Immediate Hypersensitivity Reaction to Chemotherapeutic Agents

Immediate Hypersensitivity Reaction to Chemotherapeutic Agents

Clinical Management Review Immediate Hypersensitivity Reaction to Chemotherapeutic Agents Pedro Giavina-Bianchi, MD, PhDa, Sarita U. Patil, MDb, and ...

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Clinical Management Review

Immediate Hypersensitivity Reaction to Chemotherapeutic Agents Pedro Giavina-Bianchi, MD, PhDa, Sarita U. Patil, MDb, and Aleena Banerji, MDb

An increase by 70% in new cases of cancer is expected over the next 2 decades, with more than 8 million people dying each year from the disease, an estimated 13% of all deaths worldwide. Several new chemotherapeutic agents have been rapidly developed and many of them approved through a fast-track process. In parallel, adverse reactions to chemotherapy have increased dramatically worldwide, frequently preventing the use of first-line therapy for cancer and jeopardizing patients’ treatment outcomes. The present review focuses on immediate hypersensitivity reactions (IHRs) induced by chemotherapeutic agents. We address general features of these reactions and specific characteristics of the most prevalent agents involved. On the basis of scientific evidence, we suggest classifying acute reactions to chemotherapy as toxic, systemic inflammatory response syndrome, and IHRs (anaphylactic-type reactions). IHRs to chemotherapeutic agents are unpredictable adverse reactions with potentially lethal consequences. Correct diagnosis and proper management of oncologic patients with IHRs are fundamental in order not to deprive them of the first-line treatment for their disease. In this scenario, rapid drug desensitization is a groundbreaking procedure that enables selected patients to receive the drug that induced an IHR in a safe way, minimizing the risks of anaphylaxis and treatment failure. Ó 2017 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2017;5:593-9) Key words: Hypersensitivity reactions; Chemotherapeutic agents; Anticancer drugs; Anaphylaxis; Cancer; Adverse drug reactions; Desensitization; Platinum-based agents; Taxanes; Doxorubicin

INTRODUCTION AND EPIDEMIOLOGY The average life expectancy at birth of the global population increased by 5 years between 2000 and 2015 and reached 71.4 years in 2015. In association, an increase by 70% in new cases of a

Clinical Immunology and Allergy Division, University of São Paulo, São Paulo, Brazil b Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, Mass No funding was received for this work. Conflicts of interest: S.U. Patil has received research support from the National Institutes of Health; and receives royalties from UpToDate. The rest of the authors declare they have no relevant conflicts of interest. Received for publication November 23, 2016; revised February 20, 2017; accepted for publication March 21, 2017. Corresponding author: Pedro Giavina-Bianchi, MD, PhD, Clinical Immunology and Allergy Division, University of São Paulo, R. Prof. Artur Ramos 178 ap.211A, Jd. América, São Paulo, SP 01454010, Brazil. E-mail: [email protected] 2213-2198 Ó 2017 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2017.03.015

