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 Scordo; Gunjan L. Shah; Nishi Shah; Ruth Scherz-Shouval; Marcel van den Brink; Miguel Angel Perales; Maria Lia Palomba

doi:10.1200/JCO.21.02143

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 journal › Article › peer-review

94 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 language	English
Pages (from-to)	369-381
Number of pages	13
Journal	Journal of Clinical Oncology
Volume	40
Issue number	4
DOIs	https://doi.org/10.1200/JCO.21.02143
State	Published - 1 Feb 2022
Externally published	Yes

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.

Funders	Funder number
Long Island Sound Chapter
National Institutes of Health
National Cancer Institute	P30CA008748
American Society of Hematology
Fundación Alfonso Martín Escudero
Swim Across America
Marie-Josée and Henry R. Kravis Center for Molecular Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1200/JCO.21.02143

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Shouval, R., Tomas, A. 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., ... Palomba, M. L. (2022). Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy. Journal of Clinical Oncology, 40(4), 369-381. https://doi.org/10.1200/JCO.21.02143

@article{a8e6df7fb0e441c7aba249a27d99bfa0,

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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 by American Society of Clinical Oncology.",

year = "2022",

month = feb,

day = "1",

doi = "10.1200/JCO.21.02143",

language = "אנגלית",

volume = "40",

pages = "369--381",

journal = "Journal of Clinical Oncology",

issn = "0732-183X",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

Shouval, R, Tomas, AA, Fein, JA, Flynn, JR, Markovits, E, Mayer, S, Afuye, AO, Alperovich, A, Anagnostou, T, Besser, MJ, Batlevi, CL, Dahi, PB, Devlin, SM, Fingrut, WB, Giralt, SA, Lin, RJ, Markel, G, Salles, G, Sauter, CS, Scordo, M, Shah, GL, Shah, N, Scherz-Shouval, R, van den Brink, M, Perales, MA & Palomba, ML 2022, 'Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy', Journal of Clinical Oncology, vol. 40, no. 4, pp. 369-381. https://doi.org/10.1200/JCO.21.02143

TY - JOUR

T1 - Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy

AU - Shouval, Roni

AU - Tomas, Ana Alarcon

AU - Fein, Joshua A.

AU - Flynn, Jessica R.

AU - Markovits, Ettai

AU - Mayer, Shimrit

AU - Afuye, Aishat Olaide

AU - Alperovich, Anna

AU - Anagnostou, Theodora

AU - Besser, Michal J.

AU - Batlevi, Connie Lee

AU - Dahi, Parastoo B.

AU - Devlin, Sean M.

AU - Fingrut, Warren B.

AU - Giralt, Sergio A.

AU - Lin, Richard J.

AU - Markel, Gal

AU - Salles, Gilles

AU - Sauter, Craig S.

AU - Scordo, Michael

AU - Shah, Gunjan L.

AU - Shah, Nishi

AU - Scherz-Shouval, Ruth

AU - van den Brink, Marcel

AU - Perales, Miguel Angel

AU - Palomba, Maria Lia

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

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

Abstract

Bibliographical note

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