Efficacy and safety of enasidenib and azacitidine combination in patients with IDH2 mutated acute myeloid leukemia and not eligible for intensive chemotherapy

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, 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

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://ichgcp.net/clinical-trials-registry/NCT03683433" title="See in ClinicalTrials.gov">NCT03683433.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Consort diagram of Phase II…
Fig. 1. Consort diagram of Phase II trial of ENA+AZA combination in IDH2mut AML.
Consort diagram. AML- Acute myeloid leukemia, ENA- Enasidenib, AZA- Azacitidine, HMA- hypomethylating agent, AHN- antecedent hematological neoplasm, IC- intensive chemotherapy, HSCT- Hematopoietic stem cell transplant, i- inhibitor, VEN- venetoclax, CRc- composite complete remission, CR- complete remission, CRi- complete remission with incomplete hematological recovery, MRD- measurable residual disease, FCM -Flowcytometry, NR -no response, NE- not evaluable.
Fig. 2
Fig. 2
Kaplan–Meier plot showing overall survival (OS) by line of therapy in R/R cohort. N number, E events,mOS (m) median overall survival in months.
Fig. 3
Fig. 3
Kaplan–Meier plot showing overall survival (OS) by venetoclax status in R/R cohort. N number, E events,mOS (m) median overall survival in months.
Fig. 4. Landscape of entire cohort with…
Fig. 4. Landscape of entire cohort with genomics and outcomes.
Mutational landscape of the whole cohort.

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