Early toxicity and clinical outcomes after chimeric antigen receptor T-cell (CAR-T) therapy for lymphoma.
chimeric antigen
hematologic neoplasms
immunotherapy
receptors
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
accepted:
09
07
2021
entrez:
25
8
2021
pubmed:
26
8
2021
medline:
7
1
2022
Statut:
ppublish
Résumé
Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown. From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS). Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies. Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.
Sections du résumé
BACKGROUND
Chimeric antigen receptor T-cell (CAR-T) infusion is associated with early toxicity. Yet, whether early toxicity development holds ramifications for long-term outcomes is unknown.
METHODS
From a large cohort of consecutive adult patients treated with CAR-T therapies for relapsed or refractory lymphomas from 2016 to 2019, we assessed progression-free survival (PFS), by toxicity development (cytokine release syndrome (CRS), neurotoxicity, or cardiotoxicity]. We also assessed the relationship of toxicity development to objective disease response, and overall survival (OS). Multivariable regression was utilized to evaluate relationships between standard clinical and laboratory measures and disease outcomes. Differences in outcomes, by toxicity status, were also assessed via 30-day landmark analysis. Furthermore, we assessed the effects of early anti-CRS toxicity therapy use (at ≤grade 2 toxicity) on maximum toxicity grade observed, and long-term disease outcomes (PFS and OS).
RESULTS
Overall, from 102 CAR-T-treated patients, 90 were identified as treated with single-agent therapy, of which 88.9% developed toxicity (80 CRS, 41 neurotoxicity, and 17 cardiotoxicity), including 28.9% with high-grade (≥3) events. The most common manifestations were hypotension at 96.6% and fever at 94.8%. Among patients with cardiac events, there was a non-significant trend toward a higher prevalence of concurrent or preceding high-grade (≥3) CRS. 50.0% required tocilizumab or corticosteroids. The median time to toxicity was 3 days; high grade CRS development was associated with cardiac and neurotoxicity. In multivariable regression, accounting for disease severity and traditional predictors of disease response, moderate (maximum grade 2) CRS development was associated with higher complete response at 1 year (HR: 2.34; p=0.07), and longer PFS (HR: 0.41; p=0.02, in landmark analysis), and OS (HR: 0.43; p=0.03). Among those with CRS, relative blood pressure (HR: 2.25; p=0.004), respectively, also associated with improved PFS. There was no difference in disease outcomes, or maximum toxicity grade (CRS, neurotoxicity, or cardiotoxicity) observed, based on the presence or absence of the use of early CRS-directed therapies.
CONCLUSIONS
Among adult lymphoma patients, moderate toxicity manifest as grade 2 CRS after CAR-T infusion may associate with favorable clinical outcomes. Further studies are needed to confirm these findings.
Identifiants
pubmed: 34429331
pii: jitc-2020-002303
doi: 10.1136/jitc-2020-002303
pmc: PMC8386216
pii:
doi:
Substances chimiques
Receptors, Antigen, T-Cell
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : K23 HL155890
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127442
Pays : United States
Organisme : NCATS NIH HHS
ID : KL2 TR002734
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA133250
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA090223
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
Références
N Engl J Med. 2006 Feb 16;354(7):709-18
pubmed: 16481638
J Am Coll Cardiol. 2019 Dec 24;74(25):3099-3108
pubmed: 31856966
Oncologist. 2018 Aug;23(8):943-947
pubmed: 29622697
J Clin Oncol. 2014 Sep 20;32(27):3059-68
pubmed: 25113753
Biol Blood Marrow Transplant. 2020 Dec;26(12):2211-2216
pubmed: 32966880
Transfus Med Rev. 2019 Apr;33(2):98-110
pubmed: 30948292
J Immunother Cancer. 2017 Dec 19;5(1):102
pubmed: 29254506
J Nucl Med. 2019 Jul;60(7):879-881
pubmed: 31053682
Lancet Haematol. 2019 Oct;6(10):e521-e529
pubmed: 31378662
J Hematol Oncol. 2018 Mar 2;11(1):35
pubmed: 29499750
Clin Cancer Res. 2016 Feb 15;22(4):886-94
pubmed: 26446948
N Engl J Med. 2019 Jan 3;380(1):45-56
pubmed: 30501490
Nat Rev Clin Oncol. 2018 Jan;15(1):47-62
pubmed: 28925994
Blood. 2016 Jun 30;127(26):3321-30
pubmed: 27207799
JAMA Oncol. 2018 Mar 1;4(3):374-378
pubmed: 28975219
N Engl J Med. 2014 Oct 16;371(16):1507-17
pubmed: 25317870
Lancet. 2015 Feb 7;385(9967):517-528
pubmed: 25319501
JAMA. 2019 Sep 10;322(10):923-924
pubmed: 31355862
Lancet Oncol. 2019 Jan;20(1):31-42
pubmed: 30518502
Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638
pubmed: 30592986
N Engl J Med. 2019 May 2;380(18):1726-1737
pubmed: 31042825
Blood. 2017 Jul 20;130(3):267-270
pubmed: 28490569
JAMA Oncol. 2020 Apr 1;6(4):519-527
pubmed: 31895407
N Engl J Med. 2017 Dec 28;377(26):2531-2544
pubmed: 29226797