bosutinib are referred to as second-
generation TKIs; ponatinib is referred to as a third-generation TKI.
Nilotinib is similar in structure to imatinib but 30 times more potent.
Dasatinib and bosutinib inhibit the 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 TKIs, bosutinib has no activity against c-Kit or platelet-derived
growth factor receptor (PDGFR). Ponatinib is highly effective
against wild-type and mutant BCR/ABL1 clones. It is also the only
available BCR-ABL1 TKI active against T315I, a gatekeeper
mutation resistant to the other four ATP-competitive TKIs (Table
105-2). Ponatinib also inhibits vascular endothelial growth factor
receptor (VEGFR), which may be at least partly responsible for the
high incidence of hypertension observed with this agent (Table 105-
2). 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.
Dasatinib 50 mg orally daily is as effective in frontline therapy as
100 mg daily, and significantly less toxic. All four are also approved
for salvage therapy (nilotinib 400 mg twice daily; bosutinib 500 mg
daily; others at the same dose as frontline therapy), in addition to
ponatinib (45 mg daily). Ponatinib 45 mg daily may be associated
with serious side effects: arterio-occlusive events, pancreatitis,
hypertension, and skin rashes. A response-directed dose adjusted
regimen, with a starting dose of 45 mg and reduction to 15 mg once
a cytogenetic response is achieved, has resulted in a reduced
incidence of arterio-occlusive events and has become standard.
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 accelerated phase. The sixth approved drug is omacetaxine
(Synribo), a protein synthesis inhibitor 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; thus, many experts
use shorter schedules (e.g., omacetaxine 5–7 days induction and
2–5 days maintenance), often combined with a TKI (Table 105-2).

TABLE 105-2 Medical Therapeutic Options in Chronic Myeloid

Leukemia
 Imatinib, dasatinib, bosutinib, and nilotinib are all acceptable
frontline therapies in CML. The long-term results of imatinib are very
favorable. The 10-year follow-up results show a cumulative
complete cytogenetic 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 continuing on imatinib, the annual rate of
transformation to accelerated-blastic phase in years 4–8 is <1%. In
three randomized studies, one comparing nilotinib 300 mg twice
daily or 400 mg twice daily with imatinib (ENESTnd), another
comparing dasatinib 100 mg daily with imatinib (DASISION), and a
third comparing bosutinib 400 mg daily with imatinib (BFORE), the
second-generation TKIs were associated with better outcomes in
early surrogate endpoints, including higher rates of complete
cytogenetic responses (85–87% vs 77–82%), MMRs (5-year rates
76–77% vs 60–64%), and MR4.5 (5-year rates 42–53% vs 31–
33%), with lower rates of transformation to accelerated and blastic
phase (2–5% vs 7%). However, no study has shown a survival
benefit with second-generation TKIs. This may be because the rate
of complete cytogenetic response is ultimately similarly high with
imatinib versus second-generation TKIs, and also because
sequential therapy with TKIs (following close observation and
treatment change at progression) provides highly effective therapy
for most patients; this ensures adequate long-term outcome despite
relapse or intolerance after initial therapy.
Salvage therapy in chronic phase with dasatinib, nilotinib,
bosutinib, 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,
number of prior TKIs used, and the mutations at the time of relapse.
Complete cytogenetic responses are generally durable, particularly
in the absence of clonal evolution. 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 two or more
TKIs. The estimated 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%.
The goal of CML therapy is survival prolongation. The
achievement of treatment-free remission (TFR) status has become
a therapeutic goal of increased interest (sustained DMR or CMR
after discontinuation of TKI therapy). In current practice, with the
availability of appropriate TKI therapy and with compliance,
monitoring, and changing of TKI therapy as indicated by
response/resistance and side effects, patients can have a near-
normal life expectancy, with a “relative” survival similar to that of the
general population. Therefore, in standard practice, achievement
and maintenance of a complete cytogenetic response are the aims
of therapy, because complete cytogenetic response is the only
outcome associated with survival prolongation. Lack of achievement
of an MMR (protects against events; associated with longer event-
free survival) or of DMR (offers the potential of treatment
discontinuation and of TFR) 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) are the indicators of “failure” of a particular
TKI therapy. A second emerging general practice rule is that
patients with CML 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 formally approved), except perhaps in
situations of “molecular cure” (TFR; elective discontinuation of TKI if
DMR sustained for >2 to 5 years, followed by close monitoring) or
after allogeneic 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 and bosutinib; arterio-
occlusive with nilotinib, dasatinib, and ponatinib), a goal of therapy
of increasing interest in CML is to achieve eradication of the
disease (molecular “cure” or TFR) that is prolonged and durable,
with recovery of nonneoplastic, nonclonal hematopoiesis off TKI
therapy. The first step toward this aim is to obtain the highest rates
of DMR 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.
Approximately 50–60% of those who meet these criteria and
discontinue therapy remain free from therapy and in DMR-MMR. As
a result, TFR rates are estimated to be about 15–20% after imatinib
therapy and 25–30% after 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
duration. Unfortunately, they may have been misinterpreted in
current practice because oncologists often report that their aim of
treatment is the achievement of MMR and disease eradication.
Significantly, a substantial proportion of oncologists consider a
change of TKI therapy in a patient in complete cytogenetic response
if they note loss of MMR (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 maturing 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 emphasize that no
randomized study has yet shown that a change of TKI treatment in
patients with complete cytogenetic response because of a loss of
MMR, versus changing at the time of cytogenetic relapse, improves
survival or other long-term outcomes. This is likely because of the
high efficacy of salvage 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 imatinib
therapy, common mild to moderate side effects include fluid
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%). A lower dose of dasatinib (50 mg daily instead of 100 mg
daily) used in frontline CML therapy has resulted in similar efficacy
and a lower incidence of serious side effects (pleural effusions <5%,
myelosuppression <10%). 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%).
Nilotinib 300–400 mg twice daily is associated with a 10-year
cumulative incidence of cardiovascular complications of 15–25%.
Bosutinib is associated with higher rates of liver toxicity, renal
dysfunction, and early and self-limited gastrointestinal adverse
events, particularly diarrhea (70–85%). Occasionally, the
gastrointestinal symptoms mimic chronic severe enterocolitis, which
reverses with treatment discontinuation. Ponatinib 45 mg daily is
associated with higher rates of serious 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 TKIs. 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. Among the TKIs, bosutinib is associated with the
lowest incidence of cardiovascular events. 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 100–200 mg daily; nilotinib 150 mg
twice daily or 200 mg daily; dasatinib 20 mg daily; bosutinib 200–
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
TKIs, 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
discontinuation. 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 sildenafil 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 considered 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 of 15% with nilotinib 300 mg BID and 20–25%
with 400 mg BID, compared with <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,
particularly among patients with other risk factors for such events.
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
Several studies have confirmed that TKI discontinuation among
patients who achieve DMR (MR4.5) for longer than 2–3 years can
result in TFR rates of 40–60%. Discontinuation of TKI therapy after
5+ years of CMR is associated with TFR rates of 70–80% or
greater. Since the incidence of durable MR4.5 (BCR-ABL transcripts
[IS] ≤0.0032%) is 30–60%, ∼15–30% of all patients with CML on
TKI therapy may achieve TFR. This approach is ready for
community practice provided it is done under optimal conditions.
These include the following: patients must have low or intermediate
Sokal risk CML in first chronic phase (no evidence or history of
transformation), with history of quantifiable BCR-ABL1 transcripts
(e13a2, e14a2), on long-term TKI therapy (5–8+ years), with
documented DMR for >2–3 years (assessed every 6 months during
this time span and with a PCR with adequate sensitivity), and
should be monitored at referral centers that offer rigorous testing of
residual CML disease. Patients must also be compliant to frequent
monitoring (PCR studies every 1–2 months for the first 6 months,
then every 2 months until 2 years and every 3–6 months thereafter).

ALLOGENEIC STEM CELL TRANSPLANT

Allogeneic SCT, a curative modality in CML, is associated with long-
term survival rates of 40–60% when implemented in chronic 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 ∼50–
60% (and considered as cure rates), ∼10–15% of patients die in the
subsequent 1–2 decades from subtle long-term complications of the
transplant (rather than from CML relapse). These are related to
chronic graft-versus-host disease (GVHD), organ dysfunction,
development of second cancers, occasional late relapses, and
hazard ratios for mortality higher than in the normal population.
Other significant morbidities 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 matching, preparative regimen, and
others. In accelerated-phase CML, the cure rates with allogeneic
SCT are 30–50%, depending on the definition 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 ≤20%. Post–
allogeneic SCT strategies are now implemented in the setting of
molecular or cytogenetic relapse or in hematologic
relapse/transformation. 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
considered 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
chemotherapy 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
allogeneic 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
105-3). Patients with T315I mutations at relapse should be offered
ponatinib and considered for allogeneic SCT particularly if in blastic
phase and perhaps also in accelerated phase (because of the short
follow-up with ponatinib). 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 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 allogeneic 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 105-3). 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 105-3
summarizes a general guidance to the choice of TKIs versus
allogeneic SCT.
TABLE 105-3 General Suggestions Regarding the Use of
Tyrosine Kinase Inhibitors (TKIs) and Allogeneic Stem Cell
Transplantation (SCT) in Chronic Myeloid Leukemia (CML)

MONITORING THERAPY IN CML

Achievement of complete cytogenetic response by 12 months of
imatinib therapy and its persistence later, the only consistent
prognostic factor associated with prolonged survival, is now the
main therapeutic endpoint in CML. Failure to achieve a complete
cytogenetic response by 12 months or occurrence of later
cytogenetic or hematologic relapse is considered as treatment
failure and an indication to change therapy. Because salvage
therapy with other TKIs may re-establish good outcome, it is
important to ensure patient compliance to continued TKI therapy
and change therapy when cytogenetic relapse is confirmed unless
this is related to nonadherence. Patients on frontline imatinib
therapy should be closely monitored until documentation of
complete cytogenetic response, at which time they can be
monitored every 6 months with peripheral blood PCR, or more
frequently (e.g., every 3 months), if there are concerns about
changes in BCR-ABL1 transcripts. 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
currently 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 (dasatinib, bosutinib,
nilotinib) as frontline therapy changed the monitoring approach
slightly. Patients are expected to achieve major cytogenetic
response (or BCR-ABL1 transcripts ≤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, ∼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 obvious signs of
resistance appear. Thus, slow response to therapy is considered a
warning signal, but it is not known whether changing therapy to
other TKIs at that time would improve longer-term outcome.
TREATMENT OF ACCELERATED AND BLASTIC PHASES
Patients in accelerated or blastic phase may receive therapy with
TKIs, preferably second- or third-generation TKIs (dasatinib,
nilotinib, bosutinib, ponatinib), alone or in combination with
chemotherapy, 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 show that combined TKI-chemotherapy strategies
increase the response rates and their durability 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 70% and median survival times of 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–acute
myeloid leukemia chemotherapy combined with TKIs results in CR
rates of 30–50% and median survival times of 9–12 months
(compared 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, decitabine, interferon α, hydroxyurea, or others.

OTHER TREATMENTS AND SPECIAL THERAPEUTIC

CONSIDERATIONS
Interferon α 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
investigational strategies with TKIs to eradicate residual molecular
disease.
Chemotherapeutic Agents Hydroxyurea remains a safe and
effective agent (at daily doses of 0.5–10 g) to reduce initial CML
burden, as a temporary measure in between definitive therapies, or
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
myelosuppression, Addison-like disease, pulmonary and cardiac
fibrosis, myelofibrosis), it is now rarely used in the chronic
management 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
symptoms 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 therapy 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, where the incidence
of malformations 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 reports of successful
pregnancies and deliveries of normal babies with interferon α
therapy and registry studies in essential thrombocytosis of its safety,
but interferon α has side effects that may be troublesome during
pregnancy, 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
instability 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 diagnosed
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.
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) (Figs. 105-2 and
105-3) or in clinical trials (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. It appears that the treatment penetration of
imatinib and other TKIs into CML therapy worldwide is still not
optimal.

FIGURE 105-3 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.)

The current high cost of TKI therapies poses two additional

considerations. 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 onetime cost of $20,000–100,000) despite
the associated mortality and morbidities. The second is the choice of
frontline TKI therapy. Imatinib is now available in generic forms at
affordable costs ($400–10,000 per year). Dasatinib is available in
generic forms in many geographies. Safe and effective generic TKIs
may become preferred frontline and salvage therapies in CML,
precluding the necessity of an allogeneic SCT in first salvage in
poorer nations.

■ FURTHER READING
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.
CORTES JE et al: Bosutinib versus imatinib for newly diagnosed
chronic myeloid leukemia: Results from the randomized BFORE
Trial. J Clin Oncol 36:231, 2018.
CORTES JE et al: Ponatinib efficacy and safety in Philadelphia
chromosome-positive leukemia: Final 5-year results of the phase
2 PACE trial. Blood 132:393, 2018.
HOCHHAUS A et al: Long-term outcomes of imatinib treatment for
chronic myeloid leukemia. N Engl J Med 376:917, 2017.
HOCHHAUS A et al: European LeukemiaNet 2020 recommendations
for treating chronic myeloid leukemia. Leukemia 34:966, 2020.
JABBOUR E, KANTARJIAN H: Chronic myeloid leukemia: 2020 update on
diagnosis, therapy and monitoring. Am J Hematol 95:691, 2020.
KANTARJIAN H et al: Long-term outcomes with frontline nilotinib versus
imatinib in newly diagnosed chronic myeloid leukemia in chronic
phase: ENESTnd 10-year analysis. Leukemia 35:440, 2021.
NAQVI K et al: Long-term follow-up of lower dose dasatinib (50 mg
daily) as frontline therapy in newly diagnosed chronic-phase
chronic myeloid leukemia. Cancer 126:67, 2020.
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, 2016.
SAUSSELE S et al: Discontinuation of tyrosine kinase inhibitor therapy
in chronic myeloid leukaemia (EURO-SKI): A prespecified interim
analysis of a prospective, multicentre, non-randomised trial.
Lancet Oncol 19:747, 2018.
SHIH YT et al: Treatment value of second-generation BCR-ABL1
tyrosine kinase inhibitors compared with imatinib to achieve
treatment-free remission in patients with chronic myeloid
leukaemia: A modelling study. Lancet Haematol 6:e398, 2019.
 Acute Lymphoid Leukemia
106
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 hemorrhage. 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).

■ 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 adolescents
and young adults (AYAs), decreasing in adults, but increasing again
in elderly people. Thus, Philadelphia chromosome–positive ALL
(Ph+ ALL; BCR/ABL translocation) is observed in half of elderly B-
lineage patients. The frequency of immunologic, cytogenetic, and
genetic subtypes changes substantially with age.

■ ETIOLOGY
The etiology of acute leukemias is unknown. Internal and external
factors influence the incidence of leukemia. Exposure to ionizing
radiation or to chemicals, including prior chemotherapy, is associated
with an increased risk of developing leukemia, more often observed
in acute myeloid leukemia (AML). However, increasingly, secondary
ALLs have been observed, particularly after cytostatic treatment with
alkylating agents and topoisomerase inhibitors as treatment for
primary tumors, most often for AML, myelodysplastic syndromes, or
breast cancer.

■ 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). Those with Down’s syndrome
have a twentyfold increased incidence of leukemia; ALL is increased
in childhood and AML at an older age.

■ INFECTIOUS AGENTS
No direct evidence implicates viruses as a major cause of human
acute leukemia. However, viruses are involved in the pathogenesis
of two lymphoid neoplasias. In the endemic African type of Burkitt’s
lymphoma, the Epstein-Barr virus, a DNA virus of the herpes family,
has been implicated as a potential causative agent (see Chap. 194).
Endemic infection with human T-cell leukemia virus I in Japan and
the Caribbean has been shown to be an etiologic agent for rare
cases of adult T-cell leukemia/lymphoma (see Chap. 201).

■ DIAGNOSIS AND CLASSIFICATION

The diagnosis of acute leukemia is first made by examination of the
peripheral blood and bone marrow. For further classification of the
leukemic blast cells, cytochemical stains, immunologic markers, and
cytogenetic and molecular analysis are required. The immunologic
markers are still the major criteria to subdivide into B-cell lineage or
T-cell lineage ALL leukemias.

■ 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 (WBC) count in ∼40% of ALL
patients is reduced or normal (Table 106-1). Only 16% of patients
have a WBC above 100 × 105/L. It is noteworthy that in 8% of ALL
patients, no circulating leukemic blast cells were observed. Thus, in
the frequently used automatic blood cell counting, the diagnosis may
not be detected.

TABLE 106-1 Laboratory Values at Diagnosis of Acute

Lymphoblastic Leukemia (ALL)

Peripheral blood characteristically shows anemia,

thrombocytopenia, and neutropenia. Nearly one-third of patients
have hemoglobin levels <7–8 g/dL. A platelet count below the critical
number of 20 × 109/L and neutropenia (neutrophils <0.5 × 109/L),
which is associated with a higher risk of infection, are each noted in
one-fifth of adults with ALL.
■ BONE MARROW EXAMINATION
Bone marrow aspirates/biopsies are important to assess
immunologic, cytogenetic, and genomic markers. Direct smears from
the bone marrow are essential to confirm the diagnosis of acute
leukemia and to distinguish between AML and ALL. The bone
marrow is usually heavily packed with leukemic blast cells with >90%
in ∼70% of patients, and thus, the normal hemopoietic elements are
greatly reduced or absent. A biopsy of the bone marrow will further
demonstrate marked hypercellularity with replacement of fat spaces,
normal elements, and occasionally increased fibrosis.

■ LUMBAR PUNCTURE
The examination of the cerebrospinal fluid is an essential routine
diagnostic measure for ALL. Central nervous system (CNS)
leukemia is diagnosed if ≥5 cells/μL or leukemic blast cells were
observed by morphology in cerebrospinal fluid. Opinions differ as to
when the first lumbar puncture should be done—i.e., either delay
lumbar puncture until remission is achieved to avoid seeding of the
CNS with leukemic blast cells from the peripheral blood during the
spinal tap, or perform the lumbar puncture before treatment starts,
since early recognition of CNS disease will lead to immediate CNS-
specific therapy. Lumbar puncture is restricted to patients with an
adequate platelet count (>20 × 109/L) and without manifest clinical
hemorrhages. To eliminate potentially transferred blast cells, patients
should receive intrathecal methotrexate at the first lumbar puncture.

■ MORPHOLOGIC SUBTYPES IN ALL

The French-American-British (FAB) classification distinguished three
subgroups. L1 and L2 morphology has no clinical consequences.
Only the L3 morphology, observed in up to 5% of adult patients, is
indicative for mature B-cell lineage ALL (B-ALL) (see Chap. 62).

■ IMMUNOLOGIC SUBTYPES
A series of monoclonal antibodies is employed to identify antigens
expressed on the surface of leukemic cells, corresponding to the
pathways of normal B-cell differentiation (see Fig. 108-2). The aim of
the immunologic classification is to subdivide ALLs according to the
presence or absence of B-cell or T-cell markers. A marker is
considered positive if >20% of the cells are stained with the
monoclonal antibody.
There are different immunologic classifications, such as that of
the European Group for the Immunological Characterization of
Leukemias (EGIL), with clear therapeutic implications. Table 106-2
gives a simplified correlation of immunologic subtypes, cytogenetics
and molecular aberrations, and clinical characteristics.

TABLE 106-2 Immunologic, Cytogenetic, Molecular, and

Clinical Characteristics of Adult Acute Lymphoblastic
Leukemia (ALL)

B-Cell Lineage ALL (B-ALL) More than 70% of adult ALLs are of B-
cell origin, and the most frequent immunologic subtype, common
ALL, is characterized by the presence of the ALL antigen CD10
without markers of relatively mature B cells such as cytoplasmic or
surface membrane immunoglobulins. Pre-B-ALL (early B-ALL) is
characterized by the expression of cytoplasmic immunoglobulin,
which is negative in common ALL, but otherwise is identical with
respect to all other cell markers. Pro-B-ALL corresponds to early B-
cell differentiation and was formerly termed non-T-, non-B-ALL or
null ALL because neither T-cell nor B-cell features could be
demonstrated. This subtype is HLA-DR, terminal deoxynucleotidyl
transferase, and CD19 positive and composes ∼12% of adult ALLs.
Mature B-ALL is seen in 3–4% of adults and is also known as
Burkitt’s leukemia. In mature B-ALL, blast cells express surface
antigens of mature B cells, including the sIgM.

T-Cell Lineage ALL (T-ALL) Approximately 25% of adult ALLs are

of T-cell lineage. All cases express the T-cell antigen CD7 and
cytoplasmatic CD3 (CyCD3) or surface CD3. According to their
phase of T-cell differentiation, they may express other T-cell antigens
(e.g., the E-rosette receptor CD2 and/or the cortical thymocyte
antigen CD1a). Early pro/pre-T-ALL (also termed early T precursor
ALL [ETP-ALL]), cortical or thymic T-ALL, and mature T-ALL can be
distinguished with these markers. ETP-ALL is characterized by lack
of CD1a and CD8, weak CD5 expression, and at least one
myeloid/stem cell marker.

Biphenotypic or Mixed Leukemias Biphenotypic leukemias are

defined as those expressing markers of both lymphoid and myeloid
lineages on the same leukemic cells. Bilineage leukemias are those
with two populations of blast cells with either lymphoid or myeloid
antigens. It is not clear whether these patients should receive an ALL
or AML treatment protocol. In pediatric studies, starting with a
pediatric ALL protocol seemed preferable, which was then followed
by AML consolidation elements.

■ CYTOGENETIC AND MOLECULAR ANALYSIS

Cytogenetic and molecular analyses should be performed in all
cases in ALL. They are important to define ALL subtypes, can
identify independent prognostic markers of disease-free survival, and
may determine specific targeted therapies.
 The diagnostic techniques for ALL 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-
generation sequencing recognize the newly defined ALL entities:
ETP-ALL and Ph-like ALL.
Ph-like ALL, also known as BCR-ABL1-like ALL, is characterized
by genetic lesions similar to Ph+ ALL, associated with IKZF1 (Ikaros)
gene deletion, CLRF2 (gene for cytokine-like receptor-2)
overexpression, and tyrosine kinase activating rearrangements
involving ABL1, JAK2, PDGFRB, and several other genes; however,
it is BCR-ABL1 negative. The frequency is 10% in children and 25–
30% in young adults but does not increase further with age like Ph+
ALL. Treatment based on the underlying genetic lesion with BCR-
ABL inhibitors (e.g., dasatinib) or JAK2 inhibitors (e.g., ruxolitinib)
has so far had limited success in adults.

■ MINIMAL RESIDUAL DISEASE

Minimal residual disease (MRD) is the detection of residual leukemic
cells that are 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%). With new techniques
such as next-generation sequencing (NGS) or digital droplet
polymerase chain reaction (ddPCR), the sensitivity may increase to
10–5–10–6. The phenotypic aberrations are unique to each patient
with ALL and can be detected in up to 95% of individuals. Collection
of bone marrow at diagnosis for identification of patients’ individual
markers is essential for follow-up of MRD.

■ MOLECULAR RESPONSE AFTER INDUCTION THERAPY AND

IMPACT ON OUTCOME
Achievement of molecular complete response/molecular remission is
the most relevant independent prognostic factor for disease-free
survival and overall survival in pediatric and adult ALL (Table 106-3).
Patients with molecular complete remission after induction therapy
had significantly superior outcomes in several studies, with a
disease-free survival rate of ∼70% compared to <40% for MRD-
positive patients. Patients with molecular failure after induction
should proceed to a targeted therapy to reduce the tumor load,
followed by allogeneic stem cell transplantation (SCT), if possible.

TABLE 106-3 Response Parameters According to Minimal

Residual Disease (MRD)

■ PROGNOSTIC FACTORS, RISK STRATIFICATION, AND MRD

The aim of identification of prognostic parameters at diagnosis,
which include age, white blood cell count, immunophenotype, and
cytogenetic and genetic aberrations, is to stratify patients into risk
groups: standard-risk patients are patients without any risk factor,
and high-risk patients are those with one or more risk factors. High-
risk patients are most often candidates for SCT in first complete
remission (CR). MRD is thus the most important prognostic factor
during therapy (Fig. 106-1); 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. If the MRD status of a patient is not
available, risk stratification should rely on clinical and laboratory risk
factors evaluated at diagnosis.

FIGURE 106-1 A schematic treatment algorithm in acute lymphoblastic

leukemia (ALL). 6-MP, 6-mercaptopurine; Adria, Adriamycin (doxorubicin); AraC,
cytarabine; Asp, asparaginase; BFM, Berlin-Frankfurt-Münster; CNS, central
nervous system; CR1, first complete remission; Cyclo, cyclophosphamide; Dauno,
daunorubicin; Dexa, dexamethasone; Doxo, doxorubicin; HD, high-dose; Hyper-
CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and
dexamethasone; Ida, idarubicin; MRD, minimal residual disease; MTX,
methotrexate; POMP, mercaptopurine, vincristine, methotrexate, and prednisolone;
Pred, prednisolone; Vind, vindesine; VP16, etoposide.

■ TREATMENT PRINCIPLES
Treatment of ALL consists usually of pre-phase therapy, induction
therapy, consolidation cycles, and maintenance treatment. Treatment
should start immediately when the diagnosis of ALL is established.

Pre-Phase Therapy Pre-phase therapy consisting of glucocorticoids

(prednisone 20–60 mg/d or dexamethasone 6–16 mg/d, both IV or
PO) alone or in combination with another drug (e.g., vincristine,
cyclophosphamide) is usually given for ∼5–7 days. It allows safe
tumor reduction to avoid tumor lysis syndrome, to initiate supportive
therapy, such as substitution of platelets/erythrocytes, or to treat
infections. The time required for pre-phase therapy will also allow
time to obtain results of the diagnostic workup (e.g., cytogenetics,
molecular genetics).

Induction Therapy The goal of induction therapy is the achievement

of a CR or, even better, a molecular CR. With current regimens, the
CR rate has increased to 80–90% and is higher for standard-risk
patients (>90%) and lower for high-risk patients (∼60%).
Induction regimens are centered around vincristine,
glucocorticoids, and anthracyclines with or without
cyclophosphamide or cytarabine. L-Asparaginase is the only ALL-
specific drug and is now more intensively used in adults. Pegylated
asparaginase has the advantage of a significantly longer period of
asparagine depletion. Dexamethasone is often preferred to
prednisone because it penetrates the blood-brain barrier and also
acts on resting leukemic blast cells.
Two chemotherapy regimens are widespread (Fig. 106-1). One is
patterned after the pediatric BFM (Berlin-Frankfurt-Münster) protocol,
which is mostly used in European adult ALL trials. Another approach
is to repeat two different alternating intensive chemotherapy cycles,
identical for induction and consolidation, for eight cycles, such as
Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone) protocol, which is preferentially
used in the United States but also in many other parts of the world.

Postremission Consolidation Usual protocols use six to eight

courses and often contain systemic high-dose (HD) therapy to reach
sufficient drug levels in sanctuary sites such as the CNS. Most often
HD methotrexate (1–1.5 g/m2 and up to 3–5 g/m2) and/or HD
cytarabine (4–12 doses at 1–3 g/m2) are administered.

Maintenance Therapy Maintenance therapy, a strategy transferred

from childhood ALL, is mandatory. It consists of 6-mercaptopurine
and methotrexate plus intrathecal therapy. The potential effect of
further intensification cycles during maintenance remains unclear.
The duration of maintenance therapy for T-ALL and B-ALL is 2–2.5
years, except for Burkitt’s leukemia, for which it is not required. In
Ph+ ALL, patients also require maintenance therapy that should
include a tyrosine kinase inhibitor (TKI), most likely the TKI that has
been used during induction and consolidation therapy. It is also
standard to give a TKI after allogeneic SCT. The duration of
maintenance therapy with a TKI is also 2–2.5 years and should be
guided by MRD evaluation. TKI use is often interrupted or switched
to another TKI if toxicity occurs.

■ TREATMENT OF ALL PATIENTS ACCORDING TO AGE

The outcome of ALL is strictly related to the age of a patient, with
cure rates of ∼90% in children, decreasing to <10% in elderly or frail
patients. Thus, age-adapted protocols have emerged, where the age
limits are directed by the hematologic and nonhematologic toxicities.
Table 106-4 provides a summary of the best results obtained in adult
ALL according to ALL subtype, age, and treatment. Molecular CRs
are often durable. The major risk of relapse is in the first 2 years;
thereafter, relapse is much less likely.

TABLE 106-4 Best Results in Recent Studies for Adult Acute

Lymphoblastic Leukemia (ALL)
■ PROPHYLAXIS AND TREATMENT OF CENTRAL NERVOUS
SYSTEM LEUKEMIA
Prophylactic CNS therapy in ALL is essential in order to prevent
CNS leukemia and to avoid spread of leukemic cells from the CNS
back to the periphery. Treatment options include intrathecal therapy,
systemic HD chemotherapy, and cranial radiation therapy (CRT).
Intrathecal therapy mostly consists of methotrexate as a single drug
or in combination with cytosine arabinoside (AC) with or without
glucocorticoids. The route of intrathecal therapy application is
generally lumbar puncture. Systemic HD chemotherapy may
comprise HDAC or HD methotrexate since both drugs reach
cytotoxic drug levels in the CSF and show effectiveness in overt
CNS leukemia. CRT (18–24 Gy in 12 fractions over 16 days) is also
effective as preventive treatment of CNS leukemia. Using combined
modalities for CNS prophylaxis, the CNS relapse rate has decreased
to 2–5%.
Particular attention to CNS prophylaxis is required for targeted
therapies. In Ph+ ALL, not all TKIs cross the blood-brain barrier
equally. Dasatinib and probably ponatinib do cross the blood-brain
barrier, whereas imatinib and nilotinib do not. In addition to
immunotherapy, intrathecal therapy is required because most
antibodies do not enter the CNS.
CNS involvement at diagnosis is observed in 5–10% of adult
patients and is higher in mature B-ALL (up to 10–15%) and T-ALL
(up to 10%). Treatment consists of the standard chemotherapy with
additional intrathecal applications 3–5 times per week until blast cells
are cleared in the spinal fluid. Patients with initial CNS involvement
have a similar overall survival as CNS-negative patients.
Relapse in CNS is usually accompanied by bone marrow
involvement, and if blast cells are not seen morphologically, MRD as
a sign of discrete infiltration is positive in nearly all cases. CNS
relapse requires local as well as systemic therapy. The outcome
after CNS relapse is dismal, and salvage chemotherapy followed by
allogeneic SCT is the most effective option. Chimeric antigen
receptor (CAR) T cells (most often targeting CD19) can cross the
blood-brain barrier and achieve CRs in patients with CNS relapse.

■ STEM CELL TRANSPLANTATION

SCT is an essential part of the treatment strategy for adult ALL.
Peripheral blood cells are increasingly being used as a stem cell
source, instead of bone marrow. In addition, a shift from sibling stem
cell donors to matched unrelated donors or haploidentical
transplants from relatives has occurred. Indications for SCT in first
CR are controversial. However, in most studies, SCT is
recommended for high-risk patients defined either by conventional
prognostic factors or by MRD positivity. High-risk patients
transplanted in first CR have a survival rate of 50% or greater;
decreasing transplant-related mortality from 20–30% to 10–15% has
contributed substantially to better outcomes. For standard-risk
patients with sustained molecular remission, allogeneic SCT in first
CR is not recommended. Autologous SCT should be restricted to
MRD-negative patients, BCR-ABL–negative patients, Ph+ patients,
and older patients because it is less toxic but associated with a
substantially higher relapse rate. For all relapsed adult ALL patients,
an allogeneic SCT is thus far the only curative option.

■ PEDIATRIC-INSPIRED THERAPIES FOR ADOLESCENTS AND

YOUNG ADULTS
The principle of pediatric-inspired therapies is to have higher doses
and more applications of ALL-specific drugs such as glucocorticoids,
vincristine, and L-asparaginase and fewer myeloablative
anthracyclines or alkylating agents, with strict adherence to time-
dose intensity, thereby reducing the role of SCT. The overall survival
rates for AYAs are 70–80%.

■ ADULT ALL
The treatment results for adult ALL patients have greatly improved
with more intensive chemotherapy, optimized SCT, and better
supportive care. In several recent multicenter prospective trials, the
overall survival rate for standard-risk patients was >70% with
chemotherapy alone, and for high-risk patients, the overall survival
rate has increased from 20–30% to >50%.

■ ELDERLY ALL
Palliative treatment regimens for elderly patients have failed, with CR
rates of ∼40%, a high early death rate of 24%, and a poor overall
survival of only a few months. Intensive chemotherapy has also
failed, with a higher CR rate of 56%, but still an early death rate of
23%, and only moderate improvement of overall survival to 14
months. Specific elderly ALL protocols with less intensive therapy
based on glucocorticoids, vincristine, and asparaginase, largely
avoiding anthracyclines and alkylating agents, have improved
outcomes. The early treatment-related death rate decreased to
<10%, CR rates improved to ∼90%, and overall survival of ∼30
months was noted.
Frail patients above the age of 70–75 years have very poor
survival of <10%. Hopefully, this will improve with ongoing targeted
therapies with either TKIs in Ph+ ALL or immunotherapies.

■ TARGETED THERAPIES
Substantial progress in adult ALL has been made in the past decade
by the introduction of new targeted therapies, including TKIs and
immunotherapeutic approaches (Table 106-5).

