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

Research output: Contribution to journalArticle

127 Citations (Scopus)

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/m2/d given for 10 days ± entinostat 4 mg/m2/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.

Original languageEnglish
Pages (from-to)1242-1248
Number of pages7
JournalJournal of Clinical Oncology
Volume32
Issue number12
DOIs
StatePublished - Apr 20 2014

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Azacitidine
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Leukemia
entinostat
Leukemia, Myelomonocytic, Chronic
Histone Deacetylase Inhibitors
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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

In: Journal of Clinical Oncology, Vol. 32, No. 12, 20.04.2014, p. 1242-1248.

Research output: Contribution to journalArticle

Prebet, T, Sun, Z, Figueroa, ME, Ketterling, R, Melnick, A, Greenberg, PL, Herman, J, Juckett, M, Wang, ES, Smith, MR, Malick, L, Paietta, E, Czader, M, Litzow, M, Gabrilove, J, Erba, HP, Gore, SD & Tallman, MS 2014, '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', Journal of Clinical Oncology, vol. 32, no. 12, pp. 1242-1248. https://doi.org/10.1200/JCO.2013.50.3102
Prebet, Thomas ; Sun, Zhuoxin ; Figueroa, Maria E. ; Ketterling, Rhett ; Melnick, Ari ; Greenberg, Peter L. ; Herman, James ; Juckett, Mark ; Wang, Eunice S. ; Smith, Mitchell R. ; Malick, Lisa ; Paietta, Elisabeth ; Czader, Magdalena ; Litzow, Mark ; Gabrilove, Janice ; Erba, Harry P. ; Gore, Steven D. ; Tallman, Martin S. / 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. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 12. pp. 1242-1248.
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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/m2/d given for 10 days ± entinostat 4 mg/m2/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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T2 - Results of the US Leukemia intergroup trial E1905

AU - Prebet, Thomas

AU - Sun, Zhuoxin

AU - Figueroa, Maria E.

AU - Ketterling, Rhett

AU - Melnick, Ari

AU - Greenberg, Peter L.

AU - Herman, James

AU - Juckett, Mark

AU - Wang, Eunice S.

AU - Smith, Mitchell R.

AU - Malick, Lisa

AU - Paietta, Elisabeth

AU - Czader, Magdalena

AU - Litzow, Mark

AU - Gabrilove, Janice

AU - Erba, Harry P.

AU - Gore, Steven D.

AU - Tallman, Martin S.

PY - 2014/4/20

Y1 - 2014/4/20

N2 - 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/m2/d given for 10 days ± entinostat 4 mg/m2/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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