Devimistat Results in a Low Complete Remission Rate in Heavily Pre-Treated Burkitt Lymphoma

Introduction: Patients (pts) with primary refractory or relapsed (RR) Burkitt lymphoma (BL) have a dismal prognosis with few survivors. The dysregulated MYC affects proliferation requiring tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. Devimistat is a non-redox active analogue of lipoic acid, a required cofactor for key two mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase, shutting down ATP and biosynthetic production, leading to cancer cell death. In the initial phase I trial (n=26) a multiply refractory BL pt had a partial remission (PR) sustained for over one year on ongoing Devimistat therapy consolidated by surgical resection. She remains alive 7 years later. We conducted a phase II trial to further explore efficacy in RR-BL and RR double hit lymphoma (DHL).

Methods: Multicenter trial NCT03793140 conducted in 4 referral centers enrolled 15 RR-BL and 9 DHL/THL pts January 2019 to August 2023. One response of 9 in each cohort was required to expand to 17. Eligibility: ≥ 1 prior therapy or refusing standard of care; >3 months after prior transplant. Prior leptomeningeal disease allowed with negative CSF for >4 weeks at enrollment and ongoing maintenance intrathecal therapy. Devimistat was given by central line over 2 hours daily x 5 days every 14 days x 2 cycles then maintenance x 5 days every 21 days until progression, toxicity, or transplant. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle.

Results: The DHL/THL cohort was closed after 0/9 responses. 11 pts with RR-BL were evaluable for response. In the RR-BL group: 18 % male, 91% white, 9% Asian, 36 % Hispanic. Median age 40 (21-60), 45 % ECOG>1, 27% HIV+ with median viral load 23 copies/mL, median CD4 count 200cells/mL, range (20-312), 18 % prior CNS disease. Median prior lines of therapy 3 (range, 1-9), 36 % had received CAR-T cell therapy, 18% prior allogeneic stem cell therapy (SCT) and 9% prior autologous SCT. Pts received a median of 1 cycle of devimistat (range 0.8-11) over 1 week to 9 months. Among the 11 evaluable RR-BL pts, the median follow-up was 1 month (range 0-38 months); overall and complete response (CR) rate 18%. Duration of response of 8 months and ongoing at time of data cut July 2024 (14 months). The first CR patient was 40 years old, HIV positive with a viral load of 23 copies/mL, and 4 previous lines of therapy (CODOX-M/R-IVAC, R-ICE, pembrolizumab+acalabrutinib, R-methotrexate cytarabine) before receiving 11 cycles of devimistat. He had an isolated disabling bulky thigh mass, achieved a PR after cycle 3 and a CR after cycle 7 followed by an additional 4 cycles. CR duration was 5 months, and he remains alive 25 months after the start of alternative therapy. The second CR patient was 21 years old, HIV negative, received 6 previous lines of therapy (R-CHOP, DA-R-EPOCH, R-HCVAD/R-MA and IT MTX, R-Hyper cyclophosphamide, axi-cel, allogeneic SCT). He had liver and bone lesions. He received a total of 8 cycles of devimistat with stable disease after cycle 3 and a CR after 6. He had cycle 7 dose reduction due to headache later considered unrelated and cycle 8 due to biopsy proven hepatitis leading to study drug discontinuation but unlikely to study drug and attributable to alcohol. The patient is alive and remains lymphoma free at the last follow-up 14 months post study entry and 8 months after his last dose. Three patients had grade 3 events at least possibly related to study drug: 1 neutropenia, thrombocytopenia, headache (SAE), non-cardiac chest pain (SAE), and increase of troponin. Whole exome sequencing and RNAseq of the pretreatment pathology from the 2 CR patients compared with 3 disease progression will be presented at the meeting.

Conclusions: Overall, 2/11 (18%) with RR BL and multiple prior therapies achieved a complete remission with devimistat with a duration of response of 8 months and an ongoing response at 14 months. Three prior retrospective studies noted a total of 2 survivors among 47 with RR BL, (Short 2017, Gamero 2019, Cremer 2021) and one reported 11 among 74. (Manji, ASH,2021) Despite few treatment options, it was difficult to enroll pts who were often ineligible due to poor performance status, CNS disease or logistical constraints, leading to study closure. Considering the dismal prognosis with the current standard of care, efforts should be made to improve the outcome of those with high-risk BL with their first line of therapy.