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Another IDH Inhibitor Option for Acute Myeloid Leukemia?

December 30, 2021

The IDH1 inhibitor olutasidenib, as a single agent and in combination with azacitidine, demonstrated "favorable safety and clinical activity" in patients with IDH1-mutated acute myeloid leukemia (AML), according to results from a phase I study presented by Justin M. Watts, MD, from the University of Miami Sylvester Comprehensive Cancer Center, at the 2019 ASH Annual Meeting.

As of September 12, 2019, 78 patients were enrolled in the multicenter, open-label study. Patients were assigned to be treated with either single-agent olutasidenib (n=32) or olutasidenib in combination with azacitidine (n=46). Median age was 72 years (range = 35-87) in the single-agent group and 67 years (range = 31-88) in the relapsed/refractory group. Participants had received a median of two prior therapies (range = 0-9) in the single-agent group and three prior therapies (range = 0-6) in the combination group.

As of the presentation, safety data were available for all patients, and response data were evaluable for:

  • 26 patients in the single-agent group (22 with relapsed/refractory disease and 4 with treatment-naïve disease)
  • 39 patients in the combination group (26 with relapsed/refractory disease and 13 with treatment-naïve disease)

Per study protocol, patients received olutasidenib 150 mg once daily or 300 mg once or twice daily. The median treatment duration was 4.2 months for single-agent olutasidenib (range = 1-32 months) and 4.7 months for the combination (range = 1-18 months).

During follow-up, 62 patients discontinued treatment, including 29 in the single-agent arm and 33 in the combination group, for the following reasons:

  • progressive disease (n=18; 11 single agent, 7 combination)
  • hematopoietic cell transplantation (n=14; 4 single agent, 10 combination)
  • death (n=9; 5 single agent, 4 combination)
  • other reasons (n=6; 3 single agent, 3 combination), including lack of response, transition to hospice, and alternative therapy

The investigators reported that patients in each treatment group experienced similar grade 3/4 adverse events, including:

  • thrombocytopenia (28% in the single agent group and 33% in the combination group)
  • febrile neutropenia (22% and 28%)
  • anemia (22% and 20%)
  • pneumonia (16% and 11%)
  • leukocytosis (13% and 15%)

However, compared with the single-agent treatment, participants in the combination group had higher rates of grade 3/4 neutropenia (28% and 6%, respectively), fatigue (17% and 6%), and nausea (9% and 0%). Differentiation syndrome, which occurred in 10 patients (including 4 in the single-agent group and 6 in the combination group) resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care.

While no deaths were considered treatment-related, 19 patients (24%) died during treatment or within 28 days of their last dose.

The overall response rate (defined as partial response or better) appeared to be higher in the combination group, in both patients with relapsed/refractory disease or treatment-naïve disease:

  • single agent: 9 (41%) and 1 (25%)
  • combination: 12 (46%) and 10 (77%)

Dr. Watts added that seven patients in the single-agent group and 11 patients in the combination group experienced complete remission (CR) or CR with incomplete hematologic recovery (CRh). CRs were considered durable, lasting for up to 27 months, the authors reported, adding that stable disease was observed in patients who did not meet response criteria.

Median overall survival (OS) appeared to be longer in the combination group as well, ranging from 52.6 weeks (range = 18.3 to not reached) in the relapsed/refractory group to not reached for patients with treatment-naïve disease. In the single-agent group, median OS was 37.7 weeks (range = 10.7 to not reached).

Although the results from this early-phase study are limited by the nonrandomized design and small number of enrolled patients, the researchers concluded that "olutasidenib is well tolerated, demonstrates clinical activity in a high-risk AML population, and induces IDH1 mutation clearance in patients with treatment-naïve and relapsed/refractory AML, regardless of response."

Based on these findings, olutasidenib 150 mg twice daily was selected as the recommended phase II dose. Dr. Watts added that phase II trials of olutasidenib, both as monotherapy and combined with azacitidine, in patients with IDH1-mutated AML or myelodysplastic syndromes are ongoing, and alternate combinations are being explored.

The authors report relationships with FORMA Therapeutics, which sponsored the trial.


Watts JM, Baer MR, Yang J, et al. Olutasidenib (FT-2102), an IDH1m inhibitor as a single agent or in combination with azacitidine, induces deep clinical responses with mutation clearance in patients with acute myeloid leukemia treated in a phase 1 dose escalation and expansion study. Abstract #231. Presented at the 2019 ASH Annual Meeting, December 7, 2019; Orlando, FL.


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