https://orcid.org/0009-0005-3770-1139
TO THE EDITOR:
In the past decade, advancements in the treatment of acute leukemia have led to improved relapse-free and overall survival,1,2 but allogeneic stem cell transplant (SCT) remains the standard of care to achieve cure in high-risk or relapsed acute leukemia. However, disease relapse after SCT remains the primary cause of treatment failure, with cumulative incidence of >20% depending on primary disease, donor type, and conditioning regimen intensity.3 Posttransplant maintenance therapy is a strategy to enhance post-SCT outcomes in both adults and pediatrics.4
Lysine methyltransferase 2A (KMT2A) rearranged (KMT2Ar) acute leukemia confers a high-risk disease and poor prognosis in adult and pediatric patients, with progression-free survival of 30% to 40% and overall survival of <25%.5-9 The product of KMT2A (formerly called MLL), encoded on chromosome 11q23.3, leads to a critical oncogenic factor, menin, to induce leukemogenesis through alterations in cell signaling and gene regulation including expression of the HOX gene.10,KMT2Ar, NUP98 rearranged, and NPM1 mutant acute leukemias have a common aberration of maturation arrest driving leukemogenesis owing to the overexpression of HOX and MEIS1 cluster genes mediated by an interaction between menin and KMT2A.11 At least 10% to 30% of acute leukemias harbor one of these treatment-refractory genetic alterations. More than 135 KMT2A partner genes have been identified in refractory acute leukemia,12,13 and KMT2A alterations are present in 75% of infant acute leukemias and 15% to 25% of childhood acute myeloid leukemia cases.14,15 Since the identification of menin inhibition as a possible target for KMT2Ar, NUP98 rearranged, and NPM1 mutant acute leukemias, several clinical trials including AUGMENT-101 spurred the full US Food and Drug Administration approval of revumenib in November 2024 for use in children aged >1 year and adults with relapsed or refractory (R/R) KMT2Ar leukemia.16,17
Revumenib is an orally administered small molecule that works by inhibiting the menin-KMT2A interaction, releasing the differentiation block, and promoting differentiation of immature leukemic blasts into mature leukocytes. In the AUGMENT-101 trial,18 complete remission (CR) or CR with partial hematologic recovery rate of 22.8% (P = .036) and 23.1% (P = .0014) was observed in adult and pediatric patients with R/R KMT2Ar acute leukemia, respectively. Any-grade treatment-related adverse events were observed in 81.9% of patients, with the most common being nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Approximately 54% of patients experienced grade >3 treatment-related adverse events, including differentiation syndrome (16%), febrile neutropenia (13.8%), and QTc prolongation (13.8%). No patient discontinued treatment owing to QTc prolongation or differentiation syndrome. Furthermore, remission was sustained, and 38.9% of patients (14) who achieved a response underwent allogeneic SCT. Eight of the 14 SCTs were performed when bone marrow blasts were <5%, including with incomplete or partial hematologic recovery. More than 64% of patients (9), including 2 pediatric patients, continued revumenib after SCT, with maintenance therapy lasting between 23 and 588 days.19 Nearly 50% of patients in AUGMENT-101 had a previous SCT and 7% underwent >1 previous SCT, and despite heavy previous treatment, these patients showed favorable responses to revumenib. This includes 1 patient who, after having measurable residual disease (MRD) positivity after SCT, became MRD negative while on revumenib maintenance therapy after transplant.
An ideal medication for post-SCT maintenance should show strong activity against the primary disease, have manageable nonhematologic side effects and myelotoxicity, preserve the graft-versus-tumor effect, have minimal drug-drug interactions, and prevent worsening graft-versus-host disease. Essential questions for a potential trial on the use of post-SCT revumenib include the following: should we start using it in all children with HOX pathway-mutated leukemias and should we follow a maintenance strategy similar to FLT3 inhibitors, IDH inhibitors, and hypomethylating agents4,20-23? When developing a potential trial to determine the utility of posttransplant revumenib, investigators would need to consider several key considerations to guide the initiation of revumenib therapy including interval from SCT, time since engraftment, and the risk of myelosuppression. In addition, potential interactions with post-SCT medications, such as immunosuppressants for graft-versus-host disease prophylaxis and treatment, essential prophylactic antimicrobial agents including certain azole antifungal agents, and other agents that may contribute to QTc prolongation, must be carefully evaluated. These drugs may influence dose administration and drug level in post-SCT revumenib.
The effectiveness of lower-dose revumenib in suppressing clonal expansion should be assessed, particularly in mitigating myelosuppression and minimizing drug-drug interactions. Revumenib dose reduction was used in the AUGMENT-101 and SAVE trials. In AUGMENT-101, nearly 10% patients proceeded at a lower dose due to adverse effects. Moreover, the trial built in a revumenib dose reduction strategy for patients based on the coadministration of a strong CYP34A inhibitor to mitigate toxicities. The reduction did not lead to differences in efficacy, potentially shedding light in post-SCT patients who may require dose reduction owing to possible impacts on young bone marrow or need for CYP34A inhibitors as antifungal prophylaxis. Although unlikely, investigators should be mindful of potential risks of post-SCT revumenib such as worsening SCT-related toxicities including microangiopathy, endothelial dysfunction (eg, sinusoidal obstruction syndrome), endocrine issues, liver toxicity, hemolysis, or thrombosis. Introducing maintenance therapy during molecular remission may enhance the likelihood of sustained remission compared with preemptive treatment initiated upon MRD detection. However, careful optimization of timing and dosing is essential to avoid adverse effects such as myelosuppression, which could delay engraftment or lead to secondary graft failure.
Although revumenib was studied as monotherapy in the AUGMENT-101 trial, subsequent studies such as the SAVE trial demonstrated its safe use in a multidrug combination. Based on pending analysis of the SAVE trial in which revumenib is combined with agents including venetoclax, we may learn its role in a combined regimen. This may allow investigators of a future trial to determine which individuals might benefit from monotherapy with revumenib, whereas others, particularly high-risk patients, including those with multiply relapsed leukemia, certain cytogenetics, infantile leukemia, and morphological remission after hematopoietic cell transplant but MRD positivity could require combination maintenance therapy with agents such as venetoclax for maximal benefit and improved outcomes.24
Although the longest reported duration of maintenance in the AUGMENT-101 trial was nearly 2 years, the optimal maintenance duration to minimize relapse risk remains undefined. Subanalysis of patients receiving post-SCT maintenance in revumenib trials could provide valuable insights for developing evidence-based recommendations for post-SCT management. However, with only 9 patients proceeding to SCT after achieving CR with revumenib in the AUGMENT-101 trial, a larger, multicenter trial is essential to address critical questions and refine strategies for post-SCT maintenance therapy. An important consideration is determining the most appropriate study design and evaluating the feasibility of a randomized controlled trial in a small patient population with a high-risk, but potentially curable disease.
In conclusion, with the recent US Food and Drug Administration approval of revumenib and limited but positive data available from the post-SCT maintenance arm of the AUGMENT-101 trial, revumenib offers a promising option of post-SCT maintenance therapy for patients with history of R/R KMT2Ar leukemia, warranting further investigation. Although research is needed to define its optimal use in the post-SCT setting, practitioners managing these patients should consider enrolling patients in institution or nationwide studies investigating the role of revumenib maintenance for high-risk, R/R KMT2Ar leukemia. At our institution, as we offer post-SCT revumenib as a collaboration between our pediatric leukemia and SCT teams, efforts are underway to address these considerations and tailor a standardized approach in this population.
Contributions: O.O., I.N.S., and B.C. developed the concept and manuscript design and wrote the manuscript; and D.M., A.G., M.B.G., C.N., M.R., J.C., D.P., and P.T. reviewed the draft, provided inputs that were used in the final manuscript, and reviewed the final manuscript before submission.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Olayinka Okeleji, Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1400 Pressler St, Houston, TX 77030; email: ookeleji@mdanderson.org.
