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

Abstract

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/m/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.

Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature

“…This observation is consistent with previous randomized studies in high-risk MDS but is the first demonstration that HDAC inhibitors have no impact on clinical outcomes in patients with newly diagnosed or relapsed AMLtreated with AZA (10)(11)(12). Why might our study have failed to replicate earlier single arm studies of strikingly increased clinical activity of combined AZA and HDAC inhibitor treatment (8,9,22)?…”

“…Although recent randomized trials have reported no benefit of combined AZA and HDAC inhibitor therapy in patients with high-risk MDS, there have been no randomized trials in AML (10)(11)(12).…”

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Unfortunately, all of them have failed to improve response rate and survival when compared to monotherapy with HMA [69]. Nevertheless, based on early positive signal from one of these trials [70] some combinations are currently also under investigation for treatment of relapse after allo-SCT.…”

Chronic Myelomonocytic Leukemia: a Genetic and Clinical Update

“…This has prompted combination therapy with HMA and immunomodulatory agents due to postulated synergistic effects [72]. A randomized phase II intergroup study (S1117) evaluated AZA + lenalidomide, AZA + vorinostat (HDACi), versus AZA monotherapy in MDS and CMML [73]. The median follow-up was 9 months, and no statistically significant difference was seen in response rates across all three arms.…”