Page 1078 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 961

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prognosis compared to patients with mutations in PIGA and BCOR. As discussed elsewhere in this chapter, the mechanism of patho-
It is therefore possible that these studies are defining distinct disease genesis for t-MDS has long been thought to involve the acquisition
processes within a homogeneous-appearing morphology, with ASXL1 of severe, large-scale chromosomal damage, a theory that is circum-
and DNMT3A mutations defining disease more similar to MDS, and stantially supported by the mechanism of alkylators (which induce
BCOR and PIGA mutations defining disease more akin to true, double-stranded DNA breaks) and the fact that many patients with
immune-mediated aplasia. At the same time, finding somatic muta- t-MDS have complex karyotypes. On the other hand, it has previ-
tions characteristic of the alternative diagnoses (for instance, members ously been observed that some patients with t-MDS have point
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of the telomerase family in aplastic anemia, or STAT3 mutations in mutations in TP53, which would not be expected to directly arise
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LGL ) may clarify the picture as well. from alkylator-induced damage, but which can lead to the acquisi-
tion of chromosomal rearrangements even in the absence of chemo-
Myelodysplastic Syndrome/Myeloproliferative therapy. Recent deep studies of a small group of patients with
therapy-related AML harboring TP53 mutations have shown that
Neoplasm Overlap Syndromes clones harboring the mutations preceded the development of leuke-
mia by years, and in some cases could be detected before the original
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Although previously included as a subtype of MDS, disorders with initiation of chemotherapy. This recapitulates older data showing
overlapping features of both MDS and MPN are no longer included that cytogenetic abnormalities present in the bone marrow of patients
in the WHO classification system and are now considered an entity who developed therapy-related leukemia after autologous transplant
unto themselves; they are discussed in more detail elsewhere. for lymphoma could be found in the stimulated autologous speci-
mens, which had been banked years before the development of
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t-AML. These findings suggest an alternate method of t-MDS
Myelodysplastic Syndrome With Fibrosis pathogenesis, in which rare clones harbor preexisting mutations that
either confer a selective growth advantage during marrow reconstitu-
Marked fibrosis rarely occurs in cases of MDS (Fig. 60.5F–G) without tion, tolerance of DNA damage that would otherwise trigger apop-
myeloproliferative features, but when it does occur, it can be difficult tosis, or both, thus promoting clonal selection and expansion upon
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to distinguish these cases from MPN. Evaluation for somatic muta- exposure to chemotherapy.
tions may be helpful, since finding a JAK2, CALR, or MPL mutations
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is more common in pure MPNs than in MDS, while certain other
mutations, including TET2 and SRSF2, are somewhat enriched in Refractory Anemia With Ringed
MDS-MPN overlap syndromes. 101,353 On the other hand, extensive Sideroblasts and Thrombocytosis
dysplasia is more suggestive of MDS. In addition, a few genetic
lesions appear to be more specific for pure MDS syndromes, includ- Although thrombocytopenia is the most common platelet abnormal-
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ing SF3B1 mutations and complex cytogenetics. ity in MDS, rare patients present with marked thrombocytosis.
Patients with overlapping MDS and fibrosis often have severe, This most frequently occurs in the setting of RARS, and in the second
progressive cytopenias with evidence of myelophthisis on peripheral iteration of the WHO criteria, these patients are classified as having
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smear, but the splenomegaly associated with myelofibrosis in an RARS-T. On bone marrow examination, there are often features
MPN background is less common. Nevertheless, the prognosis for of both MDS, such as frequent ringed sideroblasts, and MPNs,
these patients appears to be relatively poor. such as megakaryocytic hyperplasia. Molecularly, patients often have
concomitant SF3B1 mutations, which drive the ring sideroblast
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morphology, and JAK2 mutations, which drive the thrombocytosis
Therapy-Related Myelodysplastic Syndrome and are otherwise uncommon in MDS. Patients meeting criteria
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for RARS-T are relatively uncommon and prognostic information
t-MDS is a well-recognized and feared consequence of cytotoxic is thus limited, but one small series of patients had better 5-year
chemotherapy for other cancers, but the overall incidence is difficult survival than matched patients with RARS, perhaps because the
to estimate. 243,354 This is partly because of the fact that it is not usually proliferative drive of the JAK2 mutation helps preserve blood cell
reported as a distinct entity, and in part because it can be difficult to counts. 368
establish causality in all patients who develop MDS following treat-
ment for a prior cancer. t-MDS has been best characterized in patients
with a prior history of breast cancer, 52,355,356 lymphoma, 357,358 and TREATMENT OF PATIENTS WITH
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myeloma, where the overall incidence is usually reported at around MYELODYSPLASTIC SYNDROMES
1%. On the other hand, t-MDS is rare following treatment for other
types of tumors, such as gastrointestinal and genitourinary cancers. Treating patients with MDS presents a number of challenges. First,
This difference is largely attributed to differences in the types and MDS patients are often elderly and thus frequently have serious
intensities of chemotherapeutic agents used to treat different tumor comorbid conditions and poor performance status. Second, the
types. In particular, high doses of alkylating agents, such as cyclo- protean nature of MDS, which is particularly heterogeneous even
phosphamide, ifosfamide, melphalan, and busulfan, have been associ- compared with other cancers, means that treatments appropriate for
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ated with classic t-MDS, as has extensive radiation therapy. A some patients may be unhelpful for others. Third, a number of
distinct, well-characterized class of therapy-related myeloid malignan- biologic factors, most importantly the disease’s origin in a quiescent
cies occur after treatment with topoisomerase inhibitors but largely stem cell, make MDS highly refractory to most conventional treat-
consists of AML without an antecedent MDS phase. 54,205,362 ments like intensive cytotoxic chemotherapy (which many MDS
t-MDS has a relatively distinct clinical behavior. It is typically patients are not healthy enough to receive anyway).
characterized by a latency of years and recurrent large-scale chromo- In addition, although the biology of MDS is increasingly well
somal abnormalities, especially of chromosomes 5 and 7 or 11q23. understood, most of the common derangements, like mutations in
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Complex karyotypes are also common. These karyotypic abnor- splicing factors and epigenetic regulators, have wide-ranging, pleio-
malities, which occur in only about 10% to 15% of patients with de tropic effects that render narrowly targeted therapies infeasible. While
novo MDS, have a frequency of around 50% to 70% in t-MDS. some agents like hypomethylators and histone deacetylase inhibitors
They tend to have a more aggressive clinical course than patients with are matched to biologic processes that are frequently deranged in
de novo disease, with more frequent progression to acute leukemia. MDS, their usual clinical impact is modest at best. Allogeneic stem
They also tend to respond poorly to all classes of treatment, and even cell transplantation remains the only curative therapy for MDS, but
for those patients who undergo allogeneic stem cell transplantation, is unavailable to many because of age and comorbidities, and even
relapse is not infrequent. 364 for those who undergo it, relapse is not uncommon.