Medical Oncology

, 35:144 | Cite as

Effect of transplant status in CD19-targeted CAR T-cell therapy: a systematic review and meta-analysis

  • Kathleen NagleEmail author
  • Barbara Tafuto
  • Lisa Palladino Kim
  • J. Scott Parrott
Review Article


Chimeric antigen receptor (CAR) T-cell therapy has shown promise for relapsed/refractory malignancies. Many patients have undergone prior hematopoietic stem cell transplant (HSCT), yet effects of transplant status on CAR T-cell therapy efficacy and safety have not been reported. The purpose of the study is to systematically evaluate the likelihood of achieving optimum response, severe cytokine release syndrome (sCRS), and neurotoxicity in the context of CAR T-cell therapy for HSCT-naïve patients versus those with prior HSCT. Trials were identified in, Cochrane Library, and PubMed, and through reference pearl growing. Included studies used CD19-directed CAR T-cells for relapsed/refractory B-lineage Acute Lymphoblastic Leukemia and B cell Chronic Lymphocytic Leukemia, enrolled both HSCT-naïve and prior-HSCT patients, and denoted transplant status with outcomes. Six studies were included for optimum response, five for sCRS incidence, and four for neurotoxicity incidence. The pooled odds ratio for optimum response was 1.57 favoring HSCT-naïve patients (95% CI 0.54–4.61), whereas the pooled odds ratios for sCRS and neurotoxicity were 1.41 (95% CI 0.51–3.94) and 1.37 (95% CI 0.28–6.77), respectively, toward HSCT-naïve patients. Odds ratios were non-statistically significant. Overall risk of bias was moderate. While pooled estimates showed an advantage among HSCT-naïve patients for achieving optimum response and increased likelihood for sCRS and neurotoxicity, findings were not statistically significant. Any differences in efficacy and safety of CAR T-cell therapy cannot be verifiably attributed to transplant status, and additional controlled trials with increased sample sizes are needed to determine whether suggestive patterns favoring HSCT-naïve patients are validated.


CAR T-cell therapy Hematopoietic stem cell transplant MRD-negative complete remission Cytokine release syndrome Neurotoxicity 



The authors would like to thank Dr. Roger Strair, MD, PhD and Dr. Pranela Rameshwar, PhD, for contributing insightful comments and suggestions during the preparation of this manuscript.


This review was completed without any funding from public, commercial, or not-for-profit sources.


  1. 1.
    Brentjens RJ, Rivière I, Park JH, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011. Scholar
  2. 2.
    Singh N, Frey NV, Grupp SA, Maude SL. CAR T cell therapy in acute lymphoblastic leukemia and potential for chronic lymphocytic leukemia. Curr Treat Options Oncol. 2016. Scholar
  3. 3.
    Zhu Y, Tan Y, Ou R, et al. Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. Eur J Haematol. 2016. Scholar
  4. 4.
    Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016. Scholar
  5. 5.
    Davila ML, Riviere I, Wang X, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014. Scholar
  6. 6.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines)—acute lymphoblastic leukemia. 2014. Version 1. Accessed 15 Dec 2017.
  7. 7.
    Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the international workshop on chronic lymphocytic leukemia updating the national cancer institute-working group 1996 guidelines. Blood. 2008. Scholar
  8. 8.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines)—non-Hodgkin’s lymphoma. 2014. Version 4.2014. Accessed 15 Dec 2017.
  9. 9.
    Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014. Scholar
  10. 10.
    Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009. Scholar
  11. 11.
    Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014. Scholar
  12. 12.
    Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018. Scholar
  13. 13.
    Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015. Scholar
  14. 14.
    Ramer SL. Site-ation pearl growing: methods and librarianship history and theory. J Med Libr Assoc. 2005;93(3):397–400.PubMedPubMedCentralGoogle Scholar
  15. 15.
    U.S. Department of Health & Human Services. Agency for Healthcare Research and Quality. Systematic review data repository. Accessed 11 Aug 2018.
  16. 16.
    Higgins JP, Altman DG, Gotzsche PC, et al. The cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011. Scholar
  17. 17.
    Hu Y, Wu Z, Luo Y, et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in Chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res. 2017. Scholar
  18. 18.
    Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017. Scholar
  19. 19.
    Lee DW, Kochenderfer JN, Stetler-Stevenson M, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015. Scholar
  20. 20.
    OpenMeta[Analyst]. Accessed 11 Aug 2018.
  21. 21.
    U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common terminology criteria for adverse events (CTCAE). 2010. Accessed 15 Dec 2017.
  22. 22.
    Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Eng J Med. 2018. Scholar
  23. 23.
    Lowe KL, Mackall CL, Norry E, et al. Fludarabine and neurotoxicity in engineered T-cell therapy. Gene Ther. 2018. Scholar
  24. 24.
    Dudley ME, Wunderlich JR, Yang JC, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastatic melanoma. J Immunother. 2002;25:243–51.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pullarkat V, Slovak ML, Kopecky KJ, et al. Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of the Southwest Oncology Group 9400 study. Blood. 2008;111(5):2563–72.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Pui CH, Relling MV, Downing JR. Acute lymphoblastic leukemia. N Eng J Med. 2004;350:1535–48.CrossRefGoogle Scholar
  27. 27.
    Schrappe M, Reiter A, Ludwig WD, et al. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000;95:3310–22.PubMedGoogle Scholar
  28. 28.
    Kantarjian HM, O’Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen in adult acute lymphocytic leukemia. J Clin Oncol. 2000;18:547–61.CrossRefPubMedGoogle Scholar
  29. 29.
    Faderl S, Jeha S, Kantarjian HM. The biology and therapy of adult acute lymphoblastic leukemia. Cancer. 2003;98:1337–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Milone MC, Fish JD, Carpenito C, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Health InformaticsSchool of Health Professions, Rutgers, The State University of New JerseyNewarkUSA
  2. 2.Department of Interdisciplinary StudiesSchool of Health Professions, Rutgers, The State University of New JerseyNewarkUSA

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