On August 30, 2017, the U.S. Food and Drug Administration (US-FDA) approved tisagenlecleucel (KYMRIAH, Novartis, Basel, Switzerland), a synthetic bioimmune product of anti-CD19 chimeric antigen receptor-T cells (CAR-T), for the treatment of children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). With this new era of personalized cancer immunotherapy, multiple challenges are present ranging from implementation of a CAR-T program to safe delivery of the drug, long-term toxicity monitoring and disease assessments. To address these issues, experts representing the American Society for Blood and Marrow Transplant (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), the International Society of Cell and Gene Therapy (ISCT), and the Foundation for the Accreditation of Cellular Therapy (FACT), formed a global CAR-T task force to identify and address key questions pertinent for hematologists and transplant physicians regarding the clinical use of anti CD19 CAR-T therapy in patients with B-ALL. This article presents an initial roadmap for navigating common clinical practice scenarios that will become more prevalent now that the first commercially available CAR-T product for B-ALL has been approved.
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June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73.
Maude SL, Laetsch TW, 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.
Maus MV, Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. J Immunother Cancer. 2017;5:36.
Das Rajat SJ, Barrett D. T cell dysfunction in pediatric cancer patients at diagnosis and after chemotherapy can limit chimeric antigen receptor potential. Cancer Res. 2018;2018(78 (13 suppl)):Abstract nr 1631.
Mejstrikova E, Hrusak O, Borowitz MJ, Whitlock JA, Brethon B, Trippett TM, et al. CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 2017;7:659.
Grupp S, Maude S, Shaw P, Aplenc R, Barrett D, Callahan C, et al. Durable Remission in Children with relapsed/refractory ALL treated with T cells engineered with a CD19 - Targeted Chimeric Antigen Receptor (CTL019). In: American Society of Hematology: Blood, 2015. p 681.
Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449–59.
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.
Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, et al. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. 2017;31:2181–90.
Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab Ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740–53.
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.
Davila ML, Kloss CC, Gunset G, Sadelain M. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia. PLoS One. 2013;8:e61338.
Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.
Lee DW, Stetler-Stevenson M, Yuan C, Shah N, 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/Cyclophoshamide Preparative Regimen and Post-CAR Hematopoietic Stem Cell Transplantation. In: American Society of Hematology: Blood, 2016. p 218.
Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an Anti-CD19 chimeric antigen receptor induce remissions of B-Cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016;34:1112–21.
Shalabi H, Delbrook C, Stetler-Stevenson M, Yuan C, Steinberg S, Yates B, et al. Chimeric Antigen Receptor T-Cell Therapy Can Render Patients with ALL into PCR-Negative Remission and Can be an Effective Bridge to Transplant. In: BMT Tandem Scientific Meeting. Salt Lake City, Utah, 2018.
Grupp Stephan, Maude SL, Rives S, Baruchel A, Boyer M, Bittencourt H, et al. Updated Analysis of the Efficacy and Safety of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed/Refractory (r/r) Acute Lymphoblastic Leukemia. In: American Society of Hematology 2018. San Diego, CA, USA: Blood, 2018.
Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944–50.
Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology. 2015;4:e1027469.
Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, et al. Phase I trials using sleeping beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016;126:3363–76.
Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122:2965–73.
Smith M, Zakrzewski J, James S, Sadelain M. Posttransplant chimeric antigen receptor therapy. Blood. 2018;131:1045–52.
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95.
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. 2018;15:47–62.
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 Transplant 2018. e-pub ahead of print https://doi.org/10.1016/j.bbmt.2018.12.758.
Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739–48.
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;24:731–8.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.
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;377:2531–44.
Zheng PP, Kros JM, Li J. Approved CAR T cell therapies: ice bucket challenges on glaring safety risks and long-term impacts. Drug Discov Today 2018. https://doi.org/10.1016/j.drudis.2018.02.012.
Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics. 2016;3:16011.
Park JH, Romero FA, Taur Y, Sadelain M, Brentjens RJ, Hohl TM, et al. Cytokine Release Syndrome Grade is a Predictive Marker for Infections in Relapsed or Refractory B-cell All Patients Treated with CAR T Cells. Clin Infect Dis 2018. https://doi.org/10.1093/cid/ciy152.
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;131:121–30.
Kochenderfer JN, Somerville RPT, Lu T, Yang JC, Sherry RM, Feldman SA, et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol Ther. 2017;25:2245–53.
Bingham CO 3rd, Looney RJ, Deodhar A, Halsey N, Greenwald M, Codding C, et al. Immunization responses in rheumatoid arthritis patients treated with rituximab: results from a controlled clinical trial. Arthritis Rheum. 2010;62:64–74.
Bhoj VG, Arhontoulis D, Wertheim G, Capobianchi J, Callahan CA, Ellebrecht CT, et al. Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood. 2016;128:360–70.
