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Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

ABSTRACT: Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and day-10). A total of 47 patients [29 therapy-related myelosyspastic syndrome (t-MDS) and 18 therapy-related acute myeloid leukaemia (t-AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

SUBMITTER: Prebet T

PROVIDER: S-EPMC4794257 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

Prebet Thomas T Sun Zhuoxin Z Ketterling Rhett P RP Zeidan Amer A Greenberg Peter P Herman James J Juckett Mark M Smith Mitchell R MR Malick Lisa L Paietta Elisabeth E Czader Magdalena M Figueroa Maria M Gabrilove Janice J Erba Harry P HP Tallman Martin S MS Litzow Mark M Gore Steven D SD

British journal of haematology 20151118 3

Therapy-related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m(2) /d) +/- the histone deacetylase inhibitor entinostat (4 mg/m(2) /d PO day-3 and ...[more]

PMID: 26577691

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Project description: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.

Dataset Information

Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

Publications

Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study.

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