Real World First-Line Treatment Strategies and Outcomes in TP53 Mutated and Unmutated Mantle Cell Lymphoma

Introduction:

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) Prognosis is highly variable due to underlying biological and molecular heterogeneity. The first-line (1L) treatment paradigm for MCL continues to evolve with increasing use of bruton tyrosine kinase inhibitors (BTKi) and decreasing use of autologous stem cell transplant (ASCT). TP53 alterations are associated with inferior outcomes in MCL. The aim of this retrospective study is to determine treatment strategies and clinical outcomes in MCL patients based on TP53 gene mutation status.

Methods:

Retrospective data were collected from 19 institutions in the United States from 1/1993 to 1/2024. We examined treatment patterns and outcomes among MCL patients >18 years of age with known TP53 mutation status by sequencing. Patients who did not receive treatment were excluded. The analysis was stratified based on presence of TP53 mutations. Systemic therapies were categorized as chemo-immunotherapy (CIT), non-chemotherapy (including monoclonal antibodies, lenalidomide, venetoclax, and novel agents on clinical trial), and regimens containing BTKi. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS) and time to next treatment (TTNT). OS and PFS were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups.

Results:

645 patients were included in the study, with 468 men (72.6%) and median age was 64 years (range 30-89). 230/645 patients (35.7%) had a TP53 mutation, of which 182 (79%) were identified prior to 1L. While the male/female distribution was the same between the mutated and unmutated groups, median age at diagnosis and MIPI risk score was higher in the TP53 mutated group (age 65.9 vs 63.1 yrs, p= 0.015; MIPI 6.4 vs 6.1, p<0.001). TP53 unmutated patients had a median of 1 line of therapy vs. 2 for the mutated group (p<0.001, range 1-8). Blastoid histology and higher ki67 were also associated with the TP53 mutated group (p=0.045, 0.01 respectively)

The median OS was 14.2 years for TP53 unmutated and 8.3 years for TP53 mutated patients (p<0.0001). PFS in 1L was 0.95 years in TP53 mutated compared to 2.02 years in TP53 unmutated group (p<0.0001). Selection of 1L therapeutic strategy was not associated with presence of TP53 mutation (Χ² p= 0.21) although more patients in the TP53 unmutated group underwent ASCT (119/415 vs 38/230; Χ² p=0.0006)

TP53 mutation was associated with inferior survival compared to TP53 unmutated patients for CIT in 1L but the difference did not reach statistical significance when non-chemotherapy regimens and regimens containing BTKi were used. For CIT in 1L, 5 year OS was 78% [71-84%] for unmutated compared to 58% [48-67%] for the mutated group (p=0.0001 ). For non-chemotherapy regimens, 5 year OS for unmutated patients was 73% [52- 86%] compared to 52% [25-73%] for the mutated group (p=0.09). For regimens containing BTKi, 5 year OS for unmutated was 93% [81-97%] compared to 57% [28-78%] for mutated (p=0.07).

Within the TP53 mutated group, there were no differences in any clinical outcomes between those receiving CIT, non-chemotherapy, or BTKi in 1L. While median OS appeared numerically longer in the BTKi group (14.4 yrs vs 8.8 yrs for CIT and 6.8 yrs for non-chemotherapy), the difference did not reach statistical significance (p=0.58). In contrast,TP53 unmutated patients who received CIT in 1L had better TTNT (p=0.0039) compared to those in non-chemotherapy and BTKi groups. There was no improvement in PFS (p=0.79) or OS (p=0.47).

Conclusions

To our knowledge this is the largest retrospective real world dataset of MCL treatment outcomes stratified by TP53 mutation. As in prior studies, TP53 mutation portends a worse prognosis in MCL compared to TP53 unmutated patients, but outcomes are better than historically reported. CIT in 1L was not associated with improved OS in either group. Irrespective of TP53 mutation status, incorporation of BTKi in first line was not associated with improved clinical outcomes. The gap in OS between TP53 mutated and unmutated MCL may be narrowing as treatment paradigms shift away from intensive induction chemotherapy and ASCT, and due to an increasing number of effective therapies for relapsed patients. Clinical trials of novel agents are needed to further improve the OS of TP53 mutated MCL patients.

