A phase 1 study of R-GDP-venetoclax before autologous transplant in relapsed/refractory large B-cell lymphoma (CCTG LY.18).

Although chimeric antigen receptor T-cell therapy has supplanted autologous stem cell transplantation (ASCT) for most patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma after 1 line of therapy, ASCT may still be a suitable therapy for some patients, especially those with late relapse. Rituximab, gemcitabine, dexamethasone and cisplatin (R-GDP) is an established salvage chemotherapy regimen used to induce responses before ASCT. LY.18 is a phase I platform study aimed at adding new agents to R-GDP to determine their safety and recommended phase 2 dose. The first arm of LY.18 tested escalating dose levels of venetoclax in combination with 3 cycles of R-GDP at standard doses. In total, 24 patients were treated. The main adverse events were hematologic symptoms, infection, gastrointestinal symptoms, and fatigue. Rates of febrile neutropenia improved after an amendment introducing mandatory granulocyte colony-stimulating factor. The recommended phase 2 dose of venetoclax was 400 mg on days 4 to 10 of cycle 1 and on days 1 to 10 of cycles 2 and 3. The overall response rate (ORR) was 70.8% (95% confidence interval, 51.5-86.9), and the complete response (CR) rate was 12.5%. In a post hoc comparison with a similar cohort of patients treated contemporaneously with R-GDP, there was no difference in the event-free and overall survival, although the ORR was numerically higher. R-GDP and venetoclax has a manageable safety profile and is effective, although further development of this regimen is unlikely because of the low CR rates observed and the advent of more effective therapies for treating in R/R LBCL. This trial was registered at www.clinicaltrials.gov as NCT04161248.