clinical outcomes will be increasingly 799

important in defining classification,

prognosis, and targeting therapy.
The diagnosis of MDS can be a
challenge, even for the expert, because
sometimes subtle clinical and pathologic
features must be distinguished, and pre-
cise diagnostic categorization requires
a hematopathologist knowledgeable in
the latest classification scheme. Unfortu-
nately, agreement among pathologists on
morphologic features and classification
is imperfect; changes in the appearance
of megakaryocytes are more reliable than
loss of granules in neutrophil precursors
A B or dyserythropoiesis. Further, dysplastic
changes can be observed in normal indi-
viduals, and they can occur with vitamin
deficiencies and as drug effects. Genomic
testing is increasingly routine and can
be difficult to interpret, as in differences
between somatic and germline muta-

C D
FIGURE 102-2 Pathognomonic cells in marrow failure syndromes. A. Giant pronormoblast, the cytopathic effect of
B19 parvovirus infection of the erythroid progenitor cell. B. Uninuclear megakaryocyte and microblastic erythroid
precursors typical of the 5q– myelodysplasia syndrome. C. Ringed sideroblast showing perinuclear iron granules.
D. Tumor cells present on a touch preparation made from the marrow biopsy of a patient with metastatic carcinoma.
MYELODYSPLASTIC SYNDROMES
■ DEFINITION
The MDS are a heterogeneous group of hematologic disorders char-
acterized by both (1) cytopenias due to bone marrow failure and (2)
a high risk of development of AML. Anemia due to ineffective ery-
thropoiesis, often with thrombocytopenia and neutropenia, occurs
with dysmorphic (abnormal appearing) and usually cellular bone
marrow, or with specific chromosome abnormalities or acquired
mutations. In patients with “low-risk” MDS, marrow failure domi-
nates the clinical course. In other patients, myeloblasts are present
at diagnosis, chromosomes are abnormal, and the “high risk” is due
to leukemic progression. MDS may be fatal due, most often, to com-
plications of pancytopenia or to progression to leukemia, but a large
proportion of patients will die of concurrent disease, the comorbidities
typical in an elderly population. A useful nosology of these often-
confusing entities was first developed by the French-American-British
Cooperative Group in 1983. Five subtypes were defined then: refrac-
tory anemia (RA), refractory anemia with ringed sideroblasts (RARS),
refractory anemia with excess blasts (RAEB), refractory anemia with
excess blasts in transformation (RAEB-t), and chronic myelomono-
cytic leukemia (CMML). The World Health Organization (WHO) clas-
sification (2002) recognized that the distinction between RAEB-t and
AML was arbitrary, grouped them together as acute leukemia, and clar-
ified that CMML behaves as a myeloproliferative disease. The current
WHO classification of 2016 is more refined but also more complicated
(Table 102-5): blast percentage remains critical in defining MDS cat-
egories; erythroid predominant leukemias are now largely regarded as
MDS; defining cytogenetic abnormalities are reaffirmed; and a single
somatic mutation, in SF3B1, is now a feature of sideroblastic anemias.
Identification of somatically mutated genes and their correlation with
CHAPTER 102 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia
tions, pathogenic mutations versus those
of unknown significance (clonal hemato-
poiesis increases in frequency with age
and involves genetic changes that may be
clinically silent or convey an increased
risk of hematologic malignancy), and
clone size and changes over time. It is
important that the internist and primary
care physician be sufficiently familiar
with MDS to expedite referral to a hema-
tologist because many new therapies are
now available to improve hematopoietic
function and the judicious use of sup-
portive care can improve the patient’s
quality of life.
■ EPIDEMIOLOGY
MDS is a disease of the elderly; the mean age at onset is older than
70 years. There is a slight male predominance. MDS is a relatively
common form of bone marrow failure, with reported incidence rates
of 35 to >100 per million persons in the general population and 120 to
>500 per million in older adults. Estimates of incidence in the United
States range from 30,000 to 40,000 new cases annually and a prevalence
of 60,000–120,000 in the population. Rates of MDS have increased over
time due to better recognition of the syndrome by physicians and an
aging population.
MDS is rare in children, in whom it often has a constitutional
genetic basis that can be identified on genomic screens of myeloid
cancer predisposition panels.
Secondary or therapy-related MDS, usually related to previous iatro-
genic exposure to alkylating agents and other chemotherapy as well as
radiation, is not age related.
