European Journal of Clinical Pharmacology

, Volume 69, Issue 10, pp 1739–1746 | Cite as

Incidence, clinical features and management of hypersensitivity reactions to chemotherapeutic drugs in children with cancer

  • Antonio Ruggiero
  • Silvia Triarico
  • Giovanna Trombatore
  • Andrea Battista
  • Fabiola Dell’Acqua
  • Carmelo Rizzari
  • Riccardo Riccardi
Review Article



Hypersensitivity reactions (HSRs) may occur in children with cancer during the use of almost all chemotherapeutic drugs. HSRs may also produce a negative impact on treatment intensity and, as a consequence, worsen patients’ outcome. The aim of this review is to summarize the incidence and the clinical features of HSRs occurring in children with cancer treated with chemotherapeutic drugs and their impact on treatment efficacy, in order to outline possible adequate prevention and management strategies.


Data were collected by searching for relevant studies about incidence, clinical features and management of hypersensitivity reactions that may occur with the use of chemotherapeutic agents in children aged 0–18 years, published from January 1976 to December 2012 in the PubMed database.


In children with cancer treated with chemotherapeutic drugs (especially platinum compounds, methotrexate, L-asparaginase), HSRs commonly present with mild/moderate to severe clinical patterns. Multiple factors appear to affect reaction rates, including route, rate of administration, previous exposure, drug form, presence of excipients. The occurrence of hypersensitivity to a chemotherapeutic agent can include the avoidance of re-exposure. For sensitized patients who have derived clinically meaningful benefit from a particular agent, however, continuation of treatment with the agent is desirable. Options may include attempting a trial of desensitization or treatment with a related compound.


With the increasing use of cancer chemotherapy agents, hypersensitivity reactions to antineoplastic drugs are commonly encountered. Clinicians must not underestimate the potential risk and occurrence of HSRs in the pediatric population. Knowledge of the different presentations of these reactions can help to develop strategies for the prevention and the management of HSRs in order to ensure treatment outcome, to improve the quality of patient care and to reduce healthcare costs.


Hypersensitivity reactions Chemotherapy Children Management Desensitization Allergy 


Conflicts of interest

The Authors declare no potential conflicts of interest or financial disclosures.


