RESEARCH ARTICLE For reprint orders, please contact: [email protected]
Risk factors associated with hypersensitivity reactions to cetuximab: anti-cetuximab IgE detection as screening test Benoît Dupont*,1,2, Delphine Mariotte3, Bénédicte Clarisse4, Marie-Pierre Galais5, Karine Bouhier-Leporrier1, Jean-Michel Grellard4, Brigitte Le Mauff2,3, Jean-Marie Reimund1,2 & Radj Gervais5 ABSTRACT Aim: To describe the factors associated with a high risk of a hypersensitivity reaction to cetuximab. Patients & methods: We retrospectively studied a cohort of patients living in Normandy (France) treated with cetuximab. Results: Among the 229 treated patients, 24 (10.5%) had a hypersensitivity reaction to cetuximab, including 11 grade 3–5 reactions. Detection of anti-cetuximab IgE could be performed in 108 patients. Anticetuximab IgE was found in 13 of 17 patients (76.5%) who had a hypersensitivity reaction to cetuximab compared with 17 of 91 control patients (18.7%; adjusted odds ratio: 14.99; 95% CI: 3.59–62.63). No clinical criteria predicted the risk of allergy to cetuximab. Conclusion: Anti-cetuximab IgE may help physicians identify patients at risk of a hypersensitivity reaction to cetuximab. Cetuximab is a chimeric IgG1 monoclonal antibody directed against the EGF receptor (EGFR). Currently, it is used in daily practice for metastatic colorectal cancer [1–4] and for locally advanced or metastatic head and neck cancer [5,6] . An anaphylactic reaction is a classic side effect of monoclonal antibodies [7] . Studies that have assessed the indications for treatment with cetuximab have found the incidence of severe allergic reactions (grade 3 or 4) varied from 1.2 to 4% [1,5,6,8] . Higher incidences of severe allergic reactions, ranging from 14.4 to 22%, were also later described in North Carolina, Arkansas and Tennessee (USA) [9–11] . It is now well documented that these hypersensitivity reactions are mediated by pre-existing specific anti-cetuximab IgE. Indeed, a strong relationship between the risk of an allergic reaction and the presence of anti-cetuximab IgE in sera before a first infusion of cetuximab has been shown in 76 patients [9] . According to current published data, virtually no premedication can formally prevent hypersensitivity reactions to cetuximab. Although the administration of corticosteroids before infusion of cetuximab may limit the occurrence of anaphylaxis [12] , the addition of antihistamine drugs does not seem to be effective [13] . Several groups have attempted to highlight markers that can identify subjects at risk for a hypersensitivity reaction to cetuximab. An atopic history and Caucasian origin appear to be factors significantly associated with the occurrence of an anaphylactic reaction, but these criteria are not sufficiently discriminating to select patients at risk [10,14] . In this context, the level of specific IgE in relation to cetuximab seems to be a good candidate. Indeed, focusing on severe (grade 3 or 4) hypersensitivity reactions, Chung et al. reported in their retrospective work that an
KEYWORDS
• anaphylaxis • anti-IgE antibodies • cetuximab • colonic neoplasms • head and neck neoplasms • hypersensitivity
Department of Hepato-Gastroenterology & Nutrition, Caen University Hospital, Avenue Côte de Nacre, CHU Côte de Nacre, 14033 Caen cedex 9, France 2 Caen Basse-Normandie University, UFR Medecine, Avenue de la Côte de Nacre, 14032 Caen cedex 05, France 3 Laboratory of Immunology & Immunopathology, Caen University Hospital, Avenue Georges Clemenceau, 14033 Caen cedex 9, France 4 Clinical Research Department, Francois Baclesse Centre, 3 Avenue du Général Harris, 14000 Caen, France 5 Medical Oncology Department, Francois Baclesse Centre, 3 Avenue du Général Harris, 14000 Caen, France *Author for correspondence: Tel.: +33 2 31 06 45 44; Fax: +33 2 31 06 45 45; [email protected] 1
10.2217/FON.14.153 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2133–2140
part of
ISSN 1479-6694
2133
Research Article Dupont, Mariotte, Clarisse et al. assay for positive IgE antibodies had a sensitivity and specificity of 92 and 90%, respectively [9] . We have previously developed a reliable and reproducible anti-cetuximab IgE assay using ELISA [15] . The purpose of this study was to determine the factors associated with a high risk for a cetuximab-induced hypersensitivity reaction and, in particular, to assess the usefulness of detecting anti-cetuximab IgE monoclonal antibodies prior to cetuximab treatment. Patients & methods ●●Patients
We conducted a retrospective study on a cohort of patients who received a first infusion of cetuximab at the François Baclesse Centre (Caen, France), between 1 October 2005 and 30 November 2012. The cohort of patients from a previous study [15] was used adding new cases for which sera were collected before any treatment by cetuximab. Cetuximab was given to all patients according to its authorized and marketed indications: metastatic colorectal cancer or locally advanced or metastatic head and neck cancer. Data from patients who had participated in clinical trials that had investigated the efficacy of cetuximab for other indications were also included in this study. The first infusion was performed slowly over 2 h via an intravenous (iv.) route after premedication with 5 mg of iv. dexchlorpheniramine and iv. corticosteroids. The dosage of corticosteroids varied according to the combined chemotherapy regimen. Patients were identified using the central pharmacy database. The study was approved by the local ethics committee (Comité de Protection des Personnes, Nord-Ouest III, Caen, France). Methods ●●Clinical data
For each patient, the following parameters were collected from medical charts: height, weight, age at cetuximab administration, site of primary tumor, pathological type, date and circumstances of diagnosis, time, and appearance and location of metastases in cases of metastatic disease. We also noted a previous history of allergy (drug, food or insect allergy; a history of asthma, eczema, allergic rhinitis; and any history of shock or angioedema related to a drug administration). For patients with multiple allergies, the total number of allergies was determined.