São Paulo, Brazil; and Boston, Mass

cancer is expected over the next 2 decades, with more than 8 million people dying each year from the disease, an estimated 13% of all deaths worldwide. More than one hundred types of cancer exist, each requiring unique diagnosis and treatment.1 New chemotherapeutic agents have been rapidly developed and approved, many of them through a fast-track process with the purpose of getting important new drugs to the patient earlier. In parallel, adverse reactions to chemotherapy have increased dramatically worldwide, frequently preventing the use of firstline therapy for cancer and jeopardizing patients’ treatment outcomes. In 2010, anticancer drugs were the third leading cause of fatal drug-induced anaphylaxis in the United States.2 Hypersensitivity reactions (HRs) induced by drugs are a subgroup of important adverse drug reactions that are unpredictable and characterized by objectively reproducible symptoms and/or signs initiated by exposure to a drug at a dose tolerated by normal individuals.3 HRs can be classified as immediate and nonimmediate HRs, based on the interval between drug exposure and the onset of clinical manifestations. This classification correlates with the pathophysiological mechanism involved in the HRs and is associated with specific clinical manifestations.4,5 Immediate hypersensitivity reactions (IHRs) occur while the medication is being administered or within the first hour after drug exposure, often involve mast cell and basophil degranulation, and are characterized by urticaria, angioedema, rhinoconjunctivitis, bronchospasm, and anaphylaxis.5,6 Some authors have proposed that the immediate reactions should encompass reactions occurring up to 6 hours.7,8 HRs can be further classified as allergic, in which there is a specific immune response mediated by immunoglobulins and/or T cell, or nonallergic, without a specific immune response. Therefore, a patient can present allergic anaphylaxis, almost always mediated by IgE and, possibly, in few cases by IgG, or nonallergic anaphylaxis with direct degranulation of mast cells/basophils.9,10 However, these concepts are not recognized and used by all the experts involved in oncologic patients’ care, and many authors still use the term “hypersensitivity reaction” as described by Gell and Coombs. To avoid misunderstanding, here we will consider the 4 hypersensitivity mechanisms described by Gell and Coombs as hypersensitivity allergic reactions, types 1 to 4. Likewise, there is no standardized and widely accepted system to classify acute reactions to anticancer agents. For example, the National Cancer Institute of the National Institutes of Health published a descriptive terminology and grading system for uniform reporting of adverse events (CTCAE, version 4.0) in patients receiving cancer therapy. On the basis of current clinical practice and after reviewing the several types of acute reactions described in the literature, we suggest classifying them as toxic, systemic inflammatory response syndrome, and IHRs (anaphylactic-type reactions) (Table I).11-13 593

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Abbreviations used BAT- Basophil activation test HR- Hypersensitivity reaction IHR- Immediate hypersensitivity reaction RDD- Rapid drug desensitization sIgE- Specific IgE

We propose the term systemic inflammatory response syndrome to describe a group of acute reactions characterized by nonspecific inflammatory and immune reactions induced by anticancer agents. Actually, systemic inflammatory response syndrome has been previously described in the literature as an inflammatory and immune response to injury and traumatic insults such as infection, pancreatitis, ischemia, multiple trauma, cytokine administration, and immune-mediated organ injury, among others.14 Systemic inflammatory response syndrome needs to be further studied and characterized, but it would include different HRs and non-HRs such as the cytokine release, the tumor lysis, and the vascular leak syndromes.15-17 There is an urgent need to standardize nomenclature that will promote better health assistance and allow researchers to compare their findings. Anaphylactic-type reactions can occur during the first or after several exposures to the drug. Reactions on the first or second exposure are generally not IgE-mediated, because there is not enough time for sensitization and a specific immune response, unless the patient is sensitized to another similar substance and a cross-reaction is involved. For example, most anaphylactic-type reactions to taxanes, which occur at the first exposures, are probably not IgE-mediated. In contrast, a patient can be sensitized to a platinum-based agent after several exposures and develop an allergic anaphylactic-type reaction. Oncologic patients presenting with drug HRs are frequently and irreversibly labeled as allergic, preventing the use of first-line therapies in the treatment of primary or relapsing tumors. In this scenario, a precise clinical history, a resolutive diagnostic workup, and a proper management are mandatory and improve patient outcomes.8,18-20 Classically, anticancer drugs are classified as chemotherapy, hormonal therapy, and immunotherapy. These drugs can also be classified on the basis of their targets: tumor cells or other elements involved in carcinogenesis (endothelium, extracellular matrix, and immune system).21-23 Chemotherapy drugs are subgrouped by both their chemical structure and mechanism of action such as alkylating agents, antibiotics, antimetabolites, cytoskeletal disruptors, and drugs that directly affect DNA or protein synthesis. Immunotherapies, such as administration of cytokines, adoptive cell transfer, and the recent success of blockade of the checkpoint modulators CTLA-4, PD-1, and PDL-1, have been developed to stimulate the antitumor response to kill cancer cells. In the past years, many discoveries in the tumor microenvironment have led to changes in the management of cancer and it is raising hopes, especially to those in advanced stages. The present review focuses on IHRs induced by chemotherapeutic agents. We address general features of these reactions and specific characteristics of the most prevalent agents involved.

