Page 1061 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 60

MYELODYSPLASTIC SYNDROMES

Christopher J. Gibson, Benjamin L. Ebert, and David P. Steensma

Myelodysplastic syndromes (MDS) are clonal hematopoietic disor- The third major component of MDS, and possibly the most
ders characterized by ineffective hematopoiesis and peripheral blood prominent, is its temporal positioning as a potential preleukemic
cytopenias, abnormal cell morphology on blood and bone marrow state. This was first conceptualized in 1942 as odo-leukemia (“odo”
examination (Fig. 60.1) and a risk of progression to acute myeloid from the Greek for edge or threshold) by a group from France led by
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leukemia (AML). It has a variable clinical course, manifesting in some Paul Chevallier to describe a case of anemia evolving into leukemia,
patients as indolent cytopenias necessitating occasional transfusions which they attributed to benzene exposure. A similar disorder was
and in others as aggressive diseases that rapidly evolve into treatment- termed preleukaemic anemia by a British hematologist, J.L. Hamilton-
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refractory leukemias, with a broad spectrum of severity in between. Paterson, in 1949. This term was adopted and expanded by an
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Despite this phenotypic variability, individual cases of MDS share American group based in Chicago in the early 1950s, providing one
many pathophysiologic mechanisms at the molecular and cellular of the clearest descriptions of a disorder clinically defined by both
levels, and our understanding of these mechanisms has evolved cytopenias and a risk of leukemia. Other groups in the 1950s and
substantially in the last decade. At the same time, although MDS also 1960s published similar descriptions under different terminologies. 9
shares features with AML and other myeloid malignancies, mounting The 1970s saw some of the greatest strides toward our modern
evidence shows that it is appropriately conceived as a distinct class of conceptualization of MDS. In 1970, Dreyfus and colleagues coined
diseases, and that the older conceptualization of MDS as “preleuke- the term refractory anemia with excess blasts (RAEB, described in
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mia” is overly simplistic. French as les anémies réfractaires avec excès de myeloblasts) and later
While understanding of MDS pathophysiology is improving, the attempted to further characterize components of RAEB based on
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condition remains difficult to treat, and outcomes for patients with morphology and clinical characteristics. The term hematopoietic
MDS have unfortunately not improved substantially since the last dysplasia was used in the early 1970s to describe a heterogeneous
edition of this textbook. This chapter describes our current under- group of disorders distinct from AML, and the term was later simpli-
standing of the classification, pathobiology, clinical features, and fied to myelodysplasia.
treatment approaches for this heterogeneous group of disorders. One of the key events in the history of myeloid disease classifica-
tion was the formation of the French-American-British (FAB)
Cooperative Group in 1976, which in that year issued a comprehen-
HISTORY sive and influential categorization of AML based on the 1975
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classification of Galton and Dacie. The FAB classification persisted
Central to an understanding of how MDS is diagnosed and classified as the dominant descriptive system for AML until the early 2000s.
is the concept of morphologic dysplasia, a pathologic term that was The original FAB AML formulation from 1976 included two types
originally introduced as a shortening of the phrase dysmorphology of of “dysmyelopoietic syndromes” that should not be confused with
neoplasia. Although specific criteria for diagnosis of MDS as a distinct AML: RAEB and chronic myelomonocytic leukemia (CMML),
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clinical syndrome exist and are discussed subsequently, the term which had first been described in the late 1960s. However, it was
myelodysplasia refers more generally to an abnormal appearance of not long before MDS was recognized as a separate group of diseases
hematopoietic precursors during pathologic examination of bone and accorded a distinct classification system, described in more detail
marrow, which may result from many different causes (e.g., drug later.
toxicity, nutritional deficiency, viral infection). The process by which
our understanding of MDS has evolved from that of a morphologic
oddity to that of a distinct disease process has been a century in the CLASSIFICATION
making, propelled forward at several points by paradigmatic shifts in
pathologic and molecular characterization of hematologic diseases. 1 The currently accepted classification scheme for MDS was initially
In describing the history of MDS as a distinctly categorized disease published by the World Health Organization (WHO) in 2001 and
entity, it is perhaps most useful to separately describe the history of most recently revised in 2008 (Table 60.1), with a third revision
its major conceptual components. The earliest recognized of these, not planned for 2016. Like the classifications of the FAB group, the
surprisingly, was that of dysplasia itself. Although studies of peripheral WHO classification is principally a morphologic system and classifies
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blood in anemic patients were reported in the 19th century, the first disease chiefly based on the number of dysplastic lineages and the
real characterization of actual dysplasia was probably made by Giovanni percentage of marrow blasts, though it also includes one specific
di Guglielmo in Pavia in 1923, when he described abnormal erythroid cytogenetically defined subtype, MDS with isolated del(5q). The
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forms in the marrows of patients with various types of cytopenias. A other WHO 2008 subtypes include refractory cytopenia with unilin-
second major concept, that of ineffective hematopoiesis, was developed eage dysplasia (RCUD), which is most commonly refractory anemia
in the 1930s with the description of refractory anemia in patients (RA); refractory cytopenia with multilineage dysplasia (RCMD);
unresponsive to iron pills or liver extract (the precursor to vitamin B 12 refractory anemia with ringed sideroblasts (RARS); RAEB (subdi-
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supplementation); in the 1950s, others expanded this to include vided into RAEB-1, 5%–9% blasts, and RAEB-2, 10%–19% blasts);
similarly refractory leukopenia and thrombocytopenia and termed the and unclassifiable MDS (MDS-U) for those cases that do not clearly
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collective disorder “refractory cytopenias.” Importantly, however, fall into any other category. In addition, the WHO system classifies
ineffective hematopoiesis and marrow dysplasia were initially incom- cases with myeloproliferative features separately; this group includes
pletely linked, and the ineffective hematopoiesis of many early refrac- CMML and RARS with thrombocytosis (RARS-T).
tory anemia patients was probably rooted in other disorders, such as The WHO classification was intended to replace the prior FAB
anemia of inflammation caused by advanced rheumatologic disease or classification system, which was initially proposed in 1982 as an
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nonmyeloid neoplasia. MDS correlate to the FAB system for classifying AML. The 1982
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