Outcomes of Frontline Triplet Regimens With a Hypomethylating Agent, Venetoclax, and Isocitrate Dehydrogenase Inhibitor for Intensive Chemotherapy–Ineligible Patients With Isocitrate Dehydrogenase–Mutated AML

PURPOSE The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)–ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1 -mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes. METHODS We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with triplet regimens for isocitrate dehydrogenase ( IDH )–mutant AML. Patients received either AZA + VEN + IVO on NCT03471260 ( IDH1 -mutated patients only) or oral decitabine + VEN + IVO/enasidenib on NCT04774393 (arms for IDH1- and IDH2 -mutant disease, respectively). RESULTS The triplet regimens were well tolerated with low early mortality (n = 1 [2%] in 60 days) and a similar safety profile to HMA + VEN and isocitrate dehydrogenase inhibitor doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with an overall response rate of 95% (57/60). With a median follow-up of 27.4 months, the median overall survival (OS) has not yet been reached. The 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; the 2-year OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant, and 51% remain on study. CONCLUSION Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH -mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted.