Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Consensus Statement
  • Published:

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer

Nature Reviews Clinical Oncology volume 18, pages 435–453 (2021)Cite this article

Subjects

An Author Correction to this article was published on 17 March 2021

This article has been updated

Abstract

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Grading and management of cytokine-release syndrome2,3.
Fig. 2: Grading and management of immune effector cell-associated neurotoxicity syndrome2,3,86.

Similar content being viewed by others

Change history

References

  1. Palmer, S., Patterson, P. & Thompson, K. A national approach to improving adolescent and young adult (AYA) oncology psychosocial care: the development of AYA-specific psychosocial assessment and care tools. Palliat. Support. Care 12, 183–188 (2014).

    PubMed  Google Scholar 

  2. Mahadeo, K. M. et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat. Rev. Clin. Oncol. 16, 45–63 (2019).

    CAS  PubMed  Google Scholar 

  3. Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transpl. 25, 625–638 (2019).

    CAS  Google Scholar 

  4. FDA. Highlights of Prescribing Information: KYMRIAH. https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Package-Insert---KYMRIAH.pdf (2018).

  5. FDA. Highlights of Prescribing Information: YESCARTA. https://www.fda.gov/media/108377/download (2020).

  6. FDA. Highlights of Prescribing Information: TECARTUS. https://www.fda.gov/media/140409/download (2020).

  7. Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, D. et al. Genetically engineered T cells for cancer immunotherapy. Signal. Transduct. Target. Ther. 4, 35 (2019).

    PubMed  PubMed Central  Google Scholar 

  9. Johnson, L. A. & June, C. H. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 27, 38–58 (2017).

    CAS  PubMed  Google Scholar 

  10. Baiden-Amissah, R. E. M. & Tuyaerts, S. Contribution of aging, obesity, and microbiota on tumor immunotherapy efficacy and toxicity. Int. J. Mol. Sci. 20, 3586 (2019).

    CAS  PubMed Central  Google Scholar 

  11. Ruella, M. & Maus, M. V. Catch me if you can: leukemia escape after CD19-directed T cell immunotherapies. Comput. Struct. Biotechnol. J. 14, 357–362 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Fousek, K. et al. CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Leukemia 35, 75–89 (2021).

    CAS  PubMed  Google Scholar 

  13. György, B. Bispecific CAR T cells have a dual grasp on tumors. Sci. Transl. Med. 12, eabf2636 (2020).

    Google Scholar 

  14. Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ghorashian, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat. Med. 25, 1408–1414 (2019).

    CAS  PubMed  Google Scholar 

  16. Benjamin, R. et al. Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies. Lancet 396, 1885–1894 (2020).

    CAS  PubMed  Google Scholar 

  17. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Scott, M. C. et al. Comparative transcriptome analysis quantifies immune cell transcript levels, metastatic progression, and survival in osteosarcoma. Cancer Res. 78, 326–337 (2018).

    CAS  PubMed  Google Scholar 

  19. Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rosenberg, S. A. et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. N. Engl. J. Med. 319, 1676–1680 (1988).

    CAS  PubMed  Google Scholar 

  21. Lizee, G. et al. Harnessing the power of the immune system to target cancer. Annu. Rev. Med. 64, 71–90 (2013).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang, Z., Li, B., Ren, Y. & Ye, Z. T-cell-based immunotherapy for osteosarcoma: challenges and opportunities. Front. Immunol. 7, 353 (2016).

    PubMed  PubMed Central  Google Scholar 

  24. Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Dudley, M. E. et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298, 850–854 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rosenberg, S. A. et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J. Natl Cancer Inst. 86, 1159–1166 (1994).

    CAS  PubMed  Google Scholar 

  27. Parkhurst, M. R. et al. Unique neoantigens arise from somatic mutations in patients with gastrointestinal cancers. Cancer Discov. 9, 1022–1035 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).

    CAS  PubMed  Google Scholar 

  29. Olle Hurtado, M. et al. Tumor infiltrating lymphocytes expanded from pediatric neuroblastoma display heterogeneity of phenotype and function. PLoS ONE 14, e0216373 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Mullinax, J. E. et al. Combination of ipilimumab and adoptive cell therapy with tumor-infiltrating lymphocytes for patients with metastatic melanoma. Front. Oncol. 8, 44 (2018).

    PubMed  PubMed Central  Google Scholar 

  31. Zhao, Q. et al. Tumor-targeted IL-12 combined with tumor resection yields a survival-favorable immune profile. J. Immunother. Cancer 7, 154 (2019).

    PubMed  PubMed Central  Google Scholar 

  32. Nguyen, L. T. et al. Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2. Cancer Immunol. Immunother. 68, 773–785 (2019).

    CAS  PubMed  Google Scholar 

  33. Schwinger, W. et al. Feasibility of high-dose interleukin-2 in heavily pretreated pediatric cancer patients. Ann. Oncol. 16, 1199–1206 (2005).

    CAS  PubMed  Google Scholar 

  34. Yeh, S. et al. Ocular and systemic autoimmunity after successful tumor-infiltrating lymphocyte immunotherapy for recurrent, metastatic melanoma. Ophthalmology 116, 981–989.e1 (2009).

