Journal
BLOOD
Volume 135, Issue 19, Pages 1650-1660Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019002936
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Funding
- National Institutes of Health (NIH) National Cancer Institute [R01 CA136551, P30 CA15704, R35 CA197734]
- NIH National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK56465]
- Life Science Discovery Fund
- Bezos Family Foundation
- National Gene Vector Biorepository at Indiana University - NIH National Heart, Lung, and Blood Institute [75N92019D00018]
- Juno Therapeutics, Celgene Company
- University of British Columbia Clinical Investigator Program
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We previously reported durable responses in relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) patients treated with CD19-targeted chimeric antigen receptorengineered (CD19 CAR) T-cell immunotherapy after ibrutinib failure. Because preclinical studies showed that ibrutinib could improve CAR T cell-antitumor efficacy and reduce cytokine release syndrome (CRS), we conducted a pilot study to evaluate the safety and feasibility of administering ibrutinib concurrently with CD19 CAR T-cell immunotherapy. Nineteen CLL patients were included. The median number of prior therapies was 5, and 17 patients (89%) had high-risk cytogenetics (17p deletion and/or complex karyotype). Ibrutinib was scheduled to begin >= 2 weeks before leukapheresis and continue for >= 3 months after CAR T-cell infusion. CD19 CAR T-cell therapy with concurrent ibrutinib was well tolerated; 13 patients (68%) received ibrutinib as planned without dose reduction. The 4-week overall response rate using 2018 International Workshop on CLL (iwCLL) criteria was 83%, and 61% achieved a minimal residual disease (MRD)-negative marrow response by IGH sequencing. In this subset, the 1-year overall survival and progression-free survival (PFS) probabilities were 86% and 59%, respectively. Compared with CLL patients treated with CAR T cells without ibrutinib, CAR T cells with concurrent ibrutinib were associated with lower CRS severity and lower serum concentrations of CRS-associated cytokines, despite equivalent in vivo CAR T-cell expansion. The 1-year PFS probabilities in all evaluable patients were 38% and 50% after CD19 CAR T-cell therapy, with andwithout concurrent ibrutinib, respectively (P=.91). CD19 CAR T cells with concurrent ibrutinib for R/R CLL were well tolerated, with lowCRS severity, and led to high rates of MRD-negative response by IGH sequencing.
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