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Complications of Emerging Oncology Therapies Requiring Treatment in the Pediatric Intensive Care Unit

  • Intensive Care Medicine (E Cheung and T Connors, Section Editors)
  • Published:
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Abstract

Purpose of the Review

The development of immunotherapies has resulted in significant improvements in survival for children with cancer and congenital blood disorders. The purpose of this review is to guide the recognition and treatment of significant side of effects three increasingly used immunotherapies—T cell-mediated therapies, immune checkpoint inhibitors, and anti-GD2 antibodies.

Recent Findings

Cytokine release syndrome (CRS) is a cytokine-induced systemic inflammatory state secondary to chimeric antigen receptor T cells (CAR–T cells), a therapy used for relapsed and refractory leukemia. CRS can range from fever and mild flu-like symptoms to cardiopulmonary collapse and neurologic sequelae including encephalitis, seizures, and cerebral edema. Immune check point inhibitors work to redirect the T cell response towards cancer cells and have shown a survival advantage for patients with advanced melanoma. These agents also activate an immune response which can mimic autoimmune disease and cause organ failure and neurologic complications like Guillain–Barre and posterior reversible encephalopathy. Children with high-risk and chemotherapy-resistant neuroblastoma have seen improved survival with the use of anti-GD2, an immunotherapy directed at the highly abundant and conserved GD2 antigen expressed on neuroblastoma cells. Severe pain is the consistently reported side effect of anti-GD2, occurring in an estimated 50% of patients and often requiring narcotic and sedative agents for the duration of therapy.

Summary

Immunotherapy has become critical to the treatment of previously irremediable diseases like relapsed leukemia and refractory neuroblastoma. The survival advantage offered by these therapies requires an understanding of diagnosis and treatment of their life-threatening toxicities.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Moricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dordelmann M, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008;111(9):4477–89. https://doi.org/10.1182/blood-2007-09-112920.

    Article  PubMed  Google Scholar 

  2. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730–41. https://doi.org/10.1056/NEJMoa0900386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bokkerink JP, Bruin MC, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). Lancet Oncol. 2009;10(10):957–66. https://doi.org/10.1016/s1470-2045(09)70228-1.

    Article  CAS  PubMed  Google Scholar 

  4. Vrooman LM, Stevenson KE, Supko JG, O’Brien J, Dahlberg SE, Asselin BL, et al. Postinduction dexamethasone and individualized dosing of Escherichia coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J clin oncol: Off J Am Soc Clin Oncol. 2013;31(9):1202–10. https://doi.org/10.1200/jco.2012.43.2070.

    Article  CAS  Google Scholar 

  5. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J clin oncol: Off J Am Soc Clin Oncol. 2009;27(7):1007–13. https://doi.org/10.1200/jco.2007.13.8925.

    Article  CAS  Google Scholar 

  6. Whittle SB, Smith V, Doherty E, Zhao S, McCarty S, Zage PE. Overview and recent advances in the treatment of neuroblastoma. Expert Rev Anticancer Ther. 2017;17(4):369–86. https://doi.org/10.1080/14737140.2017.1285230.

    Article  CAS  PubMed  Google Scholar 

  7. Jaffe N. Osteosarcoma: review of the past, impact on the future. The American experience. In: Jaffe N, Bruland OS, Bielack S, editors. Pediatric and adolescent osteosarcoma. Boston, MA: Springer US; 2010. p. 239–62.

    Chapter  Google Scholar 

  8. Giulino-Roth L, Ricafort R, Kernan NA, Small TN, Trippett TM, Steinherz PG, et al. Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr Blood Cancer. 2013;60(12):2018–24. https://doi.org/10.1002/pbc.24722.

    Article  PubMed  Google Scholar 

  9. Mehta PA, Davies SM, Leemhuis T, Myers K, Kernan NA, Prockop SE, et al. Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood. 2017;129(16):2308–15. https://doi.org/10.1182/blood-2016-09-743112.

