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Clinical Trial
. 2014 Apr 20;32(12):1242-8.
doi: 10.1200/JCO.2013.50.3102. Epub 2014 Mar 24.

Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905

Thomas Prebet  1 , Zhuoxin Sun, Maria E Figueroa, Rhett Ketterling, Ari Melnick, Peter L Greenberg, James Herman, Mark Juckett, Mitchell R Smith, Lisa Malick, Elisabeth Paietta, Magdalena Czader, Mark Litzow, Janice Gabrilove, Harry P Erba, Steven D Gore, Martin S Tallman
Affiliations
Clinical Trial

Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905

Thomas Prebet et al. J Clin Oncol. .

Abstract

Purpose: Although azacitidine (AZA) improves survival in patients with high-risk myelodysplastic syndrome, the overall response remains approximately 50%. Entinostat is a histone deacetylase inhibitor that has been combined with AZA with significant clinical activity in a previous phase I dose finding study.

Design: Open label phase II randomized trial comparing AZA 50 mg/m(2)/d given for 10 days ± entinostat 4 mg/m(2)/d day 3 and day 10. All subtypes of myelodysplasia, chronic myelomonocytic leukemia, and acute myeloid leukemia with myelodysplasia-related changes were eligible for the study. The primary objective was the rate of hematologic normalization (HN; complete remission + partial remission + trilineage hematological improvement).

Results: One hundred forty-nine patients were analyzed, including 97 patients with myelodysplastic syndrome and 52 patients with acute myeloid leukemia. In the AZA group, 32% (95% CI, 22% to 44%) experienced HN and 27% (95% CI, 17% to 39%) in the AZA + entinostat group. Both arms exceeded the HN rate of historical control (Cancer and Leukemia Group B 9221 trial), but only the AZA group fulfilled the primary objective of the study. Rates of overall hematologic response were 46% and 44%, respectively. Median overall survivals were 18 months for the AZA group and 13 months for the AZA + entinostat group. The combination arm led to less demethylation compared with the monotherapy arm, suggesting pharmacodynamic antagonism.

Conclusion: Addition of entinostat to AZA did not increase clinical response as defined by the protocol and was associated with pharmacodynamic antagonism. However, the prolonged administration of AZA by itself seems to increase HN rate compared with standard dosing and warrants additional investigation.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT diagram of the E1905 protocol.
Fig 2.
Fig 2.
Kaplan-Meier representation of the azacitidine alone (arm A) and the azacitidine + entinostat (arm B) regimens for overall population (A), patients with myelodysplastic syndrome and chronic myelomonocytic leukemia (B), and patients with acute myeloid leukemia (C). Survival is represented from the day of first administration of treatment to the date of death or last follow-up. Arm A is in blue and arm B is in gold. CNSR, censored.
Fig 3.
Fig 3.
DNA methylation changes evaluated by HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction (HELP): (A) Comparison between baseline and day 15 for overall population; (B) comparison of the treatment arms at day 15. And by methyl-specific polymerase chain reaction (MSP): (C) Correlation of SOCS1 methylation and clinical response; (D) time-dependent methylation pattern of SOCS1 promoter. (A) Heatmap representation of 139 differentially methylated regions at day 15 compared with baseline for the 21 patients with paired specimens on both treatment arms. Each row represents a probe set on the array and each column represents a patient. (B) Dot plot representation of methylation difference (x-axis) versus statistical significance (y-axis) for patients on arm A (left) and arm B (right). Red dots indicate probe sets that reached our significance cutoff in each comparison. (C) Median SOCS1 promoter DNA methylation for responders (ie, patients with hematological normalization: complete remission [CR], partial remission [PR], or trilineage hematological), nonresponders, and patients who experienced CR or PR. Median SOCS1 methylation was significantly higher in nonresponders as compared with responders (42% v 13%, respectively; P = .03). Patients with CR or PR showed no difference as compared with other patients (P = .3). There was no correlation of methylation decrease with clinical response or with treatment arm. (D) Only patients with baseline methylation of SOCS1 were represented in this figure; median SOCS1 promoter methylation decreased between baseline and day 15 (P = .008), or between baseline and day 28 (P = .10). HpaII, Haemophilus parainfluenzae II restriction enzyme; MspI Moraxella sp. I restriction enzyme.
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