Skip to main content
Top

06-08-2018 | Guidelines | Article

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Journal: Nature Reviews Clinical Oncology

Authors: Kris M. Mahadeo, Sajad J. Khazal, Hisham Abdel-Azim, Julie C. Fitzgerald, Agne Taraseviciute, Catherine M. Bollard, Priti Tewari, Christine Duncan, Chani Traube, David McCall, Marie E. Steiner, Ira M. Cheifetz, Leslie E. Lehmann, Rodrigo Mejia, John M. Slopis, Rajinder Bajwa, Partow Kebriaei, Paul L. Martin, Jerelyn Moffet, Jennifer McArthur, Demetrios Petropoulos, Joan O’Hanlon Curry, Sarah Featherston, Jessica Foglesong, Basirat Shoberu, Alison Gulbis, Maria E. Mireles, Lisa Hafemeister, Cathy Nguyen, Neena Kapoor, Katayoun Rezvani, Sattva S. Neelapu, Elizabeth J. Shpall, the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

Publisher: Nature Publishing Group UK

Abstract

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.
Literature
1.
Noone, A. M. et al. SEER Cancer Statistics Review, 1975–2015. National Cancer Institute https://​seer.​cancer.​gov/​csr/​1975_​2015/​ (2018).
2.
Farber, S. & Diamond, L. K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N. Engl. J. Med. 238, 787–793 (1948).PubMedCrossRef
3.
O’Leary, M., Krailo, M., Anderson, J. R. Reaman, G. H., & Children’s Oncology Group. Progress in childhood cancer: 50 years of research collaboration, a report from the Children’s Oncology Group. Semin. Oncol. 35, 484–493 (2008).PubMedPubMedCentralCrossRef
4.
Blau, C. A. E. Donnall Thomas, M.D. (1920–2012). Stem Cells Transl Med. (2013).
5.
Ko, R. H. et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. J. Clin. Oncol. 28, 648–654 (2010).PubMedCrossRef
6.
Sun, W. et al. Outcome of children with multiply relapsed B cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia and lymphoma study. Leukemia https://​doi.​org/​10.​1038/​s41375-018-0094-0 (2018).
7.
Thomas, E. D. et al. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood 54, 468–476 (1979).PubMedCrossRef
8.
Novartis Pharmaceuticals Corporation. Package insert - KymriahTM (tisagenlecleucel). Novartis Pharmaceuticals Corporation https://​www.​fda.​gov/​downloads/​BiologicsBloodVa​ccines/​CellularGeneTher​apyProducts/​ApprovedProducts​/​UCM573941.​pdf (2018).
9.
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).PubMedPubMedCentralCrossRef
10.
Dai, H., Wang, Y., Lu, X. & Han, W. Chimeric antigen receptors modified T-cells for cancer therapy. J. Natl Cancer Inst. 108, djv439 (2016).PubMedPubMedCentralCrossRef
11.
Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).PubMedPubMedCentralCrossRef
12.
Abate-Daga, D. & Davila, M. L. CAR models: next-generation CAR modifications for enhanced T cell function. Mol. Ther. Oncolyt. 3, 16014 (2016).CrossRef
13.
Maus, M. V. & Levine, B. L. Chimeric antigen receptor T-cell therapy for the community oncologist. Oncologist 21, 608–617 (2016).PubMedPubMedCentralCrossRef
14.
Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116, 4099–4102 (2010).PubMedPubMedCentralCrossRef
15.
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).PubMedPubMedCentralCrossRef
16.
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).PubMedPubMedCentralCrossRef
17.
Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl Med. 5, 177ra138 (2013).CrossRef
18.
Cruz, C. R. 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 122, 2965–2973 (2013).PubMedPubMedCentralCrossRef
19.
Kochenderfer, J. N. et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013).PubMedPubMedCentralCrossRef
20.
Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl Med. 6, 224ra225 (2014).CrossRef
21.
Kochenderfer, J. N. 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. 33, 540–549 (2015).PubMedCrossRef
22.
Lee, D. W. 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 385, 517–528 (2015).PubMedCrossRef
23.
Garfall, A. L. et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med. 373, 1040–1047 (2015).PubMedPubMedCentralCrossRef
24.
Brudno, J. N. 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. 34, 1112–1121 (2016).PubMedPubMedCentralCrossRef
25.
Turtle, C. J. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J. Clin. Oncol. 35, 3010–3020 (2017).PubMedPubMedCentralCrossRef
26.
Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285–295 (2017).PubMedPubMedCentralCrossRef
27.
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).PubMedPubMedCentralCrossRef
28.
Kochenderfer, J. N. et al. B cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).PubMedPubMedCentralCrossRef
29.
Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).PubMedPubMedCentralCrossRef
30.
Teachey, D. T. et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121, 5154–5157 (2013).PubMedPubMedCentralCrossRef
31.
Rezvani, K. & Rouce, R. H. The application of natural killer cell immunotherapy for the treatment of cancer. Front. Immunol. 6, 578 (2015).PubMedPubMedCentralCrossRef
32.
Richman, S. A. et al. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunol. Res. 6, 36–46 (2018).
33.
Fitzgerald, J. C. et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit. Care Med. 45, e124–e131 (2017).PubMedPubMedCentralCrossRef
34.
Norelli, 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. 24, 739–748 (2018).PubMedCrossRef
35.
Giavridis, T. et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat. Med. 24, 731–738 (2018).PubMedCrossRefPubMedCentral
36.
FDA. FDA briefing document: Oncologic Drugs Advisory Committee meeting; BLA 125646; Tisagenlecleucel, Novartis Pharmaceuticals Corporation. FDA https://​www.​fda.​gov/​downloads/​AdvisoryCommitte​es/​CommitteesMeetin​gMaterials/​Drugs/​OncologicDrugsAd​visoryCommittee/​UCM566166.​pdf (2017).
37.
Neelapu, S. S. et al. Chimeric antigen receptor T cell therapy - assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).PubMedCrossRef
38.
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).PubMedPubMedCentralCrossRef
39.
Fink, A., Kosecoff, J., Chassin, M. & Brook, R. H. Consensus methods: characteristics and guidelines for use. Am. J. Publ. Health 74, 979–983 (1984).CrossRef
40.
Shekelle, P. G., Woolf, S. H., Eccles, M. & Grimshaw, J. Developing clinical guidelines. West J. Med. 170, 348–351 (1999).PubMedPubMedCentral
41.
Shields, A. F. et al. Immune modulation therapy and imaging: workshop report. J. Nucl. Med. 59, 410–417 (2018).PubMedPubMedCentralCrossRef
42.
Massad, N., Lee, S. C., Lasala, P. A. & Welch, M. R. A case of pembrolizumab-induced central nervous system toxicity in a patient with metastatic melanoma. Am. Acad. Neurol. 86, (Suppl. 16), P4.238 (2016).
43.
Hochmair, M. J., Schwab, S., Burghuber, O. C., Krenbek, D. & Prosch, H. Symptomatic pseudo-progression followed by significant treatment response in two lung cancer patients treated with immunotherapy. Lung Cancer 113, 4–6 (2017).PubMedCrossRef
44.
[No authors listed.] Informed consent, parental permission, and assent in pediatric practice. Committee on Bioethics, American Academy of Pediatrics. Pediatrics 95, 314–317 (1995).
45.
McGuirk, J. et al. Building blocks for institutional preparation of CTL019 delivery. Cytotherapy 19, 1015–1024 (2017).PubMedCrossRef
46.
Gardner, R. A. et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129, 3322–3331 (2017).PubMedPubMedCentralCrossRef
47.
Crookston, K. P. & Simon, T. L. in Apheresis: Principles and Practice 2nd edn (eds McLeod, B. C., Price, T. H. & Weinstein, R.) 71–90 (AABB Press, Bethesda, 2003).
48.
Goldstein, S. L. Therapeutic apheresis in children: special considerations. Semin. Dial 25, 165–170 (2012).PubMedCrossRef
49.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02028455 (2018).
50.
Michon, B. et al. Complications of apheresis in children. Transfusion 47, 1837–1842 (2007).PubMedCrossRef
51.
Gorlin, J. B. et al. Pediatric large volume peripheral blood progenitor cell collections from patients under 25 kg: a primer. J. Clin. Apheresis 11, 195–203 (1996).PubMedCrossRef
52.
Carausu, L., Clapisson, G., Philip, I., Sebban, H. & Marec-Berard, P. Use of totally implantable catheter for peripheral blood stem cell apheresis. Bone Marrow Transpl. 39, S131–S131 (2007).
53.
Koristek, Z., Sterba, J., Havranova, D. & Mayer, J. Technique for PBSC harvesting in children of weight under 10 kg. Bone Marrow Transpl. 29, 57–61 (2002).CrossRef
54.
