Ivosidenib combined with venetoclax and azacitidine for the treatment of newly diagnosed IDH1-mutant Acute Myeloid Leukemia: A prospective, two cohorts, multicenter study

Abstract Background: In 2009, IDH1 mutations (IDH1m) were first described in AML. Over the past 15 years, the adverse impact of IDH1m on prognosis has gradually been recognized, and treatment strategies for IDH1m have been evolving. In newly diagnosed AML, the treatment approach has progressed from single-agent ivosidenib to a dual-drug regimen with azacitidine. Recently, data have been disclosed showing the treatment efficacy of Ivosidenib(IVO)+Venetoclax(VEN) ± Azacitidine(AZA), with a 3-year survival rate reaching 71%, improving the prognosis of IDH1m AML patients. In China, we have conducted a study on IVO+VEN+AZA for newly diagnosed IDH1m AML to Explore the efficacy and safety of IVO+VEN+AZA in newly diagnosed IDH1-mutant AML in China. Methodes: This is an in-progress trial, continuous data will be summarized by descriptive statistics. Time-to-event endpoints will be estimated using the KM method. Point estimates and 95% confidence intervals will be provided where appropriate, and estimates of the median and other quantiles, as well as individual time points (eg, 3-, 6-, and 12-month rates) will be produced. Results: This is a prospective, single-arm, dual-cohort, multi-center study enrolling patients who are ≥18 years of age, have previously untreated AML, have an IDH1 mutation resulting in an R132C, R132G, R132H, R132L, or R132S substitution, and have adequate hepatic function. The study consists of two cohorts: Cohort 1 includes unfit AML patients who will receive 6 cycles of IVO+VEN+AZA. Cohort 2 includes fit AML patients who after 1-2 cycles of IVO+VEN+AZA induction therapy, will receive 4 cycles of the same regimen for consolidation if they achieve remission after completing the above treatments. Patients in both cohorts will proceed to either allo-HSCT or IVO+AZA maintenance therapy until disease progression, death, intolerable toxicity, or other predefined events. The primary objective is to determine the best composite complete remission rate (CRc), which includes both complete remission (CR) and complete remission with incomplete marrow recovery (CRi). The study will enroll 42 patients, with 27 patients in Cohort 1 and 15 patients in Cohort 2. Secondary endpoints include event-free survival (EFS), overall survival (OS), measurable residual disease (MRD) negativity rate, and others. Serial quality of life assessments and adverse event monitoring will be conducted throughout the study to fully understand the impact of IVO+VEN±AZA on patients' lives. Conclusion: Previous data showed that the multi-drug combination regimen of IVO demonstrates good tolerability and efficacy. This study will be the first to clarify the feasibility of multi-drug regimens in the treatment of IDH1m AML patients in China, providing ideas and evidence to improve the prognosis of Chinese IDH1m AML patients.