Chemotherapy Hypersensitivity

Chemotherapy Hypersensitivity – 9 Interesting Facts

Chemotherapy HSRs (hypersensitivity reactions) are systemic allergic reactions to chemotherapeutic agents that can range in severity from cutaneous-only to severe high-grade anaphylaxis
Platins (eg, cisplatin, carboplatin, oxaliplatin) and taxanes (eg, paclitaxel, docetaxel) are among the most commonly implicated classes of chemotherapy known to cause HSRs, though theoretically any agent can cause an HSR
Prevalence of chemotherapy HSRs varies according to drug; the overall incidence of chemotherapy HSR is not well-established
There are no standardized diagnostic criteria for chemotherapy HSR; this is primarily a clinical diagnosis made on the basis of compatible history and presentation
When a reaction occurs, immediate treatment depends on the severity of symptoms and can include stopping the infusion, oxygen, IV fluids, antihistamines, corticosteroids, and/or epinephrine
History of HSR to a chemotherapeutic should not lead to use of second line agents, because allergic patients can safely receive chemotherapy through desensitization
If a reaction occurs, a referral to an allergist with experience in the evaluation and management of chemotherapy reactions can