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

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...

Full description

Saved in:
Bibliographic Details
Published in:Blood Vol. 137; no. 3; p. 323
Main Authors: Gauthier, Jordan, Bezerra, Evandro D, Hirayama, Alexandre V, Fiorenza, Salvatore, Sheih, Alyssa, Chou, Cassie K, Kimble, Erik L, Pender, Barbara S, Hawkins, Reed M, Vakil, Aesha, Phi, Tinh-Doan, Steinmetz, Rachel N, Jamieson, Abby W, Bar, Merav, Cassaday, Ryan D, Chapuis, Aude G, Cowan, Andrew J, Green, Damian J, Kiem, Hans-Peter, Milano, Filippo, Shadman, Mazyar, Till, Brian G, Riddell, Stanley R, Maloney, David G, Turtle, Cameron J
Format: Journal Article
Language:English
Published: United States 21.01.2021
Subjects:
Adult
Aged
Antigens, CD19 - metabolism
Cell Proliferation
Cyclophosphamide - therapeutic use
Cytokine Release Syndrome - complications
Female
Humans
Immunotherapy, Adoptive
Leukemia, B-Cell - immunology
Leukemia, B-Cell - therapy
Leukemia, Lymphocytic, Chronic, B-Cell - immunology
Leukemia, Lymphocytic, Chronic, B-Cell - therapy
Lymphoma, Non-Hodgkin - immunology
Lymphoma, Non-Hodgkin - therapy
Male
Middle Aged
Multivariate Analysis
Precursor Cell Lymphoblastic Leukemia-Lymphoma - immunology
Precursor Cell Lymphoblastic Leukemia-Lymphoma - therapy
Progression-Free Survival
T-Lymphocytes - immunology
Treatment Outcome
Vidarabine - analogs & derivatives
Vidarabine - therapeutic use
ISSN:1528-0020, 1528-0020
Online Access:Get more information
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1528-0020
1528-0020
DOI:10.1182/blood.2020006770