Introduction

Venetoclax in combination with a hypomethylating agent has become a standard treatment for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Although this regimen is initially effective, most patients ultimately relapse, with a median overall survival (OS) of just 3.4 months following relapse (Abaza et al., 2024). Olutasidenib, a selective oral inhibitor of mutated IDH1 (mIDH1), is approved for the treatment of relapsed or refractory (R/R) mIDH1 AML. In the final 5-year results from the pivotal Phase 2 trial (NCT02719574), olutasidenib demonstrated efficacy and tolerability, achieving a complete remission (CR) or CR with partial hematologic recovery (CRh) in 35% of patients and a median CR/CRh duration of 25.3 months (Cortes et al., 2024). While clinical trials have shown encouraging efficacy of olutasidenib in the post-venetoclax setting, real-world data on its utilization and outcomes in this context remain limited.Methods

This retrospective cohort study analyzed data from Loopback Analytics' electronic health records database in the United States until September 2024, incorporating structured clinical data and abstracted data from physician notes. Eligible patients were ≥18 years old with a confirmed diagnosis of R/R AML with an IDH1 mutation, who had received a prior venetoclax regimen, were not enrolled in clinical trials, had available physician notes, received at least 25 days of olutasidenib treatment, and had a documented response status.

A manual review of treatment lines was conducted, based on predefined criteria to determine line-of-therapy transitions and classify treatment regimens. Treatment response was categorized as CR, CRh, CR with incomplete blood count recovery (CRi), and morphologic leukemia-free state (MLFS). Baseline demographics, treatment sequences, and clinical outcomes were summarized using descriptive statistics. OS was estimated using Kaplan-Meier methods. Duration of response and time to response were documented for a subset of patients with available data.Results

Fourteen olutasidenib-treated patients in the Loopback database met inclusion criteria for the study. Median age at olutasidenib initiation was 62.5 years, and 71% of patients were male. Three patients (21%) received a hematopoietic stem cell transplant (HSCT) prior to olutasidenib initiation. Additionally, most patients (79%) presented with at least one co-occurring mutation; the most common co-mutations were FLT3 (36%), NPM1 (29%), and RUNX1 (36%). The median duration of olutasidenib treatment was 4.2 months (interquartile range [IQR], 2.7-5.6 months) and it was administered in the first instance as monotherapy in 57% of patients. Treatment sequencing varied, 50 % of patients received venetoclax as first-line therapy; olutasidenib treatment immediately followed venetoclax treatment in 79% (11/14) of cases. The most common reason for olutasidenib discontinuation was disease progression.

The overall response rate (ORR) was 50% (7/14, comprising 2 CR, 2 CRi, 1 CRh, and 2 MLFS) and the composite complete remission (CRc) rate was 36% (5/14). Among patients who achieved any response, six (86%) received venetoclax immediately prior to olutasidenib. Four patients were evaluable for duration of response. One patient underwent HSCT in CR 50 days after achieving this response. Another patient had a CRi with a duration of 147 days prior to relapse. The remaining two patients were continuing olutasidenib at the time of data cutoff, with ongoing MLFS and CR responses of 69 and 362 days, respectively. Median OS from olutasidenib initiation in the full cohort was 12.2 months, with the proportion of patients surviving 6, 9, and 12 months estimated to be 88%, 70%, and 53%, respectively.Conclusion

This study offers novel real-world insights into olutasidenib treatment patterns and outcomes in patients with mIDH1 R/R AML after prior venetoclax exposure. Olutasidenib was most frequently used as monotherapy, half directly following venetoclax. In this real-world cohort, despite the small sample size, 50% of patients responded to post-venetoclax olutasidenib consistent with the clinical efficacy observed in the pivotal Phase 2 trial. These findings support the use of olutasidenib as a viable therapeutic option in post-venetoclax treatment settings although more data is required to confirm these findings.

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2025
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