■ ETIOLOGY AND PATHOPHYSIOLOGY
MDS is associated with environmental exposures such as radiation and
benzene; other risk factors have been reported inconsistently. Second-
ary, therapy-related MDS occurs as a late toxicity of cancer treatment;
radiation and the radiomimetic alkylating agents such as busulfan,
nitrosourea, or procarbazine (with a latent period of 5–7 years); or the
DNA topoisomerase inhibitors (2-year latency). Acquired aplastic ane-
mia, Fanconi anemia, and other constitutional marrow failure diseases
can evolve into MDS; occasionally, MDS in adults is recognized as due
to germline GATA2, RUNX1, or telomere gene mutations. The typical
MDS patient does not have a suggestive environmental exposure his-
tory or a preceding hematologic disease. MDS is a disease of aging,
consistent with accumulation of mutations within a hematopoietic
stem cell in an aging marrow environment.
 800
TABLE 102-5 World Health Organization (WHO) Classification of Myelodysplastic Syndromes (MDS)/Neoplasms
NAME RING SIDEROBLASTS
MDS with single lineage dysplasia (MDS-SLD) <15% (<5%)a
MDS with multilineage dysplasia (MDS-MLD) <15% (<5%)a
MDS with ring sideroblasts (MDS-RS)
MDS-RS with single lineage dysplasia (MDS-RS-SLD) ≥15% / ≥5%a
MDS-RS with multilineage dysplasia (MDS-RS-MLD) ≥15% / ≥5%a
MDS with isolated del(5q) None or any
MDS with excess blasts (MDS-EB)
MDS-EB-1 None or any
MDS-EB-2 None or any
MDS, unclassifiable (MDS-U)
• with 1% blood blasts None or any
• with single lineage dysplasia and pancytopenia None or any
• based on defining cytogenetic abnormality <15%
Refractory cytopenia of childhood None
PART 4
If SF3B1 mutation is present.
a
Abbreviations: BM, bone marrow; PB, peripheral blood.
MDS is a clonal hematopoietic stem cell disorder characterized by
Oncology and Hematology
disordered cell proliferation, impaired differentiation, and aberrant
hematopoiesis, resulting in cytopenias and risk of progression to leuke-
mia. Both chromosomal and genetic instability have been implicated;
both are aging-related. Cytogenetic abnormalities are found in approx-
imately one-half of patients, and some of the same specific lesions are
also seen in leukemia; aneuploidy (chromosome loss or gain) is more
frequent than translocations. Accelerated telomere attrition may desta-
bilize the genome in marrow failure and predispose to acquisition of
chromosomal lesions. Cytogenetic abnormalities are not random (loss
of all or part of 5, 7, and 20, trisomy of 8) and may be related to etiology
(11q23 following topoisomerase II inhibitors). The type and number
of cytogenetic abnormalities strongly correlate with the probability of
leukemic transformation and survival.
Genomics has illuminated the role of specific mutations and distinct
molecular pathways in the pathophysiology of MDS. Somatic muta-
tions in about 100 genes, which are recurrently present in myeloid neo-
plasms and are acquired in about 100 genes, are arise in the abnormal
marrow cells (and are absent in the germline). Many of the same genes
are mutated in AML and in MDS, whereas others are distinctive in
subtypes of MDS. A prominent example is SF3B1, in which mutations
strongly associate with sideroblastic anemia. Some mutations correlate
with prognosis: spliceosome defects (like SF3B1) correlate with favor-
able outcome, and mutations in EZH2, TP53, RUNX1, and ASXL1 with
poor outcome. Correlation and exclusion in the pattern of mutations
indicate a functional genomic architecture. Driver genes mutated early
are consistent with normal blood counts and marrow morphology,
but these expanded clones of cells containing them are susceptible to
malignant transformation with the acquisition of additional mutations.
