PMID- 34860572
OWN - NLM
STAT- MEDLINE
DCOM- 20220221
LR  - 20230403
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 40
IP  - 4
DP  - 2022 Feb 1
TI  - Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With 
      CD19-Chimeric Antigen Receptor T-Cell Therapy.
PG  - 369-381
LID - 10.1200/JCO.21.02143 [doi]
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.
FAU - Shouval, Roni
AU  - Shouval R
AUID- ORCID: 0000-0001-9827-8032
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Alarcon Tomas, Ana
AU  - Alarcon Tomas A
AUID- ORCID: 0000-0002-6290-1061
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Cell Therapy and Translational Medicine, University of Murcia, Murcia, Spain.
FAU - Fein, Joshua A
AU  - Fein JA
AUID- ORCID: 0000-0001-5441-1516
AD  - University of Connecticut Medical Center, Farmington, CT.
FAU - Flynn, Jessica R
AU  - Flynn JR
AUID- ORCID: 0000-0001-8310-6684
AD  - Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer 
      Center, New York, NY.
FAU - Markovits, Ettai
AU  - Markovits E
AUID- ORCID: 0000-0001-9817-0638
AD  - Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Chaim Sheba Medical 
      Center, Ramat Gan, Israel.
FAU - Mayer, Shimrit
AU  - Mayer S
AD  - Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - Olaide Afuye, Aishat
AU  - Olaide Afuye A
AUID- ORCID: 0000-0002-5751-3283
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
FAU - Alperovich, Anna
AU  - Alperovich A
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
FAU - Anagnostou, Theodora
AU  - Anagnostou T
AUID- ORCID: 0000-0003-2142-7356
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Department of Hematology and Medical Oncology, and Tisch Cancer Institute, Icahn 
      School of Medicine at Mount Sinai, New York, NY.
FAU - Besser, Michal J
AU  - Besser MJ
AD  - Ella Lemelbaum Institute for Immuno-Oncology and Melanoma, Chaim Sheba Medical 
      Center, Ramat Gan, Israel.
AD  - Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, 
      Tel Aviv University, Tel Aviv, Israel.
FAU - Batlevi, Connie Lee
AU  - Batlevi CL
AUID- ORCID: 0000-0002-9036-9463
AD  - Weill Cornell Medical College, New York, NY.
AD  - Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, 
      New York, NY.
FAU - Dahi, Parastoo B
AU  - Dahi PB
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Devlin, Sean M
AU  - Devlin SM
AUID- ORCID: 0000-0002-6801-720X
AD  - Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer 
      Center, New York, NY.
FAU - Fingrut, Warren B
AU  - Fingrut WB
AUID- ORCID: 0000-0002-5017-1583
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
FAU - Giralt, Sergio A
AU  - Giralt SA
AUID- ORCID: 0000-0003-1944-5053
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Lin, Richard J
AU  - Lin RJ
AUID- ORCID: 0000-0002-0834-7880
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Markel, Gal
AU  - Markel G
AD  - Department of Clinical Microbiology & Immunology, Sackler Faculty of Medicine, 
      Tel Aviv University, Tel Aviv, Israel.
AD  - Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva, 
      Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Salles, Gilles
AU  - Salles G
AUID- ORCID: 0000-0002-9541-8666
AD  - Weill Cornell Medical College, New York, NY.
AD  - Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, 
      New York, NY.
FAU - Sauter, Craig S
AU  - Sauter CS
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Scordo, Michael
AU  - Scordo M
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Shah, Gunjan L
AU  - Shah GL
AUID- ORCID: 0000-0002-9977-0456
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Shah, Nishi
AU  - Shah N
AUID- ORCID: 0000-0002-4723-6745
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
FAU - Scherz-Shouval, Ruth
AU  - Scherz-Shouval R
AUID- ORCID: 0000-0002-4570-121X
AD  - Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 
      Israel.
FAU - van den Brink, Marcel
AU  - van den Brink M
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Perales, Miguel-Angel
AU  - Perales MA
AUID- ORCID: 0000-0002-5910-4571
AD  - Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan 
      Kettering Cancer Center, New York, NY.
AD  - Weill Cornell Medical College, New York, NY.
FAU - Palomba, Maria Lia
AU  - Palomba ML
AUID- ORCID: 0000-0001-5099-9156
AD  - Weill Cornell Medical College, New York, NY.
