Preliminary Efficacy and Safety of a Phase 1/2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab in Patients with Relapsed/Refractory and Previously Untreated Mantle Cell Lymphoma (MAVO)
Authors: Kim Austin I. , Armand Philippe , Ryan Christine E. , Redd Robert A. , Forsyth Megan , Mai Juniper , Pazienza Samantha , Bresnahan Caitlin , Kats Vanessa M , Abdulkarim Salah , Waisgerber Susan M , Merryman Reid W. , Fisher David C. , Ahn Inhye E. , Crombie Jennifer L. , Odejide Oreofe O. , LaCasce Ann S. , Jacobson Caron A. , Jacobsen Eric D. , Parry Erin M. , Qualls David A. , Bessnow Amy C. , Davids Matthew S. , Brown Jennifer R. , Arnason Jon E. , Leukam Michael , Riedell Peter A. , Murakami Mark A. 
Published: December 2024

Introduction:
Patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) have few treatment options. TP53-aberrant treatment naïve (TN) MCL is associated with inferior outcomes (Eskelund, Blood 2017). There is interest in chemotherapy-free regimens for older, transplant-ineligible (TI) TN pts. The combination of the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, the BCL-2 inhibitor venetoclax (V), and the anti-CD20 monoclonal antibody (mAb) obinutuzumab (O) has demonstrated safety and efficacy in R/R and TN MCL (Le Gouill, Blood 2021). We hypothesized that the second-generation BTKi acalabrutinib (A), in combination with VO (AVO) would be safe and effective in R/R and TN MCL.
Methods:
In this investigator-initiated, multicenter, multi-cohort phase I/II trial (NCT04855695), eligible pts for cohort A had R/R MCL after at least one anti-CD20 mAb-based therapy. Cohort B included TN pts deemed to be TI by the treating physician or with TP53-aberrant MCL (TP53 mutation or &gt;50% p53 expression on immunohistochemistry). Key exclusion criteria were progression or relapse following prior BTKi or BCL-2 inhibitor and CNS involvement.
AVO is administered in 28-day cycles (C) with A (100 mg po bid) in 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 cycles C9-C31. AV is continued indefinitely in cohort A. In cohort B, AV is discontinued when peripheral blood (PB) minimal residual disease negative (MRD-, by ClonoSEQ® assay) complete remission (CR) is maintained for 3 months, with the earliest discontinuation allowed after 10 C of AV. AV is resumed at molecular or clinical relapse. Cohort B pts without a unique PB ClonoSEQ molecular marker received 24 C of AV. Primary endpoints were safety and tolerability for cohort A and the CR rate after 7 C of AVO induction for cohort B. CTCAE v5 and Lugano criteria were used to evaluate toxicity and efficacy.
Results:
As of April 17, 2024, 14 pts in the R/R cohort A and 12 pts in the TN cohort B were evaluable for response. Median age was 68 (range 44-81). In cohort A, median number of prior treatments was 1 (range 1-2). 25% relapsed after autologous stem cell transplant, 7% after CAR T cell therapy, and 36% had primary refractory disease. 29% complex karyotype, 43% TP53-aberrant (29% TP53 mutated, 29% p53 expression &gt; 50%), and 21% blastoid variant.
In cohort B, 83% (10/12) of pts were TP53-aberrant with 75% (9/12) TP53 mutated and 42% (5/12) p53 expression &gt; 50%. All pts had advanced stage. MIPI score was 17% low, 25% intermediate, and 58% high risk. Ki67 index ≥ 30% in 58%, 42% complex karyotype, and 8% blastoid variant.
Most common toxicities in all 26 pts were bruising (50%; all Gr 1), headache (42%; all Gr 1/2), diarrhea (27%; all Gr 1/2), and nausea (27%; all Gr 1/2). Gr ≥ 3 infections in 16% pts. Hematologic toxicity included neutropenia (42%; 20% Gr 3/4), thrombocytopenia (31%; 12% Gr 3/4), and anemia (35%; 8% Gr 3). There was no febrile neutropenia, atrial fibrillation, bleeding, or tumor lysis syndrome. There was 1 fatal toxicity, aspiration, in cohort B during C1, deemed unrelated to treatment.
Median follow-up was 14 months in cohort A (range 0.2-34.1). Best ORR was 86% (12/14) and CR rate 71% (10/14). CR rate in TP53 mutated pts was 75% (3/4) and 66% (4/6) in TP53-aberrant. 3 pts progressed prior to completing C3 V. Overall survival (OS) and progression-free survival (PFS) at 12 months were 90% and 71%.
Median follow-up was 11 months in cohort B (range 0.5-15.1). After 7 C of AVO induction, ORR was 83% (10/12) and CR rate 75% (9/12), the primary endpoint of cohort B. CR rate in TP53 mutated pts was 78% (7/9) and 70% (7/10) in TP53-aberrant. 1 pt progressed during C3 V. OS and PFS at 12 months were 92% and 83%. 9 pts had a baseline PB ClonoSEQ molecular marker: 6 pts achieved MRD- CR, 1 pt MRD+ PR, and 2 pts did not reach C8 MRD evaluation. 5/6 pts achieved MRD- CR &gt; 3 months and discontinued AV, with no relapses at median follow-up of 2 months.
Conclusions:
AVO is safe and active in pts with R/R and TP53-aberrant/transplant ineligible TN MCL. Preliminary efficacy and feasibility of an MRD-guided treatment approach is encouraging in this high-risk TN cohort B. Our data supports further investigation of a targeted triplet approach, and the phase II TN transplant eligible and TP53 wild type cohort is enrolling based on demonstrated safety and efficacy in cohort B. Updated results will be presented at the meeting.