DIAGNOSIS The diagnosis of an IHR and its cause is based on the patient’s medical history, in vivo tests (cutaneous tests and drug

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challenges), and in vitro tests (serum specific IgE [sIgE] and basophil activation test [BAT]) (Figure 1).19,24 It is difficult to develop diagnostic tests for drug allergy, because most drugs act as haptens, which bind irreversibly to proteins in order to generate antigens and induce immune responses. The picture becomes more complex, as many haptens are drug metabolites or even compound additives. Immunologists and allergists have to be trained to perform this challenging task. Protocols for skin testing to many types of chemotherapeutic agents have been described (Table II). Standard skin testing protocols use stepwise skin prick testing followed by intradermal testing if the former is negative. The skin testing also includes a positive control (0.1 mg/mL histamine base) and a negative control (saline). A positive skin test result can be defined as a wheal with a greatest diameter of 3 mm greater than that seen with saline.32 Although skin tests are the most readily available means for investigating sensitization, further studies need to evaluate their predictive values for IHR induced by most chemotherapeutic agents. Likewise, serum sIgE measurement has always been unavailable in drug allergy because most drugs act as haptens and there are difficulties with their binding to a solid-phase matrix. Although the quantification of sIgE may be less sensitive than skin tests, it has no risk of inducing cutaneous toxicity and/or anaphylaxis. There are no commercial sIgE tests for chemotherapeutic agents, but preliminary findings showed their potential in the diagnosis of IHRs to platinum-based agents.27,33,34 The BAT has been studied in the investigation of IHRs to allergens, especially when skin tests and sIgE are inconclusive or nonexistent.35,36 BAT assesses the expression of basophil activationerelated proteins (CD63 and CD203c, among others) by flow cytometry after stimulation with the allergen of interest.35 BAT has also been studied as a diagnostic tool to identify patients with IHRs to drugs, including chemotherapy.36,37 Because of limited sensitivity, a negative skin or in vitro test result does not rule out risk for IHRs to chemotherapeutic agents, and, before readministration, a drug provocation test is necessary in patients with compatible clinical history of IHRs.38,39 Drug provocation test is the criterion standard for the identification of an IHR-eliciting drug, specially when skin and serum sIgE test results are negative, not available, or not validated. Its negative predictive value is around 95%.40

MANAGEMENT Patient’s risk stratification, assessing the risk/benefit rate, is the first task to be performed. Risk stratification is based on the severity of the initial IHR, the comorbidities associated, and the drugs taken by the patient. Then, a decision has to be made: reintroduce the drug that induced the IHR or not. To reintroduce chemotherapeutic agents that were the causes of IHRs and to prevent the recurrence of these reactions, 3 procedures have been used: premedication, extension of infusion time, and desensitization. After an IHR induced by a chemotherapeutic agent, a slower reinfusion with or without added premedication does not guarantee an uneventful drug administration.41,42 There is no good evidence in the literature to support the first 2 procedures as single actions in patients who have had IHRs induced by chemotherapy. However, rapid drug desensitization (RDD) is a safe and effective method of reintroducing chemotherapeutic agents in these patients, being

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TABLE I. Types of acute adverse reactions to anticancer agents Type of acute adverse reactions

Toxic (non-HRs) Systemic inflammatory response syndrome (SIRS) (some may be IHRs)

IHR (anaphylatic-type reactions)

Mechanism of action

Example

Chemotherapeutic agent effect Unspecific inflammatory and immune reactions: cytokine release syndrome (cytokine storm); tumor lysis syndrome; vascular leak syndrome IgE-mediated mast cell/basophil degranulation (allergic) Direct mast cell/basophil degranulation (nonallergic)