AD  - Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center, 
      New York, NY.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20211203
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antigens, CD19)
RN  - 0 (Biological Products)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CD19 molecule, human)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, Chimeric Antigen)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - Q6C9WHR03O (tisagenlecleucel)
RN  - U2I8T43Y7R (axicabtagene ciloleucel)
SB  - IM
MH  - Aged
MH  - Antigens, CD19/*immunology
MH  - Biological Products/therapeutic use
MH  - Biomarkers, Tumor/*genetics
MH  - DNA Copy Number Variations
MH  - Female
MH  - Gene Dosage
MH  - Gene Expression Profiling
MH  - High-Throughput Nucleotide Sequencing
MH  - Humans
MH  - *Immunotherapy, Adoptive/adverse effects/mortality
MH  - Lymphoma, B-Cell/genetics/immunology/mortality/*therapy
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Predictive Value of Tests
MH  - Receptors, Antigen, T-Cell/therapeutic use
MH  - Receptors, Chimeric Antigen/genetics/*immunology
MH  - Retrospective Studies
MH  - Risk Assessment
MH  - Risk Factors
MH  - T-Lymphocytes/immunology/*transplantation
MH  - Time Factors
MH  - Treatment Outcome
MH  - Tumor Suppressor Protein p53/*genetics
PMC - PMC8797602
COIS- Roni ShouvalConsulting or Advisory Role: Medexus, MyBiotics Michal J. 
      BesserEmployment: Envizion Medical (I)Leadership: Envizion Medical (I)Stock and 
      Other Ownership Interests: Envizion Medical (I)Consulting or Advisory Role: 
      Biological Industries (a Sartorius Company), Gilboa TherapeuticsPatents, 
      Royalties, Other Intellectual Property: Patents at Envizion Medical (I), 
      Royalties at Biological Industries (Inst)Travel, Accommodations, Expenses: Lonza 
      Connie Lee BatleviStock and Other Ownership Interests: Moderna Therapeutics, 
      Novavax, Pfizer, Bristol Myers Squibb, Regeneron, ViatrisHonoraria: DAVA 
      OncologyConsulting or Advisory Role: LifeSci Capital, GLG, Juno Therapeutics, 
      Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm 
      TherapeuticsResearch Funding: Janssen Biotech (Inst), Novartis (Inst), Epizyme 
      (Inst), Xynomic Pharma (Inst), Bayer (Inst), Roche (Inst), Autolus (Inst)Open 
      Payments Link: https://openpaymentsdata.cms.gov/physician/2778694 Parastoo B. 
      DahiConsulting or Advisory Role: Kite, a Gilead company Sean M. DevlinThis author 
      is a member of the Journal of Clinical Oncology Editorial Board. Journal policy 
      recused the author from having any role in the peer review of this manuscript. 
      Sergio A. GiraltHonoraria: Celgene, Takeda, Amgen, Jazz Pharmaceuticals, 
      Sanofi,Consulting or Advisory Role: Celgene, Takeda, Sanofi, Jazz 
      Pharmaceuticals, Amgen, Janssen, Actinuum, Bristol Myers Squibb, Johnson & 
      Johnson, PfizerResearch Funding: Celgene (Inst), Miltenyi Biotec, Johnson & 
      Johnson, Amgen, Actinuum, SanofiTravel, Accommodations, Expenses: Celgene, 
      Sanofi, Amgen, Jazz Pharmaceuticals Richard J. LinEmployment: Pfizer 
      (I)Consulting or Advisory Role: Kite/Gilead Gal MarkelEmployment: 4C Biomed, Ella 
      TherapeuticsLeadership: 4C Biomed, Ella TherapeuticsStock and Other Ownership 
      Interests: Purple Biotech, Biond Biologics, Nucleai, Staburo GmbH, Ella 
      Therapeutics, 4C BiomedHonoraria: BMS, MSD, Novartis, Medison, RocheConsulting or 
      Advisory Role: MSD, NovartisSpeakers' Bureau: MSD, BMSResearch Funding: Novartis 
      (Inst), Immunicom (Inst)Patents, Royalties, Other Intellectual Property: Patent 