Ohara, Y. et al. Comprehensive technical and patient-care optimization in the management of pediatric apheresis for peripheral blood stem cell harvesting. Transfus Apher Sci. 55, 338–343 (2016).PubMedCrossRef
55.
Foundation for the Accreditation of Cellular Therapy. FACT Standards for Immune Effector Cells. 1st edn (FACT, 2017).
56.
Wells, J. et al. Pre-clinical activity of allogeneic anti-CD22 CAR-T cells for the treatment of B-cell acute lymphoblastic leukemia. Blood 130, 808 (2017).CrossRef
57.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT03056339 (2018).
58.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02808442 (2018).
59.
Rezvani, K., Rouce, R., Liu, E. & Shpall, E. Engineering natural killer cells for cancer immunotherapy. Mol. Ther. 25, 1769–1781 (2017).PubMedPubMedCentralCrossRef
60.
Liu, E. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 32, 520–531 (2017).PubMedPubMedCentralCrossRef
61.
Philip, B. RQR8: A universal safety switch for cellular therapies. Thesis, Univ. College London (2015).
62.
Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20, 119–122 (2014).PubMedPubMedCentralCrossRef
63.
Tomblyn, M. et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol. Blood Marrow Transplant 15, 1143–1238 (2009).PubMedPubMedCentralCrossRef
64.
Turtle, C. J. et al. CD19 CAR-T cells of defined CD4(+): CD8(+) composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).PubMedPubMedCentralCrossRef
65.
Dudley, M. E. et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23, 2346–2357 (2005).PubMedCrossRef
66.
Dummer, W. et al. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J. Clin. Invest. 110, 185–192 (2002).PubMedPubMedCentralCrossRef
67.
Klebanoff, C. A., Khong, H. T., Antony, P. A., Palmer, D. C. & Restifo, N. P. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol. 26, 111–117 (2005).PubMedPubMedCentralCrossRef
68.
Mackall, C. L., Hakim, F. T. & Gress, R. E. Restoration of T cell homeostasis after T cell depletion. Semin. Immunol. 9, 339–346 (1997).PubMedCrossRef
69.
Tanchot, C., Lemonnier, F. A., Perarnau, B., Freitas, A. A. & Rocha, B. Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science 276, 2057–2062 (1997).PubMedCrossRef
70.
Goldrath, A. W. & Bevan, M. J. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11, 183–190 (1999).PubMedPubMedCentralCrossRef
71.
Tan, J. T. et al. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells. J. Exp. Med. 195, 1523–1532 (2002).PubMedPubMedCentralCrossRef
72.
Schluns, K. S., Kieper, W. C., Jameson, S. C. & Lefrancois, L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat. Immunol. 1, 426–432 (2000).PubMedCrossRef
73.
Tan, J. T. et al. IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc. Natl Acad. Sci. USA 98, 8732–8737 (2001).PubMedCrossRefPubMedCentral
74.
Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).PubMed
75.
Colombo, M. P. & Piconese, S. Regulatory-T cell inhibition versus depletion: the right choice in cancer immunotherapy. Nat. Rev. Cancer 7, 880–887 (2007).PubMedCrossRef
76.
Wrzesinski, C. et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J. Immunother. 33, 1–7 (2010).PubMedPubMedCentralCrossRef
77.
Gattinoni, L., Powell, D. J. Jr., Rosenberg, S. A. & Restifo, N. P. Adoptive immunotherapy for cancer: building on success. Nat. Rev. Immunol. 6, 383–393 (2006).PubMedPubMedCentralCrossRef
78.
Cameron, J. et al. Addition of fludarabine to cyclophosphamide lymphodepletion improves in vivo expansion of CD19 chimeric antigen receptor-modified T cells and clinical outcome in adults with B cell acute lymphoblastic leukemia. Blood 126, 3773 (2015).CrossRef
79.
Heczey, A. et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Mol. Ther. 25, 2214–2224 (2017).PubMedPubMedCentralCrossRef
80.
Shank, B. R. et al. Chimeric antigen receptor T cells in hematologic malignancies. Pharmacotherapy 37, 334–345 (2017).PubMedCrossRef
81.
Brentjens, R. 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 118, 4817–4828 (2011).PubMedPubMedCentralCrossRef
82.
Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).PubMedPubMedCentralCrossRef
83.
US National Library of Medicine. ClinicalTrials.gov https://​clinicaltrials.​gov/​ct2/​show/​NCT02203825 (2018).
