Skip to main content
SpringerLink
Log in

Immune-Related Adverse Toxicities and Clinical Management

  • Chapter
  • First Online:
Melanoma

  • 1642 Accesses

Abstract

Checkpoint inhibitors are effective in various cancer entities. However, especially in the combination of anti-CTLA-4 antibodies with anti-PD-1 antibodies they induce considerable toxicity with around 56% grade 3/4 adverse events. These side effects may involve skin, the gastrointestinal tract, liver, the endocrine system, and other organ systems. In combination therapy in about a third of patients more than one organ system is affected. Since life-threatening and fatal immune-related adverse events (irAE) have been reported, adequate diagnosis and management is essential. Besides well-known irAE, checkpoint inhibitors can induce a plethora of side effects including neurologic and cardiotoxic events. Prompt diagnosis and management can reduce morbidity and mortality due to these autoimmune side effects.

This chapter gives an overview on how to approach side effects diagnostically and therapeutically in patients under checkpoint inhibitor therapy. It includes information on patient education, important differentials, and algorithms for therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 139.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:190–9. https://doi.org/10.1016/j.ejca.2016.02.025.

    Article  PubMed  CAS  Google Scholar 

  2. Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network. PLoS One. 2013;8:e53745. https://doi.org/10.1371/journal.pone.0053745.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I, et al. Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer. 2016;60:210–25. https://doi.org/10.1016/j.ejca.2016.02.024.

    Article  PubMed  CAS  Google Scholar 

  4. Eggermont AMM, Chiarion-Sileni V, Grob J-J, Dummer R, Wolchok JD, Schmidt H, et al. Prolonged survival in stage III melanoma with Ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55. https://doi.org/10.1056/NEJMoa1611299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Gaudy-Marqueste C, Monestier S, Franques J, Cantais E, Richard M-A, Grob J-J. A severe case of ipilimumab-induced guillain-barré syndrome revealed by an occlusive enteric neuropathy: a differential diagnosis for ipilimumab-induced colitis. J Immunother. 2013;36:77–8. https://doi.org/10.1097/CJI.0b013e31827807dd.

    Article  PubMed  Google Scholar 

  6. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23. https://doi.org/10.1056/NEJMoa1003466.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. https://doi.org/10.1056/NEJMoa1200694.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54. https://doi.org/10.1056/NEJMoa1200690.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in untreated melanoma. N Engl J Med. 2015;373:23–34. https://doi.org/10.1056/NEJMoa1504030.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64. https://doi.org/10.1016/S1470-2045(09)70334-1.

    Article  PubMed  CAS  Google Scholar 

  11. Bertrand A, Kostine M, Barnetche T, Truchetet M-E, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015;13:211. https://doi.org/10.1186/s12916-015-0455-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122–33. https://doi.org/10.1056/NEJMoa1302369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2014;372:320–30. https://doi.org/10.1056/NEJMoa1412082.

    Article  PubMed  Google Scholar 

  14. Hamid O, Robert C, Daud A, Hodi FS, Hwu W-J, Kefford R, et al. Safety and tumor responses with Lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013;369:134–44. https://doi.org/10.1056/NEJMoa1305133.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372:2521–32. https://doi.org/10.1056/NEJMoa1503093.

    Article  CAS  PubMed  Google Scholar 

  16. Bilen MA, Subudhi SK, Gao J, Tannir NM, Tu S-M, Sharma P. Acute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody. J Immunother Cancer. 2016;4:36. https://doi.org/10.1186/s40425-016-0139-8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Dasanu CA, Jen T, Skulski R. Late-onset pericardial tamponade, bilateral pleural effusions and recurrent immune monoarthritis induced by ipilimumab use for metastatic melanoma. J Oncol Pharm Pract. 2017;23(3):231–4. https://doi.org/10.1177/1078155216635853.

    Article  PubMed  Google Scholar 

  18. Kaufman HL, Russell J, Hamid O, Bhatia S, Terheyden P, D’Angelo SP, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17:1374–85. https://doi.org/10.1016/S1470-2045(16)30364-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Weber JS, Dummer R, de Pril V, Lebbé C, Hodi FS, MDX010-20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119:1675–82. https://doi.org/10.1002/cncr.27969.

