Phase I/II study of acalabrutinib, venetoclax, and obinutuzumab in patients with relapsed/refractory and previously untreated Mantle Cell Lymphoma (MAVO) Free

Background With the advent of effective targeted therapy, there is growing interest in chemotherapy-free regimens in patients (pts) with mantle cell lymphoma (MCL). Triplet combinations of the BTK inhibitors ibrutinib or zanubrutinib, venetoclax (V), and obinutuzumab (O) have demonstrated efficacy in MCL, including TP53-aberrant disease (Le Gouill, Blood 2021; Kumar, Blood 2024). We hypothesized that acalabrutinib (A), in combination with VO (AVO) would be safe and effective in relapsed/refractory (R/R) and treatment naïve (TN) MCL.

Methods In this investigator-sponsored, multicenter, phase I/II trial (NCT04855695), pts eligible for cohort A had R/R MCL after at least one anti-CD20 mAb-based therapy, cohort B had TN MCL ineligible for aggressive induction or TP53-aberrant MCL (TP53 mutation or >50% p53 expression on IHC). If safety and efficacy criteria were met in cohorts A or B, Cohort C would enroll TN TP53 wild-type pts eligible for aggressive induction.

Pts were treated with A (100 mg po bid) starting cycle 1 (C1), O in C2 (100 mg IV D1, 900 mg IV D2, 1000 mg IV D8, D15) and D1 of C3-7, and V ramp-up in C3 to a target 400 mg daily. In all cohorts, O maintenance is given every 2 Cs between C9-C31. AV is continued indefinitely in cohort A, discontinued after achieving MRD negative (<1 in 10⁶ cells by ClonoSEQ®) complete remission (CR) in peripheral blood (PB) for 3 months in cohort B, and optionally discontinued after MRD- CR in PB for 3 months in cohort C. Earliest discontinuation of AV was after 10 Cs in cohorts B and C. AV can be resumed at molecular or clinical relapse. Patients unevaluable for MRD received AV for 24 Cs. Primary endpoints were safety and tolerability for cohort A, CR rate after 7 Cs for cohort B, and MRD- CR rate after 7 Cs for cohort C.

Results As of July 25, 2025, the study is fully enrolled (n=56). 20/20 pts in R/R cohort A, 24/24 pts in TN cohort B, and 11/12 pts in TN cohort C were evaluable for response. Median age was 65 (range 36-81). In cohort A, median number of prior therapies was 1, 20% relapsed after autologous stem cell transplant, 10% after CAR T cell therapy, and 30% had primary refractory disease. In cohort B, 79% pts (19/24) were TP53-aberrant, 71% (17/24) TP53 mutated, and 96% pts had advanced stage. MIPI score was 13% low, 21% intermediate, and 67% high risk. Ki67 ≥ 30% in 50%, Ki67 ≥ 50% in 29%, 54% complex karyotype, and 8% blastoid variant. In cohort C, 92% pts had stage IV, MIPI score was 33% low, 50% intermediate, and 17% high risk. Ki67 ≥ 30% in 33%, 25% complex karyotype, and 100% classic variant.

In all pts, most common toxicities were headache (57%; all G1/2), bruising (41%; all G1), diarrhea (29%; 2% G3), and nausea (25%; all G1/2). ≥ G3 infections in 11% pts. Hematologic toxicity included neutropenia (46%; 30% G3/4), thrombocytopenia (32%; 9% G3/4), and anemia (29%; 5% G3). There was 2% febrile neutropenia, 2% atrial fibrillation, and 2 (4%) fatal toxicities due to COVID-19 and aspiration. No tumor lysis syndrome or ≥ G2 hemorrhage.

Cohort A median follow-up was 24 months (range 7.3-39.4). Best ORR was 86% and CR rate 75%. 2-year progression-free survival (PFS) and overall survival (OS) were 75% (95% CI: 58, 97) and 86% (95% CI: 69, 100).

Cohort B median follow-up was 20 months (range 0-26). Primary endpoint was met with CR rate 83% (ORR 88%). CR rate in TP53 mutated pts was 82%. 2-year PFS and OS were 78% (95% CI: 63, 97) and 96% (95% CI: 88, 100). Estimated 2-year PFS and OS for the 17 TP53 mutated TN pts were 82% (95% CI: 65, 100) and 94% (95% CI: 84, 100).

19/24 pts had evaluable MRD data. 15 pts (79%) achieved MRD- CR and 14 pts discontinued AV. 1 pt relapsed 4 months after discontinuing AV in MRD- CR and did not respond to AV retreatment. Median follow-up after AV discontinuation was 9 months.

Cohort C median follow-up was 9 months (range 2-14.2). Best ORR and CR rate are both 100% (11/11). Estimated 12-month OS and PFS are both 100%. All 8 pts with evaluable MRD data achieved MRD- CR and 4 pts discontinued AV, with no relapses after a median follow-up of 3.5 months.

Conclusions AVO is a well-tolerated and effective regimen in pts with R/R and TN MCL, with high rates of MRD- CR in TN MCL, allowing for MRD-guided time-limited therapy. The primary endpoint of TN cohort B was met, and the estimated 2 yr PFS and OS in the 17 TP53 mutated pts compare favorably with alternative regimens. Based on this data, the study will expand to include an additional 16 TP53 mutated pts.