Introduction IDH1-mutated (mIDH1) acute myeloid leukemia (AML) is defined by D-2 hydroxyglutarate-driven epigenetic disruption and blocked cellular differentiation. Ivosidenib (IVO), an oral mutant IDH1 inhibitor, is approved for newly diagnosed (ND) patients (pts) who are ineligible for intensive chemotherapy (ICi). In the AGILE phase 3 trial, IVO combined with azacitidine significantly improved survival and remission rates. IVO monotherapy has also demonstrated durable responses and a favorable safety profile in this population. However, real-world evidence (RWE) on the use and outcomes of these regimens is limited. This study evaluates RW treatment patterns, clinical outcomes, and pt characteristics for IVO in combination with hypomethylating agent (IVO+HMA) and IVO monotherapy aiming to inform individualized treatment strategies in ND mIDH1 AML.

Methods We conducted a RWE study using electronic medical records and detailed chart reviews from a multi-center cohort of pts with mIDH1 AML, ICi, treated in the frontline (FL) setting with either IVO+HMA or IVO monotherapy between May 2018 and April 2025. Baseline characteristics influencing treatment pathways included risk categories using the 2022 European LeukemiaNet criteria, incorporating genetic co-mutations and cytogenetic abnormalities such as karyotypes. Performance status (PS) was defined using Eastern Cooperative Oncology Group (ECOG) PS, Karnofsky Performance Status , Palliative Performance Scale , and Activities of Daily Living (ADL), all mapped to ECOG. AML was classified as secondary if preceded by myeloid neoplasms or cytotoxic therapy. Primary endpoints included event-free survival (EFS) at 24 weeks and overall survival (OS) at 12 months. OS was defined as the time from treatment initiation to death from any cause and EFS was defined as time from treatment initiation until death, relapse, transition from FL within 24 weeks, or treatment failure without achieving complete remission (CR) by week 24. The secondary endpoint was the composite rate of CR and complete remission with incomplete hematologic recovery (CRi). Survival distributions were estimated using Kaplan-Meier (KM) methods. A multivariable logistic regression model was used to identify predictors of treatment choice.

Results IVO+HMA cohort included 31 pts (58.1% male; median age 78 [range 65-89]), and IVO cohort included 14 pts (50% male; median age 76 [range 63-88]). At baseline, most pts had primary AML (IVO+HMA: 58.1%; IVO: 92.9%), adverse-risk disease (IVO+HMA: 83.9%; IVO: 71.4%), and co-mutations (IVO+HMA: 87.1%; IVO: 85.7%). More pts in IVO+HMA were independent in ADL (87.1%) than IVO (35.7%) as indicated by lower ECOG PS score 0-1. Pts with lower ECOG PS score, secondary AML, >75 age were more likely to be treated by IVO+HMA. In IVO+HMA cohort, common adverse events (any grade) included sepsis (25.8%), thrombocytopenia (22.6%), and differentiation syndrome (16.1%), with 25.8% switching to second-line (2L) treatment. In IVO cohort, differentiation syndrome (28.6%) and thrombocytopenia (28.6%) were most common, with 21.4% switching to 2L therapy. Based on KM analysis, the 12-month OS probability was 78.1% (95% CI: 64.0%, 95.3%) in IVO+HMA cohort and 77.9% (95% CI: 45.2%, 92.3%) in IVO cohort. The 24-week EFS probability was 66.4% (95% CI: 41.4%, 82.7%) in IVO+HMA cohort and 59.7% (95% CI: 24.1%, 82.9%) in IVO cohort. The 24-week CR rate was 35.5% in IVO+HMA cohort, increasing to 45.2% at 12 months. In IVO cohort, the CR rate was 28.6% at both time points. No pts in either cohort achieved CRi.

Conclusions This RW evaluation, despite a smaller pt population and the inherent limitations of retrospective analyses, provides valuable preliminary insight into treatment patterns and outcomes associated with IVO+HMA and IVO monotherapy in ND mIDH1 AML. Among sicker, non-trial populations, both regimens demonstrated RW effectiveness consistent with findings from controlled clinical trials, including AGILE and AG120-C-001. While the combination therapy yields better CR and EFS and may be preferentially used in this pt population, IVO monotherapy may be a viable option in setting of poor PS. These results reinforce the importance of biomarker-driven therapies in informing treatment decisions and support the use of both regimens in routine clinical practice. They also highlight the need for larger, multi-source RWE studies to further characterize treatment outcomes and strengthen overall evidence.

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2025
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