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Early and late hematologic toxicity following CD19 CAR-T cells

Bone Marrow Transplantation volume 54, pages 1643–1650 (2019)Cite this article

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Abstract

Autologous T cells transduced with CD19-directed chimeric antigen receptors have recently been approved by several regulatory agencies for the treatment of relapsed and refractory leukemia and lymphoma, after demonstrating remarkable remission rate in advanced patients. The most common adverse events reported are cytokine-release syndrome (CRS), neurotoxicity, and hematologic toxicity. Here, we focus on early and late cytopenia occurring after CD19 CAR-T cells in 38 patients treated with CD19 CAR-T cells. Neutropenia, thrombocytopenia, and anemia occur frequently (94, 80, and 51%, respectively) after CAR-T cell infusion, and are associated with a biphasic nature, as in 93% of patients hematologic toxicity occurs after 21 days from cell infusion. Late hematologic toxicity was more common in patients with high grade CRS and in patients treated after a recent stem cell transplantation. Interestingly, since these events occur late after the lymphodepleting chemotherapy and after resolution of CRS, we found perturbations in SDF-1 levels to correlate with events of late neutropenia, likely associated with B-cell recovery.

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References

  1. June CH, Sadelain M. Chimeric Antigen receptor therapy. N Engl J Med. 2018;379:64–73.

    Article  CAS  Google Scholar 

  2. Salter AI, Pont MJ, Riddell SR. Chimeric antigen receptor modified T cells: CD19 and the road beyond. Blood. 2018;131:2621–9.

  3. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, 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;118:4817–28.

    Article  CAS  Google Scholar 

  4. Turtle CJ, Riddell SR, Maloney DG, Turtle CJ, Hanafi L, Berger C, et al. CD19 CAR–T cells of defined CD4+ :CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.

    Article  Google Scholar 

  5. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent to treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129:3322–31.

    Article  CAS  Google Scholar 

  6. Lee DW, Stetler-Stevenson M, Yuan CM, Shah NN, Delbrook C, Yates B, et al. Long-term outcomes following CD19 CAR T cell therapy for B-ALL are superior in patients receiving a fludarabine/cyclophosphamide preparative regimen and post-CAR hematopoietic stem cell transplantation. Blood . 2016;128:218.

    Google Scholar 

  7. Kochenderfer JN, Somerville RPT, Lu T, Shi V, Bot A, Rossi J, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T Cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35:1803–13.

    Article  CAS  Google Scholar 

  8. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. How i treat current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2017;124:188–96.

    Article  Google Scholar 

  9. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321–31.

    Article  CAS  Google Scholar 

  10. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol. 2017;15:47–62

  11. Hay KA, Hanafi L-A, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood. 2017;130:2295–306.

    Article  CAS  Google Scholar 

  12. Gust J, Hay KA, Hanafi L-A, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T Cells. Cancer Discov. 2017;7:1404–19.

    Article  CAS  Google Scholar 

  13. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASBMT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol Blood Marrow Transpl. 2018. https://doi.org/10.1016/j.bbmt.2018.12.758.

  14. Jacoby E, Bielorai B, Avigdor A, Itzhaki O, Hutt D, Nussboim V, et al. Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Am J Hematol. 2018;93:1485–92.

  15. Dunleavy K, Hakim F, Kim HK, Janik JE, Grant N, Nakayama T, et al. B-cell recovery following rituximab-based therapy is associated with perturbations in stromal derived factor-1 and granulocyte homeostasis. Blood. 2005;106:795–802.

    Article  CAS  Google Scholar 

  16. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, 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;385:517–28.

    Article  CAS  Google Scholar 

  17. Kochenderfer JN, Dudley ME, Kassim SH, Somerville RPT, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-Cell lymphoma and indolent B-Cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2014;33:540–9.

    Article  Google Scholar 

  18. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:NEJMoa1707447.

    Article  Google Scholar 

  19. Maude SL, Latesch T, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439–48.

    Article  CAS  Google Scholar 

  20. Hill JA, Li D, Hay KA, Green ML, Cherian S, Chen X, et al. Infectious complications of CD19-targeted chimeric antigen receptor—modified T-cell immunotherapy. Blood . 2018;131:121–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Teachey DT, Rheingold S, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121:5154–8.

    Article  CAS  Google Scholar 

  22. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N. et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664–79.

    Article  CAS  Google Scholar 

  23. Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood. 2011;118:4041–52.

    Article  CAS  Google Scholar 

  24. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731–38.

  25. Cordeiro A, Bezerra ED, Hill JA, Turtle CJ, Maloney DG, Bar M. Late effects of CD19-targeted CAR-T cell therapy. Blood. 2018;132:223.

    Article  Google Scholar 

  26. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and efficacy of axicabtagene ciloleucel in refractory large B-cell lymphoma: a multicenter, single arm, phase 1–2 trial. Lancet Oncol. 2018;20:31–42.

  27. Shalabi H, Shah NN, Fry TJ, Yates B, Delbrook C. Chimeric antigen receptor induced cytopenia differs from chemotherapy induced myelosuppression. Blood . 2017;130(Suppl 1):5048.

    Google Scholar 

  28. Ram R, Bonstein L, Gafter-Gvili A, Ben-Bassat I, Shpilberg O, Raanani P. Rituximab-associated acute thrombocytopenia: an under-diagnosed phenomenon. Am J Hematol. 2009;84:247–50.

    Article  Google Scholar 

  29. Weng WK, Negrin RS, Lavori P, Horning SJ. Immunoglobulin G Fc receptor FcgammaRIIIa 158 V/F polymorphism correlates with rituximab-induced neutropenia after autologous transplantation in patients with non-Hodgkin’s lymphoma. J Clin Oncol. 2010;28:279–84.

    Article  CAS  Google Scholar 

  30. Nagasawa T. CXCL12/SDF-1 and CXCR4. Front Immunol. 2015;6(June):10–2.

    Google Scholar 

  31. Dar A, Kollet O, Lapidot T. Mutual, reciprocal SDF-1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol. 2006;34:967–75.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Israel

    Shalev Fried, Bella Bielorai, Amilia Meir, Amos Toren & Elad Jacoby

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Shalev Fried, Abraham Avigdor, Bella Bielorai, Michal J. Besser, Jacob Schachter, Avichai Shimoni & Arnon Nagler

  3. Division of Hematology and Bone Marrow Transplantation, Sheba Medical Center, Ramat Gan, Israel

    Abraham Avigdor, Avichai Shimoni, Arnon Nagler, Amos Toren & Elad Jacoby

  4. Ella Institute of Immuno-Oncology, Sheba Medical Center, Ramat Gan, Israel

    Michal J. Besser & Jacob Schachter

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  1. Shalev Fried
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Correspondence to Elad Jacoby.

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Fried, S., Avigdor, A., Bielorai, B. et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant 54, 1643–1650 (2019). https://doi.org/10.1038/s41409-019-0487-3

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