Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

By Jae H. Park, I. Rivière, Mithat Gonen, Xiuyan Wang, B. Senechal, K. Curran, C. Sauter, Yongzeng Wang, B. Santomasso, E. Mead and 5 more. New England Journal of Medicine, 2018

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Background CD19‐specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B‐cell acute lymphoblastic leukemia (ALL) and long‐term remissions in a subgroup of patients. Methods We conducted a phase 1 trial involving adults with relapsed B‐cell ALL who received an infusion of autologous T cells expressing the 19‐28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long‐term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. Results A total of 53 adults received 19‐28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow‐up of 29 months (range, 1 to 65), the median event‐free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event‐free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long‐term survival than did patients with a low disease burden. Conclusions In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19‐28z CAR T‐cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069.)

Subfields: Oncology, Pathology and Forensic Medicine, Public Health, Environmental and Occupational Health

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Citations in the corpus

ASBMT Consensus Grading for Cytokine Release Syndrome and Neurological Toxicity Associated with Immune Effector Cells (2018, methodology): “Recognizing that assays for serum cytokines are not readily available at most centers, thereby limiting the utility of this approach, MSKCC redefined the CRS grading used in their clinical trials (Table 1) [16].”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “…burden and can, therefore, be attenuated by paradoxically decreasing the number of cells infused in patients with high-volume disease; however, this association is inexact 3,61 , and fundamental modifications of CAR designs might be a better approach to ameliorate cytokine-related toxicities.”
Anti‐BCMA CAR T‐Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma (2019, background): “A total of 67% of the patients had stage II or III disease, 27% had extramedullary disease, and 45% had a high-risk cytogenetic profile, defined by the presence of del(17p), t(4;14), or t(14;16).”
Tumor Antigen Escape from CAR T-cell Therapy. (2018, background): “The cell dose administered to this patient (78) is one hundred times the maximum tolerated dose later found for CD19-CAR T cells (21).”