Joana Caiado

Acetylsalicylic acid and montelukast block mast cell mediator–related symptoms during rapid desensitization

BACKGROUND Rapid desensitization is a process in which drug-allergic patients receive their target dose in incremental steps, resulting in a state of temporary tolerization. In this manner, first-line therapy can be delivered safely, even in patients who present with severe hypersensitivity reactions (HSRs) to the given agent. A small subset of patients has persistent HSRs during rapid desensitization that can be refractory to antihistamines and corticosteroids. OBJECTIVE To increase the safety and tolerability of rapid desensitization by prostaglandin and leukotriene blockade in patients with refractory mast cell mediator-related symptoms. METHODS Fourteen adult patients developed HSRs to platinum chemotherapy that persisted during rapid desensitization. All patients had cutaneous symptoms (flushing, pruritus, or urticaria), many with associated systemic reactions. These patients were then pretreated with acetylsalicylic acid, 325 mg orally, and montelukast, 10 mg orally, 2 days before and on the day of desensitization. Response to subsequent desensitizations was assessed by medical record review and was compared with a group of matched historic control patients who received methylprednisolone for HSRs during desensitization. RESULTS Seventy-eight desensitizations in 14 patients were performed. Using acetylsalicylic acid and montelukast, 86% of patients (12/14) experienced substantial improvement in symptoms (grade 0.5 vs grade 2.14, P < .0001). Reduction in symptoms during desensitization was also significantly greater than that experienced by historic control patients who received methylprednisolone pretreatment (grade 0.5 vs grade 1.75, P = .0008). All patients received their target dose of chemotherapy, and there were no severe systemic HSRs. CONCLUSIONS Pretreatment with acetylsalicylic acid and montelukast lessens the severity of HSRs during rapid desensitization.

Carboplatin-, Oxaliplatin-, and Cisplatin–specific IgE: Cross-reactivity and Value in the Diagnosis of Carboplatin and Oxaliplatin Allergy

BACKGROUND The diagnosis of hypersensitivity reactions (HSR) to platins is based on the characterization of the reaction and the results of skin testing. Platins can be irritants when used in skin testing; therefore, in vitro testing may offer an alternative diagnostic tool. OBJECTIVE To evaluate sensitivity and specificity of platin specific IgE (sIgE) in patients with HSRs and in controls. METHODS Twenty-four patients with immediate HSR to platins were included (carboplatin, 12; oxaliplatin, 12): 19 women and 5 men (mean age, 61 years). The control group included 17 patients exposed to platin and with no HSR. Skin testing was performed on 22 patients. Carboplatin sIgE and oxaliplatin sIgE were measured in 24 patients and 17 controls; carboplatin sIgE was measured in 21 patients. RESULTS Skin test results were positive in 22 patients (carboplatin, 12/12; oxaliplatin, 10/12). Seven of 12 patients sensitive to carboplatin (59%) had positive carboplatin sIgE, 2 also had positive cisplatin sIgE, and all had negative oxaliplatin sIgE; 9 of 12 patients sensitive to oxaliplatin (75%) had positive sIgE to oxaliplatin, 8 of 12 (67%) also had positive carboplatin and cisplatin sIgE, to which they had not been exposed. All 5 carboplatin controls had negative sIgE; 3 oxaliplatin controls (25%) had positive carboplatin sIgE, and 2 had positive oxaliplatin sIgE. CONCLUSION Carboplatin sIgE is very specific but less sensitive. In contrast, oxaliplatin sIgE had higher sensitivity but lower specificity. Analysis of our data suggests that oxaliplatin exposure was more immunogenic. This could be clinically relevant because patients sensitized to carboplatin may be able to tolerate oxaliplatin, but patients sensitized to oxaliplatin may be at risk when exposed to carboplatin and cisplatin.

