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1358 Part X: Malignant Myeloid Diseases Chapter 87: Myelodysplastic Syndromes 1359

leads to remission in approximately 10 to 20 percent of patients with median age for MDS diagnosis (median age of approximately 50 years)
MDS, the median duration of remission is less than 1 year, and sur- and most were women with a normal karyotype, suggesting that they
vival has not been prolonged nor has AML progression been delayed were not representative of the typical MDS patient seen in most clinics.
compared with supportive care alone. Moreover, low-dose cytosine
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arabinoside usually is cytotoxic, inducing marrow hypoplasia and wors- Immunomodulatory Agents: Thalidomide and Lenalidomide
ening cytopenias. Although occasional reports of remission following The immunomodulatory drug (IMiD) thalidomide induced hematopoi-
low-dose cytarabine have been consistent with an effect on leukemia cell etic responses in 20 to 25 percent of patients with MDS at doses ranging
maturation, most patients experience suppression of the malignant cell from 50 to 800 mg per day, but thalidomide is difficult to tolerate (espe-
clone, leading to marrow repopulation with polyclonal hemopoiesis. This cially at higher doses) because of neuropathy, rashes, and constipation;
treatment approach is used less often since the advent of other FDA-ap- in addition, risk of teratogenicity limited distribution of the drug. 449,450
proved agents for MDS, especially as azacitidine treatment is associated Although thalidomide was initially promoted as an angiogenesis inhib-
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with superior overall survival compared to cytarabine, but may still itor following a vogue for such therapies in the 1990s, more recent data
have a role in some patients. 432 indicate that thalidomide’s effects depend on modulation of the activity
451
of cereblon, a component of an E3 ubiquitin ligase complex. Altera-
Immunosuppressive Therapy: Cyclosporine and Antithymocyte tion of ubiquitination by IMiD therapy has pleiotropic effects, such as
Globulin alteration of transcription factors, and downstream effects on levels of
In some patients with MDS, autoreactive T-lymphocyte–mediated inhi- cytokines and immune cell subsets. 452–455
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bition of hematopoiesis occurs and contributes to cytopenias. In such Lenalidomide, a thalidomide analogue with a more favorable
patients, cytopenias may be ameliorated by treatment with immunosup- risk-to-benefit ratio than the parent compound, induces improvement
pressive agents directed at T cells such as antithymocyte globulin (ATG) in approximately 85 percent of patients with lower-risk MDS associ-
or calcineurin inhibitors. In patients who recover effective hematopoie- ated with deletion of chromosome 5q, and results in RBC transfusion
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sis after immunosuppressive treatment, the Vβ (T-cell receptor-β) spec- independence in almost 70 percent of patients. 308,456 The median hemo-
tra-type representative of clonal or oligoclonal T-cell populations typically globin increment in responding patients is 5.4 g/dL and responses last
reverts to normal patterns. In one older study, a nonclonal X-chromosome a median of more than 2 years. A randomized trial of a starting dose
inactivation pattern in the marrow, as assessed by the human androgen of 5 mg/day versus 10 mg/day showed a higher cytogenetic response
receptor gene assay and the phosphoglycerated kinase-1 assay, was associ- rate with the higher dose; in that study, there was no increase in AML
457
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ated with a response to ATG. This finding was attributed to incomplete risk compared to placebo. Most responses occur in the first 8 weeks.
clonal expansion, with ATG improving normal hematopoiesis by relieving Neutropenia and thrombocytopenia can be adverse effects of lenalid-
458
the immunologic pressure on the remaining normal progenitors. Other omide, but treatment-emergent cytopenias correlate with response.
investigators have postulated that responses may result from suppression Pretreatment thrombocytopenia, in contrast, is associated with lower
of interferon-γ secretion by CD4+ T cells regardless of clonality. 435 response rate.
Some series in MDS have reported response rates to ATG of 15 to The results with lenalidomide therapy are less favorable if chro-
60 percent and longer survival times in patients who respond. 436–438 The mosome 5q is absent; patients with normal karyotype and lower-risk
mortality with ATG-based therapy is higher in MDS patients than in MDS have approximately a 25 percent response rate with a median
459
439
aplastic anemia. With cyclosporine alone, responses seem to be less response duration of less than 1 year. Case reports suggest patients
460
common than with ATG-based regimens and mostly consist of minor with trisomy 13 may respond favorably. Another thalidomide deriv-
hematologic improvements. 440,441 There are case reports of responses to ative, pomalidomide, has activity in primary myelofibrosis but has not
tacrolimus. 442 yet been studied in MDS.
HLA-DR15 (DR2) is overrepresented in MDS and predicts a
response to immunosuppressive therapy. 312,443 In one series of 60 Antitumor Necrosis Factor Therapy
patients who were treated with ATG and cyclosporine, 60 percent had Patients with MDS overlap with the anemia of chronic inflammation
hematologic improvement, and more responders had good karyotype in that they often have elevated levels of inflammatory cytokines such
or HLA-DRB1 1501. 3123 Most of the patients in this series had RA and as TNF-α, which inhibit hematopoiesis. Whereas both thalidomide
an IPSS score of intermediate-1. In a series of 129 patients who were and lenalidomide indirectly lower TNF levels, strategies more directly
treated with immunosuppressive therapy at a single institution, 30 per- inhibiting TNF also have been pursued. The soluble TNF receptor
cent had either a complete or partial response; younger patient age and fusion protein etanercept (p75 TNFR:Fc), FDA approved for rheuma-
intermediate-1 or low-risk IPSS score favored survival. 110 toid arthritis, has produced mixed results in MDS. In one pilot series,
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In some series a hypocellular marrow has predicted a higher like- moderate improvement in cytopenias was noted, whereas in another
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lihood of response, analogous to the response to immunosuppressive trial, no responses were noted in 10 patients. In another pilot study
therapy in aplastic anemia, but this has not been consistent. 439,441,444 of 3 months duration, one of 16 enrolled patients became transfu-
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Younger age, normal karyotype or trisomy 8, lack of transfusion depen- sion-independent temporarily. There is a report of two patients who
dence, and the presence of either a PNH clone or HLA-DR15 have had sustained erythroid responses during treatment with the chimeric
445
predicted response to immunosuppressive therapy, but none is a robust anti–TNF-α monoclonal antibody infliximab, which also decreased the
464
biomarker. 312 percentage of apoptotic cells in the marrow. Etanercept has been com-
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465
Not all groups have seen success with immunosuppressive therapy bined with ATG and with azacitidine, but the independent contri-
approaches. One study of ATG was stopped early because of lack of effi- bution of etanercept to the responses observed is unclear.
cacy and development of adverse reactions. Other studies also have
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reported lack of efficacy of single-agent cyclosporine. 447 Other Treatment Options in Low- or Intermediate-1–Risk
Among highly selected patients seen at the National Institutes of Patients
Health, the anti-CD52 monoclonal antibody alemtuzumab was associ- A number of miscellaneous therapies have been tried for lower-risk
ated with a response rate exceeding 90 percent in IPSS Intermediate-1 patients with MDS by analogy with other diseases such as inflammatory
448
risk patients. However, these patients were 20 years younger than the anemias or promyelocytic leukemia, or based on theoretical constructs.

Kaushansky_chapter 87_p1341-1372.indd 1359 9/21/15 11:06 AM