Post-transplant maintenance with revumenib in children with HOX-driven AML

Abstract Background: Children with HOX-driven AML, including KMT2A or NUP98 rearrangements (KMT2Ar, NUP98r), have poor outcomes, particularly following relapse. Although allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative potential, post-transplant relapse is common. In this high-risk subset, post-transplant complete remission (CR) rates as low as 19% and 0%, respectively, have been reported in large international cooperative group studies. There is a critical need for effective post-transplant maintenance therapy in this population to delay relapse and allow time for the curative graft-vs-leukemia effect. The menin inhibitor revumenib is approved for the treatment of relapsed/refractory KMT2Ar acute leukemia for age >1 year, however, outcomes with maintenance post-HSCT in children with this agent have not been fully characterized. We retrospectively analyzed pediatric patients who received revumenib maintenance following HSCT to assess safety and tolerability of this agent. Methods We identified pediatric AML patients (ages 0–18 years) treated at MD Anderson Cancer Center who underwent HSCT following response to revumenib-based therapies and had resumed revumenib monotherapy as maintenance post-HSCT between June 2022 and June 2025. Toxicities were graded per CTCAE v5.0. Results Ten pediatric patients received post-HSCT revumenib maintenance. The median follow-up was 15.5 months (range: 1–38). The median age was 10 years (range: 17 months–18 years). Molecular subtypes included KMT2Ar (n=8) and NUP98r (n=2); this was the second or greater transplant for five patients. Before transplant, revumenib was administered either as monotherapy per AUGMENT-101 (NCT04065399) (n=3) or Expanded Access (NCT05918913) (n=2) or in combination with oral decitabine and venetoclax per the SAVE protocol (NCT05360160) (n=5). The median number of revumenib-containing cycles given pre-HCT was 2 (range: 1–4). Donor sources included matched sibling donors (n=2), matched unrelated donors (n=2), haploidentical donors (n=3), and unrelated cord blood units (n=3). Conditioning regimens varied by donor and included combinations of fludarabine, busulfan, thiotepa, total body irradiation (TBI), and post-transplant cyclophosphamide (PTCy). Revumenib maintenance was initiated at a median of 111 days post-HCT (range: 58–175). All patients received concurrent strong CYP3A4 inhibitors. Dosing was weight-based: patients ≥40 kg received 160 mg orally twice daily in 28-day cycles, while those <40 kg received 95 mg/m² twice daily. All patients were in remission at the time of maintenance initiation. One patient had stable grade 2 upper gastrointestinal GVHD at baseline. No new cases of GVHD or GVHD flares were observed during treatment. No bacterial, fungal, or viral infections requiring hospitalization occurred. The most common adverse event was thrombocytopenia, observed in 6 patients; three cases were grade ≥3 (two grade 3, one grade 4), occurring primarily during the first two cycles. Temporary dose reductions or interruptions were required in five patients. Four of these patients were successfully re-escalated to the original dose and continued therapy without further complications. The single patient with baseline GVHD also experienced grade 3 thrombocytopenia and was the only patient who did not undergo dose re-escalation. Treatment was discontinued after cycle 3 due to parental preference for this patient. The median number of maintenance cycles completed was 11 (range: 1–25). At last follow-up, all 10 patients were alive with no relapses, yielding a 1-year event-free survival of 100%. Conclusion Using revumenib as maintenance post-transplant in children with HOX-driven AML was safe and showed promising early efficacy. Prospective studies are needed to confirm benefit and define optimal use.