Drug Desensitizations for Chemotherapy: Safety and Efficacy in Preventing Anaphylaxis.

Hypersensitivity reactions (HSRs) to antineoplastic drugs are increasing due to the expanding use of classical and new drugs in a wide variety of malignancies. PURPOSE OF REVIEW: The goal of this review is to provide current best practices in the diagnosis and management of HSRs based on data and evidence. RECENT FINDINGS: A plethora of studies have provided evidence of the safety and efficacy of rapid drug desensitizations (RDD) to allow for the reintroduction of antineoplastic drugs following an HSR, based on risk stratification. Recently described biomarkers such as basophil activation test, total IgE, BRCA genotyping, and serum IL-6 can aid in guiding improved precision desensitization protocols. Personalized premedication regimens and protocols have improved RDD safety and outcomes. RDD allows for the continued use of chemotherapeutic drugs without impaired drug efficacy. RDD represents the best approach to maintain cancer patients on their most effective treatments.

Rapid desensitization to antineoplastic drugs in an outpatient immunoallergology clinic: Outcomes and risk factors.

BACKGROUND: Hypersensitivity reactions to antineoplastic agents may lead to discontinuation of first-line treatments. Rapid drug desensitization (RDD) allows for a safe reintroduction in patients who are allergic to them. OBJECTIVE: To evaluate the safety and efficacy of the Brigham and Women's Hospital's 12-step RDD in a Portuguese patient population with cancer and to identify markers associated with breakthrough reactions (BTRs) to platins. METHODS: We conducted a retrospective review of desensitizations undertaken at the Immunoallergology Day-Care Unit of the Santa Maria Hospital in Lisbon, Portugal, from July 2008 to July 2019. Adult patients with cancer and with immediate hypersensitivity reactions were included. Skin testing was performed to platins, trastuzumab, and cetuximab. The 12-step protocol was used for most patients, and a shorter protocol was used in 9 patients who were taxane-reactive to resume regular infusions. RESULTS: A total of 1471 RDDs were performed in 272 patients to 136 platins, 124 taxanes, 13 monoclonal antibodies, and 10 other drugs. Skin test results were positive in 127 of patients who were platin-reactive (95.3%) and negative in patients who were cetuximab- and trastuzumab-reactive. There were 141 BTRs during RDD (9.6% of infusions), 79.4% induced by platins with the majority having mild reactions (68.8%). There were 8 patients who were paclitaxel-reactive, and who completed a shorter protocol and resumed regular infusions successfully. Multiple platin infusions (cutoff: ≥10) and total immunoglobulin E greater than or equal to 100 U/mL were identified as independent risk factors for BTRs in patients who were platin-reactive. CONCLUSION: This large single-center study confirmed the safety and efficacy of the 12-step RDD protocol in a diverse cancer population, providing evidence of its universal applications. Total immunoglobulin E is a potentially useful biomarker to identify high-risk patients who are platin-reactive.

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.

Basophil Activation Test is a Relevant Biomarker of the Outcome of Rapid Desensitization in Platinum Compounds-Allergy.

BACKGROUND: Rapid drug desensitization (RDD) has become a cornerstone in the management of immediate drug hypersensitivity reactions (DHRs) to chemotherapeutic agents. Because of the inherent risk of anaphylaxis during RDD, biomarkers to predict patients at risk of developing such severe reactions are needed. The basophil activation test (BAT) has been used in DHRs as a diagnostic tool. OBJECTIVE: We evaluated basophil CD63 and CD203c expression (BAT) as a biomarker to assess the safety and effectiveness of RDD in platinum compounds-allergic patients. METHODS: Patients allergic to platinum compounds (n = 15) undergoing RDD were assessed through clinical history, skin testing, serum tryptase levels, and BAT. BAT was performed immediately before RDD, assessing CD203c and CD63 expression on basophils. BAT was also performed in 6 patients tolerant to platinum compounds and in 6 healthy volunteers. RESULTS: BAT was positive to CD203c or CD63 in 11 out of 15 patients allergic to platinum compounds (73%), with increased expression of CD203c and CD63 in 11 (73%) and 6 (40%) patients, respectively. Increased CD63 expression tended to be associated with more severe initial reactions. All controls had negative test results. Reactions during RDD were associated with BAT positivity and increased tryptase levels. Only 1 of 4 patients with negative BAT had a mild reaction during RDD. BAT remained positive in multiple sequential RDD. CONCLUSIONS: BAT identified patients allergic to platinum compounds with an increased risk of reactions during desensitization and higher CD63 expression was observed in severe reactions. Multiple RDDs to platinum compounds did not induce persistent hyporesponsiveness on basophils. BAT is a potential biomarker for RDD.

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 Women's 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.

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.

Diagnostic tools for hypersensitivity to platinum drugs and taxanes: skin testing, specific IgE, and mast cell/basophil mediators.

Hypersensitivity reactions (HSRs) to platinum drugs and taxanes are increasing in cancer patients, and rapid drug desensitization has emerged as a safe and effective method to reintroduce these drugs in reactive patients. Optimal management of patients presenting HSRs to chemotherapy depends on the use of various diagnostic tools, which include measurement of mast cell/basophil mediator release following a HSR and skin testing. Serum tryptase should be measured in patients presenting chemotherapy HSRs, and its elevation would support mast cell/basophil activation. Skin testing to platinum drugs has a high sensitivity and specificity and is critical to guide the management of platinum-reactive patients. Taxane skin testing is also emerging as a useful diagnostic and risk stratification tool in the evaluation of patients with HSRs to taxanes. Platinum sIgE assays have been recently developed and can be helpful in combination with skin testing or as an alternative when skin testing is not available.

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.

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.

Snail allergy without house dust mites sensitisation

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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.