Abstract
Background Children with HOX-driven acute leukemias, including KMT2A and NUP98 rearrangements (r), have dismal outcomes after relapse, with complete remission (CR) rates under 20%. Revumenib, a menin inhibitor approved for relapsed/refractory KMT2Ar leukemia in patients over 1 year, can be associated with QTc prolongation in predominantly adult cohorts, but pediatric data on cardiac safety remain limited. This study focuses on the safety and efficacy of revumenib monotherapy in children with relapsed HOX-driven leukemia, primarily regarding QTc and ventricular function.
Methods We identified pediatric patients (ages 0–19 years) treated at our center who received revumenib monotherapy between June 2021 and June 2025. Data on demographics, molecular profile, prior therapies, and adverse events were collected. Toxicities were graded per CTCAE v5.0; responses were assessed by modified IWG criteria. Treatment continued until unacceptable toxicity, disease progression, or lack of response. Cardiac monitoring included serial ECGs and echocardiograms. QTc intervals were calculated using the Fridericia formula, defining prolongation as QTcF ≥450 ms. Echocardiograms assessed biplane ejection fraction (EF) and shortening fraction, with left ventricular dysfunction defined as EF <55% or SF <28%. Pleural effusion, electrolyte abnormalities, and other cardiac events were assessed in the context of prior cardiac history and treatment course.
Results A total of 30 pediatric patients received revumenib monotherapy. The median age was 7 years (range, 0.8–19). Baseline diagnoses included AML (90.0%, n=27), acute lymphoblastic leukemia (ALL; 6.7%, n=2), and acute undifferentiated leukemia (AUL; 3.3%, n=1). Molecular alterations included KMT2Ar (83.3%, n=25), NUP98r (10.0%, n=3), NPM1mutations (3.3%, n=1), and UBTF-tandem duplications (3.3%, n=1). Patients had received a median of 3 prior lines of therapy (range, 1–5) and 50% (n=15) had undergone prior allogeneic hematopoietic stem cell transplantation (HSCT). Revumenib was administered either as monotherapy per AUGMENT-101 (NCT04065399) (n=23) or Expanded Access (NCT05918913) (n=7). Revumenib was administered orally at 163 mg every 12 hours (or 95 mg/m² for patients <40 kg), alongside a strong CYP3A4 inhibitor, in continuous 28-day cycles. The median duration of therapy was two cycles (range, 1–8).
QTc interval prolongation occurred in 2 patients (6.7%): one grade 2 (3.3%) and one grade 3 (3.3%) event, both during Cycle 1. Both were adolescents (ages 16 and 19); one required a temporary dose interruption. One of the affected patients had a baseline QTc ≥450 ms. No grade 4 events, torsades de pointes, or arrhythmia-related deaths were observed. Scheduled echocardiograms detected transient, asymptomatic declines in EF <50% in 2 patients (6.66%): one after Cycle 3, in the context of septic shock, and one in Cycle 6. An additional patient developed grade 3 symptomatic cardiac dysfunction with pericardial effusion and reduced EF (40%), requiring treatment interruption; this occurred in the setting of progressive disease during Cycle 1. No grade 4 or 5 cardiac events were observed. The composite complete remission (CR/CRi/CRp/CRh/MLFS) rate was 40% (n=12) with 83% (n=10) undetectable MRD by flow cytometry. One patient was non-evaluable due to acellular bone marrow. Five patients had no response, and 12 experienced progressive disease. The median time to response was 28 days (range, 28–168). Nine patients (30%) proceeded to HSCT following revumenib.
Conclusion Revumenib was well tolerated in children with relapsed high-risk leukemia. Cardiac events were infrequent in children and rarely required dose interruption, which supports the safety and continued use of revumenib in this population.