    Article  CAS  PubMed  Google Scholar 

  10. Tomizawa D, Tanaka S, Kondo T, Hashii Y, Arai Y, Kudo K et al. Allogeneic hematopoietic stem cell transplantation for adolescents and young adults with acute myeloid leukemia. Biol blood marrow trans: J AmSoc Blood Marrow Trans 2017. doi:https://doi.org/10.1016/j.bbmt.2017.05.009.

  11. Vrooman LM, Millard HR, Brazauskas R, Majhail NS, Battiwalla M, Flowers ME, et al. Survival and late effects after allogeneic hematopoietic cell transplantation for hematologic malignancy at less than three years of age. Biol Blood Marrow Trans: J Am Soc Blood and Marrow Trans. 2017;23(8):1327–34. https://doi.org/10.1016/j.bbmt.2017.04.017.

    Article  Google Scholar 

  12. Tamburro RF, Barfield RC, Shaffer ML, Rajasekaran S, Woodard P, Morrison RR, et al. Changes in outcomes (1996–2004) for pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation. Pediatr Crit Care Med:J Soc Crit Care Med World Fed Pediatr Int Crit Care Soc. 2008;9(3):270–7. https://doi.org/10.1097/PCC.0b013e31816c7260.

    Article  Google Scholar 

  13. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18. https://doi.org/10.1056/NEJMoa1215134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mackall CL, Merchant MS, Fry TJ. Immune-based therapies for childhood cancer. Nat Rev Clin Oncol. 2014;11(12):693–703. https://doi.org/10.1038/nrclinonc.2014.177.

    Article  CAS  PubMed  Google Scholar 

  15. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83–103. https://doi.org/10.3322/caac.21219.

    Article  PubMed  Google Scholar 

  16. Bhojwani D, Pui CH. Relapsed childhood acute lymphoblastic leukaemia. Lancet Oncol. 2013;14(6):e205–17. https://doi.org/10.1016/S1470-2045(12)70580-6.

    Article  PubMed  Google Scholar 

  17. Hunger SP, Lu X, Devidas M, Camitta BM, Gaynon PS, Winick NJ, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(14):1663–9. https://doi.org/10.1200/JCO.2011.37.8018.

    Article  Google Scholar 

  18. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. https://doi.org/10.1056/NEJMoa1103849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, 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. 2010;116(20):4099–102. https://doi.org/10.1182/blood-2010-04-281931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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(16):1507–17. https://doi.org/10.1056/NEJMoa1407222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–22. https://doi.org/10.1097/PPO.0000000000000035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–79. https://doi.org/10.1158/2159-8290.CD-16-0040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. •• Fitzgerald JC, Weiss SL, Maude SL, Barrett DM, Lacey SF, Melenhorst JJ, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med. 2017;45(2):e124–e31. https://doi.org/10.1097/CCM.0000000000002053. This is the largest cohort of pediatric patients having developed cytokine release syndrome after CAR–T cell treatment for ALL.

    Article  CAS  PubMed  Google Scholar 

  24. Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood. 2015;125(26):4017–23. https://doi.org/10.1182/blood-2014-12-580068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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(2):188–95. https://doi.org/10.1182/blood-2014-05-552729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yokota S, Miyamae T, Imagawa T, Iwata N, Katakura S, Mori M, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum. 2005;52(3):818–25. https://doi.org/10.1002/art.20944.

    Article  CAS  PubMed  Google Scholar 

  27. De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95. https://doi.org/10.1056/NEJMoa1112802.

    Article  PubMed  Google Scholar 

  28. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127(26):3321–30. https://doi.org/10.1182/blood-2016-04-703751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Nishimoto N, Terao K, Mima T, Nakahara H, Takagi N, Kakehi T. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959–64. https://doi.org/10.1182/blood-2008-05-155846.

    Article  CAS  PubMed  Google Scholar 

  30. Hu Y, Sun J, Wu Z, Yu J, Cui Q, Pu C, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol. 2016;9(1):70. https://doi.org/10.1186/s13045-016-0299-5.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mei H, Jiang H, Wu Y, Guo T, Xia L, Jin R et al. Neurological toxicities and coagulation disorders in the cytokine release syndrome during CAR-T therapy. Br J Haematol 2017. doi:https://doi.org/10.1111/bjh.14680.