    PubMed  Google Scholar 

  35. Robbins, P. F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).

    CAS  PubMed  Google Scholar 

  36. Morgan, R. A. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36, 133–151 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Linette, G. P. et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood 122, 863–871 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chodon, T. et al. Adoptive transfer of MART-1 T-cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma. Clin. Cancer Res. 20, 2457–2465 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Tawara, I. et al. Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. Blood 130, 1985–1994 (2017).

    CAS  PubMed  Google Scholar 

  40. Rezvani, K., Rouce, R., Liu, E. & Shpall, E. Engineering natural killer cells for cancer immunotherapy. Mol. Ther. 25, 1769–1781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Khatua, S. et al. Phase I study of intraventricular infusions of autologous ex-vivo-expanded NK cells in children with recurrent medulloblastoma and ependymoma. Neuro Oncol. 22, 1214–1225 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Screpanti, V., Wallin, R. P., Ljunggren, H. G. & Grandien, A. A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells. J. Immunol. 167, 2068–2073 (2001).

    CAS  PubMed  Google Scholar 

  43. Vela, M. et al. Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia. Cancer Lett. 422, 107–117 (2018).

    CAS  PubMed  Google Scholar 

  44. Rubnitz, J. E. et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J. Clin. Oncol. 28, 955–959 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Nguyen, R. et al. A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia. J. Immunother. Cancer 7, 81 (2019).

    PubMed  PubMed Central  Google Scholar 

  46. Cho, D. et al. Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin. Cancer Res. 16, 3901–3909 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Fernandez, L. et al. Activated and expanded natural killer cells target osteosarcoma tumor initiating cells in an NKG2D-NKG2DL dependent manner. Cancer Lett. 368, 54–63 (2015).

    CAS  PubMed  Google Scholar 

  48. Shah, N. N. et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 125, 784–792 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pérez-Martínez, A. et al. Natural killer cells can exert a graft-vs-tumor effect in haploidentical stem cell transplantation for pediatric solid tumors. Exp. Hematol. 40, 882–891.e1 (2012).

    PubMed  Google Scholar 

  50. Kimpo, M. S., Oh, B. & Lee, S. The role of natural killer cells as a platform for immunotherapy in pediatric cancers. Curr. Oncol. Rep. 21, 93 (2019).

    PubMed  PubMed Central  Google Scholar 

  51. Denman, C. J. et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE 7, e30264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Andersen, M. H., Schrama, D., thor Straten, P. & Becker, J. C. Cytotoxic T cells. J. Invest. Dermatol. 126, 32–41 (2006).

    CAS  PubMed  Google Scholar 

  53. Van Pel, A. & Boon, T. Protection against a nonimmunogenic mouse leukemia by an immunogenic variant obtained by mutagenesis. Proc. Natl Acad. Sci. USA 79, 4718–4722 (1982).

    PubMed  PubMed Central  Google Scholar 

  54. Castelli, C. et al. T-cell recognition of melanoma-associated antigens. J. Cell. Physiol. 182, 323–331 (2000).

    CAS  PubMed  Google Scholar 

  55. Liu, Z. et al. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the prevention and treatment of EBV-associated post-transplant lymphomas. Recent. Results Cancer Res. 159, 123–133 (2002).

    CAS  PubMed  Google Scholar 

  56. Prockop, S. et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J. Clin. Invest. 130, 733–747 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Moosmann, A. et al. Effective and long-term control of EBV PTLD after transfer of peptide-selected T cells. Blood 115, 2960–2970 (2010).

    CAS  PubMed  Google Scholar 

  58. Prockop, S. E. et al. A multicenter, open label, phase 3 study of tabelecleucel for solid organ transplant subjects with Epstein-Barr virus-driven post-transplant lymphoproliferative disorder (EBV+PTLD) after failure of rituximab or rituximab and chemotherapy (ALLELE) [abstract]. Biol. Blood Marrow Transpl. 26, S274 (2020).

    Google Scholar 

  59. Prockop, S. E. et al. Long-term outcomes of patients with epstein-barr virus-driven post-transplant lymphoproliferative disease following solid organ transplant or allogeneic hematopoietic cell transplant treated with tabelecleucel in a multicenter expanded access program study [abstract]. Biol. Blood Marrow Transpl. 26, S61–S62 (2020).

    Google Scholar 

  60. Bollard, C. M. et al. Cytotoxic T lymphocyte therapy for Epstein-Barr virus+Hodgkin’s disease. J. Exp. Med. 200, 1623–1633 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Straathof, K. C. et al. Treatment of nasopharyngeal carcinoma with Epstein-Barr virus-specific T lymphocytes. Blood 105, 1898–1904 (2005).

    CAS  PubMed  Google Scholar 

  62. Schuessler, A. et al. Autologous T-cell therapy for cytomegalovirus as a consolidative treatment for recurrent glioblastoma. Cancer Res. 74, 3466–3476 (2014).

    CAS  PubMed  Google Scholar 

  63. Leen, A. M. et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121, 5113–5123 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gottschalk, S. & Rooney, C. M. Adoptive T-cell immunotherapy. Curr. Top. Microbiol. Immunol. 391, 427–454 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Muftuoglu, M. et al. Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N. Engl. J. Med. 379, 1443–1451 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pello, O. M. et al. BKV-specific T cells in the treatment of severe refractory haemorrhagic cystitis after HLA-haploidentical haematopoietic cell transplantation. Eur. J. Haematol. 98, 632–634 (2017).

