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

Literature Information ​

DOI10.1056/NEJMoa1709919
PMID29385376
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2018
Times Cited1405
KeywordsCD19 CAR therapy, acute lymphoblastic leukemia, cytokine release syndrome, long-term survival, disease burden
Literature TypeClinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages449-459
Issue378(5)
AuthorsJae H Park, Isabelle Rivière, Mithat Gonen, Xiuyan Wang, Brigitte Sénéchal, Kevin J Curran, Craig Sauter, Yongzeng Wang, Bianca Santomasso, Elena Mead, Mikhail Roshal, Peter Maslak, Marco Davila, Renier J Brentjens, Michel Sadelain

TL;DR ​

This phase 1 trial evaluated the safety and efficacy of 19-28z CAR T cells in adults with relapsed B-cell acute lymphoblastic leukemia (ALL), finding an 83% complete remission rate and a median overall survival of 12.9 months, with significantly better outcomes in patients with a low disease burden. The study highlights the importance of disease burden in predicting treatment responses and adverse effects, suggesting that lower pre-treatment burden correlates with improved survival and reduced toxicity.

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CD19 CAR therapy · acute lymphoblastic leukemia · cytokine release syndrome · long-term survival · disease burden

Abstract ​

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 .).

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Primary Questions Addressed ​

  1. What are the potential long-term side effects of CD19 CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia?
  2. How does the timing of CD19 CAR T-cell infusion impact overall survival rates in patients with different disease burdens?
  3. What are the implications of cytokine release syndrome on the management of patients undergoing CD19 CAR T-cell therapy?
  4. How do demographic factors influence the outcomes of CD19 CAR T-cell therapy in adult patients with relapsed B-cell ALL?
  5. What are the alternative therapies available for patients who experience severe adverse effects from CD19 CAR T-cell therapy?

Key Findings ​

Background and Objectives ​

The study investigates the long-term outcomes of CD19-specific chimeric antigen receptor (CAR) T-cell therapy in adults with relapsed B-cell acute lymphoblastic leukemia (ALL). While initial response rates to this therapy are high, the study aims to explore long-term remissions and identify factors influencing outcomes.

Main Methods/Materials/Experimental Design ​

A phase 1 clinical trial was conducted at the Memorial Sloan Kettering Cancer Center (MSKCC), involving 53 adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR. Key components of the study included:

  • Patient Selection: Adults with relapsed or refractory ALL were enrolled.
  • Treatment Administration: Patients underwent leukapheresis followed by CAR T-cell infusion.
  • Assessment of Outcomes: The study measured safety (cytokine release syndrome and neurotoxic effects) and efficacy (complete remission, event-free survival, and overall survival).

The study design included multiple stages to evaluate safety and efficacy across different doses and conditioning regimens.

Mermaid diagram

Key Results and Findings ​

  • Response Rates: Of the 53 patients, 44 (83%) achieved complete remission. The median event-free survival was 6.1 months, and median overall survival was 12.9 months.
  • Disease Burden Impact: Patients with low disease burden (<5% bone marrow blasts) had significantly better outcomes, with median event-free survival of 10.6 months and overall survival of 20.1 months compared to 5.3 and 12.4 months, respectively, for those with high disease burden.
  • Toxicity: Severe cytokine release syndrome occurred in 14 (26%) patients, with a notable correlation between high disease burden and increased toxicity.

Main Conclusions/Significance/Innovation ​

The study demonstrates that 19-28z CAR T-cell therapy is effective in achieving high rates of complete remission in heavily pretreated adults with relapsed or refractory B-cell ALL. The findings underscore the importance of disease burden in predicting long-term survival outcomes, with low disease burden associated with better survival and lower toxicity. This highlights the potential of CAR T-cell therapy as a viable treatment option for patients with ALL.

Research Limitations and Future Directions ​

  • Limitations: The study's small sample size limits the generalizability of the findings. Additionally, it was a single-institution trial, which may affect the applicability of results across different settings.
  • Future Directions: Further studies with larger cohorts are needed to validate these findings and explore the mechanisms underlying the observed relationships between disease burden, CAR T-cell expansion, and long-term outcomes. Additionally, investigating strategies to mitigate toxicity while enhancing therapeutic efficacy could be beneficial.

References ​

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Literatures Citing This Work ​

  1. Posttransplant chimeric antigen receptor therapy. - Melody Smith;Johannes Zakrzewski;Scott James;Michel Sadelain - Blood (2018)
  2. Immunotherapy: CAR T cell therapy efficacious against B-ALL across age groups. - Peter Sidaway - Nature reviews. Clinical oncology (2018)
  3. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. - Karlo Perica;Kevin J Curran;Renier J Brentjens;Sergio A Giralt - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2018)
  4. CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing? - Brooke L Prinzing;Stephen M Gottschalk;Giedre Krenciute - Expert review of anticancer therapy (2018)
  5. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. - Li-Na Zhang;Yongping Song;Delong Liu - Journal of hematology & oncology (2018)
  6. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. - Jordan Gauthier;Cameron J Turtle - Current research in translational medicine (2018)
  7. Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. - Eric L Smith;Mette Staehr;Reed Masakayan;Ishan J Tatake;Terence J Purdon;Xiuyan Wang;Pei Wang;Hong Liu;Yiyang Xu;Sarah C Garrett-Thomson;Steven C Almo;Isabelle Riviere;Cheng Liu;Renier J Brentjens - Molecular therapy : the journal of the American Society of Gene Therapy (2018)
  8. Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. - Leslie S Kean - Blood (2018)
  9. Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives. - Stanislaw Schmidt;Lars Tramsen;Bushra Rais;Evelyn Ullrich;Thomas Lehrnbecher - Oncotarget (2018)
  10. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. - Theodoros Giavridis;Sjoukje J C van der Stegen;Justin Eyquem;Mohamad Hamieh;Alessandra Piersigilli;Michel Sadelain - Nature medicine (2018)

... (1395 more literatures)

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