Clinical characteristics and response in olutasidenib-treated Relapsed/Refractory mIDH1 Acute Myeloid Leukemia (AML) patients with stable disease following two treatment cycles
Year: 2025
Type: conference-abstract
Abstract: Background: Olutasidenib is a potent, selective oral inhibitor of mutated IDH1 (mIDH1) approved for the treatment of relapsed or refractory (R/R) mIDH1 AML. The phase 2 pivotal cohort (NCT02719574) demonstrated the efficacy and tolerability of olutasidenib, with a complete remission (CR)/CR with partial hematologic recovery (CRh) rate of 35% and a median CR/CRh duration of 25.3 months. While early clinical response is a common benchmark of efficacy, patients without an early response may still experience meaningful clinical benefit and achieve a response with olutasidenib. This post hoc analysis reports clinical characteristics in patients who had stable disease (SD) after two treatment cycles of olutasidenib, defined as patients who had neither achieved a response nor met criteria for progressive disease per study protocol, and analyzes the outcome of these delayed responders. Methods: The pivotal cohort of the phase 2 study assessed olutasidenib 150 mg BID in adults with R/R mIDH1 AML. Clinical response, treatment duration, and overall survival (OS) were assessed along with adverse events. Results: Of 147 patients with R/R mIDH1 AML who received olutasidenib, 36 (24%) patients maintained SD after 2 cycles of treatment. The median age was 71.5 years (range: 41, 83) and 50% were female. The most common IDH1 mutation type was R132C (44%), followed by R132 L/G/S and R132H (28% each). Prior therapy included hypomethylating agents (n=16; 44%), hematopoietic stem cell transplant (n=6; 17%), and venetoclax therapy (n=2; 6%). Treatment duration ranged from 2.6-51.1 months. In these 36 patients, the response rate was 33% (n=12), including 6 (17%) CR (5 CR and 1 molecular CR), 2 (6%) CRh, 1 (3%) CR with incomplete recovery, 1 (3%) morphologic leukemia-free state, and 2 (6%) partial remission. Median time to best response was 3.7 months (range: 2.8-5.7). Eight patients (22%) remained in SD and 16 (44%) had subsequent disease progression on study. Sixty-seven percent (8/12) of the late responders had an R132C mutation. Of the patients with prior HSCT (n=6), 1 (17%) was a late responder, 2 (33%) had SD, and 3 (50%) progressed. In late responders, median duration of response, duration of CR/CRh, and duration of CR were 9.9 months (95% confidence interval [CI]:1.9, not reached [NR]), 17.3 months (95% CI: 1.8, NR), and NR months (95% CI: 8.1, NR), respectively. Additionally, of the late responders who were transfusion dependent for platelets (n=6) or red blood cells (n=9) at baseline, 5 (83%) and 8 (89%), respectively, became transfusion independent. Patients who achieved any response (n=12) had a longer median treatment duration (10.1 months) than non-responders (n=24; 4.2 months). Median OS for late responders was 23.9 months (95% CI: 9.1, NR) and 32.7 months (95% CI: 6.3, NR) for those with CR/CRh. Cox regression analysis showed that the risk of death was reduced by 88% in late responders compared with those patients who stayed in SD (hazard ratio=0.12 [95% CI: 0.03, 0.39]). Treatment-emergent adverse events (TEAEs) irrespective of relationship to olutasidenib occurred in all patients. The most frequent (>25%) were nausea, decreased appetite, cough, pyrexia, increased white blood cell count, fatigue, and hypokalemia. Grade ≥3 TEAEs occurring in >15% of patients included pneumonia, febrile neutropenia, and decreased red blood cell count. Conclusions: Patients with SD after 2 cycles of olutasidenib may experience meaningful clinical benefit with continued treatment, as one-third of these patients subsequently achieved a late response resulting in a lower risk of death compared to patients with no later response. These findings suggest that early SD does not predict treatment failure and support continuing olutasidenib for at least 6 cycles or until disease progression.
Source: Blood
Institutions: University of Miami, Sylvester Comprehensive Cancer Center, Roswell Park Comprehensive Cancer Center, University of California Davis Medical Center, University of California, Davis, Sarah Cannon, Wayne State University, The Barbara Ann Karmanos Cancer Institute, New York Medical College, The Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, Peter MacCallum Cancer Centre, Institut Gustave Roussy, Rigel (United States)
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417015697
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