    CAS  PubMed  Google Scholar 

  67. Huehls, A. M., Coupet, T. A. & Sentman, C. L. Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296 (2015).

    CAS  PubMed  Google Scholar 

  68. FDA. Highlights of Prescribing Information: Blincyto. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125557s013lbl.pdf (2018).

  69. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Toor, S. M. & Elkord, E. Therapeutic prospects of targeting myeloid-derived suppressor cells and immune checkpoints in cancer. Immunol. Cell Biol. 96, 888–897 (2018).

    PubMed  Google Scholar 

  71. Hargadon, K. M., Johnson, C. E. & Williams, C. J. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int. Immunopharmacol. 62, 29–39 (2018).

    CAS  PubMed  Google Scholar 

  72. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Merchant, M. S. et al. Phase I clinical trial of ipilimumab in pediatric patients with advanced solid tumors. Clin. Cancer Res. 22, 1364–1370 (2016).

    CAS  PubMed  Google Scholar 

  74. Geoerger, B. et al. Phase II study of ipilimumab in adolescents with unresectable stage III or IV malignant melanoma. Eur. J. Cancer 86, 358–363 (2017).

    CAS  PubMed  Google Scholar 

  75. Davis, K. L. et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 21, 541–550 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).

    CAS  PubMed  Google Scholar 

  78. Geoerger, B. et al. Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial. Lancet Oncol. 21, 121–133 (2020).

    CAS  PubMed  Google Scholar 

  79. Goldberg, S. B. et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 21, 655–663 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Kawazoe, A. et al. Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol. 21, 1057–1065 (2020).

    CAS  PubMed  Google Scholar 

  81. Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Ghosh, A. K. et al. CAR T cell therapy-related cardiovascular outcomes and management: systemic disease or direct cardiotoxicity? JACC 2, 97–109 (2020).

    PubMed  PubMed Central  Google Scholar 

  83. Feng, Y. et al. Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. Clin. Cancer Res. 19, 3977–3986 (2013).

    CAS  PubMed  Google Scholar 

  84. Ihara, K. Immune checkpoint inhibitor therapy for pediatric cancers: a mini review of endocrine adverse events. Clin. Pediatr. Endocrinol. 28, 59–68 (2019).

    PubMed  PubMed Central  Google Scholar 

  85. Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy – assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    CAS  PubMed  Google Scholar 

  86. Brahmer, J. R. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 36, 1714–1768 (2018).

    CAS  PubMed  Google Scholar 

  87. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Queudeville, M. et al. Blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Eur. J. Haematol. https://doi.org/10.1111/ejh.13569 (2020).

    Article  Google Scholar 

  89. Berg, M. D. et al. Part 13: Pediatric basic life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 122, S862–S875 (2010).

    PubMed  PubMed Central  Google Scholar 

  90. Gutierrez, C. et al. Critical care management of toxicities associated with targeted agents and immunotherapies for cancer. Crit. Care Med. 48, 10–21 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Roy, J. P. & Devarajan, P. Acute kidney injury: diagnosis and management. Indian J. Pediatr. 87, 600–607 (2020).

    PubMed  Google Scholar 

  93. Fragasso, T., Ricci, Z. & Goldstein, S. L. in Contributions to Nephrology (eds Ding, X., Rosner, M. H. & Ronco, C.) 113–126 (Karger, 2018). [Series Ed. Ronco, C. Acute Kidney Injury - Basic Research and Clinical Practice Vol. 193]

  94. Menon, S. et al. Urinary biomarker incorporation into the renal angina index early in intensive care unit admission optimizes acute kidney injury prediction in critically ill children: a prospective cohort study. Nephrol. Dial. Transpl. 31, 586–594 (2016).

    CAS  Google Scholar 

  95. Bottari, G. et al. Multimodal therapeutic approach of cytokine release syndrome developing in a child given chimeric antigen receptor-modified T cell infusion. Crit. Care Explor. 2, e0071 (2020).

    PubMed  PubMed Central  Google Scholar 

  96. Gutgarts, V. et al. Acute kidney injury after CAR-T cell therapy: low incidence and rapid recovery. Biol. Blood Marrow Transpl. 26, 1071–1076 (2020).

    CAS  Google Scholar 

  97. Gupta, S. et al. Acute kidney injury and electrolyte abnormalities after chimeric antigen receptor T-cell (CAR-T) therapy for diffuse large B-cell lymphoma. Am. J. Kidney Dis. 76, 63–71 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gutierrez, C. et al. The chimeric antigen receptor–intensive care unit (CAR-ICU) initiative: surveying intensive care unit practices in the management of CAR T-cell associated toxicities. J. Crit. Care 58, 58–64 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Dubois, M. J. et al. Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective, randomized, controlled, pilot study. Crit. Care Med. 34, 2536–2540 (2006).

    CAS  PubMed  Google Scholar 

  100. Hariri, G. et al. Albumin infusion improves endothelial function in septic shock patients: a pilot study. Intensive Care Med. 44, 669–671 (2018).

    CAS  PubMed  Google Scholar 

  101. Hu, Y., Feng, J., Shao, M. & Huang, H. Profile of capillary-leak syndrome in patients received chimeric antigen receptor T cell therapy [abstract]. Blood 132 (Suppl. 1), 5204 (2018).

