Paper Details

ABSTRACT

Introduction: Frontline (1L) treatment (tx) of MCL with chemotherapy (CT)-free, BTKi-containing tx have shown promising clinical trial results in patients (pts) who are elderly, unfit for CT, or have TP53 mutations. We performed a retrospective multicenter study of pts treated with CT-free, BTKi-based regimens in 1L MCL to determine outcomes and evaluate factors that predict progression-free survival (PFS).

Methods: Pts with MCL who received 1L tx with commercial BTKi alone or with another oral agent and/or anti-CD20 monoclonal antibody (CD20Ab) at 25 U.S. sites between 11/2013 - 9/2025 were included. Time-to-event outcomes were estimated by Kaplan-Meier method and compared by log-rank testing. Univariate (UVA) and multivariate (MVA) Cox regression identified factors associated with PFS.

Results: 226 pts were included. Key pt characteristics included: median age 72 (range: 32-91; 42% > age 75), 71% male, 90% White, and 78% ECOG PS 0-1. 84% had stage IV disease, 35% had elevated LDH and 25% had ≥1 cytopenia at diagnosis. MIPI scores were: 52% high, 12% intermediate, 16% low-risk, and 19% missing. Of pts with available data, 38/161 (24%) had Ki67 >50%, 30/223 (13%) had blastoid/pleomorphic histology, 56/151 (37%) had del17p, and 82/149 (55%) were TP53 mutated.

Median time from diagnosis to tx was 2 months (mo). Number of pts who received each tx was: BTKi monotherapy (BTKi-m): 84 (37%), BTKi + CD20Ab (BTKi/CD20): 67 (30%), BTKi + CD20Ab + venetoclax (triplet): 66 (29%), BTKi + venetoclax: 8, BTKi + lenalidomide: 1. BTKis received were ibrutinib (20%), acalabrutinib (33%), or zanubrutinib (47%). The median number of CD20Ab cycles was 7 (range: 1-24). BTKi-m, BTKi/CD20, and triplet tx groups differed in age (median: 77, 72, 65, respectively; p <0.001), blastoid/pleomorphic histology (6%, 12%, 24%; p = 0.01), Ki67>50% (7%, 19%, 24%; p = 0.04), and presence of TP53 mutation (18%, 33%, 61%; p <0.01).

For the entire cohort, the median follow-up was 32.8 mo (range: 0.2-110.6). 73 pts (32%) had disease progression and 68 pts (30%) died. Overall response rate by Lugano criteria was 77% (CR: 51%) and the median duration of response was 55.9 mo (95% CI 26.2–not reached [NR]). Median PFS was 31 mo (95% CI 22.3–58.9). Median OS was 80.5 mo (95% CI 57.7–99.5). The 2-year PFS (95% CI) in the entire cohort, BTKi-m, BTKi/CD20, and triplet groups were: 57% (50%-65%), 51% (41%-65%), 57% (46%-72%), and 66% (54%-81%), respectively. Median PFS (95% CI) for pts with TP53 mutation vs wildtype by tx group were: BTKi-m: 11.4 mo (3.5-30.6) vs 41.4 mo (10.5-NR); BTKi/CD20: 8.1 mo (1.4–NR) vs NR (12.8–NR); triplet: 24.6 mo (10.8–NR) vs NR (NR–NR).

On UVA, ECOG PS ≥2, blastoid/pleomorphic histology, elevated LDH, cytopenia at diagnosis, Ki67 >50%, del17p, and TP53 mutation were associated with shorter PFS. In MVA including these factors and tx group, elevated LDH (HR 1.7, 95% CI 1.1–2.8; p=0.03), TP53 mutation (HR 1.9, 95% CI 1.0–3.6; p=0.04), del17p (HR 2.0, 95% CI 1.2–3.4; p=0.01), and Ki67 >50% (HR 4.2, 95% CI 2.0–8.7; p <0.01) were associated with shorter PFS. BTKi/CD20 (HR 0.6, 95% CI 0.3-1.0; p=0.04) and triplet (HR 0.4, 95% CI 0.2-0.7; p <0.01) tx were associated with longer PFS compared to BTKi-m.

 37% of pts had an unplanned hospitalization and 21% had infection requiring IV antibiotics or hospitalization. 14% of pts discontinued 1L BTKi due to toxicity.

Conclusions: In a large real-world analysis of 226 pts with MCL treated with 1L BTKi-containing regimens without CT, the median PFS was over 2 years. However, PFS was shorter than reported in clinical trials: the 2-year PFS was 57% in our BTKi/CD20 cohort vs ~72% with ibrutinib/rituximab in the ENRICH trial (Lewis et al. 2025) and the median PFS in pts with TP53 mutations receiving triplet tx was 24.6 mo vs NR in the BOVen trial (Kumar et al. 2025).  These differences are likely due to both pt and disease factors; real-world pts often have a higher comorbidity burden than those on clinical trials, and our cohort had a high proportion of pts with high-risk disease. Triplet and BTKi/CD20 tx were associated with improved PFS, suggesting a benefit of combination tx. The prevalence of serious infections and unplanned hospitalizations highlights toxicities even without CT. Overall, these results demonstrate the real-world effectiveness of 1L BTKi-containing regimens for MCL and underscore the need to develop safer and more effective therapies for pts with high-risk disease and those unfit for CT.