Introduction: Revumenib is a first-in-class FDA-approved menin inhibitor that has shown efficacy in patients (pts) with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) with NPM1 mutations (NPM1m) or KMT2A-rearrangements (KMT2Ar). Given the clinical activity in R/R AML, we investigated whether revumenib can be safely added to intensive induction and consolidation therapy for newly diagnosed (ND) younger/fit AML pts. ETCTN 10596 (NCT05886049) is an ongoing phase 1 dose escalation/expansion, multicenter study assessing safety and preliminary efficacy of revumenib with standard 7+3 induction and cytarabine consolidation.

Methods: Adults aged 18-75 years with ND AML with either high-risk (HR) NPM1m/FLT3 wildtype (defined as age ≥60 yrs, secondary AML, or ELN 2022 adverse-risk genetics) or KMT2Ar were enrolled. Revumenib was combined with 7+3 induction (daunorubicin 60mg/m2 Days 1-3 and cytarabine 100mg/m2 Day 1-7) and cytarabine consolidation (1-1.5gm/m2 q12 hours (hrs) x 6 doses Days 1-3 based on age and CrCl). Revumenib dose escalation occurred independently between induction and consolidation on Days 2-28 with dose level 1 (DL1) at 226mg q12hr and dose level 2 (DL2) at 276mg q12hr without strong CYP3A4 inhibitor azoles. A Bayesian optimal interval design was used to guide decisions on dose-escalation based on dose-limiting toxicities (DLT) seen up to 42 days from the beginning of induction or consolidation separately. Reinduction was permitted. The primary endpoints for dose-escalation were safety and RP2D determination for both induction and consolidation with secondary endpoints of pharmacokinetic analysis of the combination and complete remission (CR) and CR with incomplete recovery rate.

Results: As of July 19, 2025, 12 pts were enrolled with a median age of 55 years (ranged 26-72), majority were male (8/12), and an even distribution of HR-NPM1m (6/12) and KMT2Ar (6/12). 9 pts have completed the DLT period on induction with 6 on DL1 and 3 on DL2. There has been 1 DLT on DL2 of Grade 5 typhlitis. Thus far, 8 pts have completed the consolidation DLT period with 3 on DL1 and 5 on DL2 with no DLTs noted. The most common grade >3 treatment-emergent adverse events (TEAEs) include WBC decrease (8/9), anemia (7/9), neutrophil decrease (7/9), platelet decreases (7/9), lymphocyte decrease (6/9), and febrile neutropenia (4/9). The most common non-hematologic events include skin infections, hypocalcemia, and hypokalemia. No patients have experienced differentiation syndrome or QTcF prolongation of any grade.

Of the 9 evaluable pts for response (4 HR-NPM1m and 5 KMT2Ar), 8/9 pts achieved CR with 1 pt death (HR-NPM1m) during induction. Interestingly 5 of the 8 pts who underwent mid-induction bone marrow biopsies had elevated blast counts (7-18%) and all achieved CR without requiring reinduction. For the 8 pts who have achieved CR, full hematologic recovery (ANC >1000/µL and platelets>100,000 K/µL) occurred at a median of 25.5 days (range 22-34 days). 4 pts have received allogeneic transplantation.

Conclusions: Revumenib combined with 7+3 overall appears to be well-tolerated both with 7+3 induction and consolidation. However, the grade 5 typhlitis event in induction DL2 occurred on Day 7 of treatment, earlier than expected with 7+3, and thus was deemed possibly related to revumenib. As induction DL1 has had no DLTs now in 6 patients, more data will be forthcoming on safety as additional patients have been enrolled on DL2. Pts who move forward with consolidation continue on DL2 as no DLTs have occurred to date. Other TEAEs and rates appear consistent with typical side effects with standard intensive chemotherapy. Notable clinical activity was seen to date corroborating further investigation of this regimen. Early bone marrow assessment after 7+3 + revumenib may not be informative and additional experience on this trial could inform whether this can be omitted.

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2025
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