AZA+VEN+IVO Triplet Therapy for Newly Diagnosed IDH1 AML: High Response Rates and Durable Efficacy

　　1.Background and Objective

　　The advent of targeted therapy has improved the prognosis of IDH1-mutant acute myeloid leukemia(AML).While dual regimens(venetoclax plus HMA,or azacitidine plus ivosidenib)are effective,a significant proportion of patients do not respond or eventually relapse.Combining all three agents into a"triplet"regimen may improve outcomes.This article reports the results of the fully enrolled newly diagnosed(ND)cohort from a multicenter Ib/II study(NCT03471260)of AZA+VEN+IVO in IDH1 AML.

　　2.Methods

　　Eligible adults(≥18 years)with ND IDH1 AML unfit for standard induction chemotherapy received treatment at the recommended phase 2 dose(RP2D).The regimen consisted of azacitidine 75 mg/m²(days 1-7),venetoclax 400 mg(days 1-14),and ivosidenib 500 mg(starting C1D14 continuously).Dose reductions were allowed to minimize myelosuppression.Primary endpoints were safety and overall response rate(ORR:CR+CRh+CRi+MLF).

　　3.Results

　　Forty patients from four US academic centers were enrolled.Median age was 72 years.ORR was 95%,with 93%achieving composite complete remission(CRc).Median cycle to best response was 2.Among CRc responders,92%achieved measurable residual disease(MRD)negativity by flow cytometry.With median follow-up of 35 months,median OS and duration of response(DOR)were not reached;3-year OS was 79%.45%of patients transitioned to stem cell transplantation.Estimated 3-year DOR was approximately 82%-83%.

　　Non-hematologic adverse events occurred in 80%of patients,with 30%being grade≥3,mostly infectious.Grade≥3 QTc prolongation,tumor lysis syndrome,and differentiation syndrome were infrequent and managed successfully.

　　4.Conclusion

　　In this multicenter study,the AZA+VEN+IVO triplet demonstrated a high MRD-negative response rate,durable remissions,and a safety profile comparable to dual regimens in ND IDH1 AML,representing a promising therapeutic approach.