Risk stratification and skin testing to guide re-exposure in taxane-induced hypersensitivity reactions

BACKGROUND The optimal approach to patients with hypersensitivity reactions (HSRs) to taxanes has not been established. OBJECTIVE We sought to assess the safety and efficacy of risk stratification based on the severity of the initial HSR and skin testing for guiding taxane reintroduction in patients with an HSR to these agents. METHODS Data on 164 patients treated for a taxane-related HSR from April 2011 to August 2014 at the Dana-Farber Cancer Institute and Brigham and Womens Hospital were collected retrospectively. Patients were re-exposed to taxanes either through desensitization, challenge, or regular infusion based on the severity of the initial HSR and skin test response. Depending on the initial risk stratification and tolerance to re-exposure, patients were then treated with shorter desensitization protocols, challenge, or both with the aim of resuming regular infusions, except in patients with a severe immediate initial HSR. RESULTS Of 138 patients desensitized, 29 (21%) had an immediate and 20 (14%) had a delayed HSR with the procedure. Of 49 patients challenged, 2 (4%) had a mild immediate and 1 (2%) had a delayed HSR with the procedure. No patients had a severe immediate HSR with desensitization or challenge. Thirty-six (22%) patients eventually resumed regular infusions. These patients were more likely to have negative skin test responses and to have experienced a delayed or mild immediate initial HSR. CONCLUSIONS Risk stratification based on the severity of the initial HSR and skin testing to guide taxane reintroduction is safe and allows a significant number of patients to resume regular infusions.

Drug Desensitization in the Management of Hypersensitivity Reactions to Monoclonal Antibodies and Chemotherapy

Hypersensitivity reactions to monoclonal antibodies and chemotherapy, which may vary in severity from mild to life-threatening, can lead to their discontinuation and replacement by alternative agents that are often less effective, more toxic, and/or more expensive. Drug desensitization has emerged as the best treatment modality capable of allowing re-introduction of the hypersensitivity reaction-inducing medication in highly sensitized patients in need of first line therapies. In recent years, the availability of new anti-neoplastic drugs and therapeutic monoclonal antibodies has increased, as has the potential for hypersensitivity reactions. Development of desensitization protocols for these new medications requires a careful assessment of the potential risks and benefits. The purposes of this review are to provide an overview of the presentation of hypersensitivity reactions amenable to desensitization and to increase awareness of the indications for and outcomes of desensitization protocols. Rapid drug desensitization has proven to be a safe and effective way of administering first line therapy to patients with hypersensitivity reactions, providing an extremely powerful treatment modality for patients for whom alternative drugs are deemed unacceptable. Rapid drug desensitization protocols should be administered only by highly trained allergists and nurses who have experience in determining which reactions are amenable to desensitization, and can identify high risk patients and provide them with appropriate care. Efforts should be made to increase awareness of the remarkable safety and efficacy of rapid drug desensitization among non-allergists, especially in the fields of oncology and rheumatology, so as to favor its universal application. Development of desensitization units to provide state-of-the-art care is possible only through coordinated teamwork.

Presentation and Diagnosis of Hypersensitivity to Platinum Drugs

Hypersensitivity reactions (HSRs) to platinum drugs are increasing due to their extensive use in a wide variety of malignancies and the repeated exposures in patients with increased life expectancy. Understanding the incidence of HSR to platinum drugs and associated risk factors can help with the diagnosis and may provide protection against severe HSRs. A thorough clinical history with identification of the typical and atypical symptoms, the relationship with the platin administration, and the number of previous exposures are the key to the diagnosis. An elevated serum tryptase at the time of the HSR indicates that IgE and/or mast cells/basophils were involved in the HSR. Skin testing to platinum drugs is a highly sensitive and specific diagnostic tool, which helps provide risk stratification and management recommendations. Platinum specific IgE measurement and basophil activation test (BAT) are emerging as new diagnostic tools and in combination with skin testing can help support the diagnosis and the cross-reactivity between the three most commonly used platinum drugs, namely carboplatin, cisplatin, and oxaliplatin.

Rapid desensitization to chemotherapy and monoclonal antibodies is effective and safe

