Introduction: Menin is essential for leukemogenesis in KMT2A-rearranged (KMT2Ar) and Nucleophosmin 1-mutated (NPM1c) AML. Menin inhibitors (MENINi) show promise in relapsed or refractory (R/R) KMT2Ar or NPM1c AML but resistance, including MEN1 mutations, can develop. Outcomes after MENINi failure are unknown.

Objective: To characterize treatment outcomes for pts with R/R AML after MENINi treatment.

Methods: We performed a multi-center retrospective study of adult pts with R/R AML after MENINi monotherapy at 4 U.S. academic centers (January 2020-March 2025). Relapsed AML was defined as ≥5% marrow blasts after CR, CRi, or MLFS. Refractory AML was defined as failure to respond to ≥1 cycle of MENINi, or progression after ≥14 days. ELN 2022 criteria were used.

Results: We identified 84 adult pts (median age 55, 43% male) with R/R AML after receiving MENINi monotherapy (“MENINi failure”). This cohort included 53 KMT2Ar (63%) and 19 NPM1c (23%) pts, and 12 pts with other mutations such as NUP98r (14%). At diagnosis, pts were mostly intermediate (n=34, 40%) or adverse risk (n=42, 50%), and 25% of pts had therapy-related AML. Prior to MENINi, 86% (n=72) received intensive chemotherapy (IC) and 77% (n=65) received venetoclax (VEN)-based therapy, including 65% (n=55) who had received both. Thirty-eight percent (n=32) of pts previously underwent alloSCT.

Revumenib was the most used MENINi (n=61, 73%), followed by bleximenib (n=12, 14%) and ziftomenib (n=9, %). Most pts received MENINi after 4 or more prior treatment regimens (n=45, 54%). Sixty-two pts (74%) did not respond to MENINi, and 22 (26%) achieved an overall response (19 CR/CRi, 3 MLFS) before relapse.

After MENINi failure, 40% of pts (n=34) did not receive any further therapy. The most common therapies after MENINi failure were hypomethylating agent (HMA) and VEN (n=13;15%), investigational agents (n=13, 15%), and gilteritinib-based regimens (GILT; n=9, 11%). Five pts who relapsed after responding to then discontinuing their initial MENINi, such as after alloSCT, were rechallenged with their previous MENINi. Two pts who were refractory to one MENINi were subsequently treated with a different MENINi.

Due to the heterogeneity of clinical trial therapies, our analysis focused on pts who received standard of care therapy (n=37). Of the 13 pts who received investigational therapies, the CR/CRi rate was 7.6% (n=1) Non-investigational post-MENINi therapy resulted in CR/CRi rate of 19% (n=7) and ORR of 32% (n=12). Responses were achieved with HMA/VEN (CR/CRi 15%, n=2; ORR 38%, n=5), IC+VEN (CR/CRi 67%, n=4; ORR 83%, n=5), and MENINi switching (CR/CRi 50%, n=1; ORR 100%, n=2, both bleximenib to revumenib). No responses were seen with MENINi rechallenge (n=5), GILT-based therapy (n=9, 6 of 9 GILT-naïve), or IC without VEN (n=2). There was a statistically significant difference in likelihood of response based on therapy used (CR/CRi, p = 0.016; ORR, p <0.001). Pts without prior VEN exposure were more likely to achieve an overall response (20% ORR with prior VEN, 58% ORR without, p = 0.029).

The most common mutations at the time of MENINi failure were FLT3-ITD (n=12, 32%), WT1 (n=8, 21%), and MEN1 (n=8, 21%). The FLT3-ITD and WT1 mutations were all pre-existing mutations noted prior to MENINi, whereas the MEN1 mutations were all newly emergent. No pts with a FLT3-ITD mutation achieved CR/CRi. No other individual mutations or cytogenetic features were significant predictors of response, though sample size was limited. The CR/CRi rate with WT1 and MEN1 mutations were 12.5% (n=1 each). All MEN1 mutations were seen in revumenib-treated pts, though MEN1 testing was not available for all pts.

At a median follow-up of 19.4 months, median overall survival (mOS) after non-investigational therapy was 4.4 months. Pts without prior VEN exposure trended toward longer mOS (8.5 mo vs 4.0 mo, p = 0.075). Achieving CR/CRi and ORR were associated with improved mOS (both 15.4 vs 3.4 mo, p=0.048 and p=0.0055, respectively). Among the 6 responders who proceeded to alloSCT, mOS was not reached at 18.2 month follow-up; 5 pts remain alive and 4 in remission.

Conclusions: MENINi are promising in AML, but outcomes after failure are poor. VEN-based regimens, especially in VEN-naïve pts, and MENINi switching can yield responses associated with improved survival. Studies addressing optimal sequencing as well as preventing and overcoming resistance are needed.

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2025
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