    Google Scholar 

  102. Milesi, C. et al. High-flow nasal cannula: recommendations for daily practice in pediatrics. Ann. Intensive Care 4, 29 (2014).

    PubMed  PubMed Central  Google Scholar 

  103. Dysart, K., Miller, T. L., Wolfson, M. R. & Shaffer, T. H. Research in high flow therapy: mechanisms of action. Respir. Med. 103, 1400–1405 (2009).

    PubMed  Google Scholar 

  104. McDonald, C. F. Low-flow oxygen: how much is your patient really getting? Respirology 19, 469–470 (2014).

    PubMed  Google Scholar 

  105. Kwon, J. W. High-flow nasal cannula oxygen therapy in children: a clinical review. Clin. Exp. Pediatr. 63, 3–7 (2020).

    CAS  PubMed  Google Scholar 

  106. Hutchings, F. A., Hilliard, T. N. & Davis, P. J. Heated humidified high-flow nasal cannula therapy in children. Arch. Dis. Child. 100, 571–575 (2015).

    CAS  PubMed  Google Scholar 

  107. Weiler, T. et al. The relationship between high flow nasal cannula flow rate and effort of breathing in children. J. Pediatr. 189, 66–71.e3 (2017).

    PubMed  Google Scholar 

  108. Morley, S. L. Non-invasive ventilation in paediatric critical care. Paediatr. Respir. Rev. 20, 24–31 (2016).

    PubMed  Google Scholar 

  109. Morris, J. V., Kapetanstrataki, M., Parslow, R. C., Davis, P. J. & Ramnarayan, P. Patterns of use of heated humidified high-flow nasal cannula therapy in PICUs in the United Kingdom and Republic of Ireland. Pediatr. Crit. Care Med. 20, 223–232 (2019).

    PubMed  Google Scholar 

  110. Mestermann, K. et al. The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci. Transl. Med. 11, eaau5907 (2019).

    PubMed  PubMed Central  Google Scholar 

  111. Philip, B. RQR8: A universal safety switch for cellular therapies. Thesis, University College London (2015).

  112. Gardner, R. A. et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 134, 2149–2158 (2019).

    PubMed  PubMed Central  Google Scholar 

  113. Kadauke, S. et al. Early administration of tocilizumab (Toci) for the prevention of grade 4 cytokine release syndrome (CRS) after CD19-directed CAR T-cell therapy (CTL019) [abstract]. Cytotherapy 21, e2–e3 (2019).

    Google Scholar 

  114. Yanez, L., Sanchez-Escamilla, M. & Perales, M. A. CAR T cell toxicity: current management and future directions. Hemasphere 3, e186 (2019).

    PubMed  PubMed Central  Google Scholar 

  115. Schuster, S. J. et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med. 377, 2545–2554 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Mahadeo, K. M. et al. Diagnosis, grading, and treatment recommendations for children, adolescents, and young adults with sinusoidal obstructive syndrome: an international expert position statement. Lancet Haematol. 7, e61–e72 (2020).

    PubMed  Google Scholar 

  118. Gust, J. et al. Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy. Ann. Neurol. 86, 42–54 (2019).

    CAS  PubMed  Google Scholar 

  119. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Santomasso, B. D. et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 8, 958–971 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Miettunen, P. M., Narendran, A., Jayanthan, A., Behrens, E. M. & Cron, R. Q. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology 50, 417–419 (2011).

    CAS  PubMed  Google Scholar 

  122. Henter, J. I. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48, 124–131 (2007).

    PubMed  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Glucksberg, H. et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 18, 295–304 (1974).

    CAS  PubMed  Google Scholar 

  125. Jacobsohn, D. Acute graft-versus-host disease in children. Bone Marrow Transplant. 41, 215–221 (2008).

    CAS  PubMed  Google Scholar 

  126. Harris, A. C. et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol. Blood Marrow Transpl. 22, 4–10 (2016).

    Google Scholar 

  127. Li, X., Shao, C., Shi, Y. & Han, W. Lessons learned from the blockade of immune checkpoints in cancer immunotherapy. J. Hematol. Oncol. 11, 31 (2018).

    PubMed  PubMed Central  Google Scholar 

  128. Liu, Y. H. et al. Diagnosis and management of immune related adverse events (irAEs) in cancer immunotherapy. Biomed. Pharmacother. 120, 109437 (2019).

    CAS  PubMed  Google Scholar 

  129. Khan, M. et al. Comparative analysis of immune checkpoint inhibitors and chemotherapy in the treatment of advanced non-small cell lung cancer: a meta-analysis of randomized controlled trials. Medicine 97, e11936 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. de La Rochefoucauld, J., Noel, N. & Lambotte, O. Management of immune-related adverse events associated with immune checkpoint inhibitors in cancer patients: a patient-centred approach. Intern. Emerg. Med. 15, 587–598 (2020).

    Google Scholar 

  131. Weber, J. S., Kahler, K. C. & Hauschild, A. Management of immune-related adverse events and kinetics of response with ipilimumab. J. Clin. Oncol. 30, 2691–2697 (2012).

