Page 1071 - Hematology_ Basic Principles and Practice ( PDFDrive )

954 Part VII Hematologic Malignancies

overly simplistic view that ignores the complexity and heterogeneity marrow microenvironment and beyond. Second, it will also be neces-
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of each disease on its own. Although MDS can and often does sary to integrate these biologic storylines with clinical information,
transform into secondary AML, other types of de novo AML are in the hope that a fuller understanding of MDS biology may uncover
biologically quite distinct from MDS, and conversely, some low-risk new treatment approaches and better predictive and prognostic
forms of MDS are biologically distinct from secondary AML. At the models than do single biologic features alone. Such work is already
same time, however, there is a continuum between the two diseases beginning; for instance, a recent report suggested that an algorithm
that is only now starting to become fully understood. Recently, for integrating sequencing for common driver mutations with principal
instance, it has been shown that cases of AML harboring mutations component analysis of gene expression better predicts some clinical
in any of eight genes (SF3B1, SRSF2, U2AF1, ZRSR2, ASXL1, features of MDS than sequencing or expression data considered in
EZH2, BCOR, or STAG2) are highly likely to have evolved out of isolation, and the algorithm outperformed the IPSS in predicting
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MDS, even when no antecedent stage of MDS was clinically overall survival (76% versus 64% accuracy). Thus far, however,
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evident. The converse, that AML with driver mutations in other these types of integrative studies remain in relative infancy. Making
genes must have arisen de novo, is not necessarily true; NPM1 muta- significant gains in this type of deep understanding will be a substan-
tions appear to be restricted to de novo AML, but mutations in tial undertaking, requiring large, well-coordinated clinical trials with
DNMT3A, TET2, and IDH1/2 can occur in both secondary and de rigorous banking of serial blood and marrow samples, careful annota-
novo AML and thus do not appear to be ontogeny-specific. In this tion of clinical features and outcomes, and intensive collaboration
study, TP53-mutated AML comprised its own category and was between academics, industry, and clinicians in devising strategies for
associated with prior chemotherapy and complex karyotypes, consis- rationally targeting key elements of MDS biology.
tent with prior studies.
Understanding this shared genetic basis of MDS and secondary
AML has also shed light on the transition from one to the other. CLINICAL FEATURES OF MYELODYSPLASTIC SYNDROME
Although the eight genes defining secondary ontogeny (i.e., disease
arising from antecedent MDS) have different functions, they all tend Compared to other hematologic disorders, the clinical features of
to have broad, pleiotropic effects and for the most part have in mouse MDS are often underemphasized relative to laboratory aspects of the
models been shown to be insufficient for leukemogenesis when they disease. This is in part because of the fact that the major common
occur in isolation. The fact that they occur infrequently in de novo physiologic defect, ineffective hematopoiesis, usually leads to some-
AML may imply that they have effects strong enough to commit cells what vague signs or symptoms. Nevertheless, it is important to
to an MDS phenotype, with increased self-renewal and inhibitory understand these features within the context of the disease’s pathogen-
effects on differentiation and hematopoiesis, whereas TET2 and esis and management. Some patients with MDS have distinct clinical
DNMT3A mutations may have more subtle effects that increase phenotypes that are largely related to genetics or specific pathologic
self-renewal but do not in and of themselves predispose to a specific features. MDS can also coexist with other hematologic malignancies,
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phenotype in the absence of specific secondary mutations. including multiple myeloma (even in previously untreated patients) ,
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In most cases, progression of MDS to AML involves the acquisi- hairy cell leukemia, chronic lymphocytic leukemia (CLL), non-
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tion of proproliferative mutations, which tend to be late, subclonal Hodgkin lymphoma, and large granular lymphocyte leukemia
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events. These mutations frequently occur in tyrosine kinase genes (LGL). Parsing the components of presentation that could be caused
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like FLT3, NRAS, or KIT, or in certain transcription factor by a coexisting process (e.g., in a patient with both MDS and CLL,
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genes such as CEBPA, and lead to constitutively activated growth which is the primary contributor to the patient’s cytopenias?) is an
and proliferative pathways. As discussed elsewhere, patients who important task for clinicians and pathologists.
develop secondary AML from an antecedent MDS tend to have a
poorer prognosis, with both a lower rate of complete remission and
a poorer overall survival, independent of remission, than patients with Differential Diagnosis
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de novo AML. In unselected populations, some of this difference
in outcome can be explained by proximate characteristics of the In the absence of clonal markers or excess blasts, MDS is a diagnosis
secondary AML cohorts, which tend to be older and have more of exclusion, requiring that other potential contributors to cytopenias
comorbidities, mirroring the demographics of the MDS population. and myelodysplastic morphology be ruled out to the greatest extent
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However, patients with secondary AML have inferior outcomes even possible. Since cytopenias are the most common presenting clinical
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compared to age-matched controls with de novo AML, which has feature, the differential diagnosis is in theory broad and includes
remained the case when redefining ontogeny based on the genetic numerous other entities covered in more detail elsewhere in this
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stratification outlined earlier. This inferior outcome has been pre- book. In practice, however, all patients suspected of having MDS
sumed to reflect the intrinsic refractory nature of the antecedent should undergo a bone marrow aspirate and biopsy, since the diag-
MDS, and this presumption is now being proven true by sequencing nostic criteria are almost entirely pathologic and marrow findings are
bone marrow samples from secondary AML patients who morpho- critical for risk stratification and treatment planning.
logically appear to be in remission—in fact, the proliferative muta- Several nutritional deficiencies can cause cytopenias and morphol-
tions are often eliminated but the preexisting driver mutations ogy similar to MDS. Folate deficiency can cause macrocytosis and,
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remain, suggesting that chemotherapy simply reverted the marrow to in extreme cases, megaloblastic morphology in the marrow. Vitamin
the preexisting clonal state. 58,148 Overcoming the intrinsic resistance B 12 (cobalamin) deficiency is a more classic cause of megaloblastic
to therapy that appears to be common to most patients with MDS changes, and patients with severe B 12 deficiency can have bizarre
remains one of the central challenges of treating the disease. morphology with an abundance of early forms that can occasionally
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be confused with evolving AML, especially erythroleukemia. Since
Integrating the Pathobiology of the hematologic changes of B 12 deficiency can occur in the absence
of classic neurologic symptoms, B 12 and folate levels should be
Myelodysplastic Syndrome checked on all patients in whom a potential diagnosis of MDS is
being entertained, and methylmalonic acid and homocysteine levels
With the continuous, deepening accumulation of data describing the may help clarify whether deficiency is truly present in cases with
pathogenesis underlying MDS, one of the central future challenges borderline levels. 253
will be integrating these data into coherent models that correctly Copper deficiency is less common than B 12 /folate deficiency, but
reflect fundamental aspects of the disease. The need for integration can also be mistaken for MDS. It classically arises in patients who
is twofold. First, there is a need to integrate disparate components of have had gastrectomies or certain forms of gastric bypass surgery,
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the biology itself, including somatic mutations, changes in gene particularly biliopancreatic diversion, and can also develop in
expression, epigenetic disruption, and cell-cell interactions within the patients taking high doses of zinc, which competes with copper for