Olutasidenib Displays High Response Rates in IDH1-Mutated AML Arising From a Prior Myeloproliferative Neoplasm

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The small molecule IDH 1 inhibitor olutasidenib (Rezlidhia), either as monotherapy or in combination with azacitidine, showed significant clinical activity in patients with IDH1-mutated acute myeloid leukemia (AML) arising from amyeloproliferative neoplasm (MPN), according to data from a subset analysis of the phase 1/2 Study 2102-HEM-101 (NCT02719574) published in the British Journal of Haematology.1

Patients with a prior history of a MPN that transformed to AML who received the monotherapy (n = 6) or combination (n = 9) achieved a complete remission (CR) rate of 40%, with a median duration of response (DOR) of 15.6 months (range, 1.7-44.3). The CR with incomplete hematological recovery rate was 13%. The composite CR rate was 53% with a median DOR of 13.15 months (range, 2.4-48.7). Additionally, the morphological leukemia‐free state (MLFS) rate was 7%.

“Outcomes with olutasidenib appear appreciably better than previous reports of other therapies for [patients with] blast‐phase MPN, supporting the role for olutasidenib‐based therapy in mIDH1 AML secondary to MPN,” the study authors wrote in the publication.

In December 2022, olutasidenib earned FDA approval for the treatment of adult patients with relapsed/refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test.2 The regulatory decision was supported by prior data from Study 2102-HEM-101.

Unpacking the Study Design

Study 2102-HEM-101 was a multicenter, open-label study that enrolled patients with IDH1-mutated AML or myelodysplastic syndrome.1 The subset analysis included patients 18 years of age or older with IDH1-mutated AML arising from a prior MPN with disease that was relapsed/refractory to standard therapy or treatment naive. Eligible patients also needed to have an ECOG performance status of 0 to 2, adequate liver and renal function, and a baseline QT interval by Fridericia of 450 ms or less. Those with a history of a prior malignancy, prior IDH1-targeted agent use, uncontrolled infections, metabolic disorders, or significant heart disease were ineligible.

Patients received 150 mg of olutasidenib twice daily as monotherapy or in combination with intravenous or subcutaneous azacitidine at 75 mg/m2 for 7 days per cycle every 28 days.

The coprimary end points were safety and best response, defined as a CR, CR with partial hematologic recovery, or MLFS. Secondary end points included time to response, event-free survival, DOR, overall response rate (ORR), relapse-free survival, and pharmacokinetic measures.3

At baseline, the median age in the subset analysis was 67 years (range, 48-83).1 Most patients (n = 10) had relapsed/refractory disease and the median number of prior therapies was 2 (range, 1-6). Primary MPN diagnoses included polycythemia vera (n = 3), essential thrombocythemia (n = 3), primary myelofibrosis (n = 6), and MPN not otherwise specified (n = 3). Four patients had prior splenomegaly, and the median bone marrow blast percentage was 35% (range, 8%-90%).

Additional Efficacy Data and Safety Findings

Additional findings from the subset analysis revealed that the ORR was 60% with a median DOR of 14.3 months (range, 2.4-48.7). At a median follow-up of 55.3 months, the median overall survival (OS) was 13.8 months (95% CI, 3.7-23.7), and the median OS in patients with a CR was 24.8 months (95% CI, 13.8-not reached [NR]). The median OS in responders and non-responders was 20.9 months (95% CI, 4.4-44.3) and 4.1 months (95% CI, 1.6-NR), respectively. The median time to response for CR and composite CR was 3.8 months (range, 2-7) and 1.9 months (range, 1-6), respectively.

Regarding safety, all patients included in the analysis experienced any-grade treatment-emergent adverse effects (TEAEs); grade 3 or 4 TEAEs occurred in 73% of patients. Common grade 3 or 4 TEAEs included decreased red blood count (40%), infections (33%), decreased neutrophil count (27%), and febrile neutropenia (27%). Treatment discontinuation due to TEAEs was reported in 3 patients, 1 of whom was treated with olutasidenib monotherapy.

“[Although] the results of this subset analysis are encouraging, definitive conclusions cannot be drawn due to the inherent limitations of such subset analyses,” the study authors wrote in their conclusion. “Without adequate context from the larger study, the implications of these findings may not be fully appreciated. Nonetheless, these results can help guide future study designs and treatment strategies for patients with post‐MPN IDH1-mutated AML who need safe and effective therapeutic options.”

References

1. De Botton S, Récher C, Cortes J, et al. Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukaemia arising from a prior myeloproliferative neoplasm. Br J Haematol. 2025;206(4):1121-1128. doi:10.1111/bjh.19944
2. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. News release. FDA. December 1, 2022. Accessed May 21, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation
3. Open-label study of FT-2102 with or without azacitidine or cytarabine in patients with AML or MDS with an IDH1 mutation. ClinicalTrials.gov. Updated November 5, 2024. Accessed May 21, 2025. https://clinicaltrials.gov/study/NCT02719574