Deep sequencing results in patients whose MDS evolved to AML have
shown clonal succession, with founder clones acquiring additional
mutations to produce clonal dominance. Mutations and cytogenetic
abnormalities are not independent: TP53 mutations associate with
complex cytogenetic abnormalities and TET2 mutations with normal
cytogenetics. The prevalence of abnormal cells by morphology under-
estimates bone marrow involvement by MDS clones, as cells normal
in appearance are derived from the abnormal clones. Presenting and
evolving hematologic manifestations result from the accumulation of
multiple genetic lesions: loss of tumor-suppressor genes, activating
oncogene, epigenetic pathways that affect mRNA processing and meth-
ylation status, or other harmful alterations. Pathophysiology has been
linked to mutations and chromosome abnormalities in some specific
MYELOBLASTS KARYOTYPE
BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS
with isolated del(5q)
BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS
with isolated del(5q)
BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS
with isolated del(5q)
BM <5%, PB <1%, no Auer rods Any, unless fulfills all criteria for MDS
with isolated del(5q)
BM <5%, PB <1%, no Auer rods del(5q) alone or with 1 additional
abnormality except −7 or del(7q)
BM 5–9% or PB 2–4%, no Auer rods Any
BM 10–19% or PB 5–19% or Auer rods Any
BM <5%, PB = 1%, no Auer rods Any
BM <5%, PB = 1%, no Auer rods Any
BM <5%, PB = 1%, no Auer rods MDS-defining abnormality
BM <5%, PB <2% Any
MDS syndromes. The 5q– deletion leads to heterozygous loss of a
ribosomal protein gene which mimics constitutional red cell aplasia.
An immune pathophysiology may be important in lower risk MDS,
as cytopenias can respond to immunosuppressive therapy as adminis-
tered for aplastic anemia. In general for MDS, the role of the immune
system and its cells and cytokines; the role of the hematopoietic stem
cell niche, the microenvironment, and cell–cell interactions; the fate of
normal cells in the Darwinian competitive environment of the dysplas-
tic marrow; and how mutant cells produce marrow failure in MDS are
still not completely understood.
■ CLINICAL FEATURES
Anemia dominates the early course. Most symptomatic patients com-
plain of the gradual onset of fatigue and weakness, dyspnea, and pallor,
but at least one-half of patients are asymptomatic, and their MDS is
discovered only incidentally on routine blood counts. Previous che-
motherapy or radiation exposure is an important historic fact. Fever
and weight loss are more often features of a myeloproliferative rather
than myelodysplastic process. MDS in childhood is rare and, when
diagnosed, implicates an underlying genetic disease. Children with
Down syndrome are susceptible to MDS as well as leukemia. A family
history may indicate a hereditary form of sideroblastic anemia, Fanconi
anemia, or a telomeropathy. Inherited GATA2 mutations, as in the
MonoMAC syndrome (with increased susceptibility to viral, mycobac-
terial, and fungal infections, as well as deficient numbers of monocytes,
natural killer cells, and B lymphocytes), predispose to MDS. Germline
RUNX1 mutations also confer a high risk of MDS and leukemia, often
preceded by years of modest thrombocytopenia. A family history is
important in all MDS patients, as constitutional mutations may not
result in manifest disease until adulthood.
The physical examination in MDS is remarkable for signs of anemia;
approximately 20% of patients have splenomegaly. Some unusual skin
lesions, including Sweet’s syndrome (febrile neutrophilic dermatosis),
occur with MDS. Accompanying autoimmune syndromes are not
infrequent. In the younger patient, stereotypical anomalies point to a
constitutional syndrome (short stature, abnormal thumbs in Fanconi
anemia; early graying in the telomeropathies; cutaneous warts in
GATA2 deficiency).
■ LABORATORY STUDIES
Blood Anemia is present in most cases, either alone or as part of
bi- or pancytopenia; isolated neutropenia or thrombocytopenia is
more unusual. Macrocytosis is common, as in most marrow failure
disease. Platelets also are large and lack granules. In functional studies,
they may show marked abnormalities, and patients may have bleeding
symptoms despite seemingly adequate numbers. Neutrophils are hypo-
granulated; have hyposegmented, ringed, or abnormally segmented
nuclei; contain Döhle bodies; and may be functionally deficient.
Circulating myeloblasts usually correlate with marrow blast numbers,
and their quantity is important for classification and prognosis. The
total white blood cell count (WBC) is usually normal or low, except
in CMML. As in aplastic anemia, MDS can be associated with a clonal
population of PNH cells. Genetic testing is commercially available for
constitutional syndromes.
Bone Marrow The bone marrow is usually normal or hypercellu-
lar, but in about 20% of cases, it is sufficiently hypocellular to lead to
confusion with aplastic anemia. No single characteristic feature of mar-
row morphology distinguishes MDS, but the following are commonly
observed: dyserythropoietic changes (especially nuclear abnormalities)
and ringed sideroblasts in the erythroid lineage; hypogranulation and
hyposegmentation in granulocytic precursors, with an increase in mye-
loblasts; and megakaryocytes showing reduced numbers of or disorga-
nized nuclei. Megaloblastic nuclei and defective hemoglobinization in
the erythroid lineage are common. Prognosis strongly correlates with
the proportion of marrow blasts, which should be enumerated manu-
ally on the marrow smear and by flow cytometry of an aspirate. Flow
cytometry can also reveal characteristically aberrant hematopoietic
differentiation. Cytogenetics and fluorescent in situ hybridization can
identify chromosomal abnormalities.
