Insights in the management of older adults with mantle cell lymphoma amidst a changing therapeutic landscape: Lessons from a 25-year institutional experience

Abstract

Abstract Introduction Treatment (tx) of older adults (OA) with mantle cell lymphoma (MCL) is evolving rapidly. Historically, chemoimmunotherapy (CIT) with bendamustine and rituximab (BR) +/- R maintenance was the preferred frontline (1L) treatment option in 'transplant ineligible’ patients, however, this paradigm has been challenged with the introduction of BTK inhibitors (BTKi). In OA, the ECHO study showed improved progression-free survival (PFS) of acalabrutinib-BR over BR, with acalabrutinib being continued indefinitely till progression. More recently, the ENRICH study showed an improved PFS for ibrutinib-rituximab (IR) over R-CHOP, with similar PFS as BR in OA. Concurrently, in eligible patients, high-dose chemotherapy with autologous stem cell rescue (HDC-ASCR) as 1L consolidation has been successfully challenged by incorporating BTKi in this setting. While chemo-free options with covalent BTKi+R represent an emerging, attractive tx option for OA, their limitations include indefinite tx and unique toxicities that can be challenging to manage in OA with multiple comorbidities. We interrogated the Memorial Sloan Kettering (MSK) Lymphoma Outcomes Database (LOD) to benchmark outcomes with CIT and to determine what insights can be gleaned from a predominantly CIT era to inform the future. Methods OA≥ 65 years (y) diagnosed (dx) with MCL treated at MSK from 2000-2025 were included. Pt demographics, disease/tx history and outcomes were extracted. PFS and OS were estimated using the Kaplan-Meier method, comparisons were made using log-rank test and associations between outcomes, clinical, and tx characteristics were evaluated with Fischer exact test. Results In 419 OA with MCL, median age was 72y (range 65-102y), age ≥80y 19%, male 73%, Stage 4 82%, MIPI low/intermediate/high 6%/47%/47%, blastoid/pleiomorphic 14%, Ki67 <30%/30-49%/≥50% 49%/25%/26%, p53 expression/17p deletion/TP53 mutation 10%/9%/10%. The proportion of women increased with age (p=0.06); no other age-based differences were noted at baseline. Median follow-up (f/u) was 8y (range 0.04-19.92y). Of the 28% pts managed with intent to observe at initial dx, median time on observation was 1.25 y (0.1-9.02y). Pts ≥80 yrs were more likely to be observed (p=0.036) with no age-based differences in median time on observation. Overall, 89% pts received a variety of 1L tx; majority received CIT (BR 33%, intensive regimens with intent to transplant 27%, R-CHOP 11%); 9% received BTKi in 1L; 25% pts were treated on clinical trials. After 1L therapy, 15% underwent HDC-ASCR consolidation and 22% received rituximab maintenance. Pts≥80y received anti-CD20 Ab monotherapy more frequently (24%). Overall response rate (ORR) was 75% with complete response rate (CRR) of 35%. The 5-y PFS was 37% (95% CI 32%, 43%) with 5-y OS of 61%. 5-y OS from receipt of 1L therapy was 56%. 45% pts have not required 2L tx to date. Age, gender, 1L tx type, stem cell transplant, stage, Ki67%, p53 expression, TP53 status, MIPI category, LDH level were significantly associated with PFS and OS (both from time of dx and start of 1L tx) in univariate analysis. Age, gender, 1L tx type, and Ki67% remained highly associated with PFS and OS in a multivariable model (MVA). Notably, women had a significantly better PFS to 1L tx (<0.001) and OS (<0.001) compared to men. Pts receiving intensive regimens with intent to transplant had longest mPFS (4.5y), followed by BTKi-based tx (3.6y), BR (3.1y) and R-CHOP (2y). Follow-up for BTKi exposed pts is immature to analyze the impact of BTKi use in 1L. Conclusions With a 5-y PFS of 37% and a 5-y OS of 61%, the outcomes of OA treated predominantly in the CIT era were consistent with contemporary CIT literature but suboptimal compared to modern regimens incorporating BTKi. Intensive CIT with intent to transplant led to durable remissions in carefully selected OA beyond the chronological age of 65y. PFS and OS significantly declined with advancing age despite comparable baseline characteristics suggestive of age-based bias in selecting 1L therapy and increasing toxicities to CIT. Our data highlights the need for continued investigation of chemo-free approaches in OA≥80y and the importance of incorporating fitness assessment for personalized decision making in OA. Women have a significant survival advantage over men and further analyses to understand gender-based differences in outcomes are planned.