TABLE 106-5 Targeted Therapies in Adult Acute Lymphoblastic

Leukemia (ALL)

■ TYROSINE KINASE INHIBITORS IN PHILADELPHIA-POSITIVE

ALL
Patients with Ph+ ALL constitute ∼25% of adult B-ALL patients, with
the frequency increasing to ∼50% among elderly patients. In the pre-
imatinib era, CR rates were 60–70%; survival with chemotherapy
was ∼10%, and after allogeneic SCT, it was ∼30%. With the first-
generation TKI imatinib, CR rates increased to 80–90%, the rate of
BCR-ABL negativity increased from 5 to 50%, and the 5- to 10-year
overall survival improved to 50–70%.
Faster and deeper molecular responses are achieved with
second-generation TKIs (dasatinib, nilotinib), and these responses
apparently translate into a survival benefit. The third-generation TKI
ponatinib is also effective in tumors bearing mutations (particularly
T315I) that convey resistance to earlier-generation TKIs.
Treating adult Ph+ ALL with an allogeneic SCT in first CR is still a
good treatment option for adult patients, with a 5-year overall
survival of 60–70%. In elderly patients, when low-intensity
chemotherapy was combined with dasatinib, the CR rate was >90%.
In a next step, by combining mini-chemotherapy with a TKI and
adding immunotherapy with inotuzumab (an anti-CD22 antibody), the
CR rate was >90% and the overall survival improved further. A pilot
experience with a chemotherapy-free regimen composed of
dexamethasone, the TKI dasatinib, and the bispecific antibody
blinatumomab (anti-CD19 and anti-CD3) demonstrated a CR rate of
98% and 2-year overall and disease-free survival rates of 95% and
88%, respectively. Blinatumomab eliminates Ph+ leukemic cells with
resistant mutations.

■ IMMUNOTHERAPEUTIC APPROACHES
Treatments involving monoclonal antibodies or activated T cells are
currently changing the treatment paradigm of ALL. The prerequisite
is that B-lineage blast cells express a variety of specific antigens,
such as CD19, CD20, and CD22 (Table 106-6) that are targetable
with a wide variety of monoclonal antibodies. A new treatment
principle is the activation of the patient’s T cells to destroy their
CD19+ leukemic blasts.

TABLE 106-6 Expression of Antigens in B-Cell Lineage Acute

Lymphoblastic Leukemia (ALL) for Potential Antibody Therapy
Anti-CD20 The anti-CD20 monoclonal antibody rituximab has
improved the outcome of patients with de novo Burkitt’s
leukemia/lymphoma. With repeated short cycles of intensive
chemotherapy combined with rituximab, the overall survival
increased to >80%. Rituximab is now included in most B-ALL
regimens and is given at the usual dose of 375 mg/m2 on day –1
before chemotherapy for at least eight or more cycles. This leads to
a significant increase in MRD negativity and improved survival.

Anti-CD22 Monoclonal antibodies directed against CD22 are linked

to cytotoxic agents, such as calicheamicin (inotuzumab ozogamicin),
or to plant or bacterial toxins (epratuzumab). In a randomized trial of
relapsed or refractory ALL patients, the CR rate was 66% and
significantly superior to the CR rate with standard chemotherapy.
Inotuzumab is now included in first-line therapy for Ph+ and Ph–
patients.
Anti-CD19 Targeting CD19 is of great interest because this antigen
is highly expressed in all B-lineage cells, most likely including early
lymphoid precursor cells. A new promising approach is the bispecific
antibody blinatumomab, which combines single-chain antibodies to
CD19 and CD3, such that T cells lyse the CD19-bearing B cells.
Blinatumomab is particularly effective in MRD-positive patients,
with a 70–80% conversion to MRD negativity, translating into
improved overall survival; ∼25% of MRD-negative patients survived
without any further treatment. Blinatumomab has also moved to
frontline therapy.

CAR-T Cells The adoptive transfer of CAR-modified T cells directed

against CD19 is a promising approach for the treatment of CD19+
childhood or adult ALL. In the first three larger studies in adults with
relapsed or refractory ALL, the CR rate ranged from 67 to 91% with
MRD negativity in 60–81% of the patients who achieved CR. Overall
survival is 50% or more at ≥2 years, which is remarkable for these
heavily pretreated patients. CAR-T cells are also effective in CNS
leukemia and in other extramedullary sites. CAR-T cell therapy in
relapsed or refractory ALL was first considered as a bridge to
allogeneic SCT, applied in 10–50% of patients, but the necessity for
an allogeneic SCT after CAR-T cells is unclear. CAR-T cell therapies
are also moving to the frontline. CD19-negative relapses after CAR-
T cell therapy or blinatumomab due to downregulation of CD19
expression are a relevant obstacle.

Toxicities of Immunotherapies The anti-CD22 agent inotuzumab

ozogamicin is associated with hepatotoxicity, including veno-
occlusive disease, particularly after allogeneic SCT, but can be
managed by reduced dosing and limitation of cycles. For anti-CD19
therapies, cytokine release syndrome and severe neurotoxicity are
the most prominent toxicities and often require intensive care unit
care (more so after CAR-T cells than blinatumomab). Management
of these complications has improved with early recognition. Because
toxic death after immunotherapies is very low compared to intensive
chemotherapy or allogeneic SCT, immunotherapies are now
increasingly included in frontline therapy.
■ TREATMENT OF T-ALL
Immunotherapy for T-ALL is still not available and intensive
chemotherapy is still the mainstay in combination with the T cell–
specific drug nelarabine. Currently, γ-secretase targeting NOTCH1,
checkpoint inhibitors such as bortezomib and venetoclax, and HDAC
inhibitors are being explored.

■ CONCLUSION AND FUTURE DIRECTIONS

Cytogenetic and molecular analysis at diagnosis allows identification
of ALL subentities, requiring different treatment options. Evaluation
of MRD is the most important parameter for treatment decisions. The
greatest progress has been achieved by targeted therapies, such as
TKIs for Ph+ ALL and new immunotherapeutic approaches. This will
lead to further improved outcome of adult ALL patients, 50% of
whom are already surviving 5–10 years and are most likely cured.
New options and advances, such as low-intensity chemotherapy,
reduction of SCT, incorporation of targeted therapies, and reduction
of toxicities, will improve the quality of life of patients and lead to
individualized approaches for each patient.

■ FURTHER READING
BROWN P et al: Effect of postreinduction therapy consolidation with
blinatumomab vs chemotherapy on disease-free survival in
children, adolescents, and young adults with first relapse of B-cell
acute lymphoblastic leukemia A randomized clinical trial. JAMA
325:833, 2021.
FOA R et al: Dasatinib-blinatumomab for Ph-positive acute
lymphoblastic leukemia in adults. N Engl J Med 383:1613, 2020.
FREY NV et al: Optimizing chimeric antigen receptor T-cell therapy for
adults with acute lymphoblastic leukemia. J Clin Oncol 38:415,
2020.
HOELZER D et al: Improved outcome of adult Burkitt
lymphoma/leukemia with rituximab and chemotherapy: report of a
large prospective multicenter trial. Blood 124: 3870, 2014.
HOELZER D et al: Acute lymphoblastic leukaemia in adult patients:
ESMO Clinical Practice Guidelines for diagnosis, treatment and
 follow-up. Ann Oncol 27(suppl 5):v69, 2016.
IACOBUCCI I, MULLIGHAN C: Genetic basis of acute lymphoblastic
leukemia. J Clin Oncol 35:975, 2017.
KANTARJIAN HM et al: Inotuzumab ozogamicin versus standard
therapy for acute lymphoblastic leukemia. N Engl J Med 375:740,
2016.
ROBERTS KG et al: Targetable kinase-activating lesions in Ph-like
acute lymphoblastic leukemia. N Engl J Med 371:1005, 2014.
 Chronic Lymphocytic Leukemia
107
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 some patients presenting
asymptomatically and never requiring therapy, 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
diagnosis 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-to-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
rare in the Asian population.
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,
further 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 single nucleotide polymorphisms
have been identified, which is estimated to account for 19% of the
familial risk of CLL. Genes involved in apoptosis, 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. 107-1), 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, 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 transplant studies in mice showing clonal
leukemic cell development with different characteristics from donor
leukemia after transplantation of HSCs. More work will be required to
elucidate the origins of CLL.

FIGURE 107-1 Chronic lymphoid leukemia in the peripheral blood. (From M

Lichtman et al [eds]: Williams Hematology, 7th ed. New York, McGraw-Hill, 2005.)

■ B-CELL RECEPTOR SIGNALING IN CLL

Perhaps the most important advancement in CLL biology is the
understanding 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 microenvironmental homing.
 Fitting with the role of BCR signaling in CLL, one of the most
influential prognostic factors identified in this disease is the
mutational status of the immunoglobulin heavy chain variable (IGHV)
region. During normal B-cell maturation, the variable regions of the
immunoglobulin heavy chain undergo somatic hypermutation. In
CLL, ∼60% of patients have IGHV that is ≥2% mutated from
germline. This may indicate a more mature, postgerminal center
progenitor, and is typically associated with a more indolent disease
course. Conversely, ∼40% of patients will have IGHV <2% mutated
from germline, which is associated with more rapid progression of
disease and short survival prior to the era of therapeutics that target
BCR. Unfavorable biologic properties including enhanced
telomerase activity, overexpression of activation-induced cytidine
deaminase, increased nuclear factor-κB (NF-κB) activity, high-risk
genomic mutations (e.g., NOTCH1, SF3B1, TP53, ATM), 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 IGHV 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 of these prognostic factors are widely
used but limited in their applicability. Zap-70 protein status is difficult
to measure by flow cytometry and 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
are the most robust prognostic factor clinically available in CLL.
These abnormalities are typically identified by fluorescent in situ
hybridization (FISH) analysis; however, stimulated metaphase
karyotype has a role as well. The most well-characterized
abnormalities include del(13)(q14.3), trisomy 12, del(11)(q22.3), and
del(17)(p13.1) (Fig. 107-2). The presence of sole del(13)(q14.3) is
associated with more indolent disease, prolonged survival, and good
response to traditional therapies. Usually, this abnormality is not
seen on banded karyotype analysis, and when present on karyotype,
it indicates a larger deletion involving the retinoblastoma 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
inferior prognosis, and more rapid progression to symptomatic
disease. 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,
with data indicating that increasing complexity is even more
deleterious to response and survival.
FIGURE 107-2 Outcomes among chronic lymphocytic leukemia patients with
various cytogenetic abnormalities. (From H Döhner et al: Genomic aberrations
and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910, 2000.
Copyright © (2000) Massachusetts Medical Society. Reprinted with permission
from Massachusetts Medical Society.)

Clonal evolution, or acquisition of cytogenetic or molecular

abnormalities, is common in CLL, especially in patients with IGHV
unmutated CLL. Because the tumor cytogenetics can change over
time, it is recommended that FISH, with or without cytogenetics, is
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
relatively simple, with an average CLL genome carrying ∼20
nonsynonymous 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 107-1). Most of the
identified mutations in these genes are common among different
malignancies, and with the exception of MYD88, they are generally
identified with much higher frequency in IGHV unmutated disease.

TABLE 107-1 Recurrent Mutations in CLL

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 sensitivity to CD20 antibody therapy and
increased risk of transformation to aggressive diffuse large B-cell
lymphoma (DLBCL; Richter’s transformation), although its relevance
in the era of targeted therapies is less clear. 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 patients with previously untreated early-stage disease and up to
40% with 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 prognosis and expected lack of response
to DNA-damaging therapies.
ATM mutations, which are heterogeneous and occur throughout
the 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 inhibits
antiapoptotic gene expression (including BCL2, CCND1, CCND3,
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
antiapoptotic proteins such as 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.

■ IMMUNOLOGY
CLL is characterized by dysregulation of the normal immune system
in addition to the malignant immune cells. Besides numerical
abnormalities 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 inducing 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 cause 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 interleukin 10 (IL-10).
Additionally, 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
correlation 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 or IgG 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 demonstrating an elevated lymphocyte count in asymptomatic
individuals, 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, and 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 107-2). Atypical phenotypes can be
seen as well and usually can be differentiated 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.

TABLE 107-2 Typical Immunophenotype of CLL Compared with

Other B Cell Malignancies
 Some patients will present with a small clonal proliferation of CLL
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 expression of a particular adhesion molecule.
Thus, SLL patients are managed identically to CLL patients, and
often in the later stages of disease, these patients will have blood
and bone marrow involvement as well.

MONOCLONAL B-CELL LYMPHOCYTOSIS

Patients who do not meet the diagnostic criteria for CLL based on
quantification 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 myeloma, 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 to be 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
hospitalization 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 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,
autoimmune 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 patients
attributed to infection. Owing to the immune dysfunction associated
with the disease, patients are at risk for both typical and atypical
infections. Besides this baseline risk of infections, most CLL
therapies can increase infection risk. For many nucleoside
analogue–based chemotherapy 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 chemotherapy 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
pneumococcal 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. The
recombinant zoster vaccine has approximately a 60% response in
previously untreated CLL, is safe, and should be considered for this
patient group. In contrast, live vaccines should be avoided in the
setting of CLL 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
administration 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. We also
administer at least one dose of immunoglobulin to CLL patients who
develop influenza with coexisting hypogammaglobulinemia to
diminish risk of postinfluenza pneumococcal pneumonia. IVIg is also
indicated in patients who have been hospitalized for a serious
infection and in those whose IgG level is <300–500 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, prostate, and breast cancers, although other cancers
are seen as well. Skin cancers are particularly common, with a rate
that is 8- to 15-fold higher than in the general population, and may
behave more aggressively. All CLL patients should be counseled on
the use of sunscreen while outdoors and should undergo
preventative skin examinations.
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, no specific recommendations for
increased cancer screening in CLL patients have been validated.
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. Secondary cancers are also seen in the
setting of targeted therapies. Bruton tyrosine kinase (BTK) inhibitors
appear to have a secondary cancer risk similar to what is seen in the
CLL population in general, but potentially a higher rate of
nonmelanoma skin cancers. With short follow-up, the risk of
secondary cancers appears to be slightly higher with venetoclax-
based regimens than chlorambucil-based chemoimmunotherapy,
and further evaluation of this trend is ongoing.

■ AUTOIMMUNE COMPLICATIONS
Autoimmune complications are frequent in CLL. Most commonly,
these include autoimmune cytopenias, but autoimmune
complications of other organs including glomerulonephritis,
vasculitis, and neuropathies 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, occur 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 autoimmune
cytopenias. 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
reticulocyte 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 diagnosis, although Coombs-negative cases can occur.
Immediate therapy is almost always necessary and consists of
transfusion and immunosuppression. 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
glucocorticoid 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, but should be pursued in those with severe,
symptomatic anemia. Death from uncontrolled AIHA can occur in the
absence of appropriate supportive care (Chap. 100).
ITP can be more difficult to diagnose as it may be difficult to
differentiate 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 20,000–30,000 or if evidence of bleeding complications or need
for invasive procedures develops. 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 appears, it is important to investigate the
mechanism because the approach to therapy of autoimmune
cytopenias in CLL differs from cytopenias due to marrow
replacement (Chap. 115).

■ RICHTER’S TRANSFORMATION
One of the most devastating complications of CLL is Richter’s
transformation, which is 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
transformation; 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. The prevalence of Richter’s transformation is difficult
to estimate based 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 IGHV 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.
B-cell prolymphocytic leukemia (PLL) arising from CLL is currently
classified as Richter’s transformation as well; however, clinical
features and therapy are quite different, so these two should be
differentiated for therapeutic purposes.
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 (fluorodeoxyglucose–positron emission tomography
combined with computed tomography) scan to localize an area for
biopsy. Standardized uptake values (SUVs) <5 are consistent with
CLL and can rule out Richter’s transformation in many cases. SUVs
>5 are suspicious for Richter’s transformation, with SUVs ≥10 being
very concerning. Excisional biopsy is the preferred mode of
diagnosis, and fine-needle aspiration should be discouraged.
 Therapy for DLBCL Richter’s transformation usually involves
combination chemoimmunotherapy (e.g., R-CHOP [rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisolone], dose-
adjusted EPOCH-R [etoposide, prednisone, vincristine,
cyclophosphamide, doxorubicin, and rituximab]; Chap. 108).
Outcomes may be poor with median survivals of 6–16 months in
most series for clonally related Richter’s versus ∼5 years for clonally
unrelated. For fit patients who achieve a response with therapy, stem
cell transplantation has the possibility to induce long-term remissions
and should be explored. In addition, chimeric antigen receptor T-cell
(CAR-T) therapy has shown promising results in small groups of
patients and remains an area of active clinical investigation. 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 a new diagnosis of CLL based on typical
immunophenotyping includes a detailed history of infectious disease;
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 and sequencing for TP53 and IGHV
mutation status can be performed. Imaging with CT scan is usually
not necessary unless there are symptoms and concern for
intraabdominal 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 107-3).
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 since the original description of the stages, the impact of
initial stage on survival is not as clear. Cytogenetic and genomic
testing can help refine outcomes of these staging tests. An
international collaboration integrated both clinical and genomic
staging to better predict outcome at diagnosis and time of initial
treatment, which led to development of the CLL International
Prognostic Index (Table 107-4). This index has been shown to be
useful in prediction of both time to first treatment and outcome with
chemoimmunotherapy. Validation in the setting of novel targeted
therapies has not occurred.

TABLE 107-3 Staging of CLL

TABLE 107-4 CLL International Prognostic Index

■ CRITERIA FOR THE INITIATION OF THERAPY
Currently, a watchful waiting strategy is used for most patients with
CLL, with therapy reserved for patients with symptomatic disease.
This recommendation is based on multiple trials showing no survival
advantage with earlier therapy, although this question continues to
be a focus of active investigation.
With the exception of patients participating on early intervention
studies in CLL, disease-related symptoms that require the initiation
of therapy are outlined in Table 107-5. Except for the rare patient
who presents with disease requiring urgent therapy, most times,
these symptoms can be monitored over short periods to determine
relatedness to CLL and need for therapy.

