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4406 Real World First-Line Treatment Strategies and Outcomes in TP53 Mutated and Unmutated Mantle Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Adult, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Diseases, Real-world evidence, Lymphoid Malignancies, Study Population, Human
Monday, December 9, 2024, 6:00 PM-8:00 PM

Jie Wang, MD, MS1, Jihao Zhou, MD, PhD2*, Yucai Wang, MD, PhD3, Javier L. Munoz, MD, MS, MBA4, Kevin G. Shim3*, Muhamad Alhaj Moustafa, M.D., M.S.5, Firas Baidoun, MD6, Kaitlin Annunzio, DO7, Narendranath Epperla, MD MS7, Michael McLane, MD8, Yasmin H. Karimi, MD8, Binh Luu, BS9*, Stephen E Spurgeon, MD9, Cheryl Chang, BA10*, Zihan Wan, MS11*, Diamone Gathers, MD12*, Emily R. King, BA13*, Marcus P. Watkins, PhD14*, Nancy L. Bartlett, MD13, Christine E. Ryan, MD15, Genevieve M Gerhard, MD16, Philippe Armand, MD, PhD17, Ann S. LaCasce, MD, MMSc18, Vedha Vaddaraju19*, Danielle S Wallace, MD20, Vaishalee P Kenkre, MD21, Chase Junge, MD21*, Natalie Grover, MD22, Jorge A Florindez, MD23, Reem Karmali, MD24, Alexander V. Stanisic, MD25*, Chen Zhang, MD, MS26*, Parameswaran Venugopal, MD26, Grace Ying, DO27*, Caitlin Gribbin, MD, MS28, Jia Ruan, MD, PhD29, Navika D Shukla, MD30, Sonali M. Smith, MD31, Viktoriya Zelikson, MD32, Michael E. Williams, MD ScM32, Stefan K. Barta, MD33, Omar Elghawy, MD34*, Jake Schade, BA35*, Rohini Navalekar, MPA36*, Matthew Matasar, MD, MS37, Andrew M Evens, DO MBA MSc35, Alexey V. Danilov, MD, PhD38 and Timothy S. Fenske, MD39

1Duke Cancer Institute, Hillsborough, NC
2Division of Hematology, Mayo Clinic, Rochester, MN
3Mayo Clinic, Rochester, MN
4Mayo Clinic Arizona, Phoenix, AZ
5Division of Hematology, Mayo Clinic, Jacksonville, FL
6Mayo Clinic, Jacksonville, FL
7Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH
8Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI
9Knight Cancer Institute, Oregon Health & Science University, Portland, OR
10Duke University School of Medicine, Durham, NC
11Duke Cancer Institute, Durham, NC
12Duke Cancer Institute, Durham
13Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
14Division of Oncology, Washington University School of Medicine, St. Louis, MO
15Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
16Beth Israel Deaconess Medical Center, Boston, MA
17Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
18Dana-Farber Cancer Institute, Boston, MA
19Wilmot Cancer Insititute, University of Rochester Medical Center, Rochester, NY
20Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
21University of Wisconsin School of Medicine and Public Health, Madison, WI
22University of North Carolina, Chapel Hill, NC
23Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
24Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
25Northwestern University Feinberg School of Medicine, Chicago, IL
26Rush University Medical Center, Chicago, IL
27Medical College of Wisconsin, Milwawkee, WI
28Weill Cornell Medicine, New York, NY
29Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY
30Department of Medicine, University of Chicago, Chicago, IL
31University of Chicago, Chicago, IL
32University of Virginia Comprehensive Cancer Center, Charlottesville, VA
33Abramson Cancer Center, The Fox Chase Cancer Center Foundation, Philadelphia, PA
34Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
35Rutgers Cancer Institute, New Brunswick, NJ
36Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
37Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ
38City of Hope National Medical Center, La Canada Flintridge, CA
39Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI

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.

Disclosures: 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: Genentech: Other: Institutional research funding; AstraZeneca: Honoraria. 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: Genmab: Consultancy, Honoraria. 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: Seattle Genetics: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; ADC Therapeutics: Honoraria; IMV Therapeutics: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria; Epizyme: Honoraria; Takeda: Honoraria; GM Biosciences: Consultancy, Research Funding; AstraZeneca: Honoraria; Allogene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Research Funding; Kite: Honoraria; Merck: Current equity holder in publicly-traded company; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria; Immunovaccine Technologies: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding. Evens: Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Danilov: Merck: Consultancy; Morphosys: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Bayer Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; GenMab: Consultancy, Research Funding; Cyclacel: Research Funding; Janssen: Consultancy; Incyte: Consultancy; Lilly Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Genentech: Consultancy; TG Therapeutics: Research Funding; Prelude: Consultancy; Nurix: Consultancy, Research Funding; ADCT: Consultancy; Abbvie: Consultancy, Research Funding. Fenske: AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Beigene, Janssen, Kite, Lilly, Ono Pharmaceuticals: Consultancy, Honoraria; AstraZeneca, Beigene, Kite, SeaGen: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria.

*signifies non-member of ASH