Nausea and vomiting induced by doxorubicin Reactions to mAbs

Anaphylaxis to platinum-based agents Anaphylaxis to raxanes

FIGURE 1. Management of hypersensitivity reactions to chemotherapeutic agents.19,24,25 AGEP, Acute generalized exanthematous pustulosis; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. *Some protocols propose the repetition of skin testing before proceeding to drug provocation test, because there is a risk for false negatives, specially when it is completed within 4 to 6 weeks of the initial IHR.24

supported by several studies.20,33,43 There is also good evidence supporting the utilization of premedication in the RDD protocols.20,33,43,44

Desensitization RDD is the induction of a state of unresponsiveness to a drug responsible for an IHR in a short period of time, usually several hours. RDD is the cornerstone of management of allergic and nonallergic IHRs, allowing patients to be safely exposed to the culprit drug (Figure 1). Such temporary unresponsiveness can be achieved by gradual reintroduction of small doses of the involved drug up to full target dose, reducing the risk of serious and potentially lethal HRs.45 RDD has evolved from empiricism to evidence-based therapy, and its effectiveness has been supported by successful clinical outcomes.43,46,47 RDD is indicated for patients with IHRs when the culprit chemotherapeutic agent is more effective (increased quality of life

and/or life expectancy) and/or associated with fewer side effects than alternative drugs. The procedure should be recommended after an individual risk stratification showing that the benefits outweigh the risks, and must be undertaken with caution in high-risk patients (severe initial anaphylaxis; uncontrolled and/or severe respiratory disease; uncontrolled and/or severe cardiac disease; uncontrolled and/or severe systemic diseases; use of betablockers, or angiotensin-converting enzyme inhibitors).45,48,49 Although there are some generalizable characteristics of RDDs, the procedure is drug and dose specific, and the risk stratification has to be individualized for every patient. RDD consists of the consecutive administration of small doses of the culprit drug until the full therapeutic dose is reached. The goal of the procedure is to administer low doses to the patient that will promote subthreshold stimulation of mast cells/basophils, inducing inhibitory mechanisms and rendering these cells hyporesponsive. The challenge of RDD is to gradually increase

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TABLE II. Specific characteristics of the most prevalent IHRs to chemotherapeutic agents Chemotherapeutic agents

Type of IHR

Exposure number (reaction)

26

Platinum-based agents

Allergic anaphylaxis

Taxanes

Allergic and aonallergic† First, second anaphylaxis Nonallergic anaphylaxis First

Doxorubicin

Tryptase during reaction

After repeated exposure Can be increased (typically eighth or ninth)

Evidence of IgE-mediated reaction

þ Skin tests þ serum sIgE27 þ BAT26,28-30 24

Can be increased25 þ Skin tests25,31 þ serum sIgE25,31 Can be increasedz No

Concentration of skin tests

Carboplatin SPT (10 mg/mL) ID (1 and 5 mg/mL*) Oxaliplatin SPT (5 mg/mL) ID (0.5 and 5 mg/mL) Cisplatin SPT (1 mg/mL) ID (0.1 and 1 mg/mL) SPT (1 mg/mL) ID (0.001 and 0.01 mg/mL) Skin tests not recommended

ID, Intradermal test; SPT, skin prick test. *Some authors perform the ID test with 10 mg/mL of carboplatin, but this concentration can induce skin necrosis. †Evidences suggest that most reactions to taxanes are not IgE mediated. zUnpublished case.