TABLE 107-5 Criteria for the Initiation of Therapy

■ INITIAL THERAPY FOR CLL
Over the past decade, the initial therapy of CLL has dramatically
changed. Whereas chemoimmunotherapy was once standard for all
patients, now most patients are treated with oral therapies targeted
against BTK or BCL2 with or without a CD20 monoclonal antibody.
This continues to be an area of active investigation, with standards
of care shifting rapidly. The major classes of these therapies are
outlined here.

BTK Inhibitors BTK is an attractive target in CLL because, unlike

other kinases in the BCR pathway, BTK does not have natural
redundancy and is relatively selective for B cells, so inhibition leads
to a predominant B cell–specific phenotype. The first-in-class BTK
inhibitor is ibrutinib, which is relatively selective for BTK but also
inhibits a number of structurally similar kinases. As initial therapy,
ibrutinib was initially compared with chlorambucil (RESONATE 2
study), and there was an 84% lower risk of progression or death with
ibrutinib, with 70% of ibrutinib-treated patients alive and progression-
free at 5 years. Subsequent studies compared ibrutinib alone or with
the anti-CD20 antibody rituximab to standard chemoimmunotherapy
with fludarabine plus cyclophosphamide plus rituximab (FCR) in
younger patients (<70 years; E1912 study) or bendamustine plus
rituximab (BR) in older patients (≥65 years; A041202 study). In
younger patients, ibrutinib plus rituximab (IR) showed increased
progression-free survival (PFS) and overall survival (OS) when
compared with FCR, with a 3-year PFS of 89% for IR compared with
71% for FCR. In older patients, ibrutinib alone as well as with
rituximab showed superior PFS compared with BR, with 24-month
PFS rates of 88% for IR, 87% for ibrutinib alone, and 74% for BR. IR
was not superior to ibrutinib alone, and OS was not different in this
trial at 24 months. Side effects distinct to ibrutinib include
arthralgias/myalgias, rash, diarrhea, dyspepsia, increased risk of
bleeding (particularly when on anticoagulation therapy or with
surgery), hypertension, and atrial fibrillation.
The second-generation BTK inhibitor acalabrutinib is more
specific for BTK than ibrutinib and consequentially shows better
tolerability, with less incidence of atrial fibrillation,
myalgias/arthralgias, and skin and nail changes than reported with
ibrutinib. In the frontline setting, acalabrutinib and acalabrutinib plus
obinutuzumab were compared with chlorambucil plus obinutuzumab.
Both acalabrutinib alone and acalabrutinib with obinutuzumab
showed superior 30-month PFS compared with chlorambucil plus
obinutuzumab (82%, 90%, and 34%, respectively), with improved
PFS for acalabrutinib plus obinutuzumab compared with
acalabrutinib alone in an unplanned post hoc analysis.

BCL2 Inhibitor Venetoclax is an orally bioavailable, selective

inhibitor of the antiapoptotic protein BCL2, which is upregulated in
CLL. Unlike with BTK inhibitors, where many phase 3 studies
support benefit over chemoimmunotherapy, only one study has been
published with venetoclax. The CLL14 study compared venetoclax
plus obinutuzumab (VO) to chlorambucil plus obinutuzumab in
previously untreated patients with coexisting medical conditions.
Unlike BTK inhibitors, which are administered continuously until
disease progression, VO treatment is given for a 1-year fixed
duration. At 3 years of follow-up, PFS was 82% in the VO group
compared with 50% in the chlorambucil plus obinutuzumab group.
No difference has been observed in OS with this follow-up. Side
effects associated with venetoclax include tumor lysis syndrome,
neutropenia, and nausea.

PI3K Inhibitors Inhibitors of PI3K delta have been studied in CLL

due to the specificity of the delta isoform for B lymphocytes. Two
agents, idelalisib and duvelisib, are approved for use in relapsed
CLL, but trials of idelalisib in frontline CLL demonstrated toxicity that
precluded further development in this area. Toxicities seen with
idelalisib and duvelisib include pneumonitis, diarrhea/colitis, and
transaminitis. More recently, a second-generation PI3K delta inhibitor
umbralisib was combined with the anti-CD20 antibody ublituximab in
the frontline setting and compared with chlorambucil plus
obinutuzumab. Twenty-four-month PFS was 61% for ublituximab
plus umbralisib compared with 40% with chlorambucil plus
obinutuzumab. PI3K inhibitor–specific toxicities appear to be lower
with umbralisib compared with idelalisib and duvelisib, but
comparative trials are lacking. As outcome with this combination
appears inferior to that with BTK inhibitors or BCL2 inhibitors, it is
unlikely this treatment will be used in CLL outside of rare
circumstances where other classes of drugs are contraindicated.

Chemoimmunotherapy For the most part, targeted therapy has

supplanted chemoimmunotherapy in CLL. However, long-term
follow-up of studies of FCR has demonstrated that a subset of
patients treated with this regimen can have durable responses over
10 years, with a likely cure of CLL. This group is composed almost
exclusively of patients with mutated IGHV and favorable
cytogenetics. However, despite the efficacy of this regimen, short-
and long-term toxicities limit its adaptability to many patients with
IGHV mutated disease. Short-term toxicities are mostly related to
myelosuppression and include neutropenia and infection. Long-term
cytopenias are less common, but they do occur. Also, there is about
a 3–5% risk of therapy-related myeloid neoplasm with this regimen
that is almost always fatal. In the E1912 study of FCR versus IR, at
follow-up, there was no difference in PFS or OS between FCR and
IR for patients with mutated IGHV, suggesting that there may remain
a place for this regimen in clinical practice. In addition, current
studies are focused on limiting chemotherapy and/or adding novel
agents in efforts to achieve cure but limit toxicity.

■ THERAPY OF RELAPSED CLL

Currently, the mainstays of treatment for relapsed CLL are the same
classes as initial therapy. The optimal sequencing of targeted agents
in CLL has not been established; however, the available data
suggest that the sequence of either BTK inhibitor and then BCL2
inhibitor or the reverse are both acceptable. In a trial of venetoclax
for patients who had relapsed after ibrutinib therapy, the overall
response rate (ORR) was 65% with a median PFS of ∼2 years in a
very heavily pretreated patient population. Retrospective data of BTK
inhibitor given after venetoclax suggests that this sequence is
effective as well, with an ORR of 84% and median PFS of 32
months. PI3K inhibitors also have activity in relapsed CLL; however,
activity following both BTK and BCL2 inhibitors is likely minimal. In
addition, many new agents are in development in CLL including
novel oral targeted therapies, antibodies, and immune-based
treatments.

Immune Therapies Immune therapies in CLL are currently focused

in the relapsed setting and include allogenic stem cell
transplantation, CAR-T therapy, and oral immunomodulatory agents
such as lenalidomide.
Stem cell transplantation is a curative approach to CLL. Because
most CLL patients are older and many have significant
comorbidities, myeloablative transplantations incur extensive
morbidity and mortality, making them prohibitive in many individuals.
Reduced-intensity conditioning (RIC) allogeneic transplantations
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. This is still considered a standard treatment in
CLL but has fallen out of favor with the introduction of well-tolerated
novel agents, as well as clinical trials of CAR-T cells. CD19 CAR-T
cell trials have not been as successful in CLL as they have been in
other B cell malignancies due to the immunosuppression associated
with the disease. Many current trials are focused on optimizing CD19
CAR-T cells by adding agents such as BTK inhibitors or PI3K
inhibitors or modifying the CAR-T structure, and other studies are
testing different targets outside of CD19. In addition, recent studies
have shown that natural killer (NK) cell CAR cells also can induce
clinical response in CLL patients. This area remains a focus of
intense investigation in CLL.

■ 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
examination and laboratory studies (Table 107-6). 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 complete response.

TABLE 107-6 Response Criteria in CLL

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
chemoimmunotherapy, eradication of MRD correlates with long-term
survival and potentially cure in a subset of patients receiving FCR
chemoimmunotherapy. Undetectable MRD in blood or bone marrow
is also associated with improvement in PFS in venetoclax-based
regimens. However, eradication of MRD has not been shown to be a
meaningful endpoint with BTK or PI3K inhibitors as monotherapy.
Higher sensitivity of 1 CLL in 106 leukocytes (0.0001%) can be
obtained using next-generation sequencing methods such as
ClonoSeq. This technique is currently available in clinical practice,
although at this point, there are no data confirming that increased
sensitivity is clinically meaningful, and studies are underway to
support the need for this higher sensitivity with novel combination
approaches of BTK/BCL2 inhibitor regimens.

■ CONCLUSION
CLL is treated only when it becomes symptomatic. At the time of
therapy, FCR chemoimmunotherapy in a small subset of young
patients with very-good-risk CLL is potentially curative. In the
majority of patients with symptomatic CLL, targeted therapy directed
at BTK or BCL2 can produce durable remissions and allow patients
many years of disease-free survival.

■ FURTHER READING
BURGER JA: Treatment of chronic lymphocytic leukemia. N Engl J
Med 383:460, 2020.
FISCHER K et al: Venetoclax and obinutuzumab in patients with CLL
and coexisting conditions. N Engl J Med 380:2225, 2019.
HALLEK M et al: iwCLL guidelines for diagnosis, indications for
treatment, response assessment, and supportive management of
CLL. Blood 131:2745, 2018.
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, 2016.
PUENTE XS et al: Whole-genome sequencing identifies recurrent
mutations in chronic lymphocytic leukaemia. Nature 475:101,
2011.
SHANAFELT TD et al: Ibrutinib-rituximab or chemoimmunotherapy for
chronic lymphocytic leukemia. N Engl J Med 38:432, 2019.
SHARMAN JP et al: Acalabrutinib with or without obinutuzumab versus
chlorambucil and obinutuzumab for treatment-naïve chronic
 lymphocytic leukemia (ELEVATE TN): A randomized, controlled,
phase 3 trial. Lancet 395:1278, 2020.
THOMPSON PA et al: Fludarabine, cyclophosphamide, and rituximab
treatment achieves long-term disease-free survival in IGHV-
mutated chronic lymphocytic leukemia. Blood 127:303, 2016.
WOYACH JA et al: Ibrutinib regimens versus chemoimmunotherapy in
older patients with untreated CLL. N Engl J Med 380:1680, 2018.
 Non-Hodgkin’s Lymphoma
108
Caron A. Jacobson, Dan L. Longo

Non-Hodgkin’s lymphomas (NHL) are cancers of mature B, T, and

natural killer (NK) cells. They were distinguished from Hodgkin’s
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 chemotherapy 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 108-1.

TABLE 108-1 WHO Classification of Lymphoid Malignancies

■ EPIDEMIOLOGY AND ETIOLOGY
In 2020, >77,000 new cases of NHL were diagnosed in the United
States, ∼4% of all new cancers in both males and females, making it
the seventh most common cause of cancer-related death in both
women and men. The incidence is nearly 10 times the incidence of
HL. 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 past 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 NHL. These include patients with HIV
infection, patients who have undergone organ transplantation, and
patients with inherited immune deficiencies and autoimmune
conditions. The 5-year survival rates for NHL are 72% for
Caucasians and 63% for African Americans.
The incidence of NHL and the patterns of expression of the
various subtypes differ geographically and across age groups. T-cell
lymphomas are more common in Asia than in Western countries,
whereas certain subtypes of B-cell lymphomas such as follicular
lymphoma (FL) are more common in Western countries. A specific
subtype of NHL known as the angiocentric nasal T/NK cell
lymphoma has a striking geographic occurrence, being most
frequent in southern Asia and parts of Latin America. Another
subtype of NHL 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 indolent lymphomas including FL being the most
common forms in adults. The relative frequencies of the various
types of lymphoid malignancies, including HL, plasma cell disorders,
and lymphoid leukemias, is shown in Fig. 108-1.
FIGURE 108-1 Relative frequency of lymphoid malignancies. ALL, acute
lymphoid leukemia; CLL, chronic lymphocytic leukemia; MALT, mucosa-associated
lymphoid tissue.

A number of environmental factors have been implicated in the

occurrence of NHL, including infectious agents, chemical exposures,
and medical treatments. Several studies have demonstrated an
association between exposure to agricultural chemicals and an
increased incidence of NHL. Patients treated for HL can develop
NHL; it is unclear whether this is a consequence of the HL or its
treatment, especially radiation.
Several NHLs are associated with infectious agents (Table 108-
2). Epstein-Barr virus (EBV) is associated with the development of
BL in Central Africa and the occurrence of aggressive NHL in
immunosuppressed patients in Western countries. The majority of
primary central nervous system (CNS) lymphomas are associated
with EBV. EBV infection is strongly associated with the occurrence of
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
demonstrates a long latency from infection to oncogenesis (Chap.
201). Infection with HIV predisposes to the development of
aggressive, B-cell NHL. 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
mucosa-associated lymphoid tissue (MALT) lymphomas. This
association is supported by evidence that patients treated with
antibiotics to eradicate 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
primary effusion lymphoma in HIV-infected persons and multicentric
Castleman’s disease, a diffuse lymphadenopathy associated with
systemic symptoms of fever, malaise, and weight loss.

TABLE 108-2 Infectious Agents Associated with the

Development of Lymphoid Malignancies
 In addition to infectious agents, a number of other diseases or
exposures may predispose to developing lymphoma (Table 108-3).
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 because if the immunosuppression
can be reversed, a percentage of these lymphomas regress
spontaneously. The incidence of NHL is nearly a hundredfold
increased for patients undergoing organ transplantation
necessitating chronic immunosuppression and is greatest in the first
year posttransplant. 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
immunodeficiency, including HIV infection, are frequently associated
with EBV. Histologically, DLBCLs are most frequently associated with
immunosuppression and autoimmune diseases, although almost all
histologies can be seen, especially MALT lymphomas in the context
of autoimmune diseases such as Sjögren’s syndrome and
Hashimoto’s thyroiditis. The rare inherited immunodeficiency
diseases X-linked lymphoproliferative syndrome, Wiskott-Aldrich
syndrome, Chédiak-Higashi syndrome, ataxia-telangiectasia, and
common variable immunodeficiency syndrome are complicated by
highly aggressive lymphomas. The elevated incidence of lymphoma
in iatrogenic immunosuppression, AIDS, and autoimmune disease
argues strongly for immune dysregulation contributing in the
pathogenesis of some lymphomas. An increased risk of NHL has
been observed in first-degree relatives with NHL, HL, or chronic
lymphocytic leukemia (CLL). In large database studies, ∼9% of
patients with lymphoma or CLL have a first-degree relative with a
lymphoproliferative disorder.

TABLE 108-3 Diseases or Exposures Associated with

Increased Risk of Development of Malignant Lymphoma

■ IMMUNOLOGY
All lymphoid cells are derived from a common hematopoietic
progenitor that gives rise to lymphoid, myeloid, erythroid, monocyte,
and megakaryocyte lineages. Through the ordered and sequential
activation of a series of transcription factors, the cell first becomes
committed to the lymphoid lineage and then gives rise to B and T
cells.
About 90% of all lymphomas are of B cell origin. A cell becomes
committed to B cell development when it expresses the master B
lineage transcription factor PAX5, which ultimately results in a
transcriptional program that leads to the rearrangement of its
immunoglobulin genes, which involves chromosomal recombination
as well as somatic 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. 108-2. 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 activation
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 antiapoptotic protein BCL2 in the
process of B cell development explain why the genes encoding
these proteins are commonly mutated in B-cell lymphomas.
FIGURE 108-2 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 lymphocytic leukemia; SL, small lymphocytic lymphoma.

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. 108-3.

FIGURE 108-3 Pathway of normal T-cell differentiation and relationship to T-

cell lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71
are cell markers used to distinguish stages of development. T-cell antigen
receptors (TCR) rearrange in the thymus, and mature T cells emigrate to nodes
and peripheral blood. ALL, acute lymphoid leukemia; T-ALL, T-cell ALL; T-LL, T-
cell lymphoblastic lymphoma; T-CLL, T-cell chronic lymphocytic leukemia; CTCL,
cutaneous T-cell lymphoma; NHL, non-Hodgkin’s lymphoma.
 Although lymphoid malignancies often retain the cell-surface
phenotype 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 distinguishing of specific NHL subtypes. It can be
detected by flow cytometry of single-cell suspension from blood,
bone marrow, body fluid, or disaggregated 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
associated 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 malignancies, it is presumed that they exist. As
previously discussed, 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 lymphomas contain balanced chromosomal
translocations involving the antigen receptor genes; immunoglobulin
genes on chromosomes 2, 14, 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, chromosomal translocations produce fusion genes that
encode chimeric oncogenic proteins. Examples of this include the
(2;5)(p23;q35) translocation 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 108-4 presents the most common translocations and
associated oncogenes for various subtypes of lymphoid
malignancies.

