Impact of TP53 genomic alterations in large B-cell lymphoma treated with CD19-chimeric antigen receptor T-cell therapy Journal Article
| Authors: | Shouval, R.; Alarcon Tomas, A.; Fein, J. A.; Flynn, J. R.; Markovits, E.; Mayer, S.; Afuye, A. O.; Alperovich, A.; Anagnostou, T.; Besser, M. J.; Batlevi, C. L.; Dahi, P. B.; Devlin, S. M.; Fingrut, W. B.; Giralt, S. A.; Lin, R. J.; Markel, G.; Salles, G.; Sauter, C. S.; Scordo, M.; Shah, G. L.; Shah, N.; Scherz-Shouval, R.; van den Brink, M.; Perales, M. A.; Palomba, M. L. |
| Article Title: | Impact of TP53 genomic alterations in large B-cell lymphoma treated with CD19-chimeric antigen receptor T-cell therapy |
| 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. |
| Keywords: | treatment outcome; aged; middle aged; retrospective studies; genetics; mutation; mortality; t lymphocyte; t-lymphocytes; gene expression profiling; risk factors; transplantation; retrospective study; protein p53; tumor marker; risk factor; time factors; risk assessment; b cell lymphoma; lymphoma, b-cell; immunology; receptors, antigen, t-cell; predictive value of tests; tumor suppressor protein p53; gene dosage; tp53 protein, human; adoptive immunotherapy; immunotherapy, adoptive; cd19 antigen; lymphocyte antigen receptor; antigens, cd19; biological product; biological products; predictive value; dna copy number variations; copy number variation; adverse event; time factor; high throughput sequencing; high-throughput nucleotide sequencing; humans; human; male; female; biomarkers, tumor; tisagenlecleucel t; axicabtagene ciloleucel; receptors, chimeric antigen; cd19 molecule, human |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 40 |
| Issue: | 4 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2022-02-01 |
| Start Page: | 369 |
| End Page: | 381 |
| Language: | English |
| DOI: | 10.1200/jco.21.02143 |
| PUBMED: | 34860572 |
| PROVIDER: | scopus |
| PMCID: | PMC8797602 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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