Cumulative serum drug concentration

Threshold for anaphylaxis

Cumulative Dose

Target Dose

FIGURE 2. Hypothetical mechanism of RDD.19,50

the dose of medication, increasing the threshold concentration that would induce a reaction, without triggering anaphylaxis, although mast cells/basophils may release some amount of mediators during RDD. Each administered dose would induce more cell inhibition and raises the threshold for clinical symptoms (Figure 2).19,50 There are several protocols of RDD with starting doses ranging from 1/10,000 to 1/100 of the full therapeutic dose, but it can be as low as 1/1,000,000 in very high-risk patients. In patients with positive skin test result to nonirritating concentration of a drug, the starting dose can be determined on the basis of the end-point titration. Classical protocols increase doses by doubling them every 15 to 20 minutes over the course of several hours until the therapeutic dose is reached.33,43,45,46,51 Oral and parenteral (intravenous, intramuscular, and subcutaneous) routes of administration can be used for RDD, presenting similar effectiveness. Drug RDD induces a temporary state of tolerance that depends on the drug half-life. Typically, if the patient requires further drug exposure and time after RDD exceeding 2 half-lives has elapsed, the patient will need to be re-desensitized. Breakthrough reactions during RDD are usually less severe than or similar to the initial IHR, and no deaths have been reported in

the last 15 years.52 The anaphylactic reaction induced by RDD should be treated in the same way as those induced by other agents.46 However, a higher level of medical monitoring during RDD is needed, as patients are premedicated and some symptoms of HR induced by chemotherapy are not typical of anaphylactic-like reactions. During desensitization, breakthrough IHRs are seen about 30% to 60% of the time.24,32,43,46 Mild IHRs are treated with cessation of the protocol and administration of antihistamines. More severe or recurrent IHRs are additionally treated with corticosteroids, and anaphylaxis should be treated with epinephrine 0.5 mg intramuscular. Once HR symptoms resolve, the desensitization can be resumed at the last tolerated step and continued with close monitoring for another possible reaction.

SPECIFIC CHEMOTHERAPEUTIC AGENTS Platinum-based agents Carboplatin, cisplatin, and oxaliplatin are the most common platinum-based chemotherapeutic agents associated with IHRs. These agents are commonly used in the treatment of solid tumors, including ovarian, breast, endometrial, lung, gastrointestinal, and prostate cancers. In many treatment regimens, these medications are the first-line agents, and IHRs limit their use, often resulting in the selection of an alternate, and at times, less optimal treatment regimen.53 Clinical history, skin tests, serum sIgE, and BAT show that IHRs to platinum-based agents are primarily IgE-mediated, although cytokine release syndrome with fevers and chills has also been reported.27,54 IHRs affect about 8% to 22% of adult and pediatric patients treated with carboplatin.46,55-60 To illustrate, a woman with ovarian cancer can become sensitized during the first course of chemotherapy (6 carboplatin infusions), and, when the cancer recurs after several months, her immune system is boostered during the seventh chemotherapy administration and she presents anaphylaxis on subsequent exposures. Scientific data suggest that BRCA 1/2 mutations are independent risk factors for IHR to carboplatin. Patients with these mutations develop the initial IHR with lower cumulative doses of carboplatin and are more prone to present IHR during RDD.13,61