TABLE 108-4 Genetic Features of B- and T-Cell Lymphomas

 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 importance 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 expression 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 considerably better
prognosis than those whose lymphomas have a pattern resembling
ABCs. This improved prognosis is independent of other known
prognostic factors. These subcategories have been more specifically
refined into five subcategories, using more advanced genetic
sequencing techniques, that differ with respect to biology and driver
genes, as well as prognosis, and may have important treatment
implications in the future. 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 evaluation
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 carefully 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
lymphomas, as are the presence or absence of “B” symptoms, such
as fevers, night sweats, or unexplained weight loss. Patients should
be asked about localizing symptoms that may point toward
lymphomatous involvement of specific sites, such as the chest,
abdomen, or CNS. Comorbid diagnoses that may impact therapy or
monitoring on therapy should be reviewed and acknowledged,
including a history of diabetes or congestive heart failure. A physical
examination should pay close attention to all the peripherally
accessible sites of lymph nodes; the liver and spleen size;
Waldeyer’s ring; whether there is a pleural or pericardial effusion or
abdominal ascites; whether there is an abdominal, testicular, or
breast mass; and whether there is cutaneous involvement because
all of these findings may influence further evaluation and disease
management.
Laboratory studies should include a complete blood count,
routine chemistries, liver function tests, and serum protein
electrophoresis to document the presence of circulating monoclonal
paraproteins. The serum β2-microglobulin level and serum lactate
dehydrogenase (LDH) are important independent prognostic factors
in NHL. Staging of certain diseases may involve a bone marrow
biopsy; results of other laboratory and staging studies may also
warrant a marrow evaluation. A lumbar puncture for evaluation of
lymphomatous involvement may be indicated in the setting of
concerning neurologic signs or symptoms or diseases that are high
risk for CNS involvement. The latter may include disease involving
the paranasal sinuses, testes, breast, kidneys, adrenal glands, and
epidural space, as well as highly aggressive histologies like BL.
Since HIV and hepatitis B and C infection can be risk factors for
developing NHL, and since treatment for some NHLs can result in
the potentially life-threatening reactivation of hepatitis B, patients
with a new diagnosis of NHL should be screened for these viruses
as well.
Lymphoma histology and clinical presentation dictate which
imaging studies should be ordered. Chest, abdominal, and pelvic
computed tomography (CT) scans are essential for accurate staging
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.
FDG-PET is highly sensitive for detecting both nodal and extranodal
sites involved by NHL. The intensity of FDG avidity, or standardized
uptake value (SUV), correlates with histologic aggressiveness, and
may be useful in cases when disease transformation of an indolent
lymphoma to a diffuse aggressive lymphoma is suspected. PET
scanning can also differentiate between treated disease and active
disease at the end of therapy in patients with residual masses on CT
scans. Consensus recommendations regarding PET scanning were
published as a result of an International Harmonization Project and
state that PET should only be used for DLBCL and HL, that scanning
during therapy should only be done as part of clinical trials, and that
the end-of-treatment scan should not be done before 3 weeks but
preferably 6–8 weeks after chemotherapy and 8–12 weeks after
radiation or chemoradiotherapy. There is no evidence that long-term
follow-up should include PET scanning. More recently, though, PET
scan results at the end of therapy for FL have been associated with
prognosis, with patients with residual PET-avid disease at the end of
treatment having a poorer prognosis than those who are PET
negative, and so it may be used for this prognostic purpose. Finally,
magnetic resonance imaging (MRI) is useful in detecting bone, bone
marrow, and CNS disease in the brain and spinal cord. The staging
evaluation is outlined in Table 108-5.

TABLE 108-5 Staging Evaluation for Non-Hodgkin’s Lymphoma

 The Ann Arbor staging system developed in 1971 for HL was
adapted for staging NHLs (Table 108-6). This staging system
focuses on the number of tumor sites (nodal and extranodal),
location, and the presence or absence of systemic, or B, symptoms.
Table 108-6 summarizes the essential features of the Ann Arbor
system.

TABLE 108-6 Ann Arbor Staging for Lymphomaa

 This anatomic based system is less useful in NHL, which
disseminates widely, not in an ordered stepwise fashion. A majority
of patients with NHL have advanced-stage disease at diagnosis.
Apart from early-stage disease limited to a radiation field where local
therapy with radiation is an option, all other disease is treated the
same regardless of stage. Histology and clinical parameters at
presentation are more important than stage with respect to
prognosis. The International Prognostic Index (IPI) is perhaps the
best predictor of outcome (Table 108-7). The IPI was developed
based on the analysis of >2000 patients with aggressive NHLs
treated with an anthracycline-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 (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 rates are 94, 80, and 53% for 0 and 1, 2, or
3 or more risk factors, respectively.

TABLE 108-7 International Prognostic Index for NHL

The Follicular Lymphoma International Prognostic Index (FLIPI) is

a similar predictive model for FL, derived from the analysis of >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
(intermediate risk), or three or more (high risk) of these adverse
factors were 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 tyrosine kinase (BTK) inhibitor ibrutinib
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
combination 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 lymphoma (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 lymphomas, it is not readily curable
with conventional-dose therapies.

Burkitt’s Lymphoma Burkitt’s lymphoma/leukemia (BL) is a rare

disease in adults in the United States, making up <1% of NHL, but it
makes up ∼30% of childhood NHL. 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
the bone marrow and meninges. The nonendemic form has an
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
macrophages give rise to the classic “starry sky” appearance of this
tumor (Fig. 108-4). Tumor cells are positive for B-cell antigens CD19
and 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 nonendemic 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.
FIGURE 108-4 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.

While exquisitely chemosensitive, it is imperative that treatment

for BL be initiated quickly given the rapid doubling time and high
morbidity of this disease. There are several effective intensive
combination chemotherapy regimens, all of which incorporate high
doses of cyclophosphamide. Prophylactic therapy to the CNS is
mandatory. Cure can be expected in 80–90% of patients when
treated promptly and correctly. Dose-adjusted EPOCH-R (rituximab,
infusional etoposide/vincristine/doxorubicin, cyclophosphamide,
prednisone) is highly effective. Salvage therapy has been generally
ineffective in patients whose disease 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 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 (RR) of DLBCL is higher among 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
majority of patients present with advanced-stage disease, with only
30–40% of patients having stage I or II disease; ∼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, gastrointestinal tract,
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.
The tumor consists of a diffuse proliferation of large, atypical
lymphocytes with a high proliferative index (Fig. 108-5). These cells
typically 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–germinal center or activated B cell (ABC)
subtype. BCL2 is overexpressed in anywhere from 25 to 80% of
DLBCLs, 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
rearrangements or amplification have also been described and are
also associated with a poor, albeit better, prognosis.
FIGURE 108-5 Diffuse large B-cell lymphoma. The neoplastic cells are
heterogeneous but predominantly large cells with vesicular chromatin and
prominent nucleoli.

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 prednisone (R-CHOP) improved survival beyond CHOP alone
and is the standard 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 six cycles or abbreviated chemotherapy for three
to four cycles followed by involved field radiotherapy. For advanced-
stage DLBCL, therapy is with a full course of chemotherapy. On
average, ∼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 is one such regimen. Although this
regimen did not appear to be better than R-CHOP for DLBCL in one
multicenter clinical trial, 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 chemotherapy 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
followed by autologous stem cell transplantation. However, patients
with a poor performance status or advanced age who are not
candidates for such an approach 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 bendamustine 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 combinations of drugs primarily in order
to identify patients with chemosensitive 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
∼40–50% of patients. For patients with chemorefractory disease,
chimeric antigen receptor T cells (CAR-T cells) offer a potentially
curative option. For this therapy, T cells are collected from a patient
and are then 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 persist over time. The CARs consist of an
extracellular antigen recognition domain (typically a single chain Fv
variable fragment from a monoclonal 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 chemotherapy-
insensitive disease following second-line salvage chemotherapy for
whom autologous stem cell transplant is not an option or patients
who relapse after autologous stem cell transplant. In this setting, the
response rate of CAR-T cells is >80%, with >50% of patients
achieving a complete response. These responses appear to be
durable, with 40% of patients in remission at long-term follow-up.
Targeting CD19 with the monoclonal antibody tafasitamab in
combination with lenalidomide also yielded high response rates and
prolonged response durability, leading to approval of this regimen in
relapsed disease. Reports of ongoing studies exploring bispecific
antibodies that target CD20 on malignant B cells while also binding
CD3 on T cells, thereby activating T cells to attack the malignant B
cell, have been very promising in both aggressive and indolent B-cell
NHL. The antibody-drug conjugate polatuzumab vedotin, which
combines an anti-CD79b antibody with the microtubule toxin
monomethyl aurostatin E (MMAE), was approved for the treatment of
relapsed/refractory DLBCL in combination with bendamustine and
rituximab based on the results of a randomized clinical trial against
bendamustine and rituximab alone. The oral drug selinexor, a
selective inhibitor of nuclear export, has modest activity in relapsed
DLBCL as a single agent and is approved for this indication. These
drugs, along with drugs such as lenalidomide alone or ibrutinib,
should be viewed as a bridge to allogeneic stem cell transplant for
eligible patients in whom curative therapy is the goal because they
are unlikely to lead to durable or permanent remissions.
 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
lymphoma. 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
lymphoma are similar to DLBCL. R-CHOP remains the treatment of
choice for each of these lymphomas.

Follicular Lymphoma FLs are the second leading NHL diagnosis in

the United States and Europe and make up 22% of NHLs worldwide
and at least 30% of NHLs 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. 108-6). Confirmation of B-cell
immunophenotype (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 BCL2
protein are confirmatory. While >85% of FLs will harbor a t(14;18)
and overexpress the antiapoptotic protein BCL2, this genetic event is
necessary but not sufficient 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 coexistence of
DLBCL must be considered. Patients with FL are often subclassified,
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 I to III 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
subdivisions do have prognostic significance. Patients with FL with
predominantly 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.

FIGURE 108-6 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.

The most common presentation for FL is with new, painless

lymphadenopathy. 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 or 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 transformation 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 curative, with 5-, 10-, and 15-year
freedom from treatment failure rates of 72, 46, and 39%, and 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 reasonable alternative with a
median time to treatment not reached at 7 years of follow-up in one
study. Many of these patients are diagnosed incidentally or at a time
when their lymphoma is not causing symptoms 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, asymptomatic patients should be observed.
When treatment is indicated, there are a variety of treatment
options, including the use of the monoclonal antibody against CD20,
rituximab, alone or 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 inflammatory 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 chemotherapy regimens such as 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. Thus, BR 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. A newer anti-CD20 antibody,
obinutuzumab, has been tested in combination with chemotherapy in
a randomized trial against rituximab plus chemotherapy in previously
untreated FL. The obinutuzumab combinations resulted in
improvements in minimal residual disease (MRD) negativity as well
as progression-free survival at the expense of more infection and
infusion reactions. Based on these results, both rituximab plus
chemotherapy and obinutuzumab plus chemotherapy are options for
untreated FL in need of treatment. The superiority of one over the
other has not been established.
In patients with FL, the disease nearly always recurs following
therapy, after which retreatment is again reserved for symptomatic
disease or disease interfering with organ function. Single-agent
rituximab or alternative chemotherapy regimens, with both rituximab
and obinutuzumab, can again be employed. Both autologous and
allogeneic hematopoietic stem cell transplantations 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 inhibitors
idelalisib, duvelisib, and copanlisib are active in both untreated and
relapsed FL. Inhibitors of one of the most commonly mutated genes
in FL, EZH2, have activity in both EZH2 mutated as well as
unmutated lymphomas, and one, tazemetostat, is approved for this
indication. Anti-CD19–directed CAR-T cell therapies are also being
tested in FL, with complete responses seen in >80% of patients with
multiply relapsed disease, and with many of those responses proving
durable, albeit with limited follow-up. Longer follow-up is needed to
determine if this may be a definitive treatment strategy for a subset
of relapsed FL patients. 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 primary 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 chemotherapy regimen should be
consolidated with an autologous stem cell transplant. Finally, as
discussed previously, grade IIIb 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,
extranodal 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
infiltration 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 expression of kappa or lambda light chains and with
small monoclonal immunoglobulin spikes. Treatment is often similar
to that of FL, with the exception that the BTK inhibitor ibrutinib is
highly active in this disease, while largely disappointing in FL, and is
a good treatment option for relapsed nodal MZL as well as other
MZL subtypes.
Splenic MZL is largely a disease of older Caucasian patients;
infection 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 HCL 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 estimated
progression-free survival and OS rates 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 rates at 5 years of 92 and 73%,
respectively. 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 due to either autoimmune diseases like Sjögren’s
syndrome or Hashimoto’s thyroiditis or chronic infections with
organisms like H. pylori (gastric), Borrelia burgdorferi (skin), C.
psittaci (conjunctiva), C. jejuni (intestines), and hepatitis C virus. The
essential pathologic feature of MALT lymphoma is the presence of
lymphoepithelial 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 cytogenetic 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 (NF-κB). Unlike other indolent B-cell
lymphomas, MALT lymphomas present most commonly with stage I
or II disease. In these cases, radiation therapy may be curative.
Alternatively, patients may respond to antibiotics for the associated
underlying infection. 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

LPLs, 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
Waldenström’s 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 NF-κB activation, are
present in >90% of cases. Tumor biopsies are notable for
proliferation of small lymphocytes, lymphoplasmacytic cells, and
plasma cells, and malignant 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 can cause or exacerbate
hyperviscosity. Chemoimmunotherapy with regimens such as BR
and rituximab, cyclophosphamide, and dexamethasone is active, as
are myeloma therapies such as bortezomib. Ibrutinib in combination
with rituximab is highly active in this disease and is an option for both
previously untreated and relapsed disease. Given that 85% of IgM
remains intravascular, acute relief of hyperviscosity symptoms can
be obtained by plasmapheresis. For recurrent disease, one can often
use agents that were previously used. For patients with more
refractory LPL, the mammalian target of rapamycin (mTOR) inhibitor
everolimus and the oral BTK ibrutinib are active. Selected patients
with relapsed disease are considered for high-dose therapy with
autologous or allogeneic stem cell transplantation. The results seen
are similar to those of other indolent lymphomas.

Mantle Cell Lymphoma MCL composes ∼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 poor prognosis and a
median OS of only 18 months. For other patients, prognosis is best
predicted by the biologic MCL International 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.
MCLs with a mutation in TP53 or a complex karyotype are
particularly high risk as well. Over two-thirds of patients will have
stage IV disease, mostly with bone marrow and peripheral blood
involvement, at the time of diagnosis. Another common extranodal
site of involvement is the gastrointestinal tract, where diffuse
lymphomatous polyposis may be seen.
The pathognomonic cytogenetic 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
chromosome 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
radiotherapy; however, these patients are exceedingly rare. Similarly,
patients with the indolent variant can be observed until disease
progresses 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,
cytarabine, 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 inhibitors ibrutinib and acalabrutinib have
single-agent activity with a response rate of almost 70% but a
response duration of only 18 months. These drugs are being
explored in combination with chemotherapy as well as with the BCL2
antagonist venetoclax. Anti-CD19–directed CAR-T cell therapies are
approved for the treatment of relapsed/refractory MCL; two-thirds of
patients who had progressed after chemoimmunotherapy (with or
without an autologous stem cell transplant) and BTK inhibition have
achieved complete responses, many of which are durable through
limited follow-up. As in FL, longer follow-up is needed to determine if
some of these patients may be cured, which would make this the
only curative therapy for this disease outside of an allogeneic stem
cell transplantation. Drugs such as lenalidomide, venetoclax,
bortezomib, and temsirolimus can similarly induce transient partial
responses. Appropriate patients who respond to salvage therapy,
with the exception of CAR-T cell 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, such as
mycosis fungoides, and the PTCLs, some of which are distinguished
based on specific clinical presentations or contexts or by molecular
or biologic features, but many of which fall into the category of PTCL
not otherwise specified (NOS). T-cell NHLs are significantly rarer
than 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 technologies is enhancing our ability to
understand the genetic and biologic basis of these neoplasms.

Mycosis Fungoides Mycosis fungoides is also known as cutaneous

T-cell lymphoma. This lymphoma is more often seen by
dermatologists 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 generalized 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 deacetylase inhibitors, brentuximab (for CD30+
disease), and systemic cytotoxic therapy. Mogamulizumab, an anti-
CCR4 antibody, has activity in this disease and has been approved
by the U.S. Food and Drug Administration for this indication.
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, which composes 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 eosinophilia 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 subgroups. 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 (CHOEP). The latter may provide the
most benefit to younger patients and patients with more favorable
disease risk factors. Brentuximab in combination with
cyclophosphamide, doxorubicin, and prednisone (CHP) has been
tested in a randomized clinical trial against CHOP in CD30+ T-cell
lymphomas; progression-free survival was improved with the
brentuximab-containing arm, and this was most pronounced for
patients with ALCL (see below). Autologous stem cell transplant has
been investigated for patients in their first remission and does seem
to improve progression-free survival in certain contexts. Drugs such
as gemcitabine, bendamustine, and pralatrexate have activity in
relapsed disease, as do the histone deacetylase inhibitors
romidepsin and belinostat. The PI3 kinase inhibitor duvelisib is being
investigated in these diseases with early signals of activity. 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 nonrelapse survival rates of ∼40–
50%.
Angioimmunoblastic T-Cell Lymphoma AITL constitutes ∼20% of
T-cell NHLs and ∼4% of all NHLs diagnosed. Patients present with a
variety of signs and symptoms, most often including
lymphadenopathy, hepatosplenomegaly, “B” symptoms, rash,
polyarthritis, and hemolytic anemia. Over 80% of patients have
advanced-stage disease at diagnosis, and bone marrow involvement
is common. Polyclonal 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 lymphocytes, 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 positive and may give rise to secondary EBV-positive B-cell
lymphomas at a later time. Genetic analysis of this disease has
revealed recurrent mutations in TET2 (76%), DNMT3 (33%), and
IDH2 (20%).
There is a subset of AITL that can remit with immunosuppression
with agents like glucocorticoids or methotrexate. Most patients,
however, will need combination chemotherapy with regimens like
those used in PTCL NOS. Median response duration is short, and
median OS is only 15–36 months. Treatment of relapsed disease is
similar to that of relapsed PTCL NOS.