Rubin LG, Levin MJ, Ljungman P, Davies EG, Avery R, Tomblyn M, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis 2014;58:309–318. https://doi.org/10.1093/cid/cit816.
Kroger A, Duchin J, Vázquez M. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). In. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html Accessed 12 Nov 2018.
Carpenter PA, Englund JA. How I vaccinate blood and marrow transplant recipients. Blood. 2016;127:2824–32.
Cornetta K, Duffy L, Turtle CJ, Jensen M, Forman S, Binder-Scholl G, et al. Absence of replication-competent lentivirus in the clinic: analysis of infused T cell products. Mol Ther. 2018;26:280–8.
Persons DA, Baum C. Solving the problem of gamma-retroviral vectors containing long terminal repeats. Mol Ther. 2011;19:229–31.
Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4:132ra53.
Milone MC, O’Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018;32:1529–41.
Bryan W. FDA Letter - Biologics License Application. In. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM574106.pdf. Accessed: 12 Nov 2018.
Gust J, Hay KA, Hanafi LA, 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.
We acknowledge the critical review of the manuscript and constructive feedback from the American Society for Blood and Marrow Transplant’s (ASBMT) Practice Guideline Committee, ASBMT’s Cellular Therapy committee, and the Acute Leukemia Working Party and Cell Therapy and Immunobiology Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
AK, NVF, MB, and TWL wrote the first draft of the manuscript and are first authors. All authors contributed substantially to the conception, writing, critical review and final approval of the submitted version of the manuscript.
Conflict of interest
AJK: Scientific Advisory Board–Celgene. NVF: Consultant–Novartis, Servier. TWL: Consultant–Novartis CMB: Scientific Advisory Boards: Cellectis. Stock/ownership: Mana Therapeutics, Torque and Neximmune. KK: Scientific Advisory Boards: Kite/Gilead, Novartis, Juno/Celgene, Atara, Takeda; Clinical Research Site: Kite, Iovance, Juno, Atara. CC: Consultant–Gilead, Research Funding: Gilead, Celgene, Speaker: Terumo BCT, Novartis. MAP: Honorarium: Abbvie, Bellicum, Incyte, Merck, Novartis, Nektar Therapeutics, and Takeda. Data Safety Monitoring Board: Servier and Medigene, Scientific Advisory Boards–MolMed and NexImmune. Research Funding–Incyte, Miltenyi Biotec. LA: Board of director/Scientific Advisory Board: HCLF, Consultant: AstraZeneca. VB: Research Funding–Gamida Cell, GT Biopharma, Scientific Advisory Board - Novartis, Kite, Travel funding–Amgen. CB: Research Funding–Intellia Therapeutics, Scientific Advisory Boards - TxCell, MolMed s.p.a., Travel funding–Miltenyi. SAG: Research Funding–Novartis, Servier and Kite. Consultant/Study Steering Committees/Scientific Advisory Boards–Novartis, Adaptimmune, Eureka, TCR2, Juno, GlaxoSmithKline, Cellectis, Vertex, and Roche. JAH: Consultant–Nohla Therapeutics, inc. and Amplyx, Research Funding–Karius and Shire. SK: Research funding: Humanigen, Tolero, Lentigen. Patents and Royalites: Novartis. DM: Scientific Advisory Board: Janssen, Honoraria: Seattle Genetics, Roche/Genentech, Research Funding: Juno Therapeutics, GlaxoSmithKline. MAK: Consultant–Pharmacyclics, Speaker–Incyte Corp, Seattle Genetics and Alexion Pharmaceuticals. EJ: Scientific Advisory Boards–Novartis. Speaker: Medison. AB: Scientific Advisory Boards–Novartis, Roche, Sanofi, Jazz, Adienne, Pfizer, Amgen. Research Funding: Novartis, Amgen, Takeda, Astellas, Celgene, Pfizer. JFD: Ownership/Equity–WUGEN. DLP: Research Funding–Novartis, Scientific Advisory Boards - Novartis, Kite, Patent and Royalty payments–Novartis. SIG: Research Funding–Novartis; Tmunity Therapeutics. Scientific Advisory Boards–Aileron; Fate Therapeutics; Intellia. Patent and Royalties–Novartis. Ownership/equity–Carisma Therapeutics. MS: Research Funding: Fate Theapeutics Inc, Consultant/Board of Director/Scientific Advisory Board/Patents and Royalties/Research Funding: Juno Therapeutics, MM: Lecture honoraria and Consultant- Novartis, Amgen and Pfizer. SKH: Honorarium: Mallinckrodt
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This paper was originally published in Biology of Blood and Marrow Transplantation Volume 25, Issue 3, e76 - e85 https://doi.org/10.1016/j.bbmt.2018.12.068.