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Clinical manifestations. Repeated administration of platinum-based chemotherapeutic agents is associated with an increased rate of IHR.58 Specifically with carboplatin, the incidence of HR increases from 1% after the first dose of carboplatin to 27% after 7 doses, with the peak incidence of HR at the eighth or ninth dose, which often corresponds with restarting treatment for malignancy recurrence.25,58 The onset of HR to oxaliplatin also occurs on average during the eighth course.62 IHR to platinum-based agents can range from mild cutaneous manifestations (flushing, pruritus, and urticaria) to systemic anaphylaxis, defined as reactions involving at least 2 organ systems, often with cutaneous, gastrointestinal, respiratory, and cardiac symptoms. The rate of cutaneous symptoms (flushing, erythema, pruritus, urticarial) to carboplatin can reach 80% to 100% in previously studied reactive cohorts, and around 50% of these patients can have cardiovascular involvement.32 In particular, palmar pruritus is a common presentation seen in about 50% of patients.32,43 Other commonly observed symptoms included throat tightness, nausea, emesis, and nasal symptoms. Similar to carboplatin, the most common presentation of oxaliplatin IHR is cutaneous symptoms, affecting up to 80% of patients.62 Cardiovascular (in particular hypertension or hypotension), pulmonary (dyspnea, chest tightness, and cough), and gastrointestinal reactions (nausea, emesis, diarrhea) affect about 30% of patients each. One unique characteristic is that about 20% of patients have constitutional symptoms including fever, chills/rigor, and somnolence during their HRs. Musculoskeletal symptoms have been shown to affect a small subset of these patients.62 Less commonly, delayed HRs to platinum-based agents have been usually described as mild cutaneous reactions, though more severe reactions have been reported, mainly to oxaliplatin, such as antibody-mediated thrombocytopenia, pulmonary fibrosis, and serum sickness.54,63-65 Management. Skin testing is the main diagnostic tool used to identify allergic patients to platinum-based agents, but its specificy and sensitivity are not optimal.62 Its sensitivity ranges from 40% to 80%.66 The same limitation was observed in a study assessing serum sIgE.27 Based on these preliminary results, oxaliplatin sIgE measurement appears more sensitive and carboplatin sIgE measurement more specific. Cross-reactivity among platinum-based agents could also be assessed by sIgE test.27 Because of potential false-negative skin test results in patients, particularly in those whose last exposure to the platinum-based agent occurred more than 6 months ago, we recommend repeat skin testing for patients with clinical history of IHR and negative skin test result.24,32 These recommendations are based on a longitudinal study of patients with carboplatin IHR who underwent repeat skin testing after carboplatin exposure if they had an initial reaction suggestive of an IHR and their skin test result was negative. In patients with a distant history of IHR (greater than 6 months), 80% had a negative skin test result that seroconverted to positive after additional carboplatin treatment as compared with 8% without a distant history of HR.24 Patients at risk for having IHRs to carboplatin or oxaliplatin therapy can be managed with desensitization while waiting to repeat skin testing (Figure 1).24,32,66 In those patients at lower risk of seroconversion who have negative repeat skin testing, management with outpatient infusion at 50% of the rate has been successfully used.66 In a cohort of patients with oxaliplatin HR, 2 patients

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were found to serocovert from negative to positive skin testing.62 For carboplatin skin testing, the top intradermal testing concentration is 5 mg/mL to limit the side effect of skin necrosis associated with higher doses.66 BAT using CD203c and CD63 as activation markers can identify platinum-allergic patients.26,28-30 Higher CD63 expression is associated with more severe reactions, BAT can identify patients more prone to reaction during the procedure, and multiple RDDs to platinum-based agents do not induce persistent basophil hyporesponsiveness.26 Therefore, BAT can be a diagnostic and prognostic tool for the management of IHRs to platinum-based agents. Desensitization can be successfully used in the management of patients with IHR to platinum-based agents, especially when they are the first-line therapies.43 In those with established IHR, a 12-step protocol in a monitored setting (in an inpatient setting with allergy specialist supervision) has been effective in delivering full chemotherapeutic doses to patients requiring therapy. This protocol starts at 1/1,000 to 1/10,000 of the final concentration, and doubles the dose every 15 minutes over 12 steps, using 3 different dilutions. A 13-step protocol similar to the 12-step protocol with an additional 60 mL/hour step in between steps 11 and 12 can also be used.66 The tolerance induced by desensitization is transient and, therefore, the procedure has to be repeated for each subsequent chemotherapy administration. Patients who are considered to be at lower risk, based on the clinical history of the initial HR and negative skin testing, can be safely managed with an 8-step desensitization protocol. Antihistamine premedication is recommended before the use of these desensitization protocols.24,32 Low-risk patients, who have a negative skin test performed between 6 weeks and 6 months after their initial HR and who are therefore at a lower risk of having a false-negative skin test result, may be candidates to receive carboplatin by infusion at 50% of the standard rate in an outpatient infusion center setting.66 For premedication, our group has used H1 receptor antihistamines on the evening before desensitization, the morning of desensitization, and immediately before initiation of desensitization. In addition, H2 receptor antihistamines can be used. Patients with mild cutaneous symptoms (flushing, erythema) as part of their HR may also benefit from premedication with oral aspirin 325 mg on the night before and 1 hour before their desensitization protocol begins.44

