Dordaviprone Maintenance After Allogeneic HCT for High-Risk Acute Myeloid Leukemia and Myelodysplastic Neoplasm

Dordaviprone is a first-in-class small-molecule imipridone. In preclinical studies, it is active against leukemia cells harboring a TP53 mutation or complex karyotype and leukemia stem cells while sparing normal bone marrow cells. This study aimed to determine the safety of dordaviprone maintenance after allogeneic hematopoietic cell transplantation (HCT) for high-risk acute myeloid leukemia (AML) and myelodysplastic neoplasm (MDS). In a Phase I trial (n = 20), adults with high-risk AML or MDS received escalating doses of oral dordaviprone administered weekly for up to 13 four-weekly cycles (ClinicalTrials.gov ID: NCT03932643). The primary objective was to determine the rate of dose-limiting toxicities (DLTs) and grade ≥ 3 adverse events (AEs). Participants' characteristics included a median age of 68 years (range: 39-75 years) and high-risk features such as adverse-risk AML (50%) or very poor-risk MDS (75%), TP53 mutations (36%), or measurable residual disease before HCT (41% of AML). A total of 10 patients (one unevaluable) received 250-500 mg weekly doses, whereas the remaining 10 patients received 625 mg weekly doses. Patients received a median of 8.5 cycles (range: 1-13) of dordaviprone. No DLTs or graft failures were noted. Grades 3-4 acute GVHD was noted in 5%. Grade ≥ 3 AEs occurred in 45% (15% related). Grade 3-4 cytopenias were infrequent: anemia (15%), neutropenia (10%), and thrombocytopenia (15%). At 2 years, relapse-free survival and overall survival were 60% (95% confidence interval [CI]: 42%-86%) and 70% (95% CI: 53%-93%), respectively. Posttransplant dordaviprone maintenance was determined to be safe with low rates of cytopenias and promising efficacy in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03932643.