84.
Leukemia & Lymphoma Society. Chimeric antigen receptor (CAR) T-cell therapy. Leukemia & Lymphoma Society https://​www.​lls.​org/​sites/​default/​files/​National/​USA/​Pdf/​Publications/​FSHP1_​CART_​Factsheet_​June2018_​FINAL.​pdf (2017).
85.
Brentjens, R., Yeh, R., Bernal, Y., Riviere, I. & Sadelain, M. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol. Ther. 18, 666–668 (2010).PubMedPubMedCentralCrossRef
86.
Truong, T. H. et al. Adverse reactions during stem cell infusion in children treated with autologous and allogeneic stem cell transplantation. Bone Marrow Transplant 51, 680–686 (2016).PubMedCrossRef
87.
Davis, J. M., Rowley, S. D., Braine, H. G., Piantadosi, S. & Santos, G. W. Clinical toxicity of cryopreserved bone marrow graft infusion. Blood 75, 781–786 (1990).PubMedCrossRef
88.
Stroncek, D. F. et al. Adverse reactions in patients transfused with cryopreserved marrow. Transfusion 31, 521–526 (1991).PubMedCrossRef
89.
Zambelli, A. et al. Clinical toxicity of cryopreserved circulating progenitor cells infusion. Anticancer Res. 18, 4705–4708 (1998).PubMed
90.
Zenhausern, R., Tobler, A., Leoncini, L., Hess, O. M. & Ferrari, P. Fatal cardiac arrhythmia after infusion of dimethyl sulfoxide-cryopreserved hematopoietic stem cells in a patient with severe primary cardiac amyloidosis and end-stage renal failure. Ann. Hematol. 79, 523–526 (2000).PubMedCrossRef
91.
Hoyt, R., Szer, J. & Grigg, A. Neurological events associated with the infusion of cryopreserved bone marrow and/or peripheral blood progenitor cells. Bone Marrow Transplant 25, 1285–1287 (2000).PubMedCrossRef
92.
Otrock, Z. K. et al. Transient global amnesia associated with the infusion of DMSO-cryopreserved autologous peripheral blood stem cells. Haematologica 93, e36–e37 (2008).PubMedCrossRef
93.
Miniero, R., Vai, S., Giacchino, M., Giubellino, C. & Madon, E. Severe respiratory depression after autologous bone marrow infusion. Haematologica 77, 98–99 (1992).PubMed
94.
Shu, Z., Heimfeld, S. & Gao, D. Hematopoietic stem cell transplantation with cryopreserved grafts: adverse reactions after transplantation and cryoprotectant removal prior to infusion. Bone Marrow Transpl. 49, 469–476 (2014).CrossRef
95.
Breslin, S. Cytokine-release syndrome: overview and nursing implications. Clin. J. Oncol. Nurs. 11, 37–42 (2007).PubMedCrossRef
96.
Namuduri, M. & Brentjens, R. J. Medical management of side effects related to CAR T cell therapy in hematologic malignancies. Expert Rev. Hematol. 9, 511–513 (2016).PubMedPubMedCentralCrossRef
97.
Buechner, J. et al. Global registration trial of efficacy and safety of CTL019 in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL): update to the interim analysis. Clin. Lymphoma Myeloma Leuk. 17, S263–S264 (2017).CrossRef
98.
Power, N. & Franck, L. Parent participation in the care of hospitalized children: a systematic review. J. Adv. Nurs. 62, 622–641 (2008).PubMedCrossRef
99.
U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. U.S. Department of Health and Human Services. https://​ctep.​cancer.​gov/​protocoldevelopm​ent/​electronic_​applications/​docs/​CTCAE_​v5_​Quick_​Reference_​5x7.​pdf (2017).
100.
Pediatric Acute Lung Injury Consensus Conference Group. Pediatric acute respiratory distress syndrome: consensus recommendations from the Pediatric Acute Lung Injury Consensus Conference. Pediatr. Crit. Care Med. 16, 428–439 (2015).CrossRef
101.
Rowan, C. M. et al. Pediatric acute respiratory distress syndrome in pediatric allogeneic hematopoietic stem cell transplants: a multicenter study. Pediatr. Crit. Care Med. 18, 304–309 (2017).PubMedCrossRef
102.
Rowan, C. M. et al. High-frequency oscillatory ventilation use and severe pediatric ARDS in the pediatric hematopoietic cell transplant recipient. Respir. Care 63, 404–411 (2017).PubMedCrossRef
103.