Anaplastic Large-Cell Lymphoma ALCL is the next most common

T-cell lymphoma after AITL but is more common in children,
accounting for up to 10% of pediatric lymphomas. Approximately 40–
60% of cases harbor t(2;5), which fuses a portion of the nucleolar
protein nucleophosmin-1 (NPMI) gene to a part of the anaplastic
lymphoma kinase (ALK) gene, the product of which has constitutive
tyrosine kinase activity. These patients have a much more favorable
prognosis compared to ALK-negative ALCL, akin to that of DLBCL.
There is an additional, more indolent and favorable subtype that
occurs in the breast tissue of patients with breast implants, and there
is a cutaneous variant. In general, this is a disease that is more
common in men. ALK-positive disease is a disease of younger
patients, with a median age at diagnosis of 34 years, whereas the
median age at diagnosis of ALK-negative patients is 58. With the
exception of the cutaneous variant and the variant associated with
breast implants, most patients present with rapidly growing
lymphadenopathy with or without extranodal involvement; “B”
symptoms are common.
Most cases of ALCL involve large atypical lymphocytes with
horseshoe-shaped nuclei with prominent nucleoli (“hallmark” cells).
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 fluorescence in situ hybridization (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-positive
disease. Overall, ALCL has a better prognosis than PTCL, and this is
particularly true for ALK-positive disease, which has an 8-year OS
rate 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
chemotherapy-insensitive disease or for ALK-negative disease, the
conjugated anti-CD30 antibody to MMAE brentuximab is highly
active, with a response rate of 86% and a complete response rate of
57%. As mentioned earlier, brentuximab in combination with CHP
chemotherapy is an approved frontline regimen for the treatment of
CD30+ T-cell lymphomas, including ALCL. The ALK inhibitors,
including crizotinib, are active in refractory ALK-positive ALCL with
excellent outcomes.

Other PTCL Subtypes Enteropathy-associated T-cell lymphoma,

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 prognosis 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 symptoms and is often
difficult to diagnose. Recurrent genetic events include
isochromosome 7q and trisomy 8. Treatment outcome is poor, but
regimens that include ifosfamide, such as ifosfamide, carboplatin,
and etoposide (ICE) or ifosfamide, etoposide, and 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 with panniculitis. Patients present with multiple
subcutaneous nodules, which progress and can ulcerate. There is a
more indolent form that tends to express α/β TCRs and can be
managed with immune suppression, whereas lymphomas that
express γ/δ TCRs are more aggressive and are associated with a
worse prognosis and coincident hemophagocytic syndrome. This is a
disease of young men in their fifth and sixth decades of life. Patients
with aggressive disease are managed with multiagent
chemotherapy, and responding patients should be considered for
allogeneic stem cell transplantation.

Adult T-Cell Leukemia/Lymphoma Adult T-cell leukemia/lymphoma

(ATLL) is a disease that is most prevalent in Japan and the
Caribbean basin. It is a neoplasm that is driven by HTLV-1, often
contracted through the breast milk of infected mothers. The average
age at diagnosis is 60, so there is a long latency between viral
infection and viral transformation, and only 4% of infected patients
will develop the disease. This suggests that HTLV-1 may not be
sufficient to cause the malignant phenotype. There are four disease
variants: acute (60% of patients), lymphomatous (20% of patients),
chronic (15% of patients), and smoldering (5% of patients);
prognosis varies across these groups, with median survival times of
6, 10, and 24 months, and not yet reached, respectively.
Presentation depends on the subtype, but most commonly, patients
present with circulating disease and bone marrow involvement,
hypercalcemia, lytic bone lesions, lymphadenopathy,
hepatosplenomegaly, skin lesions, and opportunistic infections.
The pathognomonic finding is the malignant “flower cell” that is
positive for CD4 and CD25, as well as CD2, CD3, and CD5 but
lacking CD7 (Fig. 108-7). Combination chemotherapy is generally
used, but for patients fortunate enough to respond, response
durations are very short. Other active agents in this disease include
the antiretroviral agent zidovudine, interferon α, and arsenic. In any
patients who do respond to therapy, allogeneic stem cell transplant
should be considered.

FIGURE 108-7 Adult T-cell leukemia/lymphoma. Peripheral blood smear

showing leukemia cells with typical “flower-shaped” nucleus.
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 at the end of
therapy is also predictive.
Treatment for early-stage disease is usually with combined-
modality therapy of chemotherapy (commonly using etoposide,
ifosfamide, cisplatin, 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 the
median OS is only 4.3 months. The most commonly used treatment
regimen is the SMILE regimen (dexamethasone, methotrexate,
ifosfamide, L-asparaginase, and etoposide).

■ FURTHER READING
HANEL W, EPPERLA N: Evolving therapeutic landscape in follicular
lymphoma: a look at emerging and investigational therapies. J
Hematol Oncol 14:104, 2021.
ROSCHEWSKI M et al: Multicenter study of risk-adapted therapy with
dose-adjusted EPOCH-R in adults with untreated Burkitt
lymphoma. J Clin Oncol 38:2519, 2020.
SAKATA-YANAGIMOTO M et al: Molecular understanding of peripheral T-
cell lymphomas, not otherwise specified (PTCL, NOS): A
complex disease category. J Clin Exp Hematop 61:61, 2021.
SILKENSTEDT E, DREYLING M: Mantle cell lymphoma–advances in
molecular biology, prognostication, and treatment approaches.
Hematol Oncol 39 Suppl 1:31, 2021.
 Hodgkin’s Lymphoma
109
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 non-Hodgkin’s lymphomas (NHLs) biologically than it
is to cHL. The majority of this chapter will be specific to cHL, with a
discussion of NLPHL at the end.
cHL is one of the success stories of modern oncology. Until the
advent of extended-field radiotherapy in the mid-twentieth century, it
was a highly fatal disease of young people. Radiation therapy cured
some patients with early-stage disease, and the introduction of
multiagent 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
malignancies 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
8480 new cases diagnosed in 2020 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 cHL that are differentiated based on their histopathologic features
(Table 109-1): nodular sclerosis, mixed cellularity, lymphocyte-rich,
and lymphocyte-depleted. Patients in the younger age groups
diagnosed in the United States largely have the nodular sclerosing
subtype of HL. Elderly patients, patients infected with HIV, and
patients in developing 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 etiologic 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.

TABLE 109-1 World Health Organization Classification of

Hodgkin’s Lymphoma

Histologically, the HRS cell is diagnostic of cHL (Fig. 109-1).

These cells are large cells with abundant cytoplasm with bilobed
and/or multiple 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, respectively. 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, macrophages, 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 signaling 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 chromosome 9p24.1, resulting in overexpression
of PD-L1, the ligand for 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 generalized immune suppression in HL patients.

FIGURE 109-1 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. (From DL
Kasper: Harrison’s Principles of Internal Medicine, 16th ed. New York, NY:
McGraw-Hill; 2005, Fig. 97-11, p. 654.)
APPROACH TO THE PATIENT

Classical 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
presentation 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
manifestations. 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 toxicity. A
physical examination should pay attention to the peripherally
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 (ESR); chemistry
studies reflecting major organ function including serum albumin;
and HIV and hepatitis virus testing. A positron emission
tomography (PET)/computed tomography (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 109-2).

TABLE 109-2 The Ann Arbor Staging System for Hodgkin’s

Lymphoma
 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
(immunoglobulin 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 therapy 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 disease (stage I
or II) or advanced-stage disease (stage III or IV). 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 1 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
Classical 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
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 survival. 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 radiotherapy. 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 (doxorubicin, bleomycin, vinblastine, and
dacarbazine). This regimen is given every other week, with each
cycle including two treatments. In patients with low-risk, or
favorable, disease, the use of four to six cycles of ABVD alone,
without radiation therapy, results in progression-free and overall
survival rates of 88–92% and 97–100%, respectively, at 5–7 years.
This may be associated with a slightly increased risk of relapse
when compared with abbreviated chemotherapy (ABVD for four
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 studies have
examined a very abbreviated chemotherapy regimen (ABVD for two
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-modality therapy of
ABVD for four cycles and 30 Gy of radiation. However, 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 regarding the duration and
extent of therapy. In one study, a negative PET/CT scan after three
cycles of ABVD predicted for excellent outcomes with no additional
therapy; in another, a negative PET/CT scan after two cycles of
ABVD predicted for good outcomes with two additional cycles of
ABVD alone, without radiation therapy.
For unfavorable-risk disease, the omission of radiation therapy
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,
treatment options would include ABVD for four cycles followed by
involved field radiation therapy or ABVD alone for six cycles.
Treatment decisions are often based on the extent of the radiation
field and the unfavorable risk factor, with patients with nonbulky
disease being candidates for chemotherapy alone if radiation would
be contraindicated 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
chemotherapy may not benefit from additional radiation therapy.
Alternative chemotherapy regimens to ABVD have been
developed and include the Stanford V regimen and escalated
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide,
vincristine, procarbazine, and prednisone). 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
addition 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 for six 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-
drug conjugate brentuximab vedotin, which is an antibody against
CD30 conjugated to the microtubule inhibitor monomethyl auristatin
E (MMAE). This drug has been combined with doxorubicin,
bleomycin, and dacarbazine in early-phase studies for advanced-
stage HL with favorable efficacy compared to historical controls.
Eschelon-1, a randomized trial of doxorubicin, vinblastine, and
dacarbazine (AVD) plus brentuximab compared to ABVD, was a
positive study in that it demonstrated an improvement in
progression-free survival for AVD plus brentuximab, especially
among younger patients, patients from North America, and patients
with higher risk disease. 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 pembrolizumab 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, including in a multicenter randomized
trial against AVD plus brentuximab as initial therapy for advanced-
stage disease.

RELAPSED DISEASE
Patients who relapse after primary therapy of HL can frequently still
be cured. Patients who relapse after an effective chemotherapy
regimen are usually not curable with subsequent chemotherapy
administered at standard doses. Alternative 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 stem cell transplantation can cure over half of patients.
Standard salvage chemotherapy regimens include ICE (ifosfamide,
carboplatin, and etoposide) and GND (gemcitabine, vinorelbine, and
doxorubicin). Newer combinations, including brentuximab with
either chemotherapy or immune checkpoint inhibitors such as
nivolumab, have also been tested with promising early results. 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 autologous 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. It is also used as a
maintenance therapy following successful autologous stem cell
transplantation based on results of a randomized trial versus
observation. The anti-PD-1 immune checkpoint inhibitors,
nivolumab and pembrolizumab, have efficacy in relapsed HL, and
many responses are durable. Increasingly, there is an appreciation
that use of checkpoint inhibitors restores the HRS cell’s sensitivity
to chemotherapy by unknown mechanisms; autologous stem cell
transplantation may be a potentially curative option for patients who
had previously been felt to have chemotherapy-resistant disease.
Finally, anti-CD30 chimeric antigen receptor (CAR) T-cell therapy
has been tested in multiply relapsed cHL with promising early
results; these products are now being tested in multicenter phase 2
clinical trials.
Two other options may be useful in the setting of disease
relapse after ABVD chemotherapy. Alkylating agent–based
combinations such as ChlVPP (chlorambucil, vincristine,
prednisone, and procarbazine) may be active in patients with
disease resistant to ABVD. In addition, relapse following bone
marrow transplant can be responsive to weekly low-dose single-
agent vinblastine.

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
(mechlorethamine, vincristine, procarbazine, and prednisone) and
BEACOPP-like regimens than with ABVD. The risk of development
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
accelerates 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.
A number of other late side effects from the treatment of HL are
well known. Patients who receive thoracic radiotherapy are at very
high risk for the eventual development of hypothyroidism and
should be observed for this complication; intermittent measurement
of thyrotropin should be made to identify the condition before it
becomes symptomatic. Lhermitte’s syndrome occurs in ∼15% of
patients who receive thoracic radiotherapy. This syndrome is
manifested 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 treatment for HL. Chemotherapy regimens containing
alkylating agents induce permanent infertility in nearly all men. The
risk of permanent infertility in women treated with alkylating agent–
containing chemotherapy is age-related, with younger women more
likely to recover fertility. Infertility is very rare after treatment with
ABVD.

NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN’S

LYMPHOMA
NLPHL is now recognized as an entity distinct from cHL. Previous
classification systems recognized that biopsies from a small subset
of patients diagnosed as having HL contained a predominance of
small lymphocytes and rare Reed-Sternberg–like cells; tumors had
a nodular growth pattern and a clinical course that varied from that
of patients with cHL. This is an unusual clinical entity and
represents <5% of cases of HL and defines NLPHL.
NLPHL has a number of characteristics that suggest its
relationship to NHL, rather than cHL, however. The HRS-like cell, or
L&H (lymphocyte and histiocyte) or “popcorn” cell, is a clonal
proliferation of B-cells that are positive for B-cell markers CD45,
CD79a, CD20, CD19, and BCL2. They do not express two markers
normally found on HRS cells, CD30 and CD15. This lymphoma
tends to have a chronic, relapsing course and sometimes
transforms to diffuse large B-cell lymphoma, including a specific
subtype of diffuse large B-cell lymphoma known as T-
cell/histiocyte–rich B-cell lymphoma, which shares an
immunophenotype with the L&H cell. This natural history most
closely resembles that of the indolent B-cell NHLs outlined in
Chaps. 108 and 110.
Patients with NLPHL are more commonly male (75%). Like cHL,
the age distribution of patients with this disease has two peaks, but
unlike cHL, these peaks include children and adults ages 30–40
years, respectively. The majority of patients diagnosed have stage I
or II disease (75%), with a minority having advanced-stage disease
at diagnosis. “B” symptoms are uncommon.
Patients with early-stage disease at diagnosis should be treated
with definitive radiotherapy. This is associated with a 15-year
nonrelapse survival rate of 82%. The treatment of patients with
advanced-stage NLPHL is controversial. Some clinicians favor no
treatment of asymptomatic disease and merely close follow-up, akin
to the indolent B-cell NHLs. For patients who need therapy due to
symptoms or signs of organ function impairment, both cHL
regimens and B-cell NHL regimens have been used, including
ABVD and R-CHOP (rituximab, cyclophosphamide, doxorubicin,
vincristine, and prednisone). A single-institution experience with R-
CHOP resulted in a 100% response rate in a small group of patients
without a single relapse with 42 months of follow-up. Although this
is short follow-up for an indolent disease, some believe R-CHOP
may be curative in this disease and advocate treating patients with
advanced-stage disease at diagnosis, regardless of symptoms or
organ function.

■ FURTHER READING
CHEN R et al: Pembrolizumab in relapsed or refractory Hodgkin
lymphoma: 2-year follow-up of KEYNOTE-087. Blood 134:1144,
2019.
GILLESSEN S et al: Intensified treatment of patients with early stage,
unfavourable Hodgkin lymphoma: Long-term follow-up of a
randomised, international phase 3 trial of the German Hodgkin
Study Group (GHSG HD14). Lancet Haematol 8:e278, 2021.
MOSKOWITZ CH et al: Five-year PFS from the AETHERA trial of
brentuximab vedotin for Hodgkin lymphoma at high risk of
progression or relapse. Blood 132:2639, 2018.
RASHIDI A et al: Allogeneic hematopoietic stem cell transplantation in
Hodgkin lymphoma: A systemic review and meta-analysis. Bone
Marrow Transplant 51:521, 2016.
STRAUS DJ et al: CALGB 50604: Risk-adapted treatment of nonbulky
early-stage Hodgkin lymphoma based on interim PET. Blood
132:1013, 2018.
STRAUS DJ et al: Brentuximab vedotin with chemotherapy for stage III
or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update
of an international, open-label, randomised, phase 3 trial. Lancet
Haematol 8:e410, 2021.
 Less Common Lymphoid and Myeloid
110 Malignancies
Ayalew Tefferi, Dan L. Longo

The most common lymphoid malignancies are discussed in Chaps.

106, 107, 108, 109, and 111, myeloid leukemias in Chaps. 104 and
105, myelodysplastic syndromes (MDS) in Chap. 102, and
myeloproliferative syndromes in Chap. 103. This chapter will focus
on the more unusual forms of hematologic malignancy. The diseases
discussed here are listed in Table 110-1. Each of these entities
accounts for <1% of hematologic neoplasms.