■ DIFFERENTIAL DIAGNOSIS
Deficiencies of vitamin B12 or folate should be excluded by appropriate
blood tests; vitamin B6 deficiency can be assessed by a therapeutic
trial of pyridoxine if the bone marrow shows ringed sideroblasts.
Copper deficiency can lead to cytopenias and dysplastic marrows of
varying cellularity. Marrow dysplasia can be observed in acute viral
infections, drug reactions, or chemical toxicity but should be tran-
sient. More difficult are the distinctions between hypocellular MDS
and aplasia or between RA with excess blasts and acute leukemia: the
WHO considers 20% blasts in the marrow as the criterion that sep-
arates AML from MDS. In young patients, underlying, predisposing
genetic diseases should be considered and appropriate genomic testing
performed (see above).
■ PROGNOSIS
The median survival varies greatly from years for patients with 5q– or
sideroblastic anemia to a few months in RA with excess blasts or severe
pancytopenia associated with monosomy 7. The International Prog-
nostic Scoring System (IPSS), revised in 2012 (Table 102-6), assists in
making predictions. Even “lower-risk” MDS has significant morbidity
and mortality. More refined (and also more complicated) prognostic
TABLE 102-6 Revised International Prognostic Scoring System
(IPSS-R)
1. New marrow blast categories
≤2%, >2%–<5%, 5–10%, >10–30%
2. Refined cytogenetic abnormalities and risk groups
16 (vs 6) specific abnormalities, 5 (vs 3) subgroupsa
3. Evaluation of depth of cytopeniasb
Clinically and statistically relevant cut points used
4. Inclusion of differentiating features
Age, performance status, serum ferritin, LDH; β2-microglobulin
5. Prognostic model with 5 (vs 4) risk categories
Improved predictive power
a
Good, normal, –Y, del(5q), del (20q); poor, complex (≥3 abnormalities) or
chromosome 7 abnormalities; intermediate, all other abnormalities. bCytopenias
at baseline, cut points: hemoglobin <80, 80–<100, or ≥100 g/L; platelet count <50,
50–100, or ≥100,000/μL, and absolute neutrophil count <800 versus ≥800/μL.
Abbreviation: LDH, lactate dehydrogenase.
scoring systems can separate those with intermediate-1 risk who have 801
relatively poor prognoses. Prognostic systems have been developed
based on survival from diagnosis, but prognosis changes over time,
and hazard ratios for survival and leukemic transformation converge
over time among risk categories, consistent with dynamic changes in
clonal architecture.
Most patients die as a result of complications of pancytopenia and
not due to leukemic transformation; perhaps one-third succumb to dis-
eases unrelated to their MDS. Precipitous worsening of pancytopenia,
acquisition of new chromosomal abnormalities on serial cytogenetic
determination, increase in the number of blasts, and marrow fibrosis
are all poor prognostic indicators. The outlook in therapy-related
MDS, regardless of type, is extremely poor, and most patients progress
within a few months to refractory AML.
TREATMENT
Myelodysplasia
Historically, therapy of MDS has been unsatisfactory, but several
drugs may not only improve blood counts but also delay onset of
leukemia and improve survival. The choice of therapy for an indi-
CHAPTER 102 Bone Marrow Failure Syndromes Including Aplastic Anemia and Myelodysplasia
vidual patient, administration of treatment, and management of
toxicities are complicated and require hematologic expertise.
Only hematopoietic stem cell transplantation offers cure of
MDS. The survival rate in selected patient cohorts is ~50% at
3 years but improving. Results using unrelated matched donors
are similar to those with siblings, and patients in their fifties and
older have been successfully transplanted. Nevertheless, treatment-
related mortality and morbidity increase with recipient age. The
transplant conundrum is that the high-risk patient (by IPSS score
and presence of monosomal karyotype), for whom the procedure is
most obviously indicated, has a high probability of a poor outcome
from transplant-related mortality or disease relapse, whereas the
low-risk patient, who is more likely to tolerate transplant, also may
do well for years with less aggressive therapies. In practice, only a
small proportion of MDS patients undergo transplantation.
