Prolonged Administration of Azacitidine with or without Entinostat Increases Rate of Hematologic Normalization for Myelodysplastic Syndrome and Acute Myeloid Leukemia with Myelodysplasia-Related Changes: Results of the US Leukemia Intergroup Trial E1905

The current standard of treatment for high risk myelodysplastic syndromes (MDS) is azacitidine (AZA) administered 75mg/m²/d days 1 – 7 (525 mg/m²/cycle) each 4 weeks. This approach improves survival; however, many AZA-treated patients (pts) continue to require blood products. The US registration trial (CALGB9221 trial; Silverman JCO 2002 and JCO 2006) showed a trilineage response rate (CR plus PR plus trilineage hematologic improvement [TL], IWG 2000) of 15%. Histone deacetylase inhibitors (HDACi) synergize with azanucleosides in vitro to re-express genes silenced through promoter methylation. In a previous phase I pilot study (J0443 study, NCT00101179), we showed that the combination of AZA and the orally bioavailable HDACi entinostat (MS-275) was effective and tolerable for pts with MDS and AML with myelodysplasia-related changes. The recommended Phase II schedule was AZA 50 mg/m²/d s.c. for 10 days (500 mg/m²/cycle) and entinostat 4 mg/m²/d PO on day 3 and day 10 of AZA on a 28 days cycle basis.

E1905 US Leukemia Intergroup study (NCT00313586) is a phase II 1:1 randomized trial of AZA (50 * 10)+ entinostat (arm B) vs AZA (50 * 10) alone (arm A). Following six cycles of treatment, pts with documented clinical response (IWG 2000: CR, PR or TL) continued for the lesser of a total of 24 cycles or disease progression. The primary objective was to determine whether either arm significantly increased the rate of hematologic normalization (HN: CR + PR + TL) compared to CALGB9221 results (i.e. 15% to 30%). Patients were stratified according to the type of disease (i.e. MDS low risk vs MDS high risk vs CMML vs AML).

150 pts were accrued and 136 analyzed (13 ineligible; 1 death before treatment), including 88 MDS, 5 CMML and 43 AML. Median age was 72 years. Poor risk cytogenetics were found in 31% of the patients. IPSS Int-2/High risk patients represented 72% (n=63) of the MDS cohort. There was no difference in pts characteristics between the 2 arms. The median number of administered cycles was 6 (range: 1–24). Toxicities in both arms were acceptable with a trend to an increase in grade IV platelet adverse events in Arm B (63% vs 46%, p=0.07) and grade III-IV fatigue in arm B (23% vs 13%, p=0.13). Overall HN rate was 28%: 10% CR, 8% PR and 10% TL. The HN rates by arm were A: 31% (12/9/10); B 24% (7/7/10) (p=NS). Non-trilineage hematologic improvement was achieved in an additional 12% of pts in arm A and 19% of pts in arm B; thus, total hematologic response was 43% and 44%. The median time to best response was 6 months in both arms (range: 1–14); median duration of response was 11 months (range: 1–18) in arm A and 10 months in arm B (range: 2–19, p=NS). With a median follow-up of 17 months, median overall survival was 18 months in arm A and 13 months in arm B (p=0.15).

The rate of hematologic normalization in response to AZA 50 mg/m²/day * 10 in Arm A was twice that observed in C9221. The addition of entinostat examined in E1905 did not improve the response rate. Confirmation of improved response following prolonged administration of lower daily doses of AZA will require direct comparison to the currently approved dose regimen.

Gore:Celgene: Consultancy, Research Funding, stock options; Syndax: Consultancy.