Page 1082 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 965

developed AML, compared to 23.2% in the 5-mg group and 21.7% the complications of long-term steroid use in this population came
in the 10-mg group, though the crossover model prevented an assess- to outweigh the benefits. Nevertheless, immunosuppressive therapy
ment of statistical significance. may be reasonable for certain subsets of MDS patients in whom
Given recent progress in understanding of lenalidomide’s mecha- autoreactive T-lymphocytes contribute to the inhibition of effective
nism of action, it is perhaps unsurprising that it demonstrates con- hematopoiesis. Patients with hypoplastic MDS, in particular, have
siderably lower efficacy in MDS patients who do not have del(5q). been shown to have similarities to aplastic anemia, and may respond
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In these patients, studies have consistently shown an overall response to treatment with ATG. Other studies have shown that patients
rate of about 25%, which on average lasts less than a year. 445,446 It is with underlying PNH clones, which can be assessed by flow cytom-
not known whether the patients who respond have abnormalities of etry for PIG-anchored glycoproteins CD55 and CD59, may also
casein kinase 1α, or whether their sensitivity to lenalidomide occurs respond to ATG, as may patients with a human leukocyte antigen
via a different mechanism. (HLA) DR15 phenotype. 459
Lenalidomide is generally well tolerated, especially compared to Retrospective analysis of data from the International Myelodys-
thalidomide. The most common side effects are neutropenia and plasia Risk Assessment Workshop showed that treatment with
thrombocytopenia, which are most common in the first month of immunosuppression was associated with an improvement in overall
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treatment and which have some correlation to treatment response. survival (8.1 vs. 5.2 years, p < .001) and a lower risk of leukemic
Pretreatment thrombocytopenia, a feature atypical of pure del(5q), transformation, but these results could have been subject to selection
appears to negatively correlate with response and perhaps serves as a bias since fewer patients with higher-risk disease are treated upfront
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phenotypic proxy for cooperating genetic events that blunt the with immunosuppression. On the other hand, a randomized study
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molecular sensitivity to the drug. Significant thromboembolism comparing ATG plus cyclosporine to best supportive care suggested
has been observed in studies of patients with myeloma who receive a slight improvement in hematologic response in the ATG + cyclo-
lenalidomide, an effect that largely seems to be confined to sporine A group, but there was no difference in disease-free or overall
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co-administration of lenalidomide and dexamethasone; the manu- survival. Subgroup analysis suggested that patients with hypocel-
facturer thus recommends thromboprophylaxis in del(5q) patients as lular marrows were more likely to respond to immunosuppression,
well, though it is not clear that the thrombotic risk is the same in again hinting at biologic similarities to aplastic anemia. In studies
these populations, and thrombocytopenia may limit the safety of this making careful distinction between MDS and aplastic anemia,
approach. however, mortality with ATG treatment was higher in MDS than in
aplastic anemia. 345
Alemtuzumab, a monoclonal antibody against anti-CD52, has
Low-Dose Cytarabine activity in highly selected subsets of MDS patients. In particular, one
small phase I/II study of patients yielded a 77% overall response rate
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Cytarabine, also known as cytosine arabinoside or Ara-c, is a pyrimi- among patients with IPSS intermediate-1 disease. Some patients
dine analog that is widely used in the treatment of a number of with cytogenetic abnormalities normalized their karyotype, and the
hematologic malignancies. In MDS, its use dates to the 1980s. 449,450 rate of complete response appeared to increase with time in those
2
The typical dosing schedule is 5–20 mg/m per day via subcutaneous patients who were not lost to follow up. However, alemtuzumab is
injection (daily or twice daily) or continuous IV infusion. Although severely immunosuppressive and the study was hampered by a high
10% to 20% of patients with MDS have some degree of pathologic rate of attrition and careful selection of patients, and the results have
response during Ara-c therapy, these tend to last only a few months, not yet been repeated. The biologic basis for the high response rate
and treatment has not been shown to improve survival or reduce the in this single study remains unclear.
rate of transformation to AML.
One of the drawbacks to treatment with cytarabine or any other
conventional chemotherapeutic agent is that they cause cytopenias as
a primary side effect, and since cytopenias are a central problem in Manipulating the Microenvironment: Vascular
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most MDS patients, the agents rapidly become limited in utility. Endothelial Growth Factor and Other Targets
The worsening of cytopenias is likely one of the primary reasons for
the lack of survival benefit for cytarabine in MDS. Observations of increased microvessel density in the bone marrow of
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MDS patients have led to some enthusiasm for targeting vascular
growth factors and other molecules associated with the marrow
Antitumor Necrosis Factor Therapy microenvironment, but results so far have been somewhat disappoint-
ing. For instance, a phase II trial of bevacizumab, a monoclonal
The observation that MDS patients often have elevated levels of antibody directed against vascular endothelial growth factor (VEGF),
inflammatory cytokines and increased rates of apoptosis led to the showed a decrease in VEGF levels and a significant reduction in
postulate that blockade of these pathways might ameliorate the inef- microvascular density, but only one of 21 patients had any type of
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fective hematopoiesis found in many patients with MDS. Etanercept, hematologic response. Similarly, a phase II study of vatalanib, an
a soluble TNF-α inhibitor, has been analyzed in two small pilot oral VEGF receptor inhibitor, showed hematologic responses in only
studies of MDS patients, with mixed results: cytopenias improved in 5% of patients, though many patients had to withdraw from the
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one trial, whereas no effect was seen in the other. The drug has study because of side effects. 465
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also been combined with both ATG and azacitidine, but in Other therapies directed at the microenvironment have similarly
neither case was it clear that the addition made a difference. A separate shown responses in only a minority of patients. For instance, the
case report described sustained erythroid responses in two patients combination of pentoxifylline, a phosphodiesterase inhibitor, with
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treated with infliximab, a monoclonal anti-TNF antibody. TNF-α dexamethasone and ciprofloxacin (PCD) has been shown to induce
and other inflammatory mediators may play a greater role in some hematologic responses in some patients, but most of these are
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subsets of MDS than others, and better delineation of these groups transient and probably represent neutrophil demargination from the
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may make future study of anti-TNF therapy reasonable in selected corticosteroid. A more recent study combining PCD with ami-
patients. fostine, an antiangiogenic agent usually used as a chemoprotectant,
showed a hematologic response rate of 66%, but long-term results
466
have not been reported. Lenalidomide and thalidomide were both
Immunosuppressive Therapy previously thought to act via effects on the microenvironment, but
467
with the discovery of lenalidomide’s role as a catalyst for cereblon-
Corticosteroid therapy was once a mainstay of treatment for MDS, mediated ubiquitination, as described earlier, the extent to which it
457
but despite reported response rates in the range of 10% to 20%, also affects the microenvironment is unclear.