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.

Trial registration: ClinicalTrials.gov NCT00101179 NCT00313586.

Keywords: acute myeloid leukaemia; azacitidine; histone deacetylase inhibitor; myelodysplasia; therapy related.

© 2015 John Wiley & Sons Ltd.

Figures

Fig 1

Kaplan Meier Estimates of overall survival for the patients treated with azacitidine (solid line) and azacitidine+entinostat (broken line). Survival is defined from the initiation of therapy to death of any causes. Time interval is in months.

Fig 2

Comparison of overall survival in patients treated in the E1905 trials for de novo (solid line) or therapy-related (dash line) myeloid neoplasms. (A) Patients treated with azacitidine single agent (B) Patients treated with azacitidine+entinostat. Survival is defined from the initiation of therapy to death of any causes. Time interval is in months. MDS, myelodysplastic syndrome; AML, acute myeloid leukaemia.