    CAS  PubMed  Google Scholar 

  132. Li, A. M. et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia [abstract]. Blood 132 (Suppl. 1), 556 (2018).

    Google Scholar 

  133. Bajciova, V. Therapeutic effect and tolerance of ipilimumam in metastatic malignant melanoma in children – a case report. Klin. Onkol. 28, 4S115–4S120 (2015).

    PubMed  Google Scholar 

  134. Blumenthal, D. T. et al. Pembrolizumab: first experience with recurrent primary central nervous system (CNS) tumors. J. Neurooncol 129, 453–460 (2016).

    CAS  PubMed  Google Scholar 

  135. Bouffet, E. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34, 2206–2211 (2016).

    CAS  PubMed  Google Scholar 

  136. Foran, A. E., Nadel, H. R., Lee, A. F., Savage, K. J. & Deyell, R. J. Nivolumab in the treatment of refractory pediatric Hodgkin lymphoma. J. Pediatr. Hematol. Oncol. 39, e263–e266 (2017).

    CAS  PubMed  Google Scholar 

  137. Shad, A. T. et al. Tolerance and effectiveness of nivolumab after pediatric T-cell replete, haploidentical, bone marrow transplantation: a case report. Pediatr. Blood Cancer 64, e26257 (2017).

    Google Scholar 

  138. Zhu, X. et al. Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report. J. Neurosurg. Pediatr. 19, 249–253 (2017).

    PubMed  Google Scholar 

  139. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    CAS  PubMed  Google Scholar 

  140. Weber, J. S., Yang, J. C., Atkins, M. B. & Disis, M. L. Toxicities of immunotherapy for the practitioner. J. Clin. Oncol. 33, 2092–2099 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Trinh, S., Le, A., Gowani, S. & La-Beck, N. M. Management of immune-related adverse events associated with immune checkpoint inhibitor therapy: a minireview of current clinical guidelines. Asia Pac. J. Oncol. Nurs. 6, 154–160 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. Livingston, E. H. & Lee, S. Percentage of burned body surface area determination in obese and nonobese patients. J. Surg. Res. 91, 106–110 (2000).

    CAS  PubMed  Google Scholar 

  143. Ham, P. & Allen, C. Adolescent health screening and counseling. Am. Fam. Phys. 86, 1109–1116 (2012).

    Google Scholar 

  144. Clotman, K., Janssens, K., Specenier, P., Weets, I. & De Block, C. E. M. Programmed cell death-1 inhibitor-induced type 1 diabetes mellitus. J. Clin. Endocrinol. Metab. 103, 3144–3154 (2018).

    PubMed  Google Scholar 

  145. Stamatouli, A. M. et al. Collateral damage: insulin-dependent diabetes induced with checkpoint inhibitors. Diabetes 67, 1471–1480 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Sakamoto, K., Fukihara, J., Morise, M. & Hashimoto, N. Clinical burden of immune checkpoint inhibitor-induced pneumonitis. Respir. Investig. 58, 305–319 (2020).

    PubMed  Google Scholar 

  147. Naidoo, J. et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J. Clin. Oncol. 35, 709–717 (2017).

    CAS  PubMed  Google Scholar 

  148. Rashdan, S., Minna, J. D. & Gerber, D. E. Diagnosis and management of pulmonary toxicity associated with cancer immunotherapy. Lancet Respir. Med. 6, 472–478 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Khwaja, A. KDIGO clinical practice guideline for acute kidney injury. Nephron. Clin. Pract. 120, c179–c184 (2012).

    PubMed  Google Scholar 

  150. Gupta, S., Cortazar, F. B., Riella, L. V. & Leaf, D. E. Immune checkpoint inhibitor nephrotoxicity: update 2020. Kidney360 1, 130–140 (2020).

    PubMed  PubMed Central  Google Scholar 

  151. Ma, Y., Wang, Q., Dong, Q., Zhan, L. & Zhang, J. How to differentiate pseudoprogression from true progression in cancer patients treated with immunotherapy. Am. J. Cancer Res. 9, 1546–1553 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Ferrara, R. et al. Do immune checkpoint inhibitors need new studies methodology? J. Thorac. Dis. 10, S1564–S1580 (2018).

    PubMed  PubMed Central  Google Scholar 

  153. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    CAS  PubMed  Google Scholar 

  154. Nishino, M. et al. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin. Cancer Res. 19, 3936–3943 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Pignon, J.-C. et al. irRECIST for the evaluation of candidate biomarkers of response to nivolumab in metastatic clear cell renal cell carcinoma: analysis of a phase II prospective clinical trial. Clin. Cancer Res. 25, 2174–2184 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 18, e143–e152 (2017).

    PubMed  PubMed Central  Google Scholar 

  157. Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 15, 7412–7420 (2009).

    CAS  PubMed  Google Scholar 

  158. Lee, J. H. et al. Association between circulating tumor DNA and pseudoprogression in patients with metastatic melanoma treated with anti-programmed cell death 1 antibodies. JAMA Oncol. 4, 717–721 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. Okada, H. et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16, e534–e542 (2015).

    PubMed  PubMed Central  Google Scholar 

  160. Di Giacomo, A. M. et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patient cases. Cancer Immunol. Immunother. 58, 1297–1306 (2009).

    PubMed  Google Scholar 

  161. Masuhiro, K., Shiroyama, T., Nagatomo, I. & Kumanogoh, A. Unique case of pseudoprogression manifesting as lung cavitation after pembrolizumab treatment. J. Thorac. Oncol. 14, e108–e109 (2019).