    Article  PubMed  CAS  Google Scholar 

  20. Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020–30. https://doi.org/10.1200/JCO.2013.53.0105.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gutzmer R, Koop A, Meier F, Hassel JC, Terheyden P, Zimmer L, et al. Programmed cell death protein-1 (PD-1) inhibitor therapy in patients with advanced melanoma and preexisting autoimmunity or ipilimumab-triggered autoimmunity. Eur J Cancer. 2017;75:24–32. https://doi.org/10.1016/j.ejca.2016.12.038.

    Article  PubMed  CAS  Google Scholar 

  22. Heinzerling L, Ott PA, Hodi FS, Husain AN, Tajmir-Riahi A, Tawbi H, et al. Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. 2016;4:50. https://doi.org/10.1186/s40425-016-0152-y.

    Article  PubMed  PubMed Central  Google Scholar 

  23. weber. Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): a pooled analysis. ASCO Annual Meeting | Abstracts | Meeting Library; 2015.

    Google Scholar 

  24. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48. https://doi.org/10.1016/j.ejca.2015.11.016.

    Article  PubMed  CAS  Google Scholar 

  25. Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691–7. https://doi.org/10.1200/JCO.2012.41.6750.

    Article  CAS  PubMed  Google Scholar 

  26. Maker AV, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, et al. Intrapatient dose escalation of anti-CTLA-4 antibody in patients with metastatic melanoma. J Immunother. 2006;29:455–63. https://doi.org/10.1097/01.cji.0000208259.73167.58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grünwald V, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev. 2016;45:7–18. https://doi.org/10.1016/j.ctrv.2016.02.003.

    Article  PubMed  CAS  Google Scholar 

  28. Spain L, Larkin J. Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma. Expert Opin Biol Ther. 2016;16:389–96. https://doi.org/10.1517/14712598.2016.1141195.

    Article  PubMed  CAS  Google Scholar 

  29. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol Off J Eur Soc Med Oncol. 2016;27:559–74. https://doi.org/10.1093/annonc/mdv623.

    Article  CAS  Google Scholar 

  30. Lankes K, Hundorfean G, Harrer T, Pommer AJ, Agaimy A, Angelovska I, et al. Anti-TNF-refractory colitis after checkpoint inhibitor therapy: possible role of CMV-mediated immunopathogenesis. Oncoimmunology. 2016;5:e1128611. https://doi.org/10.1080/2162402X.2015.1128611.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Cheng R, Cooper A, Kench J, Watson G, Bye W, McNeil C, et al. Ipilimumab-induced toxicities and the gastroenterologist. J Gastroenterol Hepatol. 2015;30:657–66. https://doi.org/10.1111/jgh.12888.

    Article  PubMed  CAS  Google Scholar 

  32. Horvat TZ, Adel NG, Dang T-O, Momtaz P, Postow MA, Callahan MK, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33:3193–8. https://doi.org/10.1200/JCO.2015.60.8448.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84. https://doi.org/10.1016/S1470-2045(15)70076-8.

    Article  PubMed  CAS  Google Scholar 

  34. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28. https://doi.org/10.1056/NEJMoa1501824.

    Article  PubMed  Google Scholar 

  35. Gupta A, De Felice KM, Loftus EV, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther. 2015;42:406–17. https://doi.org/10.1111/apt.13281.

    Article  PubMed  CAS  Google Scholar 

  36. Hundorfean G, Atreya R, Agaimy A, Heinzerling L, Kämpgen E, Schuler G, et al. Fluorescein-guided confocal laser endomicroscopy for the detection of ipilimumab-induced colitis. Endoscopy. 2012;44:E78–9. https://doi.org/10.1055/s-0031-1291603.

    Article  PubMed  Google Scholar 

  37. Uslu U, Agaimy A, Hundorfean G, Harrer T, Schuler G, Heinzerling L. Autoimmune colitis and subsequent CMV-induced hepatitis after treatment with Ipilimumab. J Immunother. 2015;38(5):212. https://doi.org/10.1097/CJI.0000000000000081.

    Article  PubMed  Google Scholar 

  38. Freie Vorträge. JDDG J Der Dtsch Dermatologischen Gesellschaft. 2015;13:1–19. https://doi.org/10.1111/ddg.12783.

  39. Gaudy C, Clévy C, Monestier S, Dubois N, Préau Y, Mallet S, et al. Anti-PD1 pembrolizumab can induce exceptional fulminant type 1 diabetes. Diabetes Care. 2015;38:e182–3. https://doi.org/10.2337/dc15-1331.