MDS has been regarded as particularly refractory to cytotoxic
chemotherapy regimens, and as in AML in the older adult, drug
toxicity is frequent and often fatal, and remissions, if achieved, are
brief. Low doses of cytotoxic drugs have been administered for their
“differentiation” potential, and from this experience, drug thera-
pies have emerged based on pyrimidine analogues. These drugs
are classified as epigenetic modulators, believed to act through
a demethylating mechanism to alter gene regulation and allow
differentiation to mature blood cells from the abnormal MDS
stem cell. The hypomethylating agents azacitidine and decitabine
are frequently used in bone marrow failure clinics. Azacitidine
improves blood counts and survival in MDS, compared to best sup-
portive care. Azacitidine is usually administered subcutaneously,
daily for 7 days, at 4-week intervals, for at least four cycles before
assessing for response. Overall, generally improved blood counts
with a decrease in transfusion requirements occurred in ~50% of
patients in published trials. Response is dependent on continued
drug administration, and most patients eventually become refrac-
tory to drug intervention and experience recurrent cytopenias or
progression to AML. Decitabine is closely related to azacitidine;
30–50% of patients show responses in blood counts, with a duration
of response of almost a year. Decitabine is usually administered by
continuous intravenous infusion in regimens of varying doses and
durations of 3–10 days in repeating cycles. The major toxicity of
azacitidine and decitabine is myelosuppression, leading to worsen-
ing blood counts. Hypomethylating agents are frequently used in
the high-risk patient who is not a candidate for stem cell transplant.
In the lower risk patient, they are also effective, but alternative ther-
apies should be considered.
Lenalidomide, a thalidomide derivative with a more favorable
toxicity profile, is particularly effective in reversing anemia in MDS
patients with 5q– syndrome; not only do a high proportion of these
 802 patients become transfusion independent with normal or near-
normal hemoglobin levels, but their cytogenetics also become nor-
mal. The drug has many biologic activities, and it is unclear which
is critical for clinical efficacy. Lenalidomide is administered orally.
Most patients will improve within 3 months of initiating therapy.
Toxicities include myelosuppression (worsening thrombocytopenia
and neutropenia, necessitating blood count monitoring) and an
increased risk of deep vein thrombosis and pulmonary embolism.
Immunosuppression also may produce sustained independence
from transfusion and improve survival. ATG, cyclosporine, and
the anti-CD52 monoclonal antibody alemtuzumab are especially
effective in younger MDS patients (<60 years old) with more
favorable IPSS. In a consortium retrospective review, about 50% of
patients with mainly refractory anemia responded to ATG, usually
combined with cyclosporine, particularly patients with hypocellular
marrow.
HGFs can improve blood counts but, as in most other marrow
failure states, have been most beneficial to patients with the least
severe pancytopenia. EPO alone or in combination with G-CSF
can improve hemoglobin levels, particularly in those with low
serum EPO levels who have no or a modest need for transfusions.
Survival may be enhanced by EPO and amelioration of anemia.
G-CSF treatment alone failed to improve survival in a controlled
trial. Thrombopoietin mimetics appear to improve platelet counts
PART 4
in some MDS patients, with no clear evidence that they increase the
rate of leukemic transformation.
New drugs for MDS are entering the clinic or are in late devel-
opment. Luspatercept, which affects transforming growth factor β–
Oncology and Hematology
mediated suppression of erythropoiesis, has been approved by the
FDA for anemia in MDS. Novel targeted therapies in trials include
inhibitors of hypoxia-inducible factor and spliceosome genes, drugs
that act to restore TP53 activity, and venetoclax, an inhibitor of the
bcl2 protein that increases programmed cell death (and is approved
for use or employed off-label in other hematologic malignancies).
The same principles of supportive care described for aplastic
anemia apply to MDS. Many patients will be anemic for years. RBC
transfusion support should be accompanied by iron chelation to
prevent secondary hemochromatosis.
MYELOPHTHISIC ANEMIAS
Fibrosis of the bone marrow (see Fig. 100-2), usually accompanied by
a characteristic blood smear picture called leukoerythroblastosis, can
occur as a primary hematologic disease, called myelofibrosis or myeloid
metaplasia (Chap. 103), and as a secondary process, called myeloph-
thisis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis
can be a response to invading tumor cells, usually an epithelial cancer
of breast, lung, or prostate origin or neuroblastoma. Marrow fibrosis
may occur with infection of mycobacteria (both Mycobacterium tuber-
culosis and Mycobacterium avium), fungi, or HIV and in sarcoidosis.