    PubMed  Google Scholar 

  162. Tanizaki, J. et al. Report of two cases of pseudoprogression in patients with non-small cell lung cancer treated with nivolumab-including histological analysis of one case after tumor regression. Lung Cancer 102, 44–48 (2016).

    PubMed  Google Scholar 

  163. 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).

    PubMed  Google Scholar 

  164. Kohorst, M. A. et al. Transfusion reactions in pediatric and adolescent young adult haematology oncology and immune effector cell patients. EClinicalMedicine 26, 100514 (2020).

    PubMed  PubMed Central  Google Scholar 

  165. Kim, J., Park, J. H. & Shin, S. Effectiveness of simulation-based nursing education depending on fidelity: a meta-analysis. BMC Med. Educ. 16, 152 (2016).

    PubMed  PubMed Central  Google Scholar 

  166. Okuda, Y. et al. The utility of simulation in medical education: what is the evidence? Mt. Sinai J. Med. 76, 330–343 (2009).

    PubMed  Google Scholar 

  167. Azoulay, E., Shimabukuro-Vornhagen, A., Darmon, M. & von Bergwelt-Baildon, M. Critical care management of chimeric antigen receptor T cell-related toxicity. Be aware and prepared. Am. J. Respir. Crit. Care Med. 200, 20–23 (2019).

    PubMed  Google Scholar 

  168. r ICU resource utilization in critically ill patients following chimeric antigen receptor T-cell therapy. Am. J. Respir Crit. Care Med. 202, 1184–1187 (2020).

    Google Scholar 

  169. Redelman-Sidi, G. et al. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (immune checkpoint inhibitors, cell adhesion inhibitors, sphingosine-1-phosphate receptor modulators and proteasome inhibitors). Clin. Microbiol. Infect. 24, S95–S107 (2018).

    PubMed  PubMed Central  Google Scholar 

  170. Davies, H. D. & Committee on Infectious Diseases. Infectious complications with the use of biologic response modifiers in infants and children. Pediatrics 138, e20161209 (2016).

    PubMed  Google Scholar 

  171. Hill, J. A. & Seo, S. K. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood 136, 925–935 (2020).

    PubMed  PubMed Central  Google Scholar 

  172. Fishman, J. A., Hogan, J. I. & Maus, M. V. Inflammatory and infectious syndromes associated with cancer immunotherapies. Clin. Infect. Dis. 69, 909–920 (2019).

    CAS  PubMed  Google Scholar 

  173. Yakoub-Agha, I. et al. Management of adults and children undergoing CAR T-cell therapy: best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Haematologica 105, 297–316 (2019).

    Google Scholar 

  174. Kelly, D. F. et al. Plasma and memory B-cell kinetics in infants following a primary schedule of CRM 197-conjugated serogroup C meningococcal polysaccharide vaccine. Immunology 127, 134–143 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 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).

    CAS  PubMed  Google Scholar 

  176. Tomblyn, M. et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol. Blood Marrow Transpl. 15, 1143–1238 (2009).

    CAS  Google Scholar 

  177. Hu, Y. et al. CAR T-cell treatment during the COVID-19 pandemic: management strategies and challenges. Curr. Res. Transl. Med. 68, 111–118 (2020).

    PubMed  PubMed Central  Google Scholar 

  178. Bisogno, G. et al. Clinical characteristics and outcome of severe acute respiratory syndrome coronavirus 2 infection in Italian pediatric oncology patients: a study from the Infectious Diseases Working Group of the Associazione Italiana di Oncologia e Ematologia Pediatrica. J. Pediatric Infect. Dis. Soc. 9, 530–534 (2020).

    CAS  PubMed  Google Scholar 

  179. Mohammadi, A., Esmaeilzadeh, E., Li, Y., Bosch, R. J. & Li, J. Z. SARS-CoV-2 detection in different respiratory sites: a systematic review and meta-analysis. EbioMedicine 59, 102903 (2020).

    PubMed  PubMed Central  Google Scholar 

  180. Zhou, X., Zhou, J. & Zhao, J. Recurrent pneumonia in a patient with new coronavirus infection after discharge from hospital for insufficient antibody production: a case report. BMC Infect. Dis. 20, 500 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Ruark, J. et al. Patient-reported neuropsychiatric outcomes of long-term survivors after chimeric antigen receptor T cell therapy. Biol. Blood Marrow Transpl. 26, 34–43 (2020).

    Google Scholar 

  182. Broome, H. E., Rassenti, L. Z., Wang, H. Y., Meyer, L. M. & Kipps, T. J. ROR1 is expressed on hematogones (non-neoplastic human B-lymphocyte precursors) and a minority of precursor-B acute lymphoblastic leukemia. Leuk. Res. 35, r–1394 (2011).

    Google Scholar 

  183. Mueller, K. T. et al. Clinical pharmacology of tisagenlecleucel in B-cell acute lymphoblastic leukemia. Clin. Cancer Res. 24, 6175–6184 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Weissert, R. Progressive multifocal leukoencephalopathy. J. Neuroimmunol. 231, 73–77 (2011).

