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 & 15 of cycle 1 and day 1 of cycles 2-6 followed by every other month through cycle 24. Venetoclax given as 400mg daily on days 4-28 of each cycles through cycle 24. Ibrutinib was administered as 560 mg daily on days 1-28 of each cycle through cycle 24. Therapy was continued for 24 cycles or until disease progression, unacceptable toxicity or voluntary withdrawal. Primary objective was CR rate at 12 months per Lugano criteria. Secondary objectives included safety, CR at 30 months, ORR (CR + PR), duration of response (DOR), PFS and OS. Exploratory Objective was to determine MRD in all responding patients.

Results: Between April 2021-May 2024, 40 patients were enrolled, 24 (60%) male and 16(40%) female. Median age at diagnosis was 60.5 years. 33/40 (82.5%) were White, 2/40 (5%) Asians and 1/40(2.5%) American Indian or Alaska native. Race was unknown for 5 patients. 20% of patients had Grade 1 disease, 33% grade 2 and 25% grade 3. 9 patients had overlapping grading and was marked as not specified. 18% had stage II, 33% stage III and 43% had stage IV disease at diagnosis.

ORR for the entire cohort was 92.5% [80% CR + 12.5% PR]. Of the 21 patients who have completed at least 12 cycles of treatment so far, the CR rate at 12 months was 76% with the remaining 5 patients achieving a PR. The 2-year PFS & OS rate was 82% and 97% respectively. At a median follow-up of 15 months for the entire cohort, median PFS, OS & DOR have not been reached. Of the 20 patients with MRD data available, 16(80%) were MRD negative at the time of last evaluation. Median number of cycles to reach MRD negativity was 7. Sub-group analysis of 7 patients who discontinued treatment due to toxicity after <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

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2025
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