  32. Diesendruck Y, Benhar I. Novel immune check point inhibiting antibodies in cancer therapy—opportunities and challenges. Drug Resist Updat. 2017;30:39–47. https://doi.org/10.1016/j.drup.2017.02.001.

    Article  PubMed  Google Scholar 

  33. Wang XY, Zuo D, Sarkar D, Fisher PB. Blockade of cytotoxic T-lymphocyte antigen-4 as a new therapeutic approach for advanced melanoma. Expert Opin Pharmacother. 2011;12(17):2695–706. https://doi.org/10.1517/14656566.2011.629187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tsiatas M, Mountzios G, Curigliano G. Future perspectives in cancer immunotherapy. Ann Transl Med. 2016;4(14):273. 10.21037/atm.2016.07.14.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Theeler BJ, Gilbert MR. Advances in the treatment of newly diagnosed glioblastoma. BMC Med. 2015;13:293. https://doi.org/10.1186/s12916-015-0536-8.

    Article  PubMed  PubMed Central  Google Scholar 

  36. •• Ring EK, Markert JM, Gillespie GY, Friedman GK. Checkpoint proteins in pediatric brain and extracranial solid tumors: opportunities for immunotherapy. Clin Cancer Res: Off J Am Assoc Cancer Res. 2017;23(2):342–50. https://doi.org/10.1158/1078-0432.CCR-16-1829. This is useful study addressing the use of checkpoint inhibitors on children with solid tumors.

    Article  CAS  Google Scholar 

  37. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55. https://doi.org/10.1056/NEJMoa1609214.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Wilgenhof S, Neyns B. Anti-CTLA-4 antibody-induced Guillain-Barre syndrome in a melanoma patient. Ann Oncol. 2011;22(4):991–3. https://doi.org/10.1093/annonc/mdr028.

    Article  CAS  PubMed  Google Scholar 

  39. Maur M, Tomasello C, Frassoldati A, Dieci MV, Barbieri E, Conte P. Posterior reversible encephalopathy syndrome during ipilimumab therapy for malignant melanoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(6):e76–8. https://doi.org/10.1200/JCO.2011.38.7886.

    Article  CAS  Google Scholar 

  40. Murakami N, Motwani S, Riella LV. Renal complications of immune checkpoint blockade. Curr Probl Cancer. 2017;41(2):100–10. https://doi.org/10.1016/j.currproblcancer.2016.12.004.

    Article  PubMed  Google Scholar 

  41. Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, et al. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res:Off J Am Assoc Cancer Res. 2016;22(24):6051–60. https://doi.org/10.1158/1078-0432.CCR-16-1320.

    Article  CAS  Google Scholar 

  42. Matthay KK. Neuroblastoma: biology and therapy. Oncology (Williston Park, NY). 1997;11(12):1857–66. discussion 69–72, 75

    CAS  Google Scholar 

  43. Matthay KK, Villablanca JG, Seeger RC, Stram DO, Harris RE, Ramsay NK, et al. Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid Children’s Cancer Group. N Engl J Med. 1999;341(16):1165–73. https://doi.org/10.1056/nejm199910143411601.

    Article  CAS  PubMed  Google Scholar 

  44. Cheung NK, Kushner BH, Yeh SD, Larson SM. 3F8 monoclonal antibody treatment of patients with stage 4 neuroblastoma: a phase II study. Int J Oncol. 1998;12(6):1299–306.

    CAS  PubMed  Google Scholar 

  45. Cheung NK, Lazarus H, Miraldi FD, Abramowsky CR, Kallick S, Saarinen UM, et al. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol: Off J Am Soc Clinical Oncol. 1987;5(9):1430–40. https://doi.org/10.1200/jco.1987.5.9.1430.

    Article  CAS  Google Scholar 

  46. Gilman AL, Ozkaynak MF, Matthay KK, Krailo M, Yu AL, Gan J, et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children’s Oncology Group. J clin oncol : off j Am Soc Clin Oncol. 2009;27(1):85–91. https://doi.org/10.1200/jco.2006.10.3564.

    Article  CAS  Google Scholar 

  47. Ozkaynak MF, Sondel PM, Krailo MD, Gan J, Javorsky B, Reisfeld RA, et al. Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: a Children’s Cancer Group Study. J Clin Oncol: Off J Am Soc Clin Oncol. 2000;18(24):4077–85. https://doi.org/10.1200/jco.2000.18.24.4077.

    Article  CAS  Google Scholar 

  48. Yu AL, Uttenreuther-Fischer MM, Huang CS, Tsui CC, Gillies SD, Reisfeld RA, et al. Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol: Off J Am Soc Clin Oncol. 1998;16(6):2169–80. https://doi.org/10.1200/jco.1998.16.6.2169.

    Article  CAS  Google Scholar 

  49. Cheung NK, Cheung IY, Kushner BH, Ostrovnaya I, Chamberlain E, Kramer K, et al. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(26):3264–70. https://doi.org/10.1200/jco.2011.41.3807.

    Article  CAS  Google Scholar 

  50. Navid F, Sondel PM, Barfield R, Shulkin BL, Kaufman RA, Allay JA, et al. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J Clin Oncol: Off J Am Soc Clin Oncol. 2014;32(14):1445–52. https://doi.org/10.1200/jco.2013.50.4423.

    Article  CAS  Google Scholar 

  51. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324–34. https://doi.org/10.1056/NEJMoa0911123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Anghelescu DL, Goldberg JL, Faughnan LG, Wu J, Mao S, Furman WL, et al. Comparison of pain outcomes between two anti-GD2 antibodies in patients with neuroblastoma. Pediatr Blood Cancer. 2015;62(2):224–8. https://doi.org/10.1002/pbc.25280.

    Article  CAS  PubMed  Google Scholar 

  53. Gorges M, West N, Deyell R, Winton P, Cheung W, Lauder G. Dexmedetomidine and hydromorphone: a novel pain management strategy for the oncology ward setting during anti-GD2 immunotherapy for high-risk neuroblastoma in children. Pediatr Blood Cancer. 2015;62(1):29–34. https://doi.org/10.1002/pbc.25197.

    Article  PubMed  Google Scholar 

  54. Kushner BH, Modak S, Basu EM, Roberts SS, Kramer K, Cheung NK. Posterior reversible encephalopathy syndrome in neuroblastoma patients receiving anti-GD2 3F8 monoclonal antibody. Cancer. 2013;119(15):2789–95. https://doi.org/10.1002/cncr.28137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schulz G, Cheresh DA, Varki NM, Yu A, Staffileno LK, Reisfeld RA. Detection of ganglioside GD2 in tumor tissues and sera of neuroblastoma patients. Cancer Res. 1984;44(12 Pt 1):5914–20.

    CAS  PubMed  Google Scholar 

  56. Kramer K, Gerald WL, Kushner BH, Larson SM, Hameed M, Cheung NK. Disialoganglioside G(D2) loss following monoclonal antibody therapy is rare in neuroblastoma. Clin Cancer Res: Off J Am Assoc Cancer Res. 1998;4(9):2135–9.

    CAS  Google Scholar 

  57. Wallace MS, Lee J, Sorkin L, Dunn JS, Yaksh T, Yu A. Intravenous lidocaine: effects on controlling pain after anti-GD2 antibody therapy in children with neuroblastoma—a report of a series. Anesth Analg. 1997;85(4):794–6.

    Article  CAS  PubMed  Google Scholar 

  58. Zama D, Morello W, Masetti R, Cordelli DM, Massaccesi E, Prete A, et al. Inflammatory disease of the central nervous system induced by anti-GD2 monoclonal antibody in a patient with high risk neuroblastoma. Pediatr Blood Cancer. 2014;61(8):1521–2. https://doi.org/10.1002/pbc.24982.

    Article  PubMed  Google Scholar 

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Funding

This study is supported by the MSK Cancer Center Support Grant/Core Grant (P30 CA008748).

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Correspondence to James S. Killinger.

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Killinger, J.S., Hurley, C., Wasserman, E. et al. Complications of Emerging Oncology Therapies Requiring Treatment in the Pediatric Intensive Care Unit. Curr Pediatr Rep 5, 220–227 (2017). https://doi.org/10.1007/s40124-017-0145-4

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