Chong, S. L. et al. A retrospective review of vital signs and clinical outcomes of febrile infants younger than 3 months old presenting to the emergency department. PLOS One 13, e0190649 (2018).PubMedPubMedCentralCrossRef
104.
Fleming, S. et al. Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies. Lancet 377, 1011–1018 (2011).PubMedPubMedCentralCrossRef
105.
Akcan-Arikan, A. et al. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 71, 1028–1035 (2007).PubMedCrossRef
106.
Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int. Suppl. 2, 1–138 (2012).CrossRef
107.
Neelapu, S. S. et al. Axicabtagene ciloleucel (AXI-CEL; KTE-C19) in patients with refractory aggressive non-hodgkin lymphomas (NHL): primary results of the pivotal trial ZUMA-1. Hematol.Oncol. 35 (Suppl.), 28 (2017).CrossRef
108.
Thudium Mueller, K. et al. CTL019 clinical pharmacology and biopharmaceutics in pediatric patients (pts) with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) [abstract ALL-146]. Clin. Lymphoma Myeloma Leuk. 17 (Suppl. 2), 217–218 (2017).CrossRef
109.
FDA. FDA approves tisagenlecleucel for B cell ALL and tocilizumab for cytokine release syndrome. FDA https://​www.​fda.​gov/​drugs/​informationondru​gs/​approveddrugs/​ucm574154.​htm (2017).
110.
Genentech. ACTEMRA® (tocilizumab) prescribing information. FDA https://​www.​accessdata.​fda.​gov/​drugsatfda_​docs/​label/​2017/​125276s114lbl.​pdf (2017).
111.
Chen, F. et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J. Immunol. Methods 434, 1–8 (2016).PubMedPubMedCentralCrossRef
112.
Minoia, F. et al. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome. J. Pediatr. 189, 72–78 (2017).PubMedCrossRef
113.
Henter, J. I. et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48, 124–131 (2007).PubMedCrossRef
114.
Frey, N. V. et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124, 2296 (2014).CrossRef
115.
Hu, Y. et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J. Hematol. Oncol. 9, 70 (2016).PubMedPubMedCentralCrossRef
116.
Traube, C. et al. Cornell assessment of pediatric delirium: a valid, rapid, observational tool for screening delirium in the PICU. Crit. Care Med. 42, 656–663 (2014).PubMedPubMedCentralCrossRef
117.
Silver, G., Kearney, J., Traube, C. & Hertzig, M. Delirium screening anchored in child development: the Cornell Assessment for Pediatric Delirium. Palliat. Support. Care 13, 1005–1011 (2015).PubMedCrossRef
118.
Gust, J. et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).PubMedPubMedCentralCrossRef
119.
Taraseviciute, A. et al. Chimeric antigen receptor T cell-mediated neurotoxicity in non-human primates. Cancer Discov. 8, 750–763 (2018).PubMedCrossRefPubMedCentral
120.
Turtle, C. J. et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl Med. 8, 355ra116 (2016).PubMedPubMedCentralCrossRef
121.
Teachey, D. T. et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 6, 664–679 (2016).PubMedPubMedCentralCrossRef
122.
Stephen, J. et al. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood 126, 183–183 (2015).CrossRef
123.
Hovinga, C. A. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy 21, 1375–1388 (2001).PubMedCrossRef
124.
Guenther, S. et al. Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans. Seizure 23, 666–669 (2014).PubMedCrossRef
125.
Perez, E. E. et al. Update on the use of immunoglobulin in human disease: a review of evidence. J. Allergy Clin. Immunol. 139, S1–S46 (2017).PubMedCrossRef
126.
Weissert, R. Progressive multifocal leukoencephalopathy. J. Neuroimmunol. 231, 73–77 (2011).PubMedCrossRef
127.
Durali, D., de Goer de Herve, M. G., Gasnault, J. & Taoufik, Y. B cells and progressive multifocal leukoencephalopathy: search for the missing link. Front. Immunol. 6, 241 (2015).PubMedPubMedCentralCrossRef
128.
Abdel-Azim, H., Elshoury, A., Mahadeo, K. M., Parkman, R. & Kapoor, N. Humoral immune reconstitution kinetics after allogeneic hematopoietic stem cell transplantation in children: a maturation block of IgM memory B cells may lead to impaired antibody immune reconstitution. Biol. Blood Marrow Transplant 23, 1437–1446 (2017).PubMedCrossRef
129.
