A Phase II trial of obinutuzumab, ibrutinib and venetoclax in patients with previously untreated follicular lymphoma; A University of California hematologic malignancies consortium study

Abstract Background Clinical management of advanced-stage follicular lymphoma (FL) remains highly variable with no universally accepted standard of care. Approximately 20% of the patients treated with rituximab based chemotherapy regimens will experience disease progression within 24 months (POD24) which is associated with significantly poorer outcomes. Previous trials in mantle cell lymphoma and chronic lymphocytic leukemia evaluating the combination of obinutuzumab, venetoclax, and ibrutinib have demonstrated promising clinical activity with sustained disease control and high rates of minimal residual disease (MRD) negativity. We hypothesized that the triplet regimen of obinutuzumab, venetoclax, and ibrutinib could exert synergistic anti-lymphoma effects by simultaneously enhancing the innate immune function, disrupting B-cell receptor (BCR) signaling, and restoring apoptotic pathways. We evaluated the safety and efficacy of this combination as frontline therapy in previously untreated FL, and present our interim analysis which was performed when 50% of the cohort had completed at least half of the planned treatment cycles. Methods This single arm, phase II, open label, prospective trial was conducted across 4 NCI-designated Comprehensive Cancer Centers, part of the University of California Hematologic Malignancies Consortium. Participants ≥18 years of age with untreated follicular lymphoma were enrolled to receive triplet therapy as follows: Obinutuzumab on Day 1, 8 1 year on treatment showed on-going MRD negative CR in all patients, at a median follow up of 30 months. Most frequent hematologic toxicities included all grade anemia in 25%, grade ≥3 in 5%, neutropenia 50% and grade ≥3 20%, thrombocytopenia 57% and grade ≥3 12%. Most frequent non hematologic toxicities were all grade fatigue 75% and grade ≥3 15%, all grade hypertension in 57% with grade ≥3 15%, all grade rash in 50% with grade ≥3 10%. All grade bleeding was reported in 45% which included all grade epistaxis 22%, all grade bruising 25% and all grade hematuria 7.5%. There was only 1 grade ≥3 event of bleeding which was an intra-cranial bleed. All grade arrythmia 35% with no grade ≥3 events, 25% patients had grade 1-2 infusion reaction from obinutuzumab with no grade 3 or higher events. Conclusion Triplet therapy with obinutuzumab, ibrutinib and venetoclax showed promising results as frontline therapy for previously untreated FL without any unexpected toxicities or new safety signals, with a small cohort of patients remaining in prolonged MRD negative CR despite early treatment discontinuation. The robust response rates, largely non-overlapping toxicity, and distinct mechanisms of action makes this combination an attractive first line therapeutic option for patients with follicular lymphoma