Abstract
Introduction: The effect of TP53 alterations on response to therapy is poorly understood in LBCL, with previous studies demonstrating worse overall survival (OS) for LBCL patients (pts) with TP53 aberrations. However, these studies pre-dated novel therapies, including chimeric antigen receptor T-cell therapy (CAR T), bispecific antibody (BsAb), and targeted therapies in LBCL. The impact of novel therapies in TP53-altered LBCL merits dedicated study in a real-world cohort.
Methods: We conducted a multicenter retrospective study of adult pts with LBCL diagnosed between 1/1/2013 to 12/31/2023 with TP53 alterations. TP53 alterations could be determined via immunohistochemistry (IHC), karyotype, fluorescent in situ hybridization (FISH), or next generation sequencing (NGS). Pts with transformed LBCL were excluded. Primary outcomes were progression-free survival (PFS) and OS for first (1L), second (2L), and third lines (3L) of therapy. Time-to-event endpoints were analyzed using Cox proportional hazard models, Kaplan-Meier curves and log-rank tests. Proportional differences were assessed via Pearson's Chi-squared test or Fisher's exact test.
Results: There were 206 pts from 14 institutions. Demographic features included median age 65 years (range 23-95), 64% male, 72% White, 8% Black, and 17% Hispanic.
The most common LBCL subtype was diffuse LBCL (DLBCL, 67%), followed by post-transplant lymphoproliferative disorder (8%), double hit lymphoma (7%) and high grade B-cell lymphoma (7%). Cell of origin was 46% germinal center (GC) and 41% non-GC. The majority (59%) were Stage IV at diagnosis, with 7% CNS involvement, 23% bulky disease, and 73% extranodal involvement, with gastrointestinal involvement as the most frequent site (35%). The majority had intermediate risk IPI (57%), with high risk IPI in 22% at diagnosis. TP53 testing was performed at diagnosis in 86% (31% IHC, 17% karyotype, 26% FISH, and 31% NGS).
Of 206 pts, 1L treatment consisted of curative intent chemoimmunotherapy (CIT) (188, 91.3%), palliative CIT (9, 4.4%), no treatment information (5, 2.4%), or other treatment (4, 1.9%). Of 92 pts receiving 2L, treatment consisted of CIT (50, 54.3%), CAR T (16, 17.4%), targeted therapy (10, 10.9%), high dose CIT with autologous stem cell transplant (HDC+ASCT) (8, 8.7%) or other (8, 8.7%). Of 59 pts receiving 3L, treatment consisted of CIT (17, 28.8%), CAR T (17, 28.8%), targeted therapy (13, 22%), other (6, 10.2%), HDC+ASCT (4, 6.8%) or CD20 BsAb (2, 3.4%).
With a median follow up of 26 months (m) (95% CI 19, 34), both median OS and 1L OS were 77 m (95% CI 49, NR). When stratified by treatment, median OS was significant: curative intent CIT 77 m (95% CI 56, NR), palliative therapy 15 m (95% CI 14, NR), and other treatments 6.1 m (95% CI 5.9, NR) (p < .0001). 1L PFS was 18 m (95% CI 13, 49) and was not statistically different by 1L treatment: curative intent CIT 20 m (95% CI 14, 54), palliative therapy 7.9 m (95% CI 3.2, NR), other treatments 5.4 m (95% CI 2.1, NR) (p = .08).
2L OS was 33 m (95% CI 20, NR) and 2L PFS was 5.1 m (95% CI 2.8, 8.9), which were not statistically different when stratified by treatment. 3L OS was 30 m (95% CI 17, NR) and PFS was 5 m (95% CI 2.7, 11). By treatment type, 3L PFS and OS were statistically different. 3L OS was as follows: CAR T 76 m (95% CI 31, NR), other therapies 33 m (95% CI 7.8, NR), CIT 17 m (95% CI 10, NR), targeted therapies 15 m (95% CI 12, NR), not reached for CD20 BsAb and HDC+ASCT (p = .031). 3L PFS was as follows: CAR T 7.9 m (95% CI 3.4, NR), CIT 4.6 m (95% CI 1.6, 22), targeted therapies 2.4 m (95% CI 1.1, NR), other therapies 0.8 m (95% CI 0.7, NR), not reached for CD20 BsAb or HDC+ASCT (p = .008).
Discussion: In this real-world cohort examining clinical outcomes of TP53-altered LBCL, there was a statistically significant difference in 3L OS indicating that CAR T may portend better PFS and OS in LBCL pts with TP53 alterations. Although 3L survival was also improved in pts receiving BsAb, sample sizes were small and the impacts of different cellular therapies on survival in this high-risk LBCL subset merits further study. Expansion of this real-world cohort with longer follow-up time will enable analysis to see if CAR T improves outcomes in the 2L setting for TP53-altered LBCL and if novel cellular therapies result in superior OS over CIT. Further study into the survival implications of various testing mechanisms for TP53 alterations, and type of alteration, will be performed to examine the impact of these molecular findings.
Hill:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Research Funding. Shadman:Bristol Myers Squibb: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Kite Pharma: Consultancy; Eli Lilly: Consultancy; Fate therapeutics: Consultancy; Nurix: Consultancy; Merck: Consultancy; Mustang Bio: Research Funding; Vincerx: Research Funding; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Bristol Myers Squibb (spouse): Current Employment; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; Genmab: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ahmed:BMS: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees. Lutfi:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Johnson:AstraZeneca Pharmaceuticals LP: Consultancy, Research Funding; Seagen: Consultancy; Bristol Myers Squibb: Consultancy; Medically Home: Research Funding; ADC Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; Abbvie: Consultancy. Patel:AbbVie: Consultancy; Adaptive Biotechnologies: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Caribou Biosciences: Consultancy; CRISPR Therapeutics: Research Funding; Curis, Inc: Research Funding; Epizyme: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Genentech/Roche: Consultancy, Research Funding; Kite: Consultancy, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Morphosys: Consultancy; Nurix: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding; Sunesis Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Consultancy, Speakers Bureau; Trillium Therapeutics/Pfizer: Consultancy, Research Funding; Xencor: Consultancy, Research Funding. Karmali:BeiGene: Speakers Bureau; BMS: Honoraria; Genmab: Honoraria; Ipsen: Speakers Bureau; AstraZeneca: Speakers Bureau; Incyte: Speakers Bureau; Abbvie: Honoraria; Genentech/Roche: Honoraria. Frosch:Fox Chase Cancer Center: Current Employment; Seagen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; BeiGene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Genmab: Research Funding; AstraZeneca: Research Funding; Antegene: Research Funding; Sanofi: Research Funding; Roche: Research Funding. Ip:MJH life sciences Graticule: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Speakers Bureau; COTA: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seagen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bair:Kura Oncology: Consultancy. Major:Roche/Genentech: Consultancy; Incyte: Research Funding.