Intracellular lipid deposition in Gaucher disease and obliteration of the
marrow space related to absence of osteoclast remodeling in congenital
osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a
late consequence of radiation therapy or treatment with radiomimetic
drugs. Usually the infectious or malignant underlying processes are
obvious. Marrow fibrosis can also be a feature of a variety of hemato-
logic syndromes, especially chronic myeloid leukemia, multiple mye-
loma, lymphomas, myeloma, and hairy cell leukemia.
The pathophysiology has three distinct features: proliferation of
fibroblasts in the marrow space (myelofibrosis); the extension of
hematopoiesis into the long bones and into extramedullary sites,
usually the spleen, liver, and lymph nodes (myeloid metaplasia); and
ineffective erythropoiesis. The etiology of the fibrosis is unknown
but most likely involves dysregulated production of growth factors:
platelet-derived growth factor and transforming growth factor β have
been implicated. Abnormal regulation of other hematopoietins would
lead to localization of blood-producing cells in nonhematopoietic
tissues and uncoupling of the usually balanced processes of stem
cell proliferation and differentiation. Myelofibrosis is remarkable for
pancytopenia despite very large numbers of circulating hematopoietic
progenitor cells.
Anemia is dominant in secondary myelofibrosis, usually normocytic
and normochromic. The diagnosis is suggested by the characteristic
leukoerythroblastic smear (see Fig. 100-1). Erythrocyte morphology
is highly abnormal, with circulating nucleated RBCs, teardrops, and
shape distortions. WBC numbers are often elevated, sometimes mim-
icking a leukemoid reaction, with circulating myelocytes, promyelo-
cytes, and myeloblasts. Platelets may be abundant and are often of giant
size. Inability to aspirate the bone marrow, the characteristic “dry tap,”
can allow a presumptive diagnosis in the appropriate setting before the
biopsy is decalcified.
The course of secondary myelofibrosis is determined by its etiology,
usually a metastatic tumor or an advanced hematologic malignancy.
Treatable causes must be excluded, especially tuberculosis and fungus.
Transfusion support can relieve symptoms.
■ FURTHER READING
Arber DA et al: The 2016 revision to the World Health Organization
(WHO) classification of myeloid neoplasms and acute leukemia.
Blood 127:2391, 2016.
Attalah E et al: Comparison of patient age groups in transplantation
for myelodysplastic syndrome: The Medicare coverage with evidence
development study. JAMA Oncol 6:486, 2020.
DeZern AE et al: Haplotidentical BMT for severe aplastic anemia with
intensive GVHD prophylaxis including posttransplant cyclophosfa-
mide. Blood Adv 4: 1770, 2020.
Greenberg PL et al: Revised international prognostic scoring system
for myelodysplastic syndromes. Blood 120:2454, 2012.
Mustjoki S, Young NS: Somatic mutations in “benign” disease. N
Engl J Med 384:2039, 2021.
Ogawa S: Genetics of MDS. Blood 133:1049, 2019.
Platzbecker U: Treatment of MDS. Blood 133:1096, 2019.
Sallman DA, List AF: The central role of inflammatory signaling
in the pathogenesis of myelodysplastic syndromes. Blood 133:1039,
2019.
Townsley DM et al: Eltrombopag added to standard immunosuppres-
sion for aplastic anemia. N Engl J Med 376:1540, 2017.
Yoshizato T et al: Somatic mutations and clonal hematopoiesis in
aplastic anemia. N Engl J Med 373:35, 2015.
Young NS: Aplastic anemia. N Engl J Med 379:1643, 2018.
103 Polycythemia Vera and
Other Myeloproliferative
Neoplasms
Jerry L. Spivak
The World Health Organization (WHO) classification of the chronic
myeloproliferative neoplasms (MPNs) includes eight disorders, some
of which are rare or poorly characterized (Table 103-1) but all of which
share an origin in a hematopoietic cell; overproduction of one or more
of the formed elements of the blood without significant dysplasia; and
a predilection to extramedullary hematopoiesis, myelofibrosis, and
transformation at varying rates to acute leukemia. Within this broad
classification, however, significant phenotypic heterogeneity exists.
Some diseases such as chronic myelogenous leukemia (CML), chronic
neutrophilic leukemia (CNL), and chronic eosinophilic leukemia
(CEL) express primarily a myeloid phenotype, whereas in other dis-
eases, such as polycythemia vera (PV), primary myelofibrosis (PMF),
and essential thrombocytosis (ET), erythroid or megakaryocytic