Background: Alterations to the tumor suppressorTP53 in mantle cell lymphoma (MCL) are one of the strongest predictors of poor responses to immunochemotherapy (ICT) and early mortality. Recent BSH guidelines (Eyre et al, 2024) recommend TP53 mutation analysis is undertaken on all new MCL diagnoses, and in the United Kingdom (UK) testing is now commonplace. With adverse outcomes observed with conventional ICT in clinical trials, the optimal management for these patients (pts) remains poorly defined. There is limited real-world data to guide clinical practice, providing an imperative to review outcomes of this cohort treated within an integrated healthcare framework. This study aims to provide insights on treatment efficacy; refine prognostic understanding and guide future management. Aims: Assess outcomes of pts receiving first-line (1L) systemic therapy (tx) for TP53 aberrant MCL treated within the UK in the modern era. Methods: A multicenter, retrospective analysis of anonymised data from pts with TP53 aberrant MCL treated with 1L systemic tx at 28 centers across the UK. Patients commenced 1L tx between January 2018 and March 2025. Response to tx was defined as per Lugano classification (Cheson et al, 2014). Data was collected on baseline characteristics and subsequent lines of therapy. Primary outcome was overall survival (OS) from start of 1L tx. Secondary outcomes included tx failure free survival (FFS), defined as time to next line tx, progression of disease or death. Predictors of OS were determined using univariate Cox regression. Results: Data was collected on 120 patients: median age 65 years (range 41-82) with 70% male. TP53 alterations included 113 pts with mutations, and 7 pts with deletions. Prior to 1L tx clinical phenotype was defined as nodal in 69% and leukemic, non-nodal in 31%; LDH ratio >1.5 in 40%; ECOG performance status ≥2 in 17%; blastoid morphology in 21%; Ki67 ≥50% in 46%; and MIPI high risk in 68%. 1L tx was high intensity ICT (rituximab + high dose cytarabine based) in 60 pts (50%), intermediate intensity ICT (R-CHOP/R-Bendamustine/R-BAC/VR-CAP) in 39 pts (33%), non-ICT (BTK inhibitor (BTKi) based) in 17 pts (14%), and low intensity ICT in 4 pts (3%). Ten pts were consolidated at 1L with autologous SCT; 8 pts with allogeneic SCT. Overall response rate to 1L was 68%, complete response rate was 45%. At a median follow up of 23 months (mo), 69 pts progressed, of which, 49 pts had died. Four pts died without relapse. The median 1L FFS was 13.9 mo (95% CI 8.9-18.9), and estimated median OS was 29.8 mo (95% CI 20.8-38.8). The median FFS according to 1L tx was 22.3 mo (95% CI 6.2-38.4) for high intensity ICT; 8.9 mo (95% CI 3.8-14.0) for intermediate intensity ICT; and 14.6 mo (95% CI 4.5-24.7) for non-ICT. On univariate Cox regression, LDH ratio >1.5 was predictive of OS (HR 2.3, 95% CI 1.3-4.3; p=0.007). Age >65 years, nodal vs non-nodal, blastoid morphology, Ki67 ≥50% and MIPI high risk were not predictive Of 69 pts at relapse: 11 pts died without 2L therapy; 48 pts received BTKi, 7 pts received ICT, 3 pts had not commenced 2L. Of 48 pts receiving 2L BTKi, 41 pts progressed and 33 had died. The median FFS from start 2L BTKi was 2.5 mo (95% CI 1.5-3.5), and median OS 5.6 mo (95% CI 4.0-7.2). Of 41 pts progressing on BTKi, only 10 were subsequently infused with 3L brexucabtagene autolecel (brexu-cel) (24%). Conclusion: Relative to contemporary real-world datasets, the OS analysis highlights that current management of TP53 aberrant MCL is inadequate, and there is urgent need to evolve novel strategies that combat this uniquely aggressive biology. Relatively high initial response rates to 1L tx were generally not durable, and subsequent outcomes with 2L BTKi were poor. The low proportion of pts ultimately proceeding to 3L+ brexu-cel intimates the challenge of delivering this therapy to pts with rapidly progressive disease, and provides a rationale for earlier use in this subgroup. Baseline characteristics demonstrated frequent markers of poor prognosis, with LDH ratio >1.5 the only characteristic predictive of OS. Pts presenting with markedly elevated LDH may be most suitable for aggressive 1L management strategies.
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