    Article  PubMed  Google Scholar 

  40. Belum VR, Benhuri B, Postow MA, Hellmann MD, Lesokhin AM, Segal NH, et al. Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor. Eur J Cancer. 2016;60:12–25. https://doi.org/10.1016/j.ejca.2016.02.010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Sibaud V, Meyer N, Lamant L, Vigarios E, Mazieres J, Delord JP. Dermatologic complications of anti-PD-1/PD-L1 immune checkpoint antibodies. Curr Opin Oncol. 2016;28:254–63. https://doi.org/10.1097/CCO.0000000000000290.

    Article  PubMed  CAS  Google Scholar 

  42. Carlos G, Anforth R, Chou S, Clements A, Fernandez-Peñas P. A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab. Melanoma Res. 2015;25:265–8. https://doi.org/10.1097/CMR.0000000000000155.

    Article  PubMed  Google Scholar 

  43. Naidoo J, Schindler K, Querfeld C, Busam K, Cunningham J, Page DB, et al. Autoimmune bullous skin disorders with immune checkpoint inhibitors targeting PD-1 and PD-L1. Cancer Immunol Res. 2016;4:383–9. https://doi.org/10.1158/2326-6066.CIR-15-0123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Jour G, Glitza IC, Ellis RM, Torres-Cabala CA, Tetzlaff MT, Li JY, et al. Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions. J Cutan Pathol. 2016;43:688–96. https://doi.org/10.1111/cup.12717.

    Article  PubMed  Google Scholar 

  45. Goldinger SM, Stieger P, Meier B, Micaletto S, Contassot E, French LE, et al. Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy. Clin Cancer Res. 2016;22:4023–9. https://doi.org/10.1158/1078-0432.CCR-15-2872.

    Article  PubMed  CAS  Google Scholar 

  46. Hwang SJE, Carlos G, Wakade D, Byth K, Kong BY, Chou S, et al. Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: a single-institution cohort. J Am Acad Dermatol. 2016;74:455–61. https://doi.org/10.1016/j.jaad.2015.10.029.

    Article  PubMed  Google Scholar 

  47. Mutgi KAJ, Milhem M, Swick BL, Liu V. Pityriasis lichenoides chronica–like drug eruption developing during pembrolizumab treatment for metastatic melanoma. JAAD Case Reports. 2016;2:343–5. https://doi.org/10.1016/j.jdcr.2016.06.012.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Uemura M, Faisal F, Haymaker C, McQuail N, Sirmans E, Hudgens CW, et al. A case report of Grover’s disease from immunotherapy-a skin toxicity induced by inhibition of CTLA-4 but not PD-1. J Immunother Cancer. 2016;4:55. https://doi.org/10.1186/s40425-016-0157-6.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Cappelli LC, Gutierrez AK, Baer AN, Albayda J, Manno RL, Haque U, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis. 2016:1–8. https://doi.org/10.1136/annrheumdis-2016-209595.

  50. Ryder M, Callahan M, Postow MA, Wolchok J, Fagin JA. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr Relat Cancer. 2014;21:371–81. https://doi.org/10.1530/ERC-13-0499.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26:2375–91. https://doi.org/10.1093/annonc/mdv383.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. de Filette J, Jansen Y, Schreuer M, Everaert H, Velkeniers B, Neyns B, et al. Incidence of thyroid-related adverse events in melanoma patients treated with pembrolizumab. J Clin Endocrinol Metab. 2016;101(11):4431–9. https://doi.org/10.1210/jc.2016-2300.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Orlov S, Salari F, Kashat L, Walfish PG. Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies. J Clin Endocrinol Metab. 2015;100:1738–41. https://doi.org/10.1210/jc.2014-4560.

    Article  PubMed  CAS  Google Scholar 

  54. Verma I, Modi A, Tripathi H, Agrawal A. Nivolumab causing painless thyroiditis in a patient with adenocarcinoma of the lung. BMJ Case Rep. 2016:bcr2015213692. https://doi.org/10.1136/bcr-2015-213692.

  55. Okano Y, Satoh T, Horiguchi K, Toyoda M, Osaki A, Matsumoto S, et al. Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma. Endocr J. 2016;63:905–12. https://doi.org/10.1507/endocrj.EJ16-0161.

    Article  PubMed  Google Scholar 

  56. Ishikawa M, Oashi K. Case of hypophysitis caused by nivolumab. J Dermatol. 2016;44(1):109–10. https://doi.org/10.1111/1346-8138.13437.

