Novel Devimistat Results in Complete Remissions in Heavily Pre-Treated Burkitt Lymphoma in a phase II trial Open Access

• A targeted approach to block enzymes in the TCA cycle had limited efficacy in the treatment of patients with relapsed Burkitt lymphoma.

• The unique biology of the two diseases in the two responding patients may have played a role.

Patients with primary refractory or relapsed (RR) MYC-driven aggressive B-cell lymphomas, such as Burkitt lymphoma (BL), plasmablastic lymphoma (PBL), and double/triple hit lymphoma (DHL), 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 ATP and biosynthetic intermediates. We conducted a Phase II trial to explore the efficacy of devimistat in RR-BL, RR-PBL, and RR-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 enrolled 2 RR-PBL and 9 RR-DHL/THL patients. Among the 13 RR-BL patients, 2 had a complete response (CR), resulting in a CR rate (CRR) of 15%, while the others experienced rapid disease progression. The median follow-up time for RR-BL patients was 1 month (range, 0-47 months). Among the 2 RR-BL CR patients, the response duration was 8 months in one and ongoing at the time of data cutoff, 17 months post-study entry. Three patients had grade 3 events at least possibly related to the study drug: neutropenia, thrombocytopenia, headache, non-cardiac chest pain, and increase of troponin. Considering the dismal prognosis of RR 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 RR setting. NCT03793140