  1. 1.
    Pagani M (2010) The complex clinical picture of presumably allergic side effects to cytostatic drugs: symptoms, pathomechanism, reexposure, and desensitization. Med Clin North Am 94(4):835–852PubMedCrossRefGoogle Scholar
  2. 2.
    Davila Gonzales I, Salazar Saez R, Moreno Rodilla E et al (2000) Hypersensitivity reactions to chemotherapy drugs. Allergol Immunol Clin 15:161–181Google Scholar
  3. 3.
    Johansson S, Hourihane J, Bousquet J et al (2001) A revised nomenclature for allergy An EAACI position statement from the EAACI nomenclature task force. Allergy 56:813–824PubMedCrossRefGoogle Scholar
  4. 4.
    Aronson JK, Ferner RE (2005) Clarification of terminology in drug safety. Drug Saf 28(10):851–870PubMedCrossRefGoogle Scholar
  5. 5.
    Shepherd GM (2003) Hypersensitivity reactions to chemotherapeutic drugs. Clin Rev Allergy Immunol 24(3):253–262PubMedCrossRefGoogle Scholar
  6. 6.
    Lee C, Gianos M, Klaustermeyer WB (2009) Diagnosis and management of hypersensitivity reactions related to common cancer chemotherapy agents. Ann Allergy Asthma Immunol 102(3):179–187, quiz 187–9,222PubMedCrossRefGoogle Scholar
  7. 7.
    Genc DB, Canpolat C, Berrak SG (2012) Clinical features and management of carboplatin-related hypersensitivity reactions in pediatric low-grade glioma. Supp Care Cancer 20(2):385–393CrossRefGoogle Scholar
  8. 8.
    Yu DY, Dahl GV, Shames RS et al (2001) Weekly dosing of carboplatin increases risk of allergy in children. J Pediatr Hematol Oncol 23(6):349–352PubMedCrossRefGoogle Scholar
  9. 9.
    Zanotti KM, Rybicki LA, Kennedy AW et al (2001) Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 19(12):3126–3129PubMedGoogle Scholar
  10. 10.
    Markman M, Zanotti K, Peterson G et al (2003) Expanded experience with an intradermal skin test to predict for the presence or absence of carboplatin hypersensitivity. J Clin Oncol 21(24):4611–4614PubMedCrossRefGoogle Scholar
  11. 11.
    Lafay-Cousin L, Sung L, Carret AS et al (2008) Carboplatin hypersensitivity reaction in pediatric patients with low-grade glioma: a Canadian Pediatric Brain Tumor Consortium experience. Cancer 112(4):892–899PubMedCrossRefGoogle Scholar
  12. 12.
    Castells M, Sancho-Serra Mdel C, Simarro M (2012) Hypersensitivity to antineoplastic agents: mechanisms and treatment with rapid desensitization. Cancer Immunol Immunother 61(9):1575–1584PubMedCrossRefGoogle Scholar
  13. 13.
    Castells M (2006) Rapid desensitization for hypersensitivity reactions to chemotherapy agents. Curr Opin Allergy Clin Immunol 6(4):271–277PubMedCrossRefGoogle Scholar
  14. 14.
    Lazzareschi I, Ruggiero A, Riccardi R et al (2002) Hypersensitivity reactions to carboplatin in children. J Neurooncol 58(1):33–37PubMedCrossRefGoogle Scholar
  15. 15.
    Vrooman LM, Supko JG, Neuberg DS et al (2010) Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 54(2):199–205PubMedGoogle Scholar
  16. 16.
    Soyer OU, Aytac S, Tuncer A et al (2009) Alternative algorithm for L-asparaginase allergy in children with acute lymphoblastic leukemia. J Allergy Clin Immunol 123(4):895–899PubMedCrossRefGoogle Scholar
  17. 17.
    Körholz D, Wahn U, Jürgens H et al (1990) Allergic reactions in treatment with L-asparaginase. Significance of specific IgE antibodies. Monatsschr Kinderheilkd 138(1):23–25PubMedGoogle Scholar
  18. 18.
    Pession A, Valsecchi MG, Masera G et al (2005) Long-term results of a randomized trial on extended use of high dose L-asparaginase for standard risk childhood acute lymphoblastic leukemia. J Clin Oncol 23(28):7161–7167PubMedCrossRefGoogle Scholar
  19. 19.
    Amylon MD, Shuster J, Pullen J et al (1999) Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia 13(3):335–342PubMedCrossRefGoogle Scholar
  20. 20.
    Salzer W, Seibel N, Smith M (2012) Erwinia asparaginase in pediatric acute lymphoblastic leukemia. Expert Opin Biol Ther 12(10):1407–1414PubMedCrossRefGoogle Scholar
  21. 21.
    Panosyan EH, Seibel NL, Martin-Aragon S et al (2004) Asparaginase antibody and asparaginase activity in children with higher-risk acute lymphoblastic leukemia: Children’s Cancer Group Study CCG-1961. J Pediatr Hematol Oncol 26(4):217–226PubMedCrossRefGoogle Scholar
  22. 22.
    Woo MH, Hak LJ, Storm MC et al (1998) Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia. Leukemia 12(10):1527–1533PubMedCrossRefGoogle Scholar
  23. 23.
    Zalewska-Szewczyk B, Andrzejewski W, Bodalski J (2004) Development of anti-asparaginase antibodies in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 43(5):600–602PubMedCrossRefGoogle Scholar
  24. 24.
    Woo MH, Hak LJ, Storm MC et al (2000) Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia. J Clin Oncol 18(7):1525–1532PubMedGoogle Scholar
  25. 25.
    Zalewska-Szewczyk B, Andrzejewski W, Młynarski W et al (2007) The anti-asparagines antibodies correlate with L-asparagines activity and may affect clinical outcome of childhood acute lymphoblastic leukemia. Leuk Lymphoma 48(5):931–936PubMedCrossRefGoogle Scholar
  26. 26.
    Avramis VI, Sencer S, Periclou AP et al (2002) A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children’s Cancer Group study. Blood 99(6):1986–1994PubMedCrossRefGoogle Scholar
  27. 27.