We would like to acknowledge Madrigal-Burgaleta et al. (1) for their wonderful report on rapid desensitization (RD) to antineoplastic drugs, with the description of 189 desensitizations performed in 23 patients. Continued reports on the safety and efficacy of RD to drugs emerging from different institutions are essential to allow the dissemination of desensitization programmes. The authors’ RD protocol is not novel, being based on the Brigham and Women’s Hospital/ Dana Farber Cancer Institute (BWH/DFCI) desensitization protocol (2, 3), with fewer steps and higher starting dose, which may not be applicable universally to high-risk patients. Faster desensitization protocols in immediate and delayed drug hypersensitivity reactions have exhibited higher risks and failure rates (4, 5). The starting dose of the Madrigal-Burgaleta et al. protocol is 80-fold higher than the one used in the 12-step BWH/DFCI protocol and is equivalent to its step 7 (2, 3). In a cohort of 98 patients desensitized with the BWH/DFCI protocol, of which 80% had a severe initial reaction, 25% of all reactions induced by desensitization occurred during the first 8 steps, highlighting the potential risks of higher starting doses (2). Also, despite the use of different grading systems for assessing the severity of immediate HSRs between the two studies, it could be argued that a higher percentage of patients with severe initial reactions were included in the BWH/DFCI series (80%) compared with the present study in which 30% were considered to have had a severe reaction. Madrigal-Burgaleta et al. used a grading system based on the ‘Common Terminology Criteria for Adverse Events’ guidelines developed to describe adverse drug reactions induced by chemotherapy in patients with cancer, whereas the BWH/DFCI studies used the classification proposed by Brown (6). In this light, further data are needed before the modifications made to the BWH/ DFCI protocol by Madrigal-Burgaleta et al. can be considered safe for all patients with HSRs to antineoplastic drugs. The recent EAACI position paper of the Drug Allergy Interest Group includes as future needs for improving drug desensitization (5): (i) multicenter clinical trials with standardized and well-characterized patients; (ii) comparison of different protocols in one well-characterized patient group and comparison of one protocol in various, well-characterized patient groups. Although the authors suggest starting with higher doses, they also state that more dilute initial doses could be used, depending on skin test endpoint titration. However, the predictive values of skin tests to antineoplastic drugs were not determined, and, currently, studies outcomes and consensus support the use of more dilute starting solutions in all RD, despite the higher total time of administration (2–4). The authors showed that 70% of their patients with negative skin tests to oxaliplatin who undergone controlled provocation had positive challenges, indicating a poor predictive value for oxaliplatin skin testing. Although other reports indicate a higher rate of positive skin test to oxaliplatin, the true predictive value of a negative skin test is not available (7). As suggested by the authors, recent preliminary data with oxaliplatin-specific serum IgE indicate that in vitro testing could be a very promising complementary diagnostic tool for the identification of allergic patients (7). It should be emphasized that the BWH/DFCI desensitization protocol complies with safety measures for hazardous drug handling. The tubing of each bag is primed by pharmacy with the antineoplastic drug and is equipped with a connecting device that prevents any contact with the drug. The system is then connected to a running saline line in close proximity to the patient, allowing delivery of small volumes during the initial steps of desensitization (2, 3). This method avoids unnecessary priming steps with saline that prolongs and interrupts desensitization. Desensitization has become a cornerstone in the management of immediate hypersensitivity reactions (HSRs) to chemotherapy and monoclonal antibodies among other medications. It is the only effective procedure for overcoming HSRs to first-line therapy, thus representing an important advance in patients’ treatment and prognosis. This initially empiric procedure is now supported by in vivo and in vitro evidence (2, 3, 8) and we thank Madrigal-Burgaleta et al. for providing further evidence of its efficacy.

Anaphylaxis to Long-Acting Release Exenatide

1. Barranco P, Pérez-Francés C, Quirce S, Gómez-Torrijos E, Cárdenas R, Sánchez-García S, et al. Consensus Document on the Diagnosis of Severe Uncontrolled Asthma. J Investig Allergol Clin Immunol. 2012;22:460-75. 2. McCleary N, Nwaru BI, Nurmatov UB, Critchley H, Sheikh A. Endogenous and exogenous sex steroid hormones in asthma and allergy in females: a systematic review and meta-analysis. J Allergy Clin Immunol. 2018. doi: 10.1016/j.jaci.2017.11.034 (in press). 3. Rao C, Moore C, Blecker E, Busse WW, Calhoun W, Castro M, et al. Characteristics of Perimenstrual Asthma and its Relation to Asthma Severity and Control. Chest. 2013;143:984-92. 4. Brenner BE, Holmes TM, Mazal B, Camargo CA Jr. Relation between phase of the menstrual cycle and asthma presentations in the emergency department. Thorax. 2005;60:806-9. 5. Skoczynski S, Smik-Orzech A, Pierzchala E, Rzepka-Wrona P, Kolodziejcyk K, Pierzchala W. Exacerbations in perimenstrual asthma. Clinical significance of peripheral blood eosinophilia and BMI. Wild Lek. 2016;69:117-22 (abstract). 6. Dávila I, Domínguez-Ortega J, Navarro-Pulido A, Alonso A, Antolín-Amerigo D, González-Mancebo E, et al. Consensus document on dog and cat allergy. Allergy. 2018;00:1-17. 7. Bito T, Kanda E, Tanaka M, Fukunaga A, Horikawa T, Nishigori C. Cow Milk-Dependent Exercise Induce Anaphylaxis under the condition of a premenstrual or ovulatory phase following skin sensitization. Allergology International. 2008;57:437-9. 8. Catherine L Haggerty, Roberta B Ness, Sheryl Kelsey, Grant W Waterer. The impact of estrogen and progesterone on asthma. Ann Allergy Asthma Immunol. 2003;90:284-91. 9. Normansell R, Walker S, Milan SJ, Walters E, Nair P. Omalizumab for asthma in adults and children. Cochrane Database of Syst Rev. 2014:CD003559. 10. Quirce S, Delgado J, Entrenas LM, Grande M, Llorente C, López Viña A, et al. Quality Indicators of Asthma Care Derived From the Spanish Guidelines for Asthma Management (GEMA 4.0): A Multidisciplinary Team Report. J Investig Allergol Clin Immunol. 2017:27:69-73. Anaphylaxis to Long-Acting Release Exenatide

