Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy. Issue 4 (1st February 2022)

• Record Type: Journal Article
• Authors: Shouval, Roni; Alarcon Tomas, Ana; Fein, Joshua A.; Flynn, Jessica R.; Markovits, Ettai; Mayer, Shimrit; Olaide Afuye, Aishat; Alperovich, Anna; Anagnostou, Theodora; Besser, Michal J.; Batlevi, Connie Lee; Dahi, Parastoo B.; Devlin, Sean M.; Fingrut, Warren B.; Giralt, Sergio A.; Lin, Richard J.; Markel, Gal; Salles, Gilles; Sauter, Craig S.; Scordo, Michael; Shah, Gunjan L.; Shah, Nishi; Scherz-Shouval, Ruth; van den Brink, Marcel; Perales, Miguel-Angel; Palomba, Maria Lia
• Is Part Of: Journal of clinical oncology. Volume 40:Issue 4(2022)
• Page Start: 369
• Page End: 381
• Publication Date: 2022-02-01
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.21.02143
• Languages: English
• ISSNs: 0732-183X

Abstract

Abstract : PURPOSE: Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS: Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS: We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53 -altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION: TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts. Abstract :