TABLE 110-1 Unusual Lymphoid and Myeloid Malignancies

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 malignancy of
medium-sized (about twice the size of a normal small lymphocyte),
round lymphocytes with a prominent nucleolus and light blue
cytoplasm on Wright’s stain. It predominantly 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 consequence 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 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 (cyclophosphamide, doxorubicin,
vincristine, and prednisone [CHOP]) have produced responses.
CHOP plus rituximab may be more effective than CHOP alone, but
the disease is sufficiently rare that large series have not been
reported. Splenectomy can produce palliation of symptoms but
appears to have little or no impact on the course of the disease. BM
transplantation may be curative. Imatinib may also have activity.

Splenic Marginal Zone Lymphoma (SMZL) This tumor of mainly

small lymphocytes originates in the marginal zone of the spleen
white pulp, grows to efface the germinal centers and mantle, and
invades the red pulp. Splenic hilar nodes, BM, and peripheral blood
(PB) may be involved. The circulating tumor cells have short surface
villi and are called villous lymphocytes. Table 110-2 shows
differences in tumor cells of a number of neoplasms of small
lymphocytes that aid in the differential diagnosis. SMZL cells express
surface immunoglobulin and CD20 but are negative for CD5, CD10,
CD43, and CD103. Lack of CD5 distinguishes SMZL from CLL, and
lack of CD103 separates SMZL from hairy cell leukemia.

TABLE 110-2 Immunophenotype of Tumors of Small

Lymphocytes

The median age of patients with SMZL is mid-fifties, and men

and women are equally represented. Patients present with incidental
or symptomatic splenomegaly or incidental detection of
lymphocytosis in the PB with villous lymphocytes. Autoimmune
anemia or thrombocytopenia may be present. The immunoglobulin
produced by these cells contains somatic mutations that reflect
transit through a germinal 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 marginal zone lymphomas (e.g.,
trisomy 3 and t[11;18]) are uncommon in SMZL.
The clinical course of disease is generally indolent with median
survivals 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, ibrutinib, and PI3 kinase inhibitors are
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
completely clear and may be mediated by both inhibitory cytokines
and 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 110-3).
Monocytopenia is profound and may explain a predisposition to
atypical mycobacterial infection that is observed clinically. The tumor
cells have strong expression of CD22, CD25, and CD103; soluble
CD25 level in serum is an excellent tumor marker for disease
activity. The cells also express tartrate-resistant acid phosphatase.
The immunoglobulin genes are rearranged and mutated, indicating
the influence of a germinal center. No specific cytogenetic
abnormality has been found, but most cases contain the activating
BRAF mutation V600E.

TABLE 110-3 Differential Diagnosis of “Dry Tap”—Inability to

Aspirate Bone Marrow

The median age of affected patients is mid-fifties, and the male-

to-female ratio is 5:1. Treatment options are numerous. Splenectomy
is often associated with prolonged remission. Nucleosides including
cladribine and deoxycoformycin are highly active but are also
associated with further immunosuppression and can increase the
risk of certain opportunistic infections. However, after brief courses of
these agents, patients usually obtain very durable remissions during
which immune function spontaneously recovers. Interferon α is also
an effective therapy but is not as effective as nucleosides.
Chemotherapy-refractory patients have responded to vemurafenib, a
BRAF inhibitor. Vemurafenib does not appear to be curative, but
responses can be maintained with chronic treatment. More durable
remissions occur when rituximab is added to vemurafenib.

Nodal Marginal Zone B Cell Lymphoma This rare node-based

disease bears an uncertain relationship with extranodal marginal
zone lymphomas, which are often mucosa-associated and are called
mucosa-associated lymphoid tissue (MALT) lymphomas, and
SMZLs. 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 patients may have extranodal involvement, and
involvement of the lymph nodes can be secondary to the spread of a
mucosal primary lesion. In authentic nodal primaries, the cytogenetic
abnormalities associated with MALT lymphomas (trisomy 3 and
t[11;18]) are very rare. The clinical course is indolent. Patients often
respond to combination 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 in 5–10% of cases, disease 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
paucity 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
overexpressed 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 human
leukocyte antigen (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,
vincristine, 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,
cyclophosphamide, 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, especially 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 consistent picture
has emerged to define a clinical syndrome or its epidemiologic 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. A subset of
patients have tumors with MYD88 or CD79B mutations. 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 or at autopsy.

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.
The malignant effusions contain cells positive for HHV-8/KSHV,
and many are also co-infected with Epstein-Barr virus. The cells are
large with large nuclei and prominent nucleoli that can be confused
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
markers such as CD3 or rearranged T-cell receptor genes. No
characteristic genetic lesions have been reported, but gains in
chromosome 12 and X material have 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.
Highly active antiretroviral 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 outnumbered 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 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 leukemia of
medium-sized prolymphocytes involving the blood, marrow, 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 analogues, 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 alemtuzumab or conventional-dose therapy.

T-Cell Large Granular Lymphocytic Leukemia T-cell large

granular lymphocytic (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 evidence of systemic
autoimmune disease, including rheumatoid arthritis,
hypergammaglobulinemia, autoantibodies, and circulating immune
complexes. BM involvement is mainly interstitial in pattern, with
<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.
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 virus and are not accompanied by
pancytopenia or autoimmune disease.

Extranodal NK/T-Cell Lymphoma, Nasal Type Like lymphomatoid

granulomatosis, extranodal NK/T-cell lymphoma tends 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, polymorphic 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 gastrointestinal tract, or the testis. In some
cases, hemophagocytic syndrome (HPS) may influence the clinical
picture. Patients may have B symptoms. 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 development 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 poor (median
survival is 7 months), but some patients have a good response to
CHOP chemotherapy. Patients who respond can develop bowel
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 lymphoma

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 Subcutaneous

panniculitis-like T-cell lymphoma involves multiple subcutaneous
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,
particularly in the setting of immunosuppression. The cells are
negative for Epstein-Barr virus. Patients may have an 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, ∼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
perforin 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 complication of silicone or 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 immunotoxin 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 Angioimmunoblastic T-cell

lymphoma is a systemic disease that accounts for ∼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
including cold agglutinins, rheumatoid factor, and circulating immune
complexes. 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 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, and cytogenetic and molecular
genetic tests in order to classify myeloid malignancies into several
major categories (Table 110-4). Among them, acute myeloid
leukemia (AML) is discussed in Chap. 104, myelodysplastic
syndromes (MDS) in Chap. 102, chronic myeloid leukemia (CML) in
Chap. 105, and JAK2 mutation–enriched myeloproliferative
neoplasms (MPNs) in Chap. 103. In this chapter, we focus on the
rest (listed in Table 110-4) including chronic neutrophilic leukemia
(CNL); atypical CML, BCR-ABL1 negative (aCML); chronic
myelomonocytic 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
sideroblasts and thrombocytosis (MDS/MPN-RS-T); and
myeloid/lymphoid neoplasms with eosinophilia and rearrangements
of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2. This chapter
also includes histiocytic and dendritic cell neoplasms, transient
myeloproliferative disorders, and a broader discussion on primary
eosinophilic disorders including hypereosinophilic syndrome (HES).

TABLE 110-4 World Health Organization Classification of

Myeloid Malignancies
■ CHRONIC NEUTROPHILIC LEUKEMIA
CNL is a clonal proliferation of mature neutrophils with few or no
circulating immature granulocytes. In 2013, CNL was described to be
associated with activating mutations of the gene (CSF3R) encoding
for the receptor for 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, splenomegaly, anemia, and thrombocytopenia. Median
survival is approximately 2 years and causes of death include
leukemic transformation, progressive disease associated with severe
cytopenias and marked treatment-refractory leukocytosis. The true
incidence of CNL is not known due to diagnostic uncertainty with
>200 currently reported cases. Median age at diagnosis is
approximately 67 years with a slight male preponderance in gender
distribution.

Pathogenesis CSF3 is the main growth factor for granulocyte

proliferation 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 patients who experience leukemic
transformation. SCN-associated CSF3R mutations occur in the
region of the gene coding for the cytoplasmic 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 mutations
were found to be specific to WHO-defined CNL. About 40% of the
T618I-mutated cases also harbored SETBP1 mutations. CSF3R
T618I 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

common causes of neutrophilia including infections and inflammatory
processes. In addition, one should be mindful of the association
between some forms of metastatic cancer or plasma cell neoplasms
with secondary neutrophilia. Neoplastic neutrophilia also occurs in
other BCR-ABL1-negative 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 110-5): 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 hypercellular and
displays increased number and percentage of neutrophils with a very
high myeloid-to-erythroid ratio and minimal left shift, myeloid
dysplasia, or reticulin fibrosis.

TABLE 110-5 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)
 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 110-5). In
practical 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 leukocytosis. Unfortunately, several exclusionary criteria
still need to be met for diagnosing CNL in the absence of CSF3R
mutations (Table 110-5).

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 hematopoietic stem cell transplant (AHSCT) is reasonable
to consider in the presence of symptomatic disease, especially in
younger patients. Otherwise, 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 α 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 was often incomplete and temporary. In a recently reported
phase 2 study of ruxolitinib in 44 patients with CNL or aCML, 21
patients had CNL (76% harbored CSF3R mutations), of whom only 4
(20%) experienced complete or partial response according to
conventional response criteria.

■ 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
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 diagnostic criteria for aCML are listed in Table 110-5 and
include granulocytosis; 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, primary myelofibrosis (PMF),
polycythemia vera (PV), or essential thrombocytopenia (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 patients express SETBP1 mutations, which are,
however, also found in several other myeloid malignancies, including
CNL and CMML. SETBP1 mutations in aCML are prognostically
detrimental and mostly located between codons 858 and 871; similar
mutations are seen with Schinzel-Giedion syndrome (a congenital
disease with severe developmental delay and various physical
stigmata including midface retraction, large forehead, and
macroglossia). More recently, a somatic missense mutation in
ethanolamine kinase 1 (ETNK1 N244S) 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 MPNs.
In a series of 55 patients with WHO-defined aCML, median age
at diagnosis was 62 years with female preponderance (57%);
splenomegaly 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 leukocytosis, transfusion requirement, and
increased immature cells in the PB. In a more recent Mayo Clinic
study of 25 molecularly annotated and strictly WHO-defined aCML
patients, median age was 70 years and 84% were male. Cytogenetic
abnormalities were seen in 36% and gene mutations in 100%.
Mutational frequencies were as follows: ASXL1 28%, TET2 16%,
NRAS 16%, SETBP1 12%, RUNX1 12%, ETNK1 8%, and PTPN11
4%. Median survival was 10.8 months, and at last follow-up (median
11 months), 17 deaths (68%) and 2 leukemic transformations (8%)
were documented. In multivariable analysis, advanced age, low
hemoglobin, and TET2 mutations were shown to carry independent
prognostic significance; other mutations, including ASXL1 and
SETBP1, lacked prognostic significance. Conventional
chemotherapy is largely ineffective in the treatment of aCML.
Similarly, treatment response to the JAK1/2 inhibitor ruxolitinib has
not been impressive. However, a favorable experience with
autologous stem cell transplantation (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 from 65 to 75 years, and there is a 2:1 male
predominance. 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 features 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 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. Clonal cytogenetic abnormalities are seen in about a third of
patients with CMML and include trisomy 8 and abnormalities of
chromosome 7. More recent studies have demonstrated the
presence of BM dendritic cell aggregates suggesting systemic
immune dysregulation and distinct phenotypic features of monocytes
in CMML.
Diagnosis Reactive monocytosis is uncommon but has been
reported in association with certain infections and inflammatory
conditions. 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 110-5 and
include persistent PB monocyte count of ≥1 × 109/L with monocyte
percentage of ≥10%; absence of BCR-ABL1, PDGFRA, PDGFRB,
FGFR1, or PCM1-JAK2 rearrangements; not meeting WHO criteria
for CML, PV, ET, or PMF; <20% blasts and promonocytes in the PB
and BM; and dysplasia involving one or more myeloid lineages or, in
the absence of dysplasia, presence of an acquired clonal cytogenetic
or molecular genetic abnormality or nonreactive 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 nonspecific 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 simultaneously (dual esterase
staining). Monocytosis can be associated with reactive as well as
other myeloid neoplasms. Based on flow cytometric expression of
CD14/CD16, monocytes can be classified into classical MO1
(CD14+/CD16–), intermediate MO2 (CD14+/CD16+), and
nonclassical MO3 (CD14−/CD16+) fractions, with MO1 constituting
the major monocyte population (85%) in healthy conditions. Recent
studies have suggested characteristic increase in classical
monocytes in CMML patients, distinguishing them from other causes
of reactive and clonal monocytosis.

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 g/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.
Another prognostic model referred to as the CMML-specific
prognostic scoring system (CPSS) identified four variables as being
prognostic for both overall survival and leukemia-free survival:
French-American-British (FAB) and WHO CMML subtypes, red blood
cell transfusion dependency, and the Spanish cytogenetic risk
stratification system. 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 g/dL in females and
<11 g/dL in males (2 points). This model stratified patients into three
groups: low (0–4 points), intermediate (5–7 points), and high risk (8–
12 points), with median survivals of not reached and 38.5 and 14.4
months, respectively. More recent studies have highlighted the
adverse prognostic effect of ASXL1 and DNMT3A mutations in
CMML. To further clarify the prognostic relevance of ASXL1
mutations, an international collaborative cohort of 466 CMML
patients was analyzed. In multivariable analysis, ASXL1 mutations,
AMC >10 × 109/L, hemoglobin <10 g/dL, platelets <100 × 109/L, and
circulating immature myeloid cells were independently predictive of
shortened overall survival. More recently, the aforementioned CPSS
model was updated to include molecular abnormalities including
ASXL1, RUNX1, NRAS, and SETBP1 mutations (CPSS-Mol). In a
report of 171 patients with blast phase CMML (median age 71
years), treatment included best supportive care in 25%,
hypomethylating agent therapy in 10%, AML-like induction
chemotherapy in 38%, AML-like induction chemotherapy followed by
AHSCT in 15%, upfront AHSCT in 2%, and clinical trials in 11%.
After a median follow-up of 4.4 months, 141 deaths (82%) were
recorded. Median overall survival was 6 months with 1-, 3-, and 5-
year survival rates of 25%, 9%, and 6%, respectively.
Treatment Current treatment in CMML consists of hydroxyurea and
supportive care, including red cell transfusions and use of
erythropoiesis-stimulating agents (ESAs). 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. AHSCT 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 recent 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. In a recent Mayo Clinic report, among 406
consecutive CMML patients (age ≤75 years at diagnosis) seen
between January 1990 and December 2018, 70 (17%) underwent
AHSCT (median age 58 years) including 46 (66%) in chronic phase
and 24 (34%) in blast phase. At a median follow-up of 70 months,
there were 22 deaths (31%) in the chronic phase transplant group,
11 (24%) from disease relapse and 9 (20%) from nonrelapse
mortality. Posttransplant median survival was 67 months in the
chronic phase and 16 months in the blast phase (p <.01) transplant
groups; 5-year survival rates were 51% and 19%, respectively.

■ 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
granulocyte-macrophage colony-stimulating factor (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, whereas the incidence of NF1 in patients without
neurofibromatosis type 1 (NF1) and RAS mutations is ∼15% each. In
general, ∼85% of JMML cases have one of the classical RAS
pathway mutations (PTPN11, NRAS, KRAS, NF1, or CBL); in
addition, a myriad of other mutations, such as ASXL1, RUNX1,
SETBP1, JAK3, and CUX1, have recently been reported. Drug
therapy is relatively ineffective in JMML, and the treatment of choice
is AHSCT, which results in a 5-year survival of approximately 50%.
The 2016 revised WHO diagnostic criteria for JMML require the
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 considered 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 category includes CMML, aCML, and JMML, which have been
discussed 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 the WHO classification document has changed the
term RARS-T to MDS/MPN-RS-T.
In a representative study of 85 patients with MDS/MPN-U,
median age was 70 years and 72% were male. Splenomegaly at
presentation was present in 33%, thrombocytosis in 13%,
leukocytosis in 18%, JAK2 mutations in 30%, and abnormal
karyotype in 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 AHSCT 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, or PCM1-JAK2
mutations or t(3;3)(q21;q26), inv(3)(q21q26), or del(5q). These new
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.
In a recent study, 111 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 cases versus 3.3
years in unmutated cases. Six-year survival was 67% in JAK2
mutated cases versus 32% in unmutated cases. Multivariable
analysis identified younger age and JAK2 and SF3B1 mutations as
favorable factors. Predictors of poor survival in MDS/MPN-RS-T
include anemia, abnormal karyotype, and presence of ASXL1 or
SETBP1 mutations. Interestingly, the presence of SF3B1 mutations
in MDS/MPN-RS-T was recently shown to be associated with
increased risk of thrombosis. Several case reports have suggested
that treatment with lenalidomide might induce red cell transfusion
independency and complete remissions in MDS/MPN-RS-T. Most
recently, luspatercept, a recombinant fusion protein that binds
transforming growth factor β superfamily ligands to reduce SMAD
signaling, has also been shown to benefit some patients with MDS-
RS-T; in a recently published phase 3 trial involving 229 patients with
transfusion-dependent very-low- to intermediate-risk MDS-RS-T,
transfusion independence for ≥8 weeks was achieved in 38% of the
patients receiving luspatercept versus 13% of patients in the placebo
group (p <.01).

