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Cited by 205CAR-T cell therapy researchImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Factors associated with outcomes after a second CD19-targeted CAR T-cell infusion for refractory B-cell malignancies

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Gauthier, Jordan, Bezerra, Evandro D., Hirayama, Alexandre V., Fiorenza, Salvatore, Sheih, Alyssa, Chou, Cassie K., Kimble, Erik L., Pender, Barbara S. +17 more·2021·Blood
DOI 10.1182/blood.2020006770PMC PMC7819764
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Abstract

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T-cell therapy has shown significant efficacy for relapsed or refractory (R/R) B-cell malignancies. Yet, CD19 CAR T cells fail to induce durable responses in most patients. Second infusions of CD19 CAR T cells (CART2) have been considered as a possible approach to improve outcomes. We analyzed data from 44 patients with R/R B-cell malignancies (acute lymphoblastic leukemia [ALL], n = 14; chronic lymphocytic leukemia [CLL], n = 9; non-Hodgkin lymphoma [NHL], n = 21) who received CART2 on a phase 1/2 trial (NCT01865617) at our institution. Despite a CART2 dose increase in 82% of patients, we observed a low incidence of severe toxicity after CART2 (grade ≥3 cytokine release syndrome, 9%; grade ≥3 neurotoxicity, 11%). After CART2, complete response (CR) was achieved in 22% of CLL, 19% of NHL, and 21% of ALL patients. The median durations of response after CART2 in CLL, NHL, and ALL patients were 33, 6, and 4 months, respectively. Addition of fludarabine to cyclophosphamide-based lymphodepletion before the first CAR T-cell infusion (CART1) and an increase in the CART2 dose compared with CART1 were independently associated with higher overall response rates and longer progression-free survival after CART2. We observed durable CAR T-cell persistence after CART2 in patients who received cyclophosphamide and fludarabine (Cy-Flu) lymphodepletion before CART1 and a higher CART2 compared with CART1 cell dose. The identification of 2 modifiable pretreatment factors independently associated with better outcomes after CART2 suggests strategies to improve in vivo CAR T-cell kinetics and responses after repeat CAR T-cell infusions, and has implications for the design of trials of novel CAR T-cell products after failure of prior CAR T-cell immunotherapies.

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References 45 · Cited by 205

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Authors
Gauthier, J., Bezerra, E. D., Hirayama, A. V., Fiorenza, S., Sheih, A., Chou, C. K., Kimble, E. L., Pender, B. S., Hawkins, R. M., Vakil, A., Phi, T.-D., Steinmetz, R. N., Jamieson, A. W., Bar, M., Cassaday, R. D., Chapuis, A. G., Cowan, A. J., Green, D. J., Kiem, H.-P., Milano, F., Shadman, M., Till, B. G., Riddell, S. R., Maloney, D. G., & Turtle, C. J.
Affiliations
  • Fred Hutch Cancer Center (US)
  • Department of Medicine and
  • Clinical Research Division and
  • University of Washington (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2021-01-21
Volume
137
Issue
3
Pages
323-335
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020006770
PMC
PMC7819764
OpenAlex
W3088453061
Cited by
205
References
45
Citations by year
2026: 21 · 2025: 31 · 2024: 44 · 2023: 50 · 2022: 34 · 2021: 24 · 2020: 1
FWCI
10.11
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (T32HL007093)
  • National Cancer Institute (R01CA136551, K12CA076930, P30CA015704)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK056465)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
CD19 CAR T-cell therapy, relapsed or refractory B-cell malignancies, acute lymphoblastic leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, CAR T cell persistence, cytokine release syndrome, neurotoxicity, complete response, progression-free survival, dose escalation, CAR T-cell kinetics
MeSH terms
Progression-Free Survival, Cytokine Release Syndrome, Adult, Aged, Cyclophosphamide, Female, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, T-Lymphocytes, Vidarabine, Leukemia, B-Cell, Leukemia, Lymphocytic, Chronic, B-Cell, Multivariate Analysis, Immunotherapy, Adoptive, Treatment Outcome, Antigens, CD19, Cell Proliferation, Precursor Cell Lymphoblastic Leukemia-Lymphoma

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