Olutasidenib Shows Promise for Relapsed/Refractory IDH1-Mutated Acute Myeloid Leukemia

Olutasidenib, an investigational IDH1 inhibitor selective for mutant IDH1, was well tolerated and associated with durable complete remissions (CRs) in patients with high-risk, relapsed/refractory IDH1-mutated acute myeloid leukemia (AML), according to interim findings from a phase II trial presented at the 2021 American Society of Clinical Oncology Annual Meeting.

Current data regarding olutasidenib in IDH1-mutated AML are contained to small phase I/II trials with short follow-up periods, said presenter Stéphane De Botton, MD, PhD, of the Institut Gustave Roussy in Villejuif, France. While the small sample size and short follow-up are inherent limitations of these olutasidenib studies, the data so far have proved promising in terms of helping patients safely achieve remission, he added.

This recent study by Dr. De Botton and colleagues suggests that olutasidenib could hold clinical utility for a subset of patients with acquired mutations who otherwise have a fairly poor prognosis.

A total of 153 patients with relapsed/refractory, IDH1-mutated AML were enrolled in the phase II trial and received olutasidenib 150 mg twice daily as monotherapy. Dr. De Botton shared findings from an efficacy-evaluable cohort consisting of 123 patients. Investigators evaluated the rate of CR and CR with partial hematologic recovery (CRh) after a median follow-up of 9.7 months. For the study, CRh was defined as:

  • bone marrow blasts <5%
  • absolute neutrophil count >0.5×109/L
  • platelet count >50×109/L

At follow-up, a total of 43 patients (28%) were still on treatment, while 110 (72%) had discontinued. Primary reasons for treatment discontinuation were disease progression (31%), adverse events (AEs; 14%), death (10%), and transplant (8%).

In the efficacy-evaluable cohort, participants’ median age was 71 years (range = 32-87), and patients had received a median of two prior therapies (range = 1-7).

Dr. De Botton reported that, based on the observed response rates, the trial met early stopping criteria. Fifty-seven patients had a treatment response, for an overall response rate of 46%. This included a high CR+CRh rate of 33% and a CR rate of 30%.

Among all responders, response lasted for a median of 11.7 months. In the CR+CRh group, the median duration of response had not been reached. However, in the sensitivity analysis, the median duration of CR+CRh was 13.8 months when end of response was defined by hematopoietic cell transplantation or relapse.

The investigators also observed high rates of 56-day platelet transfusion independence and red blood cell transfusion independence (100% and 83%, respectively) among responders who were transfusion-dependent at baseline and achieved CR+CRh. In contrast, patients who did not achieve CR+CRh had platelet or red blood cell transfusion independence rates of 56% and 50%, respectively.

In terms of survival, the median overall survival (OS) was 10.5 months. While the median OS was not reached at time of data cutoff, the estimated 18-month OS was 87% among patients who achieved CR+CRh. “Better response is strongly associated with longer survival time,” Dr. De Botton said.

The most frequently reported treatment-emergent AEs included nausea (38%), constipation (25%), and leukocytosis (25%). Grade 3/4 all-causality treatment-emergent AEs reported in more than 10% of patients included febrile neutropenia (20%), anemia (19%), thrombocytopenia (16%), and neutropenia (13%). In addition, 21 patients (14%) developed investigator-assessed IDH1 differentiation syndrome. Most cases were resolved with treatment, but one case was fatal, the authors noted.

Based on these findings, olutasidenib induced durable CRs in this patient population and clinical benefit appeared to extend to patients who did not achieve CR+CRh. Also, while the safety profile was consistent with that of other IDH inhibitors, Dr. De Botton added that patients should be monitored for differentiation syndrome and liver abnormalities.

Study authors report relationships with Forma Therapeutics, which sponsored this trial.


De Botton S, Yee KWL, Recher C, et al. Effect of olutasidenib (FT-2102) on complete remissions in patients with relapsed/refractory (R/R) mIDH1 acute myeloid leukemia (AML): Results from a planned interim analysis of a phase 2 clinical trial. Abstract #7006. Presented at the 2021 American Society of Clinical Oncology Annual Meeting, June 4-8, 2021.