■ 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
(Table 110-4). 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. Specific treatment interventions might not be necessary in
asymptomatic patients with MPN-U, whereas patients with arterial
thrombotic complications might require cytoreductive and aspirin
therapy and those with venous thrombosis might require systemic
anticoagulation.

■ MYELOID NEOPLASMS WITH GERMLINE PREDISPOSITION

The 2016 WHO revision on the classification of myeloid neoplasms
added a section referred to as “myeloid neoplasms with germline
predisposition” and that includes cases of AML, MDS, and
MDS/MPN that arise in the setting of a germline 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 syndrome, neurofibromatosis, and
telomeropathies.
■ TRANSIENT MYELOPROLIFERATIVE DISORDER (TMD)
TMD, also referred to as transient abnormal myelopoiesis (TAM),
constitutes an often but not always transient phenomenon of
abnormal megakaryoblast proliferation, which occurs in ∼10% of
infants with Down syndrome. TMD is usually recognized at birth and
either undergoes spontaneous regression (75% of cases) or
progresses to acute megakaryoblastic leukemia (AMKL) (25% of
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 thrombocytopenia 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 >1500 × 109/L.
Eosinophilia is operationally classified into secondary (nonneoplastic
proliferation 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 with infections, especially those related to tissue-
invasive helminths, allergic/vasculitic diseases, drugs, and
metastatic cancer. Primary eosinophilia 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 persistent AEC of ≥1.5 × 109/L and associated with
eosinophil-mediated organ damage (Table 110-6). An HES-like
disorder that is associated with clonal or phenotypically abnormal T
cells is referred to as lymphocytic variant hypereosinophilia (Table
110-6).

TABLE 110-6 Primary Eosinophilia Classification

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 eosinophilia and rearrangement of platelet-derived growth factor
receptor (PDGFR) α/β or fibroblast growth factor receptor 1 (FGFR1)
or with PCM1-JAK2 (Table 110-4).
The diagnostic workup for clonal eosinophilia that is not
associated 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 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 translocations predicts favorable response
to treatment with imatinib mesylate and presence of t(8;9)
(p22;p24.1) predicts a transient response to ruxolitinib, whereas
8p11.2 translocations are associated with aggressive myeloid
malignancies 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
clinicopathologically 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 as 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.
In a recent Mayo Clinic survey of 1416 patients with PB
eosinophilia evaluated between 2008 and 2019, 17 patients (1.2%)
fulfilled the WHO 2016 criteria for CEL-NOS. Median age was 63
years (range 25–92 years) with the vast majority of patients (88%)
presenting with systemic symptoms. Organ involvement was a
prominent feature, and involved organs included spleen, cardiac and
pulmonary organs, and distal esophagus. Laboratory abnormalities
included anemia, leukocytosis, and eosinophilia (median eosinophil
count of 6.4 × 109/L; range 2.0–53.1). The most common BM
abnormalities included abnormal eosinophils, abnormal and
increased megakaryocytes, and fibrosis (18%). Cytogenetic
abnormalities occurred in 88% of patients and included trisomy 8,
complex karyotype, 13q–, 20q–, and chromosome 1 abnormalities.
All seven patients with next-generation sequencing studies harbored
one or more mutations, including ASXL1 (43%) and IDH1 (29%).
Half of patients treated with hydroxyurea-based regimens responded
with a persistent decline in eosinophil count for a median duration of
18 months. One-third of patients treated with prednisone responded,
with a median duration of response of 13 months. Three patients
were treated with imatinib, of whom two had normalization of
eosinophil count. At a median follow-up of 13 months, nine patients
had died including three patients who underwent leukemic
transformation.

PDGFR Mutated Eosinophilia Both platelet-derived growth factor

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 regard 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 studies 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 constitutively active fusion tyrosine kinase, wherein a
∼800-kb interstitial deletion within 4q12 fuses the 5′ portion of
FIP1L1 to the 3′ portion of PDGFRA. FIP1L1-PDGFRA occurs in a
very small subset of patients who present with the phenotypic
features of either systemic mastocytosis (SM) or HES, but the
presence of the mutation reliably predicts complete hematologic and
molecular response to imatinib therapy.
In a recent retrospective survey of 151 patients with FIP1L1-
PDGFRA–associated eosinophilia (143 males; mean age at
diagnosis 49 years), organopathy involved the spleen (44%), skin
(32%), lungs (30%), heart (19%), and central nervous system (9%);
none of 31 patients initially treated with corticosteroids achieved
complete hematologic remission, whereas all 148 patients treated
with imatinib achieved complete hematologic responses and also
molecular responses, when evaluated. Treatment discontinuation
was documented in 46 patients followed by a 57% relapse rate; the
1-, 5-, and 10-year overall survival rates in imatinib-treated patients
were 99%, 95%, and 84%, respectively. Other studies have
confirmed the possibility of treatment-free remissions in some
patients after imatinib discontinuation. Infrequent occurrence of
FIP1L1-PDGFRA mutated acute myeloid leukemia associated with
eosinophilia has also been shown to respond to low-dose imatinib
therapy (100 mg/d).
 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 demonstrated. 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, and cell line
transformation and MPD induction in mice have been demonstrated.
Imatinib therapy was shown to be effective when employed.

FGFR1 Mutated Eosinophilia The 8p11 myeloproliferative

syndrome (EMS) (also known as human stem cell
leukemic/lymphoma syndrome) constitutes a clinical phenotype with
features of both lymphoma and eosinophilic MPN and is
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 demonstrating 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 (ZNF198 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 combination 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
eosinophilia referred to as “myeloid/lymphoid neoplasms with PCM1-
JAK2.” The entity is characterized by the t(8;9)(p22;p24.1)
cytogenetic abnormality and a phenotype that displays marked male
predominance, hepatosplenomegaly, eosinophilia, and 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 ruxolitinib
therapy.

Hypereosinophilic Syndrome Blood eosinophilia that is neither

secondary nor clonal is operationally labeled as being “idiopathic.”
HES is a subcategory of idiopathic eosinophilia with persistent
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
addition, some patients manifest thromboembolic complications,
hepatosplenomegaly, and either cytopenia or cytosis.
BM histologic and cytogenetic/molecular studies should be
examined 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
mastocytosis and warrants molecular studies to detect FIP1L1-
PDGFRA), T-cell immunophenotyping, and T-cell receptor antigen
gene rearrangement 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
echocardiographic findings in HES include ventricular apical
thrombus, posterior mitral leaflet or tricuspid valve abnormality,
endocardial thickening, dilated left ventricle, and pericardial effusion.
In a recent Mayo Clinic study of 98 consecutive patients with
idiopathic eosinophilia, including HES, median age was 53 years
(55% males) and overt organ involvement was seen in >80% of the
cases, including 54% involving organs other than the skin. The
frequencies of cardiac involvement, hepatosplenomegaly, and
increased serum tryptase and interleukin 5 (IL-5) levels were 8%,
4%, 24%, and 31%, respectively. The study also revealed that 11%
of the affected patients harbored pathogenetic mutations 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
hepatosplenomegaly as risk factors for survival.
Corticosteroids are the cornerstone of therapy in HES. Treatment
with oral prednisone is usually started at 1 mg/kg/d and continued for
1–2 weeks before the dose is tapered slowly over the ensuing 2–3
months. If symptoms recur at a prednisone dose level of >10 mg/d,
either hydroxyurea or interferon α is used as a steroid-sparing agent.
In patients who fail usual therapy as outlined above, mepolizumab or
alemtuzumab might be considered. Mepolizumab is a monoclonal
antibody that targets IL-5, which is 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.
In a recently reported, placebo-controlled, phase 3 study, HES
patients received subcutaneous mepolizumab (300 mg) every 4
weeks, in addition to their preprotocol therapy, and experienced
significantly fewer disease flare ups or treatment discontinuations
(28 vs 56% for placebo), without excess adverse events.
Mepolizumab was approved by the U.S. Food and Drug
Administration (FDA) for use in HES on September 25, 2020. In a
smaller phase 2 study, benralizumab (monoclonal antibody targeting
the receptor for IL-5; 30 mg given subcutaneously every 4 weeks)
was also shown to reduce eosinophil count more efficiently
compared to placebo (90 vs 30%).

■ MASTOCYTOSIS
Mast cell disease (MCD) is defined as tissue infiltration by
morphologically and immunophenotypically abnormal mast cells.
MCD is classified into two broad categories: cutaneous mastocytosis
(CM) and systemic mastocytosis (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 symptoms (e.g.,
headache, flushing, lightheadedness, syncope, anaphylaxis, pruritus,
urticaria, angioedema, nausea, diarrhea, abdominal cramps), and
organ damage (lytic bone lesions, osteoporosis,
hepatosplenomegaly, cytopenia). Aggressive SM can be associated
with another myeloid malignancy, including MPN, MDS, or
MDS/MPN overlap (e.g., CMML), or present as overt mast cell
leukemia. In general, life expectancy 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
immunophenotyping 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 KIT D816V, in the majority of patients.
Accordingly, mutation screening for KIT D816V is diagnostically
useful. However, the ability to detect KIT D816V depends on assay
sensitivity and mast cell content of the test sample. The 2016 WHO
classification of mastocytosis includes (1) CM, (2) SM, and (3) mast
cell sarcoma (MCS). SM is further classified into (1) indolent SM
(ISM), (2) smoldering SM (SSM), (3) SM with an associated
hematologic neoplasm (SM-AHN), (4) aggressive SM (ASM), and (5)
mast cell leukemia (MCL).
In a recent Mayo Clinic study of 580 patients (median age 55
years; range 18–88 years) with SM, morphologic subcategories were
indolent/smoldering in 291 patients (50%) and advanced in 289
patients (50%), including SM-AHN in 199, ASM in 85, and MCL in 5.
Multivariable analysis of clinical variables identified age >60 years,
advanced SM, thrombocytopenia <150 × 109/L, anemia below sex-
adjusted normal, and increased alkaline phosphatase as
independent risk factors for survival. In addition, ASXL1, RUNX1,
and NRAS mutations were also independently associated with
inferior survival. Combined clinical, cytogenetic, and molecular risk
factor analysis confirmed the independent prognostic contribution of
adverse mutations, advanced SM, thrombocytopenia, increased
alkaline phosphatase, and age >60 years. These data were
subsequently used to develop clinical and hybrid clinical-molecular
risk models. The clinical risk model uses six readily accessible risk
variables including age >60 years, platelet count <150 × 109/L,
anemia, hypoalbuminemia, increased alkaline phosphatase, and
morphologic classification as advanced SM. Accordingly, median
survival times were not reached, 148, 65, 31, 18, and 5 months in
the presence of ≤1, 2, 3, 4, 5, and 6 of these risk factors,
respectively.
Both ISM and ASM patients might experience mast cell mediator
release symptoms, which are usually managed by both H1 and H2
histamine receptor blockers as well as cromolyn sodium. In addition,
patients with propensity to vasodilatory shock should wear a medical
alert bracelet and 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 ISM, and
instead, such patients are managed with use of H1 and H2 blockers,
leukotriene antagonists, sodium cromolyn, phototherapy, topical
steroids, and osteoporosis prevention with diphosphonates including
alendronate and pamidronate. In ASM, either interferon α or
cladribine is considered first-line therapy and benefits the majority of
patients. Cladribine is administered by 2-h infusion (5 mg/m2) daily
for 5 days, repeated monthly for 4–6 cycles; expected overall
response is ∼ 50%, including major response in ∼38%. 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 a reported cumulative symptomatic response rate of
18.7% versus 7.4% for placebo. Treatment responses were more
impressive in another study that used the multikinase inhibitor
midostaurin in patients with the more aggressive forms of SM, with
45% of the patients achieving major response. Most recently, equally
impressive responses were seen with the use of another kinase
inhibitor, avapritinib (specifically targets KIT D816V), in both ISM and
ASM; however, significant drug-related toxicity, including intracranial
bleed, cognitive impairment, and moderate to severe cytopenias, has
been observed.

■ DENDRITIC AND HISTIOCYTIC NEOPLASMS

Dendritic cell (DC) and histiocyte/macrophage neoplasms are
extremely rare. DCs are antigen-presenting cells, whereas
histiocytes/macrophages are antigen-processing. BM myeloid stem
cells (CD34+) give rise to monocyte (CD14+, CD68+, CD11c+,
CD1a–) and DC (CD14–, CD11c+/–, CD1a+/–) precursors.
Monocyte precursors, in turn, give rise to macrophages (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
histiocytosis, and the latter includes Langerhans cell histiocytosis,
Langerhans cell 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
lymphoma, MDS, or germ cell tumors at time of disease
presentation. The three typical disease sites are lymph nodes, skin,
and gastrointestinal system. Patients may or may not have systemic
symptoms including fever and weight loss, and other symptoms
include hepatosplenomegaly, 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 treatment often ineffective. The term
malignant histiocytosis (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 Langerhans cells (LCs) are

specialized DCs that reside in mucocutaneous tissue and, upon
activation, become specialized for antigen presentation to T cells. LC
histiocytosis (LCH; also known as histiocytosis X) represents
neoplastic proliferation of LCs (S100+, 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 unifocal (eosinophilic granuloma) or
multifocal. The former usually affects bones and less frequently
lymph nodes, skin, and lung, whereas the latter is more
disseminated. Unifocal disease often affects older children and
adults, whereas 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 BRAF
V600E gain-of-function mutations, which indicates high-risk disease
and resistance to first-line therapy; however, responses to targeted
therapy with vemurafenib have been reported. Other forms of
treatment for LCH include combination chemotherapy and MEK
inhibitors in BRAF wild-type disease with other MAPK pathway
mutations. Unfortunately, such targeted therapy has not secured
long-lasting, treatment-free remissions.

Langerhans Cell Sarcoma Langerhans cell sarcoma (LCS) also

represents neoplastic proliferation of LCs with overtly malignant
morphology. 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. Prognosis 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
S100 positivity and negativity for vimentin and CD1a. Prognosis
ranges from benign local disease to widespread lethal disease.

Follicular Dendritic Cell Sarcoma FDCs reside in B-cell follicles

and present antigen to B cells. FDC neoplasms (FDCNs) 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
maxillary, mediastinal, and retroperitoneal lymph nodes; oral cavity;
gastrointestinal system; skin; and breasts. 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 Syndrome Hemophagocytic syndrome (HPS),

also known as hemophagocytic lymphohistiocytosis (HLH),
represents nonneoplastic proliferation and activation of
macrophages that induce cytokine-mediated BM suppression and
features of intense phagocytosis in BM and liver. HPS may result
from genetic (primary) or acquired (secondary) disorders of
macrophages. The former entail genetically determined inability to
regulate macrophage proliferation and activation and might include
alterations in familial HLH genes (PRF1, UNC13D, STXBP2, and
STX11), granule/pigment abnormality genes (RAB27A, LYST, and
AP3B1), or X-linked lymphoproliferative disease genes (SH2D1A
and XIAP). Acquired HPS is often precipitated by viral infections,
most notably Epstein-Barr virus. HPS might also accompany certain
malignancies such as T-cell lymphoma and autoimmune diseases.
Clinical presentation includes fever, severe constitutional symptoms,
enlarged lymph nodes, hepatosplenomegaly, neurologic dysfunction,
and abnormalities in multiple organ function tests. Diagnosis is
accomplished by either detection of HLH-related mutations or
meeting five of the following eight conventional criteria: (1)
hemophagocytosis in the BM/spleen/lymph nodes; (2) serum ferritin
≥500 μg/L; (3) hypofibrinogenemia (fibrinogen ≤1.5 g/L) or
hypertriglyceridemia (triglycerides ≥3 mmol/L); (4) low NK cell
activity; (5) elevated soluble IL-2 receptor (CD25) ≥2400 U/mL; (6)
bi- or tricytopenia (platelets <100 × 109/L, hemoglobin <9 g/dL,
absolute neutrophil count <1 × 109/L); (7) splenomegaly palpable >3
cm below left costal margin; and (8) fever. Clinical course is often
fulminant and fatal. Current therapeutic approaches for primary or
secondary HLH include the so-called “HLH-94 protocol,” which
consists of weekly treatments with etoposide and dexamethasone,
stem cell transplantation, emapalumab (a monoclonal antibody that
binds and neutralizes interferon γ), and the JAK1/2 inhibitor
ruxolitinib. Emapalumab was FDA approved in November 2018 for
use in pediatric and adult patients with primary HLH with refractory
or progressive disease.

■ FURTHER READING
ALLEN CE et al: The coming of age of Langerhans cell histiocytosis.
Nat Immunol 21:1, 2020.
DAO KT et al: Efficacy of ruxolitinib in patients with chronic
neutrophilic leukemia and atypical chronic myeloid leukemia. J
Clin Oncol 38:1006, 2020.
MAURER M et al: Results from PIONEER: A randomized, double-
blind, placebo-controlled, phase 2 study of avapritinib in patients
with indolent systemic mastocytosis (ISM). Oncol Res Treat
43:77, 2020.
PATNAIK MM, TEFFERI A: Chronic myelomonocytic leukemia: 2020
update on diagnosis, risk stratification and management. Am J
Hematol 95:97, 2020.
ROUFOSSE F et al: Efficacy and safety of mepolizumab in
hypereosinophilic syndrome: A phase III, randomized, placebo-
controlled trial. J Allergy Clin Immunol 146:1397, 2020.