    Article  PubMed  Google Scholar 

  57. Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257–65. https://doi.org/10.1016/S1470-2045(15)70054-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. O’Kane GM, Lyons TG, Colleran GC, Ahmad MW, Alken S, Kavanagh EC, et al. Late-onset paraplegia after complete response to two cycles of Ipilimumab for metastatic melanoma. Oncol Res Treat. 2014;37:757–60. https://doi.org/10.1159/000368316.

    Article  PubMed  CAS  Google Scholar 

  59. Tarhini A. Immune-mediated adverse events associated with Ipilimumab CTLA-4 blockade therapy: the underlying mechanisms and clinical management. Scientifica (Cairo). 2013;2013:1–19. https://doi.org/10.1155/2013/857519.

    Article  CAS  Google Scholar 

  60. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30. https://doi.org/10.1097/CJI.0b013e318156e47e.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S. Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology. 2014;16:589–93. https://doi.org/10.1093/neuonc/nou001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with Ipilimumab: a report of 2 cases. J Immunother. 2015;38:77–9. https://doi.org/10.1097/CJI.0000000000000070.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Johnson DB, Saranga-Perry V, Lavin PJM, Bryan Burnette W, Clark SW, Uskavitch DR, et al. Myasthenia gravis induced by ipilimumab in patients with metastatic melanoma. J Clin Oncol. 2015;33:e122–4. https://doi.org/10.1200/JCO.2013.51.1683.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Abdallah A-O, Herlopian A, Ravilla R, Bansal M, Chandra-Reddy S, Mahmoud F, et al. Ipilimumab-induced necrotic myelopathy in a patient with metastatic melanoma: a case report and review of literature. J Oncol Pharm Pract. 2016;22:537–42. https://doi.org/10.1177/1078155215572932.

    Article  PubMed  CAS  Google Scholar 

  65. Murphy KP, Kennedy MP, Barry JE, O’Regan KN, Power DG. New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing CTLA4 monoclonal antibody treatment. Oncol Res Treat. 2014;37:351–3. https://doi.org/10.1159/000362614.

    Article  PubMed  CAS  Google Scholar 

  66. Maurice C, Schneider R, Kiehl T-R, Bavi P, Roehrl MHA, Mason WP, et al. Subacute CNS demyelination after treatment with nivolumab for melanoma. Cancer Immunol Res. 2015;3:1299–302. https://doi.org/10.1158/2326-6066.CIR-15-0141.

    Article  PubMed  CAS  Google Scholar 

  67. Mandel JJ, Olar A, Aldape KD, Tremont-Lukats IW. Lambrolizumab induced central nervous system (CNS) toxicity. J Neurol Sci. 2014;344:229–31. https://doi.org/10.1016/j.jns.2014.06.023.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Vogel WV, Guislain A, Kvistborg P, Schumacher TNM, Haanen JBAG, Blank CU. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J Clin Oncol. 2012;30:e7–10. https://doi.org/10.1200/JCO.2011.37.9693.

    Article  PubMed  Google Scholar 

  69. Eckert A, Schoeffler A, Dalle S, Phan A, Kiakouama L, Thomas L. Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient. Dermatology. 2009;218:69–70. https://doi.org/10.1159/000161122.

    Article  PubMed  CAS  Google Scholar 

  70. Wilgenhof S, Morlion V, Seghers AC, Du Four S, Vanderlinden E, Hanon S, et al. Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor. Anticancer Res. 2012;32:1355–9.

    PubMed  CAS  Google Scholar 

  71. Barjaktarevic IZ, Qadir N, Suri A, Santamauro JT, Stover D. Organizing pneumonia as a side effect of Ipilimumab treatment of melanoma. Chest. 2013;143:858–61. https://doi.org/10.1378/chest.12-1467.

    Article  PubMed  Google Scholar 

  72. Berthod G, Lazor R, Letovanec I, Romano E, Noirez L, Stalder JM, et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30:e156–9. https://doi.org/10.1200/JCO.2011.39.3298.

    Article  PubMed  Google Scholar 

  73. Nishino M, Chambers ES, Chong CR, Ramaiya NH, Gray SW, Marcoux JP, et al. Anti-PD-1 inhibitor-related pneumonitis in non-small cell lung cancer. Cancer Immunol Res. 2016;4:289–93. https://doi.org/10.1158/2326-6066.CIR-15-0267.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Steenbruggen TG, van den Heuvel MM, Blank CU, van Dieren JM, Haanen JBAG, Kok M. No hair loss, but colitis or pneumonitis: unique side effects of immune checkpoint inhibitors for cancer. Ned Tijdschr Geneeskd. 2016;160:A9873.

