Venetoclax combined with R‐ICE (VICER) for second line treatment of diffuse large B cell lymphoma refractory or relapsed after initial chemoimmunotherapy

Introduction: Patients (pts) with diffuse large B cell lymphoma (DLBCL) refractory or relapsed (r/r) after initial therapy have poor survival. The overall response (OR) rate to platinum-based second line therapy is approximately 50% with complete response (CR) rate of 30%. Preclinical studies indicate venetoclax (VEN) may sensitize DLBCL to chemotherapy. We conducted a phase 1–2 trial evaluating the combination of VEN with rituximab, ifosfamide, carboplatin and etoposide (VICER). Methods: Adult, transplant-eligible pts with r/r DLBCL after ≤2 lines of therapy, including anthracycline and rituximab were eligible. Pts received up to 3 cycles of treatment. In phase 1 (n = 18), VEN was given on days 1–10 of each cycle. Dose escalation followed a 3 + 3 schema; the MTD of VEN was 800 mg/day (Blood (2018) 132;(Suppl 1): 397). In phase 2, a shorter course VEN was given (days 1–5) to decrease risk of cytopenias. VEN dose was initially 800 mg/day (n = 29); the protocol was amended to reduce VEN dose to 400 mg/day (n = 19) to evaluate efficacy and hematologic toxicity at lower dose. Results: 66 pts enrolled. Median age was 59 years (range 27–77). 49 pts (74%) had primary refractory disease or relapsed <12 months after initial therapy. Median number of cycles was 3 (range 1–3); 3 pts discontinued treatment after 1 cycle (disease progression, toxicity, and pt preference, 1 each). The most frequent grade ≥3 TEAEs were thrombocytopenia (70%), neutropenia (59%) and anemia (47%). Among 174 VICER cycles, there were 23 febrile neutropenia events (13%) in 19 pts; with a lower rate for pts treated with 400 mg of VEN (2/22 vs. 17/41, p < 0.01). 64 pts were evaluable (1 pt died prior to response assessment, 1 pt withdrew consent). OR rate was 81%, CR rate was 63%. There were no statistically significant differences in OR and CR rates based on Bcl-2 expression or dose level. Eight pts in CR did not proceed to ASCT (mobilization failure, 2; pt preference, 3, CAR-T consolidation, 3) while 39 pts underwent ASCT (CR, 33; PR, 6). Eight pts had consolidative CAR-T cell therapy (CR, 3; PR, 5). Median follow up was 26 months (IQR 13–32), 32 (48%) pts had progressive disease. Median progression-free survival (PFS) was 25 months (95% CI: 16–33), with 2-year PFS estimate of 52%. Median PFS was not reached for patients in CR and 16 months for pts in PR. Median OS was 33 months (95% CI 18-NR). 2-year OS estimate was 59%. 7 pts died from non-relapse causes (MDS, 2; sepsis during transplant, 2; sepsis during VICER; COVID 19; and unknown, 1 each). The research was funded by: Genentech Keywords: Aggressive B-cell non-Hodgkin lymphoma, Combination Therapies Conflicts of interests pertinent to the abstract. P. F. Caimi Consultant or advisory role: ADC Therapeutics, Genmab, Genentech, MEI Pharma, Novartis, Kite Pharma, BMS/Celgene, Incyte Research funding: Genentech, ADC Therapeutics, Abbvie