272 | ACALABRUTINIB IN COMBINATION WITH RITUXIMAB IS HIGHLY EFFECTIVE FRONTLINE TREATMENT FOR OLDER PATIENTS WITH MANTLE CELL LYMPHOMA

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Introduction: Chemo-free targeted therapies, which are safe and effective, are increasingly sought for older MCL patients. We investigated acalabrutinib with rituximab (AR) as an initial treatment for patients with MCL Methods: We enrolled 50 previously untreated patients in this single-institution, single-arm Phase 2 trial (NCT05214183). Patients received acalabrutinib 100 mg orally twice daily and rituximab weekly for four weeks, then monthly for 12 months, and every two months up to 24 months. Acalabrutinib was continued beyond 24 months. The primary objective was to evaluate the best overall response rate (ORR) after AR. ClonoSEQ-based MRD assessment and multiomic analysis were conducted on serial blood, plasma, and tissue samples Results: Among 50 pts, the median age was 69 years (range: 65–81). Forty-six pts had classic, 3 had blastoid, and 1 was pleomorphic morphology. TP53 aberration status (mutations or deletion) was available in 43/50 pts and 12 pts had aberrant TP53. High risk MCL in 20/50 pts (40%). One pt was not evaluable for response at 12 weeks. Best PET-CT response at 12 weeks was 93%, 78%, 16% and 7% for overall, CR, PR and NR. Early responder pts (CR at end of 12 weeks) were 80% (37/50), and late responders (PR), 20% (9/46). Best PET-CT based response rates were 94% ORR and 94% CR; 6% were non-responders. The study met its primary end point of 40% CR at end of 12 weeks. MRD assessments at 3, 6, 12, 18 and 24 months in evaluable patients, demonstrated an MRD negative rate of 30%, 54%, 87%, 92% and 93% respectively. With a median follow up of 38.7 months, the overall median PFS and OS were not reached (3-year PFS 84%, OS 94%). 3-year PFS in pts with aberrant TP53 was 71% and 86% in wile type TP53 (p = NS). Survival outcomes were not significantly different between various prognostic subgroups, however, ultra-high-risk pts (> 1 high risk factor) had significantly inferior PFS of 15.7 months compared to low and high-risk pts. Nineteen pts (38%) came off study (5 for disease progression). Overall, 3 pts died (2 with primary progression and another with unknown reason in remission). The most common all-grade toxicities were fatigue (86%), myalgia (70%), diarrhea (60%), infections (54%), headache (40%), 1% toxicities were grade 3 or higher. One pt had recurrence of grade 2 atrial fibrillation (2%), one pt had palpitations grade 2 and one pt had recurrence of grade 3 unstable angina. Early responders had significant amplification of PI3KCA and TBL1XR1 genes. Serial blood RNA-seq detected significant sustained reduction in SOX11 (p < 0.0001) and B-cell gene expression (p = 0.01). Paired sample single cell RNA sequencing in primary refractory case demonstrated high fraction of clonal B cells and exhausted CD8 T cells at progression. CD8 effector memory T cells were elevated in late responders and high-risk patients Conclusions: AR combination is highly effective, safe, and impacts the genomic and immune landscape in older MCL patients Research funding declaration: Astra Zeneca, Lymphoma research Foundation Carrier development award grant Keywords: genomics, epigenomics, and other -omics; aggressive b-cell non-Hodgkin lymphoma; combination therapies Potential sources of conflict of interest: P. Jain Employment or leadership position: NA Consultant or advisory role: Eli Lilly, Kite, Astra Zeneca, LOXO Oncology, Incyte, Janssen-PCYC, Kite, Expert perspectives Stock ownership: NA Honoraria: Aptitude Health, Pharmacy times, Dava Oncology, Adaptive biotech, Eli Lilly, Beigene, Genentech Educational grants: NA Other remuneration: NA