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Data on all treatments (surgery, radiotherapy or chemotherapy) previous to the first dose of cetuximab were collected. The date of the first infusion of cetuximab, and the applied prophylactic protocol and concurrent medications were also included. In cases where there was a hypersensitivity reaction to cetuximab, the time that elapsed between the infusion and the reaction, the type of reaction (flushing, rash, urticaria, dyspnea, hypotension and anaphylaxis), the grade of reaction (according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 [16]), and the initial management of the allergic reaction (cetuximab stopped, drug prescriptions and the need for hospitalization in an intensive care unit [ICU]) were recorded. ●●Anti-cetuximab IgE assay
We performed an anti-cetuximab IgE assay for each participating patient who had serum collected prior to the first infusion of cetuximab. Detection of IgE antibodies against cetuximab was performed using an ELISA developed in the Laboratory of Immunology and Immunopathology of Caen University Hospital (France) [15] . The results were expressed in arbitrary units of IgE (UAE) using a standard calibration established with a positive serum diluted to 1/20, 1/60, 1/180 and 1/540. A threshold over 29 UAE was previously chosen to define the positivity of specific anti-cetuximab IgE [15] . ●●Statistical analyses
Statistical analyses were performed using Stata® software version 10 (StataCorp LP, TX, USA). The type I error rate was 0.05 for all analyses. The primary end point was to determine the number of hypersensitivity reactions to cetuximab. The second end point was to identify useful factors related to the risk of this reaction. Patients who had a hypersensitivity reaction to cetuximab were compared with those who did not experience any allergic reaction to cetuximab using the χ2 test for categorical variables and Student’s t-test for continuous variables. Multivariate logistic regression analysis, containing all variables with a p-value of
Risk factors associated with hypersensitivity reactions to cetuximab: anti-cetuximab IgE detection as screening test Benoît Dupont*,1,2, Delphine Mariotte3, Bénédicte Clarisse4, Marie-Pierre Galais5, Karine Bouhier-Leporrier1, Jean-Michel Grellard4, Brigitte Le Mauff2,3, Jean-Marie Reimund1,2 & Radj Gervais5 ABSTRACT Aim: To describe the factors associated with a high risk of a hypersensitivity reaction to cetuximab. Patients & methods: We retrospectively studied a cohort of patients living in Normandy (France) treated with cetuximab. Results: Among the 229 treated patients, 24 (10.5%) had a hypersensitivity reaction to cetuximab, including 11 grade 3–5 reactions. Detection of anti-cetuximab IgE could be performed in 108 patients. Anticetuximab IgE was found in 13 of 17 patients (76.5%) who had a hypersensitivity reaction to cetuximab compared with 17 of 91 control patients (18.7%; adjusted odds ratio: 14.99; 95% CI: 3.59–62.63). No clinical criteria predicted the risk of allergy to cetuximab. Conclusion: Anti-cetuximab IgE may help physicians identify patients at risk of a hypersensitivity reaction to cetuximab. Cetuximab is a chimeric IgG1 monoclonal antibody directed against the EGF receptor (EGFR). Currently, it is used in daily practice for metastatic colorectal cancer [1–4] and for locally advanced or metastatic head and neck cancer [5,6] . An anaphylactic reaction is a classic side effect of monoclonal antibodies [7] . Studies that have assessed the indications for treatment with cetuximab have found the incidence of severe allergic reactions (grade 3 or 4) varied from 1.2 to 4% [1,5,6,8] . Higher incidences of severe allergic reactions, ranging from 14.4 to 22%, were also later described in North Carolina, Arkansas and Tennessee (USA) [9–11] . It is now well documented that these hypersensitivity reactions are mediated by pre-existing specific anti-cetuximab IgE. Indeed, a strong relationship between the risk of an allergic reaction and the presence of anti-cetuximab IgE in sera before a first infusion of cetuximab has been shown in 76 patients [9] . According to current published data, virtually no premedication can formally prevent hypersensitivity reactions to cetuximab. Although the administration of corticosteroids before infusion of cetuximab may limit the occurrence of anaphylaxis [12] , the addition of antihistamine drugs does not seem to be effective [13] . Several groups have attempted to highlight markers that can identify subjects at risk for a hypersensitivity reaction to cetuximab. An atopic history and Caucasian origin appear to be factors significantly associated with the occurrence of an anaphylactic reaction, but these criteria are not sufficiently discriminating to select patients at risk [10,14] . In this context, the level of specific IgE in relation to cetuximab seems to be a good candidate. Indeed, focusing on severe (grade 3 or 4) hypersensitivity reactions, Chung et al. reported in their retrospective work that an
KEYWORDS
• anaphylaxis • anti-IgE antibodies • cetuximab • colonic neoplasms • head and neck neoplasms • hypersensitivity
Department of Hepato-Gastroenterology & Nutrition, Caen University Hospital, Avenue Côte de Nacre, CHU Côte de Nacre, 14033 Caen cedex 9, France 2 Caen Basse-Normandie University, UFR Medecine, Avenue de la Côte de Nacre, 14032 Caen cedex 05, France 3 Laboratory of Immunology & Immunopathology, Caen University Hospital, Avenue Georges Clemenceau, 14033 Caen cedex 9, France 4 Clinical Research Department, Francois Baclesse Centre, 3 Avenue du Général Harris, 14000 Caen, France 5 Medical Oncology Department, Francois Baclesse Centre, 3 Avenue du Général Harris, 14000 Caen, France *Author for correspondence: Tel.: +33 2 31 06 45 44; Fax: +33 2 31 06 45 45; [email protected] 1
10.2217/FON.14.153 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2133–2140
part of
ISSN 1479-6694
2133
Research Article Dupont, Mariotte, Clarisse et al. assay for positive IgE antibodies had a sensitivity and specificity of 92 and 90%, respectively [9] . We have previously developed a reliable and reproducible anti-cetuximab IgE assay using ELISA [15] . The purpose of this study was to determine the factors associated with a high risk for a cetuximab-induced hypersensitivity reaction and, in particular, to assess the usefulness of detecting anti-cetuximab IgE monoclonal antibodies prior to cetuximab treatment. Patients & methods ●●Patients
We conducted a retrospective study on a cohort of patients who received a first infusion of cetuximab at the François Baclesse Centre (Caen, France), between 1 October 2005 and 30 November 2012. The cohort of patients from a previous study [15] was used adding new cases for which sera were collected before any treatment by cetuximab. Cetuximab was given to all patients according to its authorized and marketed indications: metastatic colorectal cancer or locally advanced or metastatic head and neck cancer. Data from patients who had participated in clinical trials that had investigated the efficacy of cetuximab for other indications were also included in this study. The first infusion was performed slowly over 2 h via an intravenous (iv.) route after premedication with 5 mg of iv. dexchlorpheniramine and iv. corticosteroids. The dosage of corticosteroids varied according to the combined chemotherapy regimen. Patients were identified using the central pharmacy database. The study was approved by the local ethics committee (Comité de Protection des Personnes, Nord-Ouest III, Caen, France). Methods ●●Clinical data
For each patient, the following parameters were collected from medical charts: height, weight, age at cetuximab administration, site of primary tumor, pathological type, date and circumstances of diagnosis, time, and appearance and location of metastases in cases of metastatic disease. We also noted a previous history of allergy (drug, food or insect allergy; a history of asthma, eczema, allergic rhinitis; and any history of shock or angioedema related to a drug administration). For patients with multiple allergies, the total number of allergies was determined.
2134
Future Oncol. (2014) 10(14)
Data on all treatments (surgery, radiotherapy or chemotherapy) previous to the first dose of cetuximab were collected. The date of the first infusion of cetuximab, and the applied prophylactic protocol and concurrent medications were also included. In cases where there was a hypersensitivity reaction to cetuximab, the time that elapsed between the infusion and the reaction, the type of reaction (flushing, rash, urticaria, dyspnea, hypotension and anaphylaxis), the grade of reaction (according to National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 [16]), and the initial management of the allergic reaction (cetuximab stopped, drug prescriptions and the need for hospitalization in an intensive care unit [ICU]) were recorded. ●●Anti-cetuximab IgE assay
We performed an anti-cetuximab IgE assay for each participating patient who had serum collected prior to the first infusion of cetuximab. Detection of IgE antibodies against cetuximab was performed using an ELISA developed in the Laboratory of Immunology and Immunopathology of Caen University Hospital (France) [15] . The results were expressed in arbitrary units of IgE (UAE) using a standard calibration established with a positive serum diluted to 1/20, 1/60, 1/180 and 1/540. A threshold over 29 UAE was previously chosen to define the positivity of specific anti-cetuximab IgE [15] . ●●Statistical analyses
Statistical analyses were performed using Stata® software version 10 (StataCorp LP, TX, USA). The type I error rate was 0.05 for all analyses. The primary end point was to determine the number of hypersensitivity reactions to cetuximab. The second end point was to identify useful factors related to the risk of this reaction. Patients who had a hypersensitivity reaction to cetuximab were compared with those who did not experience any allergic reaction to cetuximab using the χ2 test for categorical variables and Student’s t-test for continuous variables. Multivariate logistic regression analysis, containing all variables with a p-value of
