Biallelic TP53 alterations predict poorer survival in Mantle Cell Lymphoma: Insights from a national real-world cohort high-touch project

Abstract Background: Mantle Cell Lymphoma (MCL) is an uncommon B-cell lymphoma with a heterogenous disease course. While relapse is common, outcomes have improved with the usage of rituximab, and recently, BTK inhibitors. Patients (pts) with TP53 mutations have worse outcomes and commonly do not respond to chemoimmunotherapy compared to those without. Presence of deletion 17p (del17p) is thought to confer similar poor outcomes; however some studies show no effect on overall survival (OS). Prior studies included fewer pts with both del17p and TP53 mutations (biallelic alterations), therefore, in our study we aim to evaluate the real world overall survival (rwOS) estimates for TP53 altered MCL pts with a focus on different subgroups of TP53 alterations. Methods: We utilized the US-based, EHR-derived Flatiron Health Research Database. Flatiron Health collects longitudinal, patient-level, real-world data from electronic health records of pts receiving care at academic and community cancer centers across the US. The Flatiron Health network includes access to over 5M patient records from over 280 oncology practices at 800+ unique sites of care in the US. Flatiron Health data are derived from electronic health records and other sources (e.g., obituary data) and include structured (predefined data points: e.g., patient sex or birth date) and unstructured (free text: e.g., clinician notes) data. Inclusion criteria was pts diagnosed with MCL between January 1, 2014, and April 30, 2024. To characterize the patient population, baseline variables including age, sex, practice type, disease subtype, Ann Arbor stage, presence of del17p, presence of TP53 Mutation, lactate dehydrogenase (LDH), WBC count, Eastern Co-operative Oncology Group (ECOG) performance status at first line therapy were collected within (-30, +7) days of the first line start date. The primary objective was to evaluate the impact of TP53 alteration; either mutation, deletion, or both, on rwOS. We utilized Kaplan-Meier curves to determine rwOS, calculated from the date of diagnosis to the date of death or censored to the date for last confirmed activity date or treatment activity abstracted from the EHR. The rwOS amongst groups was compared using the log-rank test. Pairwise comparisons using Bonferroni correction amongst different genetic subtypes was performed with a statistical significance level of 0.05. Population: 5,275 pts with MCL were evaluated. Median age was 70 and most pts received care in the community (75%). Amongst pts with available performance status (60%), 87% were ECOG 0-1 and 13% were ECOG 2-4. MIPI scores were available for 3,208 (61%) (median 6.3): of these 500 (16%) were low, 863 (27%) intermediate, 1,845 (57%) high. LDH was available for 3,439 pts (65%), of these 2,356 were normal (69%) and 1,083 (31%) were elevated. Amongst 5,275 pts, 370 pts had both del17p and TP53 mutation status available. Of 370 pts, 41 pts were +del17p/+TP53, 27 +del17p/-TP53, 53 -del17p/+TP53, and 249 -del17p/-TP53. Results: Median rwOS was 74.3 months (95% CI 69.68, 77.40) for the entire cohort. The rwOS was highest in -del17p/-TP53 mutation (NR, CI 76.02, NR) and lowest amongst +del17p/+TP53 mutation at 23 months (CI 16.72, 45.17), p 0.001 . In pairwise comparisons, median rwOS was 34 months (CI 24.74, NR) in pts with +del17p/-TP53 and 30 months (CI 24.15, NR) in pts with -del17p/+TP53 with p-values of 0.004 and 0.001 when compared to pts with -del17p/-TP53. Similarly, median rwOS was numerically lower in pts with +del17p/+TP53 (23 months) compared to -del17p/+TP53 (30 months) and +del17p/-TP53 (33 months), though not statistically significant. Conclusion: Our data is the first to show numerically inferior rwOS amongst pts with both del17p and mutated TP53 compared to those with only one or neither abnormality. These findings, derived from a large, real-world cohort provide meaningful survival benchmarks and support early molecular testing to identify high risk pts. Given the poorer prognosis of those with biallelic alterations, newer therapeutic approaches should be prioritized for this population.