    PubMed  CAS  Google Scholar 

  75. Sano T, Uhara H, Mikoshiba Y, Kobayashi A, Uchiyama R, Tateishi K, et al. Nivolumab-induced organizing pneumonia in a melanoma patient. Jpn J Clin Oncol. 2016;46:270–2. https://doi.org/10.1093/jjco/hyv199.

    Article  PubMed  Google Scholar 

  76. Nishino M, Sholl LM, Hatabu H, Ramaiya NH, Hodi FS. Anti–PD-1–related pneumonitis during cancer immunotherapy. N Engl J Med. 2015;373:288–90. https://doi.org/10.1056/NEJMc1505197.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Voskens C, Cavallaro A, Erdmann M, Dippel O, Kaempgen E, Schuler G, et al. Anti-cytotoxic T-cell lymphocyte antigen-4-induced regression of spinal cord metastases in association with renal failure, atypical pneumonia, vision loss, and hearing loss. J Clin Oncol. 2012;30:e356–7. https://doi.org/10.1200/JCO.2011.41.4359.

    Article  PubMed  Google Scholar 

  78. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody–induced lupus nephritis. N Engl J Med. 2009;361(2):211. https://doi.org/10.1056/NEJMc0904283.

    Article  PubMed  CAS  Google Scholar 

  79. 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;375:1749–55. https://doi.org/10.1056/NEJMoa1609214.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, Kirchberger MC. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018. https://doi.org/10.1016/j.jacc.2018.02.037.

  81. Tajmir-Riahi A, Bergmann T, Schmid M, Agaimy A, Schuler G, Heinzerling L. Life-threatening Autoimmune Cardiomyopathy Reproducibly Induced in a Patient by Checkpoint Inhibitor Therapy. J Immunother. 2018;41(1):35–8. https://doi.org/10.1097/CJI.0000000000000190.

    Article  CAS  PubMed  Google Scholar 

  82. Delyon J, Mateus C, Lambert T. Hemophilia a induced by ipilimumab. N Engl J Med. 2011;365:1747–8. https://doi.org/10.1056/NEJMc1110923.

    Article  PubMed  CAS  Google Scholar 

  83. Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen Y-B, et al. Disabling immune tolerance by programmed Death-1 blockade with Pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31:4199–206. https://doi.org/10.1200/JCO.2012.48.3685.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. du Rusquec P, Saint-Jean M, Brocard A, Peuvrel L, Khammari A, Quéreux G, et al. Ipilimumab-induced autoimmune pancytopenia in a case of metastatic melanoma. J Immunother. 2014;37:348–50. https://doi.org/10.1097/CJI.0000000000000041.

    Article  PubMed  Google Scholar 

  85. Freeman-Keller M, Kim Y, Cronin H, Richards A, Gibney G, Weber JS. Nivolumab in resected and Unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94. https://doi.org/10.1158/1078-0432.CCR-15-1136.

    Article  PubMed  CAS  Google Scholar 

  86. Hua C, Boussemart L, Mateus C, Routier E, Boutros C, Cazenave H, et al. Association of vitiligo with tumor response in patients with metastatic melanoma treated with pembrolizumab. JAMA Dermatol. 2016;152:45. https://doi.org/10.1001/jamadermatol.2015.2707.

    Article  PubMed  Google Scholar 

  87. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–84. https://doi.org/10.1126/science.aad1329.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Dermatology, University Hospital Erlangen, Erlangen, Germany

    Michael Constantin Kirchberger M.D. & Lucie Heinzerling M.D., M.P.H., Ph.D.

Authors
  1. Michael Constantin Kirchberger M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lucie Heinzerling M.D., M.P.H., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lucie Heinzerling M.D., M.P.H., Ph.D. .

Editor information

Editors and Affiliations

  1. Louisiana State University, New Orleans, Louisiana, USA

    Adam I. Riker

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Kirchberger, M.C., Heinzerling, L. (2018). Immune-Related Adverse Toxicities and Clinical Management. In: Riker, A. (eds) Melanoma. Springer, Cham. https://doi.org/10.1007/978-3-319-78310-9_36

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-78310-9_36

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-78309-3

  • Online ISBN: 978-3-319-78310-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation