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

doi:10.1200/JCO.2013.50.3102

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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

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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, …

Journal of clinical oncology, Vol.32(12), pp.1242-1248

2014-04-20

DOI: https://doi.org/10.1200/JCO.2013.50.3102

PMCID: PMC3986386

PMID: 24663049

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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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.103 Blood Disorders; 1.103.155 Acute Myeloid Leukemia
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: 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
Creators: Thomas Prebet - 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; Eunice S. Wang, Roswell Park Cancer
Zhuoxin Sun - 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; Eunice S. Wang, Roswell Park Cancer
Maria E Figueroa - 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; Eunice S. Wang, Roswell Park Cancer
Rhett Ketterling - 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; Eunice S. Wang, Roswell Park Cancer
Ari Melnick - 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; Eunice S. Wang, Roswell Park Cancer
Peter L Greenberg - 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; Eunice S. Wang, Roswell Park Cancer
James Herman - 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; Eunice S. Wang, Roswell Park Cancer
Mark Juckett - 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; Eunice S. Wang, Roswell Park Cancer
Eunice S Wang - 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; Eunice S. Wang, Roswell Park Cancer
Mitchell R Smith - 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; Eunice S. Wang, Roswell Park Cancer
Lisa Malick - 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; Eunice S. Wang, Roswell Park Cancer
Elisabeth Paietta - 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; Eunice S. Wang, Roswell Park Cancer
Magdalena Czader - 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; Eunice S. Wang, Roswell Park Cancer
Mark Litzow - 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; Eunice S. Wang, Roswell Park Cancer
Janice Gabrilove - 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; Eunice S. Wang, Roswell Park Cancer
Harry P Erba - 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; Eunice S. Wang, Roswell Park Cancer
Steven D Gore - 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; Eunice S. Wang, Roswell Park Cancer
Martin S Tallman - 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; Eunice S. Wang, Roswell Park Cancer
Publication Details: Journal of clinical oncology, Vol.32(12), pp.1242-1248
Academic Unit: Miller School of Medicine; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 24663049
PMCID: PMC3986386
Record Identifier: 991031598804802976