Background
Phase 2, open-label, single-arm, multicenter registrational trial (NCT02719574). N=153 adults (147 efficacy-evaluable) with IDH1-mutated relapsed/refractory AML receiving olutasidenib monotherapy. Olutasidenib (FT-2102, REZLIDHIA) is a potent, selective oral inhibitor of mutant IDH1 (R132H/C/L/G/S) that blocks 2-hydroxyglutarate production. 66% had ≥2 prior regimens and 39% had received a prior hypomethylating agent. FDA approved 1 December 2022 on the interim analysis; 5-year final data published J Hematol Oncol 2025.
Interventions and follow up
Regimen: Olutasidenib 150 mg PO twice daily (continuous) in R/R IDH1-mutated AML
Primary endpoint: CR + CRh rate
Median follow-up: 5 years (final analysis, data cut-off June 2023)
Primary endpoint: CR + CRh rate
Median follow-up: 5 years (final analysis, data cut-off June 2023)
Results
CR/CRh (primary, N=147 evaluable): 35% (51/147), 95% CI 27–43
ORR: 48% (71/147), 95% CI 40–56.7
Median time to CR/CRh: 1.9 months (range 0.9–5.6)
Median duration of CR/CRh: 25.3 months (95% CI 13.5–NR)
Median OS (all): 11.5 months (95% CI 8.3–15.5)
By prior lines: 1–2 prior: CR/CRh 41%, mOS 13 months; ≥3 prior: CR/CRh 24%, mOS 8.9 months
By IDH1 subtype: R132C 42%, R132L/G/S 33%, R132H 17% — R132H less responsive
ORR: 48% (71/147), 95% CI 40–56.7
Median time to CR/CRh: 1.9 months (range 0.9–5.6)
Median duration of CR/CRh: 25.3 months (95% CI 13.5–NR)
Median OS (all): 11.5 months (95% CI 8.3–15.5)
By prior lines: 1–2 prior: CR/CRh 41%, mOS 13 months; ≥3 prior: CR/CRh 24%, mOS 8.9 months
By IDH1 subtype: R132C 42%, R132L/G/S 33%, R132H 17% — R132H less responsive
Adverse events
Haematologic (grade ≥3, ≥20%): Thrombocytopenia 28%, febrile neutropenia 22%, anaemia 22%
Differentiation syndrome: Key monitored AE (class effect of IDH inhibitors); grade ≥3 DS in a minority
Other: QTc prolongation monitored (grade ≥3 low); hepatotoxicity grade ≥3 ~10%; no new discontinuations due to AEs beyond year 3 (durable safety profile)
Differentiation syndrome: Key monitored AE (class effect of IDH inhibitors); grade ≥3 DS in a minority
Other: QTc prolongation monitored (grade ≥3 low); hepatotoxicity grade ≥3 ~10%; no new discontinuations due to AEs beyond year 3 (durable safety profile)
Conclusions
Olutasidenib achieved a 35% CR/CRh rate (ORR 48%) in heavily pretreated IDH1-mutated R/R AML, with a median response duration of 25.3 months — supporting durable remissions in this molecularly defined population. The 5-year data confirm the durability of the safety profile and clinical benefit.
Key Limitations
Single-arm, non-randomized design with no comparator, so relative benefit over alternative salvage therapies cannot be quantified. Modest CR/CRh rate (35%) leaves most patients without deep remission. R132H mutation subtype responds poorly (17%), limiting applicability across IDH1 genotypes. No head-to-head comparison with ivosidenib (the other IDH1 inhibitor). Median OS of 11.5 months reflects the poor prognosis of R/R AML; durability data are confined to responders.
Clinical Context
Olutasidenib (REZLIDHIA) received FDA approval in December 2022 for adults with R/R AML and a susceptible IDH1 mutation, providing a second oral IDH1 inhibitor option alongside ivosidenib. It offers a chemotherapy-free, targeted salvage option with durable responses in a subset of patients. ELN considers IDH1 inhibitors a reasonable option for IDH1-mutated R/R AML. Differentiation syndrome monitoring is required per the prescribing label.