May-June 2011, Volume 8, Issue 3
Immunosuppression in Myelodysplastic Syndrome: Where Do We Go From Here?
Published on: May 01, 2011
Dr. Gotlib indicated no relevant conflicts of interest.
Passweg JR, Giagounidis AA, Simcock M, et al. Immunosuppressive therapy for patients with myelodysplastic syndrome: a prospective randomized multicenter phase III trial comparing antithymocyte globulin plus cyclosporine with best supportive care—SAKK 33/99. J Clin Oncol. 2011;29:303-309.
Four therapies are currently FDA-approved for myelodysplastic syndromes: azacitidine, decitabine, lenalidomide, and deferasirox for iron overload. These success stories are notable exceptions along the historical highway of MDS treatment, which has been littered with numerous underwhelming investigational agents. Antithymocyte globulin (ATG) and cyclosporine (CSA) have been studied in MDS based on the premise that a subset of patients experience cytopenias due to suppression of hematopoiesis by cytotoxic T cells, similar to the mechanism in aplastic anemia. In the current National Comprehensive Cancer Network (NCCN) guidelines for MDS, immunosuppressive therapy with ATG and CSA is recommended as an option in low/intermediate-1 risk international prognostic scoring system (IPSS) patients in whom the serum EPO level is greater than 500 mU/ml and who have a good probability of response. In addition to lower-risk disease, younger age, hypoplastic marrows, HLA-DR15, shorter duration of disease or red blood cell transfusion dependence, and PNH clone positivity have been identified as predictors of response.
On behalf of the Swiss Group for Clinical Cancer Research and the German Myelodysplastic Syndrome Study Group, Passweg and colleagues report on a multicenter, randomized phase III trial comparing horse ATG 15 mg/kg for five days plus CSA for 180 days (n=45) versus best supportive care (BSC, n=43). BSC included transfusions, antibiotics, iron chelation, and growth factors. Patients were stratified by IPSS risk group and were eligible if transfusion dependence was ongoing for less than 24 months. Most enrolled patients belonged to low or intermediate-1 risk groups, but patients with higher blast counts (> 10%) were eligible if other therapy was not available. The primary endpoint was hematologic response at six months, with cross-over to the ATG plus CSA arm permitted upon disease progress or lack of response to BSC after six months. Based on an intent-to-treat analysis, there was a statistically significant higher hematologic response rate of 13/45 (29%, CR+PR) among ATG plus CSA-treated patients (median response duration 16.4 months) versus patients treated with BSC (4/43, 9%). With a median follow-up of 2.3 years, the two-year transformation-free, leukemia-free, and overall survival rates were similar between the two groups, although the study was not powered to detect differences in the latter and the cross-over design confounded such analyses. Low marrow cellularity and treatment with ATG plus CSA retained significance in a multivariate analysis of factors predicting response at six months. Not surprisingly, there was a higher adverse event rate in the ATG plus CSA arm, but no difference in the death rate was observed between the two groups.
The current randomized trial recapitulates prior single-arm studies or pooled retrospective analyses identifying a benefit of immunotherapy in selected patients with MDS. In the aggregate, these studies show a response rate of approximately 30 percent. The typical qualifiers likely account for some of the differences in response across trials — study design, the IPSS risk status of patients, ATG preparation (equine vs. rabbit), and the evolution of MDS response criteria over the last 10-15 years. At this time, it is not clear whether additional trials of ATG (with CSA) will provide new or useful clinical information that has not already been gleaned. Where we go from here may rest more squarely on identifying the basis for immune-mediated marrow failure with more biologic specificity and translating these findings into novel therapeutics.
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