Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy

Roni Shouval, Ana Alarcon Tomas, Joshua A. Fein, Jessica R. Flynn, Ettai Markovits, Shimrit Mayer, Aishat Olaide Afuye, Anna Alperovich, Theodora Anagnostou, Michal J. Besser, Connie Lee Batlevi, Parastoo B. Dahi, Sean M. Devlin, Warren B. Fingrut, Sergio A. Giralt, Richard J. Lin, Gal Markel, Gilles Salles, Craig S. Sauter, Michael ScordoGunjan L. Shah, Nishi Shah, Ruth Scherz-Shouval, Marcel van den Brink, Miguel Angel Perales, Maria Lia Palomba

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

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.

Original languageEnglish
Pages (from-to)369-381
Number of pages13
JournalJournal of Clinical Oncology
Volume40
Issue number4
DOIs
StatePublished - 1 Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 by American Society of Clinical Oncology.

Funding

Supported by the Memorial Sloan Kettering Cancer Center Core grant (P30 CA008748) from the National Institutes of Health/National Cancer Institute, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and a grant from the Long Island Sound Chapter, Swim Across America. A.A.T. was supported by a grant from the Alfonso Martin Escudero Foundation. J.A.F. was supported by a grant from the American Society for Hematology. R.S. was supported by the American Society of Hematology Fellow Scholar Award.

FundersFunder number
Long Island Sound Chapter
National Institutes of Health
National Cancer InstituteP30CA008748
American Society of Hematology
Fundación Alfonso Martín Escudero
Swim Across America
Marie-Josée and Henry R. Kravis Center for Molecular Oncology

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