      on anti-CEACAM1 blocking antibodiesTravel, Accommodations, Expenses: BMS, 
      Novartis, MSD Gilles SallesHonoraria: Roche/Genentech, Janssen, Celgene, Gilead 
      Sciences, Novartis, AbbVie, MorphoSysConsulting or Advisory Role: 
      Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, 
      Alimera Sciences, Genmab, Debiopharm Group, Velosbio, BMS, BeiGene, Incyte, 
      Miltenyi Biotec, Ipsen Craig S. SauterConsulting or Advisory Role: Spectrum 
      Pharmaceuticals, Juno Therapeutics, Sanofi, Gilead Sciences, Novartis  Precision 
      BioSciences, Gamida Cell, Karyopharm Therapeutics, GlaxoSmithKline, 
      GenmabResearch Funding: Juno Therapeutics (Inst), Sanofi (Inst), Precision 
      BioSciences (Inst), BMS (Inst), Actinium Pharmaceuticals (Inst)Travel, 
      Accommodations, Expenses: Juno Therapeutics, Sanofi, Gilead Sciences, Novartis 
      Michael ScordoHonoraria: i3 CMEConsulting or Advisory Role: McKinsey & Company, 
      Angiocrine Bioscience, OmerosResearch Funding: Angiocrine Bioscience, Omeros 
      (Inst)Travel, Accommodations, Expenses: Kite/Gilead Gunjan L. ShahResearch 
      Funding: Amgen (Inst), Janssen (Inst) Marcel van den BrinkHonoraria: Seres 
      Therapeutics, Merck, Magenta Therapeutics, WindMIL, Rheos Medicines, Frazier 
      Healthcare Partners, Nektar, Notch Therapeutics, Forty Seven, Priothera, 
      Ceramedix, LyGenesis, Pluto Therapeutics, GlaxoSmithKline, Da Volterra, Novartis 
      (I), Synthekine (I), BeiGene (I)Consulting or Advisory Role: Seres 
      TherapeuticsResearch Funding: Seres TherapeuticsPatents, Royalties, Other 
      Intellectual Property: Dr van den Brink receives royalties from Wolters Kluwer, 
      and he has intellectual property Licensing with Seres Therapeutics and Juno 
      TherapeuticsTravel, Accommodations, Expenses: Rheos MedicinesOther Relationship: 
      DKMSUncompensated Relationships: Seres therapeutics, Notch Therapeutics, Pluto 
      Therapeutics Miguel-Angel PeralesStock and Other Ownership Interests: 
      NexImmuneHonoraria: MorphoSysConsulting or Advisory Role: Incyte, Merck, 
      Servier/Pfizer, NexImmune, Novartis, MolMed, Medigene, Takeda, Nektar, AbbVie, 
      Cidara Therapeutics, Celgene, Kite/Gilead, Bristol Myers Squibb, Omeros, Vor 
      BiopharmaResearch Funding: Incyte (Inst), Miltenyi Biotec (Inst), Novartis 
      (Inst), Kite, a Gilead company (Inst), Nektar (Inst) Maria Lia PalombaStock and 
      Other Ownership Interests: Seres Therapeutics (I)Honoraria: Flagship Biosciences 
      (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), Therakos (I), Amgen (I), 
      Merck (I), Seres Therapeutics (I)Consulting or Advisory Role: Flagship 
      Biosciences (I), Novartis (I), Evelo Therapeutics (I), Jazz Pharmaceuticals (I), 
      Therakos (I), Amgen (I), Merck (I), Seres Therapeutics (I), Kite, a Gilead 
      company, Novartis, BeiGene, SynthekineResearch Funding: Seres Therapeutics 
      (I)Patents, Royalties, Other Intellectual Property: Intellectual Property Rights 
      (I), Juno intellectual property rights (Inst)No other potential conflicts of 
      interest were reported.
EDAT- 2021/12/04 06:00
MHDA- 2022/02/22 06:00
PMCR- 2023/02/01
CRDT- 2021/12/03 17:16
PHST- 2021/12/04 06:00 [pubmed]
PHST- 2022/02/22 06:00 [medline]
PHST- 2021/12/03 17:16 [entrez]
PHST- 2023/02/01 00:00 [pmc-release]
AID - JCO.21.02143 [pii]
AID - 10.1200/JCO.21.02143 [doi]
PST - ppublish
SO  - J Clin Oncol. 2022 Feb 1;40(4):369-381. doi: 10.1200/JCO.21.02143. Epub 2021 Dec 
      3.