Olutasidenib Monotherapy Yields Responses in Primary Refractory IDH1-Mutant AML

Olutasidenib (Rezlidhia) monotherapy generated clinically meaningful and durable responses in patients with IDH1-mutant acute myeloid leukemia (AML) whose disease was refractory to prior induction therapy, according to findings from a post hoc analysis of the phase 2 2102-HEM-101 trial (NCT02719574), which were presented at the 2025 SOHO Annual Meeting.1

Among primary refractory patients treated with olutasidenib (n = 46), the complete response (CR)/CR with partial hematologic recovery (CRh) rate was 30% (CR, 28%; CRh, 2%), and the median duration of CR/CRh was 17.6 months (95% CI, 3.7-not reached; range, 1.8-54.6). The overall response rate (ORR) was 50%, and the median duration of response (DOR) was 6.7 months (95% CI, 3.7-17.6). Additional response outcomes included CR with incomplete hematologic recovery (13%), morphologic leukemia-free state/partial response (7%), clinical benefit/stable disease/resistant disease (26%), progressive disease (2%), and not evaluated/not determined (22%). Furthermore, the median overall survival (OS) was 8.9 months (95% CI, 5.4-13.8).

“Olutasidenib monotherapy may offer an effective and tolerable treatment option for patients with primary refractory disease, a population traditionally associated with poor outcomes,” lead study author Justin M. Watts, MD, and coauthors wrote in a poster of the data.

Watts is the Pap Corps Endowed Professorship in Leukemia, an associate professor of clinical medicine in the Division of Hematology, and chief of the Leukemia Section at the University of Miami Miller School of Medicine in Florida.

Where does olutasidenib fit into the AML treatment paradigm?

Olutasidenib is a potent IDH1 inhibitor that is selective for the mutant form of the gene. It binds and inhibits both single- and double-mutant IDH1.

In 2022, the FDA approved this agent for the treatment of adult patients with relapsed/refractory AML with a susceptible IDH1 mutation as detected by an FDA-approved test.1,2 This regulatory decision was based on data from the 2102-HEM-101 trial, in which patients with IDH1 mutations who received olutasidenib (n = 147) achieved a CR/CRh rate of 35% (95% CI, 27%-43%).

However, the poster authors noted that patients with IDH1-mutant AML who do not achieve a CR with initial or subsequent induction therapy often have worse OS outcomes compared with patients who relapse following remission.1 Therefore, they conducted a post hoc analysis of the pivotal phase 2 trial to assess the efficacy and safety of olutasidenib in a subset of patients with primary refractory disease.

What was the design of the phase 2 study that led to the FDA approval of olutasidenib, and what were the baseline characteristics of the primary refractory population?

In the phase 2 trial, patients received olutasidenib at 150 mg twice a day in continuous 28-day cycles. Key efficacy end points included CR/CRh rate, ORR, DOR, and OS.

Among the primary refractory patients, the median age was 71 years (range, 45-87), and 46% were female. In total, 72%, 26%, and 2% had ECOG performance statuses of 0 or 1, 2, and 3, respectively. Cytogenetic risk statuses were favorable (4%), intermediate (74%), poor (15%), or unknown (7%).

Patients have received 1 (61%), 2 (28%), or at least 3 (11%) prior therapies. Prior chemotherapy regimens included intensive chemotherapy (39%), non-intensive chemotherapy (54%), and unknown (7%). Prior anticancer therapies comprising patients’ overall treatment histories included cytarabine (50%), cytarabine plus an anthracycline (43%), a hypomethylating agent (HMA; 54%), venetoclax (7%), a HMA plus venetoclax (4%), and hematopoietic stem cell transplant (4%). IDH1 mutation types included R132C (63%), R132H (22%), and R132L/R132G/R132S (15%). Additionally, 7%, 52%, and 20% of patients had 0, 1 to 3, and 4 or more co-mutations; co-mutation information was missing for 22% of patients. The most commonly observed co-mutations were ASXL1 (n = 11), DNMT3A (n = 9), NPM1 (n = 7), SRSF2 (n = 6), PHF6 (n = 5), RUNX1 (n = 5), and JAK2 (n = 5).

What were the key safety findings with olutasidenib in primary refractory AML?

All patients reported at least 1 treatment-emergent adverse effect (TEAE). Grade 3 or higher TEAEs were reported in 93% of patients, and 85% of patients had a serious TEAE. The most commonly reported any-grade TEAEs included nausea (41%), vomiting (30%), increased white blood cell counts (30%), pyrexia (28%), dyspnea (26%), decreased red blood cell counts (26%), constipation (24%), hypokalemia (24%), decreased platelet counts (24%), diarrhea (22%), and differentiation syndrome (22%). Notably, increased alanine aminotransferase and aspartate aminotransferase levels were reported in fewer than 20% of patients. Additionally, investigators reported no grade 3 or higher QT prolongation.

“No new safety signals were identified in this subset; the safety profile was consistent with previously reported findings for olutasidenib,” the authors concluded.

References

1. Watts JM, Curti A, de Botton S, et al. Efficacy and safety of olutasidenib monotherapy in primary refractory acute myeloid leukemia: a post hoc analysis of a phase 2 study. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Abstract AML-606.
2. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. FDA. December 1, 2022. Accessed September 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olutasidenib-relapsed-or-refractory-acute-myeloid-leukemia-susceptible-idh1-mutation?utm_medium=email&utm_source=govdelivery