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J Clin Oncol. 2017 Aug 20;35(24):2745-2753. doi: 10.1200/JCO.2015.66.2510. Epub 2017 May 9.

Randomized Phase II Study of Azacitidine Alone or in Combination With Lenalidomide or With Vorinostat in Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: North American Intergroup Study SWOG S1117.

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Mikkael A. Sekeres and Aziz Nazha, Cleveland Clinic, Cleveland; Clara D. Bloomfield, The Ohio State University Comprehensive Cancer Center, Columbus, OH; Megan Othus and Anna Moseley, SWOG Statistical Center; Min Fang and Frederick R. Appelbaum, Fred Hutchinson Cancer Research Center, Seattle, WA; Alan F. List, H. Lee Moffitt Cancer Center, Tampa, FL; Olatoyosi Odenike, University of Chicago, Chicago; Mario R. Velasco, Heartland NCORP/Cancer Care Specialists of Central Illinois, Decatur, IL; Richard M. Stone, Dana Farber Cancer Institute; Eyal C. Attar, Massachusetts General Hospital, Boston, MA; Steven D. Gore, Yale University, New Haven, CT; Mark R. Litzow, Mayo Clinic, Rochester, MN; Rena Buckstein, Sunnybrook Health Sciences Centre, Toronto; Elina K. Cook, Alyssa H. Cull, and Michael J. Rauh, Queen's University, Kingston, Ontario, Canada; Diane Roulston, University of Michigan, Ann Arbor, MI; Yanming Zhang, Memorial Sloan-Kettering Cancer Center, New York, NY; Rakesh Gaur, Kansas City National Cancer Institute Community Oncology Research Program, Prairie Village, KS; Ehab Atallah, Medical College of Wisconsin, Milwaukee, WI; and Harry P. Erba, University of Alabama, Birmingham, AL.


Purpose Azacitidine is standard, first-line therapy in higher-risk myelodysplastic syndromes (MDS). Whether azacitidine-based combinations with lenalidomide or vorinostat produce superior overall response rates (ORRs) to azacitidine is not known. Patients and Methods North American Intergroup Study S1117 is a phase II/III trial that randomly assigned patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML) 1:1:1 to azacitidine (75 mg/m2/day on days 1 to 7 of a 28-day cycle); azacitidine plus lenalidomide (10 mg/day on days 1 to 21); or azacitidine plus vorinostat (300 mg twice daily on days 3 to 9). The primary phase II end point was improved ORR. Results Of 277 patients from 90 centers, 92 received azacitidine, 93 received azacitidine plus lenalidomide, and 92 received azacitidine plus vorinostat. Median age was 70 years (range, 28 to 93 years), 85 patients (31%) were female, and 53 patients (19%) had CMML. Serious adverse events were similar across arms, although combination-arm patients were more likely to undergo nonprotocol-defined dose modifications ( P < .001).With a median follow-up of 23 months (range, 1 to 43 months), the ORR was 38% for patients receiving azacitidine, 49% for azacitidine plus lenalidomide ( P = .14 v azacitidine), and 27% for azacitidine plus vorinostat ( P = .16 v azacitidine). For patients with CMML, ORR was higher for azacitidine plus lenalidomide versus azacitidine (68% v 28%, P = .02) but similar for all arms across cytogenetic subgroups, as was remission duration and overall survival. ORR was higher with mutations in DNMT3A and lower for SRSF2, whereas ORR duration improved with fewer mutations. Lenalidomide dose reduction was associated with worse overall survival (hazard ratio, 1.30; P = .05). Conclusion Patients with higher-risk MDS treated with azacitidine-based combinations had similar ORR to azacitidine monotherapy, although patients with CMML benefitted from azacitidine plus lenalidomide. The efficacy of combination regimens may have been affected by dose modifications.

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