On December 1, 2022, the IDH1 inhibitor olutasidenib was approved for the treatment of adults with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation, as detected by a U.S. Food and Drug Administration (FDA)-approved test.1 The FDA simultaneously approved the Abbott RealTime IDH1 Assay to select patients for treatment with olutasidenib.
Supporting Efficacy Data
Approval was based on findings in the multicenter Study 2102-HEM-101 (ClinicalTrials.gov identifier NCT02719574), in which 147 patients with IDH1 mutation confirmed by the previously mentioned assay received oral olutasidenib at 150 mg twice daily until disease progression, unacceptable toxicity, or hematopoietic stem cell transplantation (HSCT). Median treatment duration was 4.7 months (range = 0.1–26 months). A total of 16 patients (11%) underwent HSCT following olutasidenib administration.
OF NOTE
Olutasidenib has a boxed warning for differentiation syndrome, which can be fatal. Olutasidenib has warnings/precautions for hepatotoxicity
Complete remission or complete remission with partial hematologic recovery occurred in 51 patients (35%, 95% confidence interval [CI] = 27%–43%), with complete remission in 47 (32%). Median duration of such response was 25.9 months (95% CI = 13.5 months to not reached). Median time to response was 1.9 months, with a range of 0.9 to 5.6 months. Among 86 patients with red blood cell– or platelet-transfusion dependence at baseline, 29 (34%) became transfusion-independent during any 56-day postbaseline period. Among 61 patients who were transfusion-independent, 39 (64%) remained transfusion-independent during any 56-day postbaseline period.
How It Is Used
Patients must be selected for treatment based on the presence of IDH1 mutations in blood or bone marrow. The recommended olutasidenib dose is 150 mg twice daily until disease progression or unacceptable toxicity. In the absence of disease progression or unacceptable toxicity, treatment is recommended for a minimum of 6 months to allow for clinical response. Product labeling provides instructions on dosage modification, including dose reduction, for adverse reactions including differentiation syndrome, noninfectious leukocytosis, and grade 3 or 4 hepatotoxicity.
Safety Profile
Among 153 patients receiving olutasidenib in Study 2102-HEM-101, the most common adverse events of any grade were nausea (38%), fatigue/malaise (36%), arthralgia (28%), constipation (26%), leukocytosis (25%), dyspnea (24%), pyrexia (24%), rash (24%), mucositis (23%), diarrhea (20%), and transaminitis (20%). The most common grade 3 or 4 adverse events included transaminitis (12%), leukocytosis (9%), and differentiation syndrome (8%, any grade in 19%). The most common grade 3 or 4 laboratory abnormalities were increased alanine aminotransferase (13%) and aspartate aminotransferase (10%).
KEY POINTS
- Olutasidenib was approved for treatment of adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.
- The recommended olutasidenib dose is 150 mg twice daily until disease progression or unacceptable toxicity.
Serious adverse events were reported in 25% of patients, most commonly differentiation syndrome (9%) and transaminitis (6%). Adverse events—including transaminitis, differentiation syndrome, and gallbladder disorders (≥ 1% each)—led to discontinuation of treatment in 8% of patients. Fatal adverse events (differentiation syndrome) occurred in 1% of patients.
Olutasidenib has a boxed warning for differentiation syndrome, which can be fatal. Olutasidenib has warnings/precautions for hepatotoxicity. Patients should be advised not to breastfeed while receiving olutasidenib.
REFERENCE
1. Rezlidhia (olutasidenib) capsules, for oral use, prescribing information, Forma Therapeutics, Inc., December 2022. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf. Accessed December 12, 2022.
