Abstract
Study Rationale. Relapse remains a major cause of treatment failure following allogeneic hematopoietic cell transplantation (alloHCT) in patients with acute myeloid leukemia (AML), with rates approaching 40%. Mutations in IDH1 are prevalent in approximately 7-14% of AML, MDS, and CMML cases. Presence of these high risk mutations have been associated with increased rates of post-transplant relapse. Olutasidenib, a selective oral inhibitor of mutant IDH1 (mIDH1), has demonstrated clinical activity and safety in patients with relapsed/refractory mIDH1+ AML in prior phase 1/2 studies. This trial investigates the role of olutasidenib as maintenance therapy post-alloHCT to prevent relapse and improve leukemia-free survival (LFS) in patients with mIDH1+ myeloid malignancies.
Design and Methods. This is a single-arm, investigator-initiated pilot trial (NCT06543381) evaluating the safety, feasibility, and preliminary efficacy of olutasidenib maintenance following alloHCT in patients with mIDH1+ AML, MDS, or CMML. A total of 15 patients will be enrolled over a 3-year period. Olutasidenib will be administered at 150 mg orally twice daily for up to 24 months, beginning between days +50 to +120 post-transplant. Patients will be monitored for toxicity, disease relapse, and graft-versus-host disease (GVHD) outcomes. The primary objective will be to assess the safety and tolerability of olutasidenib as post-transplant maintenance therapy in patients with mIDH1+ AML, MDS, or CMML. The secondary objectives will include; i) Evaluation of overall survival (OS) and leukemia-free survival (LFS) at 1 and 2 years; ii) estimate cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and GVHD-free relapse-free survival (GRFS); and iii) Characterize incidence of acute (grades 2–4 and 3–4) and chronic GVHD. The exploratory objectives will include, i) assessment of measurable residual disease (MRD) status at initiation and during therapy via multiparameter flow cytometry and IDH1-specific NGS-PCR; ii) Measure mIDH1 variant allele fraction (VAF) using ddPCR BEAMing technology at defined intervals. For eligibility, patients must have confirmed mIDH1+ AML, MDS, or CMML at diagnosis, have undergone alloHCT, and demonstrate morphologic remission (≤5% blasts). Patients must have ECOG ≤2 or KPS ≥70 and adequate organ function. Exclusion criteria include active grade II–IV GVHD requiring systemic steroids and uncontrolled infections.
For statistical analysis, a Bayesian toxicity monitoring rule will be used to suspend accrual for excessive toxicity. The study includes three cohorts of five patients each, with a maximum acceptable probability of dose-limiting toxicity of 20%. This study is actively enrolling participants. No data are yet available for analysis. As of August 5, 2025, five pts have been screened, with three successfully enrolled and on study.
In summary, this trial aims to establish the safety and feasibility of olutasidenib maintenance post-alloHCT in patients with mIDH1+ myeloid malignancies. Given the high risk of relapse in this population and the promising activity of olutasidenib, this study may provide critical groundwork for larger prospective maintenance strategies in the post-transplant setting.
