Background: Frontline mantle cell lymphoma (MCL) treatments are rapidly evolving with incorporation of targeted therapies. We previously demonstrated the safety and efficacy of the BOVen triplet (Zanubrutinib, Obinutuzumab, and Venetoclax) in high-risk pts with TP53-mutant MCL (Kumar Blood 2025). In this phase II, multi-center, investigator-initiated clinical trial, we evaluated the safety and efficacy of BOVen for older MCL pts using a minimal residual disease (MRD)-driven, time-limited approach.

Methods: Eligible pts had previously untreated MCL, requiring therapy, ≥65 years (yrs) of age or with comorbidities precluding autologous stem cell transplantation, and ECOG PS ≤2, ANC >1, PLT >75, HGB ≥9 (unless due to MCL). BOVen was administered in 28D cycles: Zanubrutinib (Zanu) 160 mg PO BID starting D1; Obinutuzumab (Obin) 1000 mg IV D1 or split D1-2, 8, 15 of C1, and D1 of C2-8; and Venetoclax (Ven) with standard ramp up dosing initiated C3D1 (target 400 mg QD). The minimum treatment duration was 24 cycles and if uMRD6 complete response (CR) was achieved after 24 cycles, then Zanu and Ven were stopped. The primary endpoint was 3-year progression-free survival (PFS). Responses were assessed per Lugano criteria. MRD was assessed serially using Adaptive clonoSEQ®in peripheral blood (PB) and bone marrow (BM).

Results: 50 pts were enrolled across 3 sites; data cut April 30, 2025. The median age at enrollment was 72 years (range 47-89); 1 patient was <65 years of age, but transplant-ineligible due to cardiac comorbidity; 64% were male (32/50); various histologic subtypes were included (35 conventional MCL, 7 non-nodal leukemic, and 6 blastoid variant; 2 unclassified); by MIPI risk: 70% high (35/50), 22% intermediate (11/50), and 8% low (4/50); 51% Ki67≥30% (25/49); 29% Ki67≥50% (14/49); 28% TP53 mutation (13/46), and 20% 17p deletion (10/50).

Median follow-up was 25 months (range 1.4-33.9). The best overall PET-based response rate was 98% (49/50) with 94% (47/50) achieving a CR. One patient with TP53, NOTCH2, CXCR4, BIRC3, and SMARCA4 baselinemutations progressed before cycle 3 and subsequently died of lymphoma. Three progressions and 5 deaths (2 disease-related, 1 viral encephalitis (possibly treatment-related), 1 hypoxemic respiratory failure due to aspiration pneumonia (treatment unrelated), and 1 sudden death likely due to an acute cardiac event (treatment unrelated)) were observed. One pt was lost to follow-up after C16. The 2-year PFS was 86% (95% CI: 77, 97). The 2-year OS was 92% (95% CI: 84, 100).

MRD was evaluable in 98% (49/50) pts. MRD rates at a sensitivity level of 1x10-6 (uMRD6) were 28% at C3 (13/47; 1 without baseline ID sample, 1 early progressor, and 1 missed sample), 87% at C13 (39/45; 1 without baseline ID sample, 1 early progressor, 3 pts yet to reach C13), and 93% at EOT (28/30; 1 without baseline ID sample, 3 progressors, 3 deaths, 1 lost to follow-up, 12 pts yet to reach C24).

30 pts completed 24 cycles. Of these pts, 100% (30/30) achieved a CR and 24 stopped Zanu and Ven at EOT after achieving uMRD6 in PB. Of the 6 patients continued on oral therapy, 1 pt was MRD detectable (dMRD) in PB and BM at 1X10-6; and 5 patients were dMRD in BM, but uMRD6 in PB.

The most common treatment-related AEs (TrAE, all grades, ≥10%) were predominantly low-grade and included diarrhea (n=23, 46%), neutropenia (n=17, 34%), thrombocytopenia (n=15, 30%), COVID-19 infection (n=14, 28%), fatigue (n=12, 24%), nausea (n=12, 24%), anemia (n=9, 18%), and infusion-related reaction (n=8, 16%), pneumonia (n=7, 14%), and upper respiratory infection (n=6, 12%). The most common grade 3 or higher TrAEs were neutropenia (n=10, 20%) including 2 grade 3 febrile neutropenia events and thrombocytopenia without bleeding (n=4, 8%). 11 patients experienced grade 3 or higher infectious events (1 viral encephalitis, 1 listeria bacteremia, 2 lung infections, 2 COVID-19 infections, 3 urinary tract infections, 1 prostatitis, and 1 upper respiratory infection).

Summary/Conclusion: The MRD response-adapted BOVen triplet is highly active in older MCL patients with high rates of clinical and molecular response. The 2-year PFS rate of 86% is encouraging; however, extended follow-up is necessary to evaluate the 3-year PFS endpoint and the durability of response off treatment. Overall the regimen is safe and well-tolerated in older patients, with a toxicity profile similar to the prior experience with this triplet.

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2025
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