BACKGROUND Patients (pts) with lysine methyltransferase 2A–rearranged (KMT2Ar)acute leukemia (AL) have a poor prognosis. The menin-KMT2A interaction is a key driver of leukemogenesis. Revumenib is a first-in-class, oral, selective inhibitor of the menin-KMT2A interaction. The AUGMENT-101 phase 2 analysis included pts with different leukemia types: ALL, AML, and mixed-phenotype AL (MPAL). Recent results (data cutoff [DCO]: Feb 29, 2024; efficacy-evaluable population, n=97; safety population, N=116) showed a complete remission (CR) or CR with partial hematologic recovery (CR+CRh) rate of 23% and an overall response rate (ORR) of 64% as well as a generally well-tolerated safety profile (Aldoss et al. ASH 2024. Abstract 211). Here we report outcomes by AL subtype (ALL, AML, and MPAL) in pts with KMT2Ar AL from the DCO (Feb 29, 2024).METHODS Pts aged ≥30 d with R/R KMT2Ar AL were eligible to enroll and receive revumenib 163 mg (95 mg/m2 if body weight <40 kg) every 12 h with a strong CYP3A4 inhibitor in 28-d continuous cycles. Treatment continued until unacceptable toxicity, disease progression, or lack of response after ≤4 cycles. Primary endpoints were CR+CRh rate, safety, and tolerability. Key secondary endpoints included ORR (composite CR+MLFS+partial remission) and duration of response (DOR). Pts with centrally confirmed KMT2Ar AL and ≥5% baseline bone marrow blasts within 28 d prior to the start of study treatment made up the efficacy-evaluable population. Measurable residual disease (MRD) was assessed locally by flow cytometry or PCR at investigators' discretion. The analysis of outcomes by AL type was descriptive and was not powered for statistical comparisons.

RESULTS As of the DCO, 97 pts comprised the efficacy-evaluable population (AML, 78 pts [80%]; ALL, 13 [13%]; MPAL, 6 [6%]). Median (range) age was 38 y (1-75) in pts with AML, 37 y (1-73) in pts with ALL, and 16 y (1-53) in pts with MPAL; 14 pts (18%) with AML, 3 (23%) with ALL, and 3 (50%) with MPAL were pediatric pts (aged <18 y). Median (range) number of prior lines of therapy was 2 (1-11) in pts with AML, 3 (1-8) in pts with ALL, and 2 (1-4) in pts with MPAL.

In the efficacy-evaluable population, ORR was 67% (95% CI, 55%–77%) in pts with AML, 46% (95% CI, 19%–75%) in pts with ALL, and 67% (95% CI, 22%–96%) in pts with MPAL. CR+CRh rate was 23% (18/78 pts; 95% CI, 14%–34%) in pts with AML, 23% (3/13; 95% CI, 5%–54%) in pts with ALL, and 17% (1/6; 95% CI, 0%–64%) in pts with MPAL. Median DOR (95% CI) was 7.7 mo (3.4–not reached [NR]), NR (0.9–NR), and 1.8 mo (NR–NR), respectively. Among pts who achieved CR/CRh, 18 had MRD status available (17 by flow; 1 by PCR) and 11 achieved MRD negativity. For evaluable responders with AML, ALL, and MPAL, MRD negativity was 64% (9/14), 33% (1/3), and 100% (1/1), respectively. Twenty-one pts proceeded to HSCT while in remission, including 19 with AML and 2 with MPAL; 9 pts with AML resumed revumenib post HSCT as maintenance.

In the safety population (N=116 [AML, n=95; ALL, n=15; MPAL, n=6]), 88 pts with AML (93%), 12 pts with ALL (80%), and 6 pts with MPAL (100%) experienced a grade ≥3 treatment-emergent AE (TEAE); 55 pts (58%), 4 pts (27%), and 4 pts (67%), respectively, experienced a grade ≥3 treatment-related AE (TRAE). In pts with AML, the most common (≥15%) grade ≥3 TRAEs were differentiation syndrome (DS; 14 [15%]), febrile neutropenia (FN; 14 [15%]), and QTc prolongation (15 [16%]; all grade 3). In pts with ALL, the most common (≥10%) grade ≥3 TRAEs were FN, DS, and nausea (2 [13%] each). In pts with MPAL, the most common (occurring in ≥2 pts) TRAEs were FN, anemia, decreased platelet count, and decreased neutrophil count (2 [33%] each). Six pts (5%) discontinued treatment due to a TRAE (AML, 5 pts [1 event each of cardiac failure, intracranial hemorrhage, myocardial ischemia, pneumonia, and respiratory failure]; ALL, 1 pt [nausea and vomiting]). DS events were experienced by 28% of pts with AML, 13% with ALL, and 33% with MPAL. Four deaths due to TRAEs occurred (1 event each of intracranial hemorrhage, myocardial ischemia, pneumonia, and respiratory failure), all in pts with AML.

CONCLUSIONS Revumenib monotherapy provides clinically meaningful and durable responses, including high rates of MRD negativity, in heavily pretreated pts with R/R KMT2Ar AL regardless of leukemia type: AML, ALL, or MPAL. The safety profile of revumenib is consistent with prior reports and is generally similar across AL subtypes.

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2025
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