Wang:Regeneron: Research Funding. Wang:Kite: Honoraria; InnoCare, AbbVie: Consultancy; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board. Munoz:Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/BMS, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis, Morphosys/Incyte: Consultancy; Targeted Oncology, OncView, Curio, Genzyme, and Physicians' Education Resource: Honoraria; Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, BeiGene: Research Funding. Alhaj Moustafa:AbbVie: Consultancy. Epperla:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Incyte Corporation: Research Funding; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Research Funding, Speakers Bureau. Karimi:Roche/Genentech: Other: Travel Expenses, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Merck: Research Funding; Lilly/Loxo: Research Funding; AstraZeneca: Research Funding; Xencor: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Bartlett:Washington University School of Medicine: Current Employment; ADC Therapeutics: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Janssen: Research Funding; Kite Pharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Celegne: Research Funding; BMS: Research Funding; Autolus: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Foresight Diagnostics: Membership on an entity's Board of Directors or advisory committees. Ryan:AstraZeneca Brazil: Honoraria; Genentech: Other: Research Funding to institution. Armand:Merck: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Genmab: Consultancy; Enterome: Consultancy; Genentech/Roche: Consultancy, Research Funding; ATB Therapeutics: Consultancy; Foresight: Consultancy; Regeneron: Consultancy; Kite: Research Funding; Adaptive: Research Funding; IGM: Research Funding; AstraZeneca: Research Funding. LaCasce:Research to Practice: Speakers Bureau; Genmab: Consultancy. Wallace:Integrity CME: Honoraria. Kenkre:Ipsen: Research Funding. Grover:Sangamo: Current holder of stock options in a privately-held company; Novartis: Honoraria; Regeneron: Honoraria, Research Funding; ADC Therapeutics: Honoraria; BMS: Honoraria, Research Funding; Caribou: Honoraria; Ono Pharma: Honoraria; Genentech: Honoraria; Cabaletta: Research Funding; Janssen: Honoraria; Kite: Honoraria; Seagen: Honoraria. Karmali:Ipsen: Speakers Bureau; BeiGene: Speakers Bureau; Incyte: Speakers Bureau; AstraZeneca: Speakers Bureau; BMS: Honoraria; Abbvie: Honoraria; Genentech/Roche: Honoraria; Genmab: Honoraria. Ruan:Genentech: Research Funding; BMS: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria. Smith:Regeneron: Other: Educational lecture; Genmab: Consultancy; Ono Pharmaceutical: Consultancy; Caris Life Sciences: Other: Spouse is employed by Caris Life Sciences. Barta:BMS: Consultancy; Kyowa Kirin: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Acrotech: Consultancy. Matasar:Takeda: Honoraria; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; GM Biosciences: Consultancy, Research Funding; IMV Therapeutics: Honoraria; Bayer: Consultancy, Honoraria, Research Funding; Kite: Honoraria; Genentech: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Honoraria; AstraZeneca: Honoraria; BMS/Celgene: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Current equity holder in publicly-traded company; Immunovaccine Technologies: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Epizyme: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria. Evens:Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Danilov:Genentech: Consultancy; Cyclacel: Research Funding; TG Therapeutics: Research Funding; Takeda Oncology: Research Funding; Nurix: Consultancy, Research Funding; Lilly Oncology: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Incyte: Consultancy; Janssen: Consultancy; GenMab: Consultancy, Research Funding; Morphosys: Consultancy; Merck: Consultancy; ADCT: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; Bayer Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Abbvie: Consultancy, Research Funding; Prelude: Consultancy. Fenske:AstraZeneca, Beigene, Kite, SeaGen: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria; AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Lilly, Ono Pharmaceuticals: Consultancy, Honoraria.