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CHAPTER 87 basophilic stippling are features of the abnormal red cells. The marrow usually

MYELODYSPLASTIC contains increased erythroid precursors with dysmorphic features, including
nuclear distortions and scanty, poorly hemoglobinized cytoplasm or macroery-
SYNDROMES throblasts. Pathologic ring sideroblasts are a common feature used to define
particular subtypes of MDS. Neutrophils may have bilobed or hypersegmented
nuclei and hypogranulated cytoplasm in association with increased marrow
granulocyte precursors. Giant and microcytic platelets, sometimes with abnor-
Rafael Bejar and David P. Steensma* mal or absent granulation, in the blood are associated with megakaryocytic
hyperplasia and atypical lobulation of the nucleus, megakaryocyte cluster-
ing, and decreased marrow megakaryocyte size. Clonal cytogenetic abnor-
malities occur in approximately 50 percent of patients, typically as recurrent
SUMMARY deletions of entire chromosomes or chromosomal segments. Trisomy 8 is the
only frequent copy number gain and recurrent translocations are rare. Various
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal prognostic models for MDS incorporate cytogenetic abnormalities along with
hematopoietic neoplasms defined by morphologic dysmorphia, one or more marrow blast proportion and blood cytopenias to predict the mortality and
blood cytopenias, and an increased risk of clonal evolution to acute myel- risk of clonal evolution to AML. The selection and timing of therapy for MDS
ogenous leukemia (AML). These disorders can occur at any age but have an is largely driven by risk stratification. Newer prognostic scoring systems have
incidence that rises exponentially after age 40 years with a median age at begun to consider somatic mutations as markers of disease-associated risk
diagnosis of 72 years. Most cases are acquired de novo through the accumu- as pathogenic driver mutations can be identified in almost all cases of MDS
lation of somatic mutations, although a small fraction arises after exposure and several lesions have a prognostic significance that is independent of other
to DNA damaging agents, such as chemotherapy and radiation. A minority of known risk factors. As detectable somatic events, driver mutations are markers
cases are the result of inherited mutations that predispose to the development of clonal hematopoiesis and could help establish the diagnosis in some cases.
of MDS and related myeloid disorders. Subtypes of MDS are largely defined Recurrent somatic mutations identify the heterogenous molecular pathways
by clinical features and range from refractory cytopenias (typically including frequently disordered in MDS. These include mutations in multiple components
anemia) to oligoblastic myelogenous leukemia with an increase in marrow of the RNA splicing machinery, several epigenetic regulators of DNA methyla-
myeloblasts (5 to 19 percent). Cases with 20 percent or more myeloblasts in the tion and histone modifications, various hematopoietic transcription factors,
marrow (an arbitrary boundary) or specific chromosomal translocations are and growth factor signaling pathway members among others. Certain muta-
defined as AML. The diagnostic criteria for MDS include dysmorphogenesis in tions are tightly associated with clinical features including ring sideroblasts,
one or more blood cell lineages, often resulting in exaggerated apoptosis dur- chromosomal instability, and severe cytopenias. Current treatment guidelines
ing later stages of maturation. Poikilocytosis, anisocytosis, anisochromia, and for MDS are based on clinical risk assessments and generally do not consider
genetic abnormalities. The exception are cases with del(5q) and noncomplex
karyotypes that have a high rate of deep and sustained responses to the immu-
nomodulator drug lenalidomide. Many patients with lower-risk MDS may not
Acronyms and Abbreviations: AHSCT, allogeneic hematopoietic stem cell transplan- require treatment. Others may benefit from hematopoietic growth factor sup-
tation; ALIP, abnormal localized immature precursor; ALL, acute lymphocytic leukemia; port or immune suppression with antithymocyte globulin and a calcineurin
AML, acute myelogenous leukemia; ATG, antithymocyte globulin; ATRA, all-trans-
retinoic acid; aUPD, acquired uniparental disomy; CALGB, Cancer and Leukemia Group inhibitor, depending on specific clinical features. Higher-risk MDS is typically
B; CDR, commonly deleted region; CLL, chronic lymphocytic leukemia; CMML, treated with one of the hypomethylating agents, azacitidine or decitabine,
chronic myelomonocytic leukemia; ESA, erythropoiesis-stimulating agent; FAB, and eligible patients are evaluated for hematopoietic allogeneic hematopoi-
French-American-British; FPD, familial platelet disorder; G-CSF, granulocyte colony- etic stem cell transplantation, the only potentially curative treatment for MDS.
stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; Despite these treatment options, outcomes for persons with MDS remain poor
HLA, human leukocyte antigens; IDH, isocitrate dehydrogenase; IL, interleukin; IPSS, overall. Novel therapies targeting recently identified molecular pathways have
International Prognosis Scoring System; IPSS-R, International Prognosis Scoring been developed and are being pursued in clinical trials.
System Revised; LGL, large granular lymphocyte; MAP, mitogen-activated protein;
M-CSF, monocyte colony-stimulating factor; MDS, myelodysplastic syndrome; MDS/
MPN, myelodysplastic syndrome/myeloproliferative neoplasm; miRNA, microRNA;
NCI, National Cancer Institute; NK, natural killer; PLK, polo-like kinase; PRC,
protein-repressive complex; RA, refractory anemia; RAEB, refractory anemia with DEFINITION
excess blasts; RAEB-t, refractory anemia with excess blasts in transformation; RARS,
refractory anemia with ring sideroblasts; RARS-t, refractory anemia with ring side- Myelodysplastic syndromes (MDS) represent a collection of hemapoietic
roblasts and thrombocytosis; RBC, red blood cell; SEER, Surveillance, Epidemiology neoplasms characterized by abnormal differentiation, dysmorphology,
and End Results; snRNP, small nuclear riboprotein complex; TET, ten-eleven translo- and resultant blood cytopenias. The hallmarks of these clonal disor-
cation; TGF, transforming growth factor; TNF, tumor necrosis factor; WT, Wilms tumor; ders include exaggerated apoptosis of hematopoietic precursors in the
WHO, World Health Organization. marrow, common chromosomal abnormalities, frequent somatic gene
mutations, and a variable predilection to undergo clonal evolution to
acute myelogenous leukemia (AML). The clinical course of patients
* We acknowledge Drs. Marshall Lichtman and Jane Liesveld who wrote this with MDS is variable and ranges from relatively indolent clonal cytope-
chapter in previous editions of this text. We have retained sections of their nias (e.g., refractory anemia) with a low rate of AML transformation, to
previous chapter. more aggressive disease defined by an increased proportion of marrow

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