Dalba, C., Bellier, B., Kasahara, N. & Klatzmann, D. Replication-competent vectors and empty virus-like particles: new retroviral vector designs for cancer gene therapy or vaccines. Mol. Ther. 15, 457–466 (2007).PubMedCrossRef
130.
Centre for Biologics Evaluation and Research. Gene therapy clinical trials–observing subjects for delayed adverse events. FDA https://​www.​fda.​gov/​downloads/​BiologicsBloodVa​ccines/​GuidanceComplian​ceRegulatoryInfo​rmation/​Guidances/​CellularandGeneT​herapy/​ucm078719.​pdf (2006).
131.
Centre for Biologics Evaluation and Research. Supplemental guidance on testing for replication competent retrovirus in retroviral vector based gene therapy products and during follow-up of patients in clinical trials using retroviral vectors. FDA https://​www.​fda.​gov/​downloads/​biologicsbloodva​ccines/​guidancecomplian​ceregulatoryinfo​rmation/​guidances/​cellularandgenet​herapy/​ucm078723.​pdf (2006).
132.
Bennett, T. D. et al. Existing data analysis in pediatric critical care research. Front. Pediatr. 2, 79 (2014).PubMedPubMedCentralCrossRef
133.
Cope, S. et al. Expert elicitation of long-term survival for pediatric acute lymphoblastic leukemia patients receiving CTL019 in Eliana phase II study. Blood 130, 3377 (2017).
134.
Jackson, H. J. & Brentjens, R. J. Overcoming antigen escape with CAR T cell therapy. Cancer Discov. 5, 1238–1240 (2015).PubMedPubMedCentralCrossRef
135.
Doorenbos, A. et al. Palliative care in the pediatric ICU: challenges and opportunities for family-centered practice. J. Soc. Work End Life Palliat Care 8, 297–315 (2012).PubMedPubMedCentralCrossRef
136.
Yanni Hao, L. K. Cost-effectiveness analysis of CTL019 for the treatment of pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia in the United States. Blood 130, 609 (2017).
137.
LaMattina, J. Pharma’s paradox: cure a deadly childhood disease and then get attacked on price. Forbes https://​www.​forbes.​com/​sites/​johnlamattina/​2017/​11/​28/​cure-a-deadly-childhood-disease-and-then-get-attacked-on-price/​#7089d1696479 (2017).
138.
Prasad, V. Immunotherapy: tisagenlecleucel - the first approved CAR-T cell therapy: implications for payers and policy makers. Nat. Rev. Clin. Oncol. 15, 11–12 (2018).PubMedCrossRef
139.
Sanders, G. D. et al. Recommendations for conduct, methodological practices, and reporting of cost-effectiveness analyses: second panel on cost-effectiveness in health and medicine. JAMA 316, 1093–1103 (2016).CrossRefPubMed
140.
Gold, M. Panel on cost-effectiveness in health and medicine. Med. Care 34, DS197–199 (1996).PubMedCrossRef
142.
Antonelli, R. C., Stille, C. J. & Antonelli, D. M. Care coordination for children and youth with special health care needs: a descriptive, multisite study of activities, personnel costs, and outcomes. Pediatrics 122, e209–e216 (2008).PubMedCrossRef
143.
FDA. Approved Risk Evaluation and Mitigation Strategies (REMS) for KymriahTM(tisagenlecleucel). FDA https://​www.​Accessdata.​fda.​gov/​Scripts/​Cder/​Rems/​Index.​cfm?​Event=​IndvRemsDetails.​Page&​REMS=​368 (2017).
144.
Bayntun, C., Rockenschaub, G. & Murray, V. Developing a health system approach to disaster management: A qualitative analysis of the core literature to complement the WHO Toolkit for assessing health-system capacity for crisis management. PLOS Curr. 4, e5028b6037259a (2012).PubMedPubMedCentral
145.
Kevin, H., Morchel, H., Raheem, M. & Stevens, L. Electronic health records access during a disaster. Online J. Publ. Health Inform 5, 232 (2014).
146.
Wingard, J. R. et al. Preparing for the unthinkable: emergency preparedness for the hematopoietic cell transplant program. Biol. Blood Marrow Transplant 12, 1229–1238 (2006).PubMedCrossRefPubMedCentral
147.
Frisen, L. Swelling of the optic nerve head: a staging scheme. J. Neurol. Neurosurg. Psychiatry 45, 13–18 (1982).PubMedPubMedCentralCrossRef