Taxanes Taxanes are chemotherapeutic agents that are mainly used in the treatment of ovarian, endometrial, breast, nonesmall cell lung, head and neck, pancreatic, gastric adenocarcinoma, and prostate cancer. The 2 main taxane molecules are paclitaxel and docetaxel. Paclitaxel (Taxol) is a natural molecule that was originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) in the 1960s and docetaxel is a semi-synthetic molecule derived from a taxoid precursor found in European yew tree needles. Given their low solubility, they are formulated with solvents to allow intravenous administration. Because solvents used in the formulation of taxanes were associated with IHRs, a solvent-free paclitaxel formulation (nanoparticule albumin-bound paclitaxel) was developed. It can be infused faster, without premedication, and presents a lower rate of IHRs.67,68

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Clinical manifestations. The mechanism of IHRs to taxanes remains uncertain and can be more than 1. Typical symptoms and signs of anaphylaxis, such as flushing, dyspnea, throat tightness, and hypotension, are observed during reactions to taxanes. However, patients also report symptoms that are atypical for IHRs such as crushing chest, back, and/or pelvis pain.43 Most reactions occur during the first or second lifetime infusion, after few minutes have elapsed, which suggests a nonallergic mechanism. Solvents used to solubilize the taxane molecules (cremophor for paclitaxel and polysorbate 80 for docetaxel) can cause complement activation leading to anaphylatoxins production and mast cell activation.69 More recently, IgE-mediated IHR to the taxane molecule itself has been reported, supporting the use of skin test to evaluate patients.25,31 Management. At the beginning, IHRs to taxanes were very frequent and led to the use of premedication with corticosteroids and antihistamine, significantly reducing the rate of IHRs. However, even with premedication and with lower infusion rates, IHRs occur in 5% to 15% of patients, being severe in 1% of them.70,71 A recent study showed that risk stratification based on skin testing and the severity of the initial HR can safely guide patients’ management.25 In patients who react to taxanes, RDD has been shown to be a safe and effective means of reintroducing the drug.43 Doxorubicin The most common adverse reaction to doxorubicin is the hand-foot syndrome, or palmar-plantar erythrodysesthesia, which presents as painful erythema of the palms, soles, and fingers and can also evolve to include blisters and erosions, seen in up to 40% of treated patients, especially with high and/or frequent doses. This reaction can also result in cumulative damage.72 In contrast, IHRs are less frequently observed. Clinical manifestations. Clinical manifestations of IHRs with doxorubicin and liposomal doxorubicin can occur with the first infusion and include symptoms such as flushing, dyspnea, chest pain, and syncope.43,73 Management. Skin testing with doxorubicin and liposomal doxorubicin is not recommended because of the high frequency of skin toxicity including skin necrosis, which has also been seen at sites of doxorubicin extravasation.72,74 A 12-step desensitization protocol has been successfully used for readministration of doxorubicin and liposomal doxorubicin in patients with IHRs, according to the literature and to our clinical experience.43,73 CONCLUSIONS IHRs to chemotherapeutic agents are unpredictable adverse reactions with potentially lethal consequences. These reactions have become more frequent with the growing incidence of cancer and increased utilization of chemotherapy. Correct diagnosis and proper management of oncologic patients with IHRs are fundamental in order not to deprive them of the first-line treatment for their disease. In this scenario, RDD is a groundbreaking procedure that enables selected patients to receive the drug that induced an IHR in a safe way, minimizing the risks of anaphylaxis and treatment failure. Allergist-immunologists have to be well trained to perform these tasks. In this review, we updated and discussed the IHRs to chemotherapeutic agents,

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