    Kawedia JD, Liu C, Pei D et al (2012) Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia. Blood 119(7):1658–1664PubMedCrossRefGoogle Scholar
  28. 28.
    van Dalen EC, van As JW, de Camargo B (2011) Methotrexate for high-grade osteosarcoma in children and young adults. Cochrane Database Syst Rev 5, CD006325PubMedGoogle Scholar
  29. 29.
    Lateef O, Shakoor N, Balk RA (2005) Methotrexate pulmonary toxicity. Expert Opin Drug Saf 4(4):723–730PubMedCrossRefGoogle Scholar
  30. 30.
    Ozguven AA, Uysal K, Gunes D et al (2009) Delayed renal excretion of methotrexate after a severe anaphylactic reaction to methotrexate in a child with osteosarcoma. J Pediatr Hematol Oncol 31(4):289–291PubMedCrossRefGoogle Scholar
  31. 31.
    Lluch-Bernal M, Cuesta-Herranz J, De las Heras M et al (1997) Anaphylactic reaction to methotrexate. Allergy 52(11):1150–1151PubMedCrossRefGoogle Scholar
  32. 32.
    Pugi A, Benemei S, Vietri M et al (2012) Anaphylaxis during the first course of high-dose methotrexate: a case report and literature review. J Clin Pharm Ther 37(2):245–248PubMedCrossRefGoogle Scholar
  33. 33.
    Bouchireb K, Dodille A, Ponvert C et al (2009) Management and successful desensitization in methotrexate-induced anaphylaxis. Pediatr Blood Cancer 52(2):295–297PubMedCrossRefGoogle Scholar
  34. 34.
    Oulego-Erroz I, Maneiro-Freire M, Bouzón-Alejandro M et al (2010) Anaphylactoid reaction to high-dose methotrexate and successful desensitization. Pediatr Blood Cancer 55(3):557–559PubMedCrossRefGoogle Scholar
  35. 35.
    Woessmann W, Seidemann K, Mann G et al (2005) The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105(3):948–958PubMedCrossRefGoogle Scholar
  36. 36.
    Weiss RB, Donehower RC, Wiernik PH et al (1990) Hypersensitivity reactions from taxol. J Clin Oncol 8(7):1263–1268PubMedGoogle Scholar
  37. 37.
    Bookman MA, Kloth DD, Kover PE et al (1997) Intravenous prophylaxis for paclitaxel-related hypersensitivity reactions. Semin Oncol 24(6 Suppl 19):S19-13–S19-15Google Scholar
  38. 38.
    Markman M, Kennedy A, Webster K et al (1999) An effective and more convenient drug regimen for prophylaxis against paclitaxel-associated hypersensitivity reactions. J Cancer Res Clin Oncol 125(7):427–429PubMedCrossRefGoogle Scholar
  39. 39.
    Kwon JS, Elit L, Finn M et al (2002) A comparison of two prophylactic regimens for hypersensitivity reactions to paclitaxel. Gynecol Oncol 84(3):420–425PubMedCrossRefGoogle Scholar
  40. 40.
    Castells MC, Tennant NM, Sloane DE et al (2008) Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 122(3):574–580PubMedCrossRefGoogle Scholar
  41. 41.
    Feldweg AM, Lee CW, Matulonis UA et al (2005) Rapid desensitization for hypersensitivity reactions to paclitaxel and docetaxel: a new standard protocol used in 77 successful treatments. Gynecol Oncol 96(3):824–829PubMedCrossRefGoogle Scholar
  42. 42.
    Kellie SJ, Crist WM, Pui CH et al (1991) Hypersensitivity reactions to epipodophyllotoxins in children with acute lymphoblastic leukemia. Cancer 67(4):1070–1075PubMedCrossRefGoogle Scholar
  43. 43.
    Hudson MM, Weinstein HJ, Donaldson SS et al (1993) Acute hypersensitivity reactions to etoposide in a VEPA regimen for Hodgkin’s disease. J Clin Oncol 11(6):1080–1084PubMedGoogle Scholar
  44. 44.
    Siderov J, Prasad P, De Boer R et al (2002) Safe administration of etoposide phosphate after hypersensitivity reaction to intravenous etoposide. Br J Cancer 86(1):12–13PubMedCrossRefGoogle Scholar
  45. 45.
    Lehmann DF, Hurteau TE, Newman N et al (1997) Anticonvulsant usage is associated with an increased risk of procarbazine hypersensitivity reactions in patients with brain tumors. Clin Pharmacol Ther 62(2):225–229PubMedCrossRefGoogle Scholar
  46. 46.
    Mahmood T, Mudad R (2002) Pulmonary toxicity secondary to procarbazine. Am J Clin Oncol 25(2):187–188PubMedCrossRefGoogle Scholar
  47. 47.
    Chan A, Shih V, Tham Chee K (2007) Liposomal doxorubicin-associated acute hypersensitivity despite appropriate preventive measures. J Oncol Pharm Pract 13(2):105–107PubMedCrossRefGoogle Scholar
  48. 48.
    Popescu NA, Sheehan MG, Kouides PA et al (1996) Allergic reactions to cyclophosphamide: delayed clinical expression associated with positive immediate skin tests to drug metabolites in five patients. J Allergy Clin Immunol 97(1 Pt 1):26–33PubMedCrossRefGoogle Scholar
  49. 49.
    Khaw SL, Downie PA, Waters KD et al (2007) Adverse hypersensitivity reactions to mesna as adjunctive therapy for cyclophosphamide. Pediatr Blood Cancer 49(3):341–343PubMedCrossRefGoogle Scholar
  50. 50.
    Blanca M, Torres MJ, Girón M et al (1997) Successful administration of cytarabine after a previous anaphylactic reaction. Allergy 52(10):1009–1011PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Antonio Ruggiero
    • 1
    • 3
  • Silvia Triarico
    • 1
  • Giovanna Trombatore
    • 1
  • Andrea Battista
    • 1
  • Fabiola Dell’Acqua
    • 2
  • Carmelo Rizzari
    • 2
  • Riccardo Riccardi
    • 1
  1. 1.Division of Pediatric OncologyCatholic University of RomeRomeItaly
  2. 2.Department of PediatricsS. Gerardo HospitalMonzaItaly
  3. 3.Division of Paediatric Oncology, A. Gemelli HospitalCatholic University of RomeRomeItaly

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