The Contribution of the Basophil Activation Test to the Diagnosis of Hypersensitivity Reactions to Oxaliplatin

Cytostatics, mainly oxaliplatin, are widely used to treat oncological diseases. There has been an increase in hypersensitivity reactions to these drugs, mostly IgE-mediated. Skin tests are the main diagnostic method used but they may induce irritant local reactions and contamination by health care professionals. The main goals of this work were to evaluate the contribution of the basophil activation test (BAT) as a diagnostic tool for hypersensitivity reactions to oxaliplatin, and to compare the expression of CD63 and CD203c molecules. BAT was performed with oxaliplatin in 6 oncological patients with previous documented hypersensitivity reactions to oxaliplatin and in 5 controls (4 oncological patients tolerant to oxaliplatin and 1 healthy control), assessing CD63 and CD203c expression on basophil population. We found higher values for the basophil activation percentage and mean stimulation index for CD203c expression with all oxaliplatin concentrations tested (most significant at 150 μg/mL: p = 0,0087; p = 0.0222) in the patients than in controls. The same did not occur, with statistical significance, for CD63 expression. When we compared the 2 activation markers in the patients, we observed a more enhanced expression of CD203c in both evaluations, with statistical significance at the 150-μg/mL concentration (p = 0,026; p = 0,0129). These data show a higher positivity of BAT with oxaliplatin in patients with previous hypersensitivity reactions, when compared to controls, suggesting that BAT may be a promising diagnostic method as an alternative to skin tests. CD203c appears to play a more prominent role than CD63, which is consistent with what is published in the literature.

Desensitization induces hyporesponsiveness and cell-surface phenotype changes on wild-type and humanized mouse mast cells

Background Rapid drug desensitization (DST) protocols have been developed based on clinical evidence, but in vitro studies are lacking. Understanding the mechanisms involved in the early stages of DST will allow improvements in patients’ treatment. The aim of this study is to demonstrate and characterize the induction of hyporesponsiveness in murine mast cells by desensitization. Methods We assessed the effect of rapid desensitization on murine bone marrow derived mast cells (BMMC). Experiments with three diferent types of murine BMMC were done: wild-type, LILRB4-/-, and transgenic expressing the human receptor FceRI. Wild-type and LILRB4-/- BMMC were sensitized with anti-DNP IgE and stimulated with DNP, while transgenic BMMC were sensitized with concentrated human serum of allergic subjects and stimulated with the respective allergen. BMMC were stimulated through desensitization or single activation, with optimal or suboptimal doses of antigen. Comparisions were made according to the percentage of b-Hexosaminidase (b-Hex) release by BMMC and the expression of LAMP-1 on the surface of these cells. Furthermore, expression of FceRI, PDL1 and LILRB4 on the surface of BMMC were also assessed. Results

Basophil activation test as a biomarker in allergic patients to platins undergoing rapid desensitization

Background Rapid Drug Desensitization (RDD) has become a cornerstone of the management of immediate hypersensitivity reactions (HSRs) to chemotherapeutic agents, including biologicals. It is the only effective procedure for overcoming HSRs to first-line therapy, thus representing an important advance in patients’ treatment and prognosis. Biomarkers to assess drug sensitization and monitor RDD safety and efficacy are lacking. Preliminary data suggested that in addition to skin testing, basophil activation test (BAT) could be used to assess patient’s IgE sensitization to platins and provide markers of activation to evaluate the response to RDD.