Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL Journal Article

Authors: Geyer, M. B.; Riviere, I.; Senechal, B.; Wang, X.; Wang, Y.; Purdon, T. J.; Hsu, M.; Devlin, S. M.; Palomba, M. L.; Halton, E.; Bernal, Y.; van Leeuwen, D. G.; Sadelain, M.; Park, J. H.; Brentjens, R. J.
Article Title: Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL
Abstract: BACKGROUND. Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CART cells for these patients. Here, we report safety and long-term follow-up of CART cell therapy with or without conditioning chemotherapy for patients with RJR CLL and indolent B cell non-Hodgkin lymphoma (B-NHL). METHODS. We conducted a phase I clinical trial investigating CD19-targeted CART cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of twenty patients received conditioning chemotherapy prior to CART cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CART cell administration. RESULTS. This analysis included 16 patients with RJR CLL and 4 patients with RJR indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CART cells with the CD62L(+)CD127(+) immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, am subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease-negative CR). All patients achieving CR remained progression free at median follow-up of 53 months. CONCLUSION. Conditioning chemotherapy and 19-28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with RJR CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. lbrutinib therapy may modulate autologous T cell phenotype.
Keywords: fludarabine; rituximab; cyclophosphamide; antigen; therapy; b-cell; efficacy; cd8(+); chronic lymphocytic-leukemia; antitumor; checkpoint blockade
Journal Title: JCI Insight
Volume: 4
Issue: 9
ISSN: 2379-3708
Publisher: Amer Soc Clinical Investigation Inc  
Date Published: 2019-05-02
Start Page: e122627
Language: English
ACCESSION: WOS:000466814100002
DOI: 10.1172/jci.insight.122627
PMCID: PMC6538317
PUBMED: 30938714
Notes: Article -- Source: Wos
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MSK Authors
  1. Meier Hsu
    107 Hsu
  2. Renier J Brentjens
    207 Brentjens
  3. Maria Lia Palomba
    144 Palomba
  4. Jae Hong Park
    156 Park
  5. Elizabeth F Halton
    27 Halton
  6. Michel W J Sadelain
    470 Sadelain
  7. Isabelle C Riviere
    175 Riviere
  8. Xiuyan Wang
    74 Wang
  9. Sean McCarthy Devlin
    309 Devlin
  10. Yvette J Bernal
    26 Bernal
  11. Terence John Purdon
    42 Purdon
  12. Yongzeng   Wang
    16 Wang
  13. Mark Blaine Geyer
    22 Geyer