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 C Issa,Xuemei Wang,Bueso-Ramos Carlos,Musa Yilmaz,Tapan M. Kadia,Michael Andreeff,Farhad Ravandi,Marina Konopleva,Hagop M. Kantarjian,Courtney D. DiNardo +18 more
TLDR
In this article , enasidenib and azacitidine (ENA + AZA) were combined with venetoclax (VEN) for IDH 2 mutated acute myeloid leukemia (IDH2 mut AML).Abstract:
Abstract Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH 2 mutated acute myeloid leukemia ( IDH2 mut AML). This open label phase II trial enrolled patients (pts) with documented IDH2 mut AML. All patients received AZA 75 mg/m 2 /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 IDH2 mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2 mut AML. Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433 read more
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Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
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TL;DR: In previously untreated patients with confirmed AML who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received zsitidine alone.
Journal ArticleDOI
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia
Eytan M. Stein,Eytan M. Stein,Courtney D. DiNardo,Daniel A. Pollyea,Amir T. Fathi,Gail J. Roboz,Gail J. Roboz,Jessica K. Altman,Richard Stone,Daniel J. DeAngelo,Ross L. Levine,Ian W. Flinn,Hagop M. Kantarjian,Robert H. Collins,Manish R. Patel,Arthur E. Frankel,Anthony S. Stein,Mikkael A. Sekeres,Ronan T. Swords,Bruno C. Medeiros,Christophe Willekens,Christophe Willekens,Paresh Vyas,Alessandra Tosolini,Qiang Xu,Robert Knight,Katharine E. Yen,Sam Agresta,Stéphane de Botton,Stéphane de Botton,Martin S. Tallman,Martin S. Tallman +31 more
TL;DR: Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib, a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes.
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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 C Issa,Xuemei Wang,Bueso-Ramos Carlos,Musa Yilmaz,Tapan M. Kadia,Michael Andreeff,Farhad Ravandi,Marina Konopleva,Hagop M. Kantarjian,Courtney D. DiNardo +18 more