Efficacy and Safety of Enasidenib and Azacitidine Combination in Patients With IDH2 Mutated Acute Myeloid Leukemia and Not Eligible for Intensive Chemotherapy

Authors

Sangeetha Venugopal
Koichi Takahashi
Naval Daver
Abhishek Maiti
Gautam Borthakur
Sanam Loghavi
Nicholas J Short
Maro Ohanian
Lucia Masarova
Ghayas Issa
Xuemei Wang
Bueso-Ramos Carlos
Musa Yilmaz
Tapan Kadia
Michael Andreeff
Farhad Ravandi
Marina Konopleva
Hagop M Kantarjian
Courtney D DiNardo

Publication Date

1-25-2022

Journal

Blood Cancer Journal

Abstract

Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24-88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07-0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433.

Keywords

Adult, Aged, Aged, 80 and over, Aminopyridines, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Female, Humans, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Male, Middle Aged, Mutation, Treatment Outcome, Triazines, Young Adult, Acute myeloid leukaemia, Drug development

DOI

10.1038/s41408-021-00604-2

PMID

35078972

PMCID

PMC8789767

PubMedCentral® Posted Date

1-25-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes