Novel devimistat results in complete remissions in heavily pretreated Burkitt lymphoma in a phase 2 trial

Patients with primary refractory or relapsed (R/R) MYC-driven aggressive B-cell lymphomas, such as Burkitt lymphoma (BL), plasmablastic lymphoma (PBL), and double-hit lymphoma (DHL)/triple-hit lymphoma (THL), have a dismal prognosis with few survivors. The deregulated MYC protein drives proliferation with dependence on tricarboxylic acid cycle intermediates as biosynthetic precursors. Devimistat disrupts mitochondrial production of adenosine triphosphate and biosynthetic intermediates. We conducted a phase 2 trial to explore the efficacy of devimistat in R/R-BL, R/R-PBL, and R/R-DHL, administered daily for 5 days every 14 days for 2 cycles, followed by maintenance for 5 days every 21 days until progression, toxicity, or transplant. No responses were seen in the 2 enrolled patients with R/R-PBL and 9 with R/R-DHL/THL. Among the 13 patients with R/R-BL, 2 had a complete response (CR), resulting in a CR rate (CRR) of 15%, whereas the others experienced rapid disease progression. The median follow-up time for patients with R/R-BL was 1 month (range, 0-47). Among the 2 patients with R/R-BL CR, the response duration was 8 months in 1 and ongoing at the time of data cutoff, 17 months after study entry. Overall, 3 patients had grade 3 events at least possibly related to the study drug: neutropenia, thrombocytopenia, headache, noncardiac chest pain, and increase of troponin. Considering the dismal prognosis of R/R MYC-driven aggressive B-cell lymphomas with the current standard of care and low CRR with devimistat, efforts should be made to improve the outcome of these malignancies with their first line of therapy and explore novel therapies in the R/R setting. This trial was registered at www.ClinicalTrials.gov as #NCT03793140.