Olutasidenib Elicits Durable Remissions With/Without Azacitidine in IDH1-Mutant MDS

Olutasidenib alone or administered with azacitidine was safe and clinically effective in patients with IDH1-mutated myelodysplastic syndrome.

Olutasidenib With/Without Azacitidine in IDH1-Mutant MDS

Olutasidenib With/Without Azacitidine

in IDH1-Mutant MDS

Treatment with olutasidenib (Rezlidhia) as both a monotherapy or in combination with azacitidine (Vidaza) elicited high, durable responses and displayed a manageable safety profile in patients with intermediate- to very high–risk IDH1-mutated myelodysplastic syndrome (MDS) across varying treatment backgrounds, according to analyses of a phase 1/2 trial (NCT02719574) presented at the 28th Annual International Congress on Hematologic Malignancies®.1

Pooled phase 1 and 2 data showed that 27% of patients treated with either the monotherapy or combination (n = 22) achieved a complete response (CR) and 32% achieved marrow CR, translating to an overall response rate (ORR) of 59%. Stable disease was achieved by 18% of patients and disease progression was experienced by 5% of patients. The median time to first response (TTR) was 2.0 months (range, 1.0-13.0), with a median duration of response (DOR) that was not reached (NR) at (range, 0-NR at 30.1+ months).

Further evaluation of responses in the monotherapy (n = 6) and combination (n = 16) arms showed ORRs of 33% vs 69%, respectively. In the monotherapy arm, the CR rate was 17% and the marrow CR rate was 17%; SD was achieved in 17% of patients and 17% experienced progressive disease (PD). In the combination arm, 31% of patients achieved a CR and 38% had a marrow CR; 19% had SD and no patients experienced PD. The median TTR was 4.7 months (range, 1.0-8.3) with the monotherapy vs 2.0 months (range, 1.0-13.0) with the combination. The median DOR was NR.

Patients receiving monotherapy at the approved dose level of 150 mg twice daily (n = 3) experienced a response rate of 66%; however, none of the 3 patients who received olutasidenib monotherapy at a lower dose level responded to treatment. In treatment-naive patients, the ORR was 86% vs 47% in relapsed/refractory patients.

Among patients dependent on red blood cell (RBC) transfusions at baseline (n = 13), 62% achieved 56-day transfusion independence (TI), and 63% of platelet-dependent patients (n = 8) achieved 56-day TI.

“These encouraging results show that olutasidenib has clinically meaningful activity in patients with IDH1-mutant MDS,” lead study author Amber Thomassen, APRN, of Rigel Pharmaceuticals, Inc., and colleagues, wrote in a poster of the data.

Olutasidenib is a potent and selective oral small molecule inhibitor of mutant IDH1. In 2022, the agent gained FDA approval for the treatment of adult patients with relapsed/refractory AML and a susceptible IDH1 mutation, as detected by an FDA-approved test.2

This regulatory decision was based on findings from the pivotal cohort of the registrational phase 1/2 Study 2102-HEM-101 trial (NCT02719574), in which patients with IDH1-mutant acute myeloid leukemia (AML) who received olutasidenib (n = 147) experienced a CR plus CR with partial hematologic recovery (CRh) rate of 35% (95% CI, 27%-43%); this included a CR rate of 32% and a CRh rate of 2.7%. The median time to CR+CRh was 1.9 months (range, 0.9-5.6), and the median duration of CR+CRh was 25.9 months (95% CI, 13.5-NR).

Additionally, olutasidenib was added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology in January 2023, as a recommended targeted therapy for the treatment of adult patients with relapsed/refractory AML with an IDH1 mutation.3

Notably, the open-label, multicenter phase 1/2 study comprised adult patients with AML as well as MDS.1 Further analyses were warranted to provide deeper insights into olutasidenib’s efficacy within this specific patient population.

The trial enrolled patients with either relapsed/refractory or treatment-naive disease in cases where standard therapy was contraindicated. Patients with MDS were classified as having intermediate-, high-, or very high–risk disease, and all harbored an IDH1Arg132X mutation. Other key inclusion criteria included adequate cardiac, renal, and hepatic function; as well as an ECOG performance status of 0 to 2.

Patients enrolled onto the phase 1 dose-expansion cohort of the study received 150 mg of olutasidenib twice daily in a continuous 28-day cycle alone or in combination with 75 mg/m2 of azacitidine twice daily on days 1 to 7 of each cycle. Those who continued onto the phase 2 portion were treated with the combination.

The study’s primary end point was CR+CRh rate per modified 2003 International Working Group criteria. Key secondary end points included ORR, duration of CR+CRh, DOR, RBC-TI rate, and overall survival.

Across both cohorts, the median patient age was 74 years (range, 59-87) and the majority were male (59%). Sixty-eight percent of patients had relapsed/refractory MDS, and 32% were treatment naive. Moreover, patients received a median of 1 prior lines of therapy (range, 1-4). Fourteen percent of patients received olutasidenib as a monotherapy at a once-daily dose ranging from 100 mg to 150 mg, 14% of patients received single-agent olutasidenib at the twice-daily 150-mg dose, and 73% of patients received the combination.

Regarding MDS risk type, 14% of patients were classified as intermediate risk, 64% were classified as high risk, and 23% were classified as very high risk. The distribution of patients classified as having good, intermediate, poor, very poor, and unknown cytogenetic risk was 45%, 18%, 9%, 9%, and 18%, respectively. IDH1 R132H mutations were present in 55% of patients, with IDH1 R132C and IDH1 R132G mutations present in 32% and 9% of patients, respectively.

Regarding safety, the overall toxicity profile of olutasidenib in patients with MDS remained consistent with the findings reported in patients with AML within this study.

The most frequently reported treatment-emergent adverse effects (TEAEs) included fatigue (any-grade, 64%; grade 3/4, 14%), nausea (59%; 5%), constipation (45%; 0%), thrombocytopenia (41%; 27%), vomiting (36%; 0%), febrile neutropenia (27%; 27%), diarrhea (27%; 5%), differentiation syndrome (14%; 5%), increased alanine aminotransferase (14%; 14%), and QT prolongation (5%; 5%).

Grade 3 or greater TEAEs were documented in 95% of patients, with grade 4 or higher TEAEs occurring in 55% of patients. The most common grade 3/4 TEAEs were cytopenias. Notably, grade 3 transaminitis was observed in 1 patient. Moreover, grade 3 differentiation syndrome occurred in another patient, who subsequently discontinued treatment due to pneumonia leading to respiratory failure and death after 23 days.

TEAEs led to death in 5 patients, with causes including disease progression (n = 3), pneumonia (n = 1), and chest fungal infection (n = 1). All of these events were deemed to be unrelated to the study treatment.


  1. Thomassen A, Cortes J, Yang J, et al. Olutasidenib alone or in combination with azacitidine induces durable complete remissions in patients with mIDH1 myelodysplastic syndromes/neoplasms (MDS). Presented at: 28th International Congress on Hematologic Malignancies; February 29-March 3, 2024. Miami, Florida.
  2. National Comprehensive Cancer Network® adds newly approved Rezlidhia™ (olutasidenib) to Clinical Practice Guidelines in Oncology for acute myeloid leukemia. News release. Rigel Pharmaceuticals, Inc. January 18, 2023. Accessed April 4, 2024.
  3. FDA approves olutasidenib for relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation. FDA. December 1, 2022. Accessed April 4, 2024.
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