    CAS  PubMed  Google Scholar 

  185. Brown, P. et al. Pediatric acute lymphoblastic leukemia, version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J. Natl Compr. Canc Netw. 18, 81–112 (2020).

    CAS  PubMed  Google Scholar 

  186. Maude, S. L. et al. Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory acute lymphoblastic leukemia [abstract]. Blood. 128, 217 (2016).

    Google Scholar 

  187. Maude, S. L. et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL [abstract]. J. Clin. Oncol. 34, 3011 (2016).

    Google Scholar 

  188. Lanza, F. et al. CD22 expression in B-cell acute lymphoblastic leukemia: biological significance and implications for inotuzumab therapy in adults. Cancers 12, 303 (2020).

    CAS  PubMed Central  Google Scholar 

  189. Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).

    CAS  PubMed  Google Scholar 

  190. Shah, N. N. et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. J. Clin. Oncol. 38, 1938–1950 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. Neelapu, S. S. et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat. Rev. Clin. Oncol. 15, 218 (2018).

    PubMed  PubMed Central  Google Scholar 

  192. Dufner, V. et al. Long-term outcome of patients with relapsed/refractory B-cell non-Hodgkin lymphoma treated with blinatumomab. Blood Adv. 3, 2491–2498 (2019).

    PubMed  PubMed Central  Google Scholar 

  193. Lund, C. C. The estimation of areas of burns. Surg. Gynecol. Obste 79, 352–358 (1944).

    Google Scholar 

Download references

Acknowledgements

We thank the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program, The University of Texas MD Anderson Cancer Center, the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup and the PALISI Network Scientific Committee, the Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC), the Extracorporeal Life Support Organization (ELSO) and the Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT). D.R., S.J.K., D.McC., B.C., B.S., J.M., P.T., D.P., F.N.H.T., P.K., K.R., S.S.N, E.J.S. and K.M.M. are members of the CARTOX Program. H.A, A.H.A., M.D.N., B.S., M.E.S. and K.M.M. are members of the PALISI HCT–CI subgroup. H.A.A., J.A., S.W.C. and K.M.M are members of the PTCTC. M.D.N. is a member of ELSO. S.C. is a member of the PDWP of the EBMT. We thank our patients and families who inspire and guide us towards continuous improvement. We thank our respective nursing unit staffs and key stakeholders who work to ensure access to novel therapies for our patients. C.M.R. is the recipient of a K23 grant (1K23HL150244) from the National Heart, Lung and Blood Institute.

Author information

Authors and Affiliations

  1. Department of Pediatrics, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Dristhi Ragoonanan, Sajad J. Khazal, David McCall, Branko Cuglievan, Ali Haider Ahmad, Basirat Shoberu, Jeffrey Miller, Priti Tewari, Demetrios Petropoulos, Jonathan B. Gill, Fiorela N. Hernandez Tejada & Kris M. Mahadeo

  2. Department of Pediatrics, Blood and Marrow Transplantation Program, Keck School of Medicine, University of Southern California, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Hisham Abdel-Azim & Neena Kapoor

  3. UOC SIT–TMO AORN Santobono–Pausilipon, Napoli, Italy

    Francesco Paolo Tambaro

  4. Department of Pediatrics, Division of Critical Care, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, USA

    Courtney M. Rowan

  5. Department of Critical Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Cristina Gutierrez

  6. Department of Pediatrics Research, Center for Energy Balance in Cancer Prevention and Survivorship, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Keri Schadler

  7. Department of Pediatrics Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shulin Li

  8. Pediatric Intensive Care Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Matteo Di Nardo

  9. Division of Diagnostic Imaging, Neuroradiology Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Linda Chi

  10. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Alison M. Gulbis & Maria E. Mireles

  11. Department of Pediatrics, Division of Critical Care, St Jude Children’s Research Hospital, Memphis, TN, USA

    Jennifer McArthur

  12. Department of Pediatrics, Division of Critical Care, Medical College of Wisconsin, Milwaukee, WI, USA

    Jennifer McArthur

  13. Department of Anesthesia and Critical Care, University of Pennsylvania Perelman School of Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Julie C. Fitzgerald

  14. Pediatric Hematology-Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA

    Christine N. Duncan & Leslie E. Lehmann

  15. Department of Pediatrics, University of Washington School of Medicine, Division of Nephrology, Seattle Childrens and the Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Sangeeta Hingorani

  16. Renal Section, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA

    Joseph R. Angelo

  17. Department of Pediatrics, Division of Pediatric Nephrology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX, USA

    Rita D. Swinford

  18. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA

    Marie E. Steiner

  19. Department of Pediatrics, Division of Transplant and Cellular Therapy, Duke Children’s Hospital, Duke University, Durham, NC, USA

    Paul L. Martin

  20. Division of Hematology, Oncology, Bone Marrow Transplant and Infectious Diseases, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, USA

    Jeffery Auletta

  21. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Sung Won Choi

  22. Division of Pediatric Hematology/Oncology/Blood and Marrow Transplantation, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, USA

    Rajinder Bajwa

  23. Department of Infectious Disease, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Natalie Dailey Garnes

  24. Department of Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Partow Kebriaei, Katayoun Rezvani & Elizabeth J. Shpall

  25. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    William G. Wierda

  26. Department of Lymphoma and Myeloma, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Sattva S. Neelapu

  27. Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, University of Regensburg, Regensburg, Germany

