Roni Shouval1,2, Ana Alarcon Tomas1,3, Joshua A Fein4, Jessica R Flynn5, Ettai Markovits6, Shimrit Mayer7, Aishat Olaide Afuye1, Anna Alperovich1, Theodora Anagnostou1,8, Michal J Besser6,9, Connie Lee Batlevi2,10, Parastoo B Dahi1,2, Sean M Devlin5, Warren B Fingrut1, Sergio A Giralt1,2, Richard J Lin1,2, Gal Markel9,11, Gilles Salles2,10, Craig S Sauter1,2, Michael Scordo1,2, Gunjan L Shah1,2, Nishi Shah1, Ruth Scherz-Shouval7, Marcel van den Brink1,2, Miguel-Angel Perales1,2, Maria Lia Palomba2,10. 1. Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, NY. 2. Weill Cornell Medical College, New York, NY. 3. Cell Therapy and Translational Medicine, University of Murcia, Murcia, Spain. 4. University of Connecticut Medical Center, Farmington, CT. 5. Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, NY. 6. Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Chaim Sheba Medical Center, Ramat Gan, Israel. 7. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. 8. Department of Hematology and Medical Oncology, and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY. 9. Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. 10. Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY. 11. Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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.
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.
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