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.
Author(s): Prebet T(1), Sun Z, Figueroa ME, Ketterling R, Melnick A, Greenberg PL, Herman J,
Juckett M, Smith MR, Malick L, Paietta E, Czader M, Litzow M, Gabrilove J, Erba
HP, Gore SD, Tallman MS.
Affiliation(s): Author information:
(1)Thomas Prebet, James Herman, Lisa Malick, and Steven D. Gore, Sidney Kimmel
Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Zhuoxin Sun,
Dana-Farber Cancer Institute, Boston, MA; Maria E. Figueroa and Ari Melnick,
Weill Cornell Medical College; Janice Gabrilove, Mount Sinai School of Medicine;
Martin S. Tallman, Leukemia Service, Memorial Sloane-Kettering Cancer Center, New
York; Elisabeth Paietta, North Division, Montefiore Medical Center, Bronx, NY;
Rhett Ketterling and Mark Litzow, Mayo Clinic, Rochester, MN; Peter L. Greenberg,
Stanford University Cancer Center, Stanford, CA; Mark Juckett, University of
Wisconsin, Madison, WI; Mitchell R. Smith, Fox Chase Cancer Center, Philadelphia,
PA; Magdalena Czader, Indiana University Cancer Center, Indianapolis, IN; and
Harry P. Erba, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.
Publication date & source: 2014, J Clin Oncol. , 32(12):1242-8
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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