    Selim Corbacioglu

Authors
  1. Dristhi Ragoonanan
    View author publications

    Search author on:PubMed Google Scholar

  2. Sajad J. Khazal
    View author publications

    Search author on:PubMed Google Scholar

  3. Hisham Abdel-Azim
    View author publications

    Search author on:PubMed Google Scholar

  4. David McCall
    View author publications

    Search author on:PubMed Google Scholar

  5. Branko Cuglievan
    View author publications

    Search author on:PubMed Google Scholar

  6. Francesco Paolo Tambaro
    View author publications

    Search author on:PubMed Google Scholar

  7. Ali Haider Ahmad
    View author publications

    Search author on:PubMed Google Scholar

  8. Courtney M. Rowan
    View author publications

    Search author on:PubMed Google Scholar

  9. Cristina Gutierrez
    View author publications

    Search author on:PubMed Google Scholar

  10. Keri Schadler
    View author publications

    Search author on:PubMed Google Scholar

  11. Shulin Li
    View author publications

    Search author on:PubMed Google Scholar

  12. Matteo Di Nardo
    View author publications

    Search author on:PubMed Google Scholar

  13. Linda Chi
    View author publications

    Search author on:PubMed Google Scholar

  14. Alison M. Gulbis
    View author publications

    Search author on:PubMed Google Scholar

  15. Basirat Shoberu
    View author publications

    Search author on:PubMed Google Scholar

  16. Maria E. Mireles
    View author publications

    Search author on:PubMed Google Scholar

  17. Jennifer McArthur
    View author publications

    Search author on:PubMed Google Scholar

  18. Neena Kapoor
    View author publications

    Search author on:PubMed Google Scholar

  19. Jeffrey Miller
    View author publications

    Search author on:PubMed Google Scholar

  20. Julie C. Fitzgerald
    View author publications

    Search author on:PubMed Google Scholar

  21. Priti Tewari
    View author publications

    Search author on:PubMed Google Scholar

  22. Demetrios Petropoulos
    View author publications

    Search author on:PubMed Google Scholar

  23. Jonathan B. Gill
    View author publications

    Search author on:PubMed Google Scholar

  24. Christine N. Duncan
    View author publications

    Search author on:PubMed Google Scholar

  25. Leslie E. Lehmann
    View author publications

    Search author on:PubMed Google Scholar

  26. Sangeeta Hingorani
    View author publications

    Search author on:PubMed Google Scholar

  27. Joseph R. Angelo
    View author publications

    Search author on:PubMed Google Scholar

  28. Rita D. Swinford
    View author publications

    Search author on:PubMed Google Scholar

  29. Marie E. Steiner
    View author publications

    Search author on:PubMed Google Scholar

  30. Fiorela N. Hernandez Tejada
    View author publications

    Search author on:PubMed Google Scholar

  31. Paul L. Martin
    View author publications

    Search author on:PubMed Google Scholar

  32. Jeffery Auletta
    View author publications

    Search author on:PubMed Google Scholar

  33. Sung Won Choi
    View author publications

    Search author on:PubMed Google Scholar

  34. Rajinder Bajwa
    View author publications

    Search author on:PubMed Google Scholar

  35. Natalie Dailey Garnes
    View author publications

    Search author on:PubMed Google Scholar

  36. Partow Kebriaei
    View author publications

    Search author on:PubMed Google Scholar

  37. Katayoun Rezvani
    View author publications

    Search author on:PubMed Google Scholar

  38. William G. Wierda
    View author publications

    Search author on:PubMed Google Scholar

  39. Sattva S. Neelapu
    View author publications

    Search author on:PubMed Google Scholar

  40. Elizabeth J. Shpall
    View author publications

    Search author on:PubMed Google Scholar

  41. Selim Corbacioglu
    View author publications

    Search author on:PubMed Google Scholar

  42. Kris M. Mahadeo
    View author publications

    Search author on:PubMed Google Scholar

Contributions

D.R., S.J.K.,H.A., D.McC., A.H.A., B.C., C.G., L.C., B.S., R.D.S., E.J.S. and K.M.M. wrote the manuscript. All authors made meaningful contributions to and reviewed the manuscript.

Corresponding author

Correspondence to Dristhi Ragoonanan.

Ethics declarations

Competing interests

C.G. has served on the advisory board for Janssen and Legend Biotech. A relative of J.B.G. is a consultant to Acceleron and Celgene. K.R. and E.J.S. have a licence agreement with Takeda. E.J.S. has served on the advisory boards of Adaptimmune, Axio, Bayer, Celgene, Magenta, Mesoblast and Novartis. K.M.M. serves as a site investigator for, receives research funding from and has served as a medical consultant for Atara Biotherapeutics, and has received research and medical education funds from and served as a medical consultant for Jazz Pharmaceuticals. All other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Clinical Oncology thanks B. Geoerger and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Foundation for the Accreditation of Cellular Therapy: http://www.factwebsite.org

US NIH ClinicalTrials.gov database: https://www.clinicaltrials.gov

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ragoonanan, D., Khazal, S.J., Abdel-Azim, H. et al. Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer. Nat Rev Clin Oncol 18, 435–453 (2021). https://doi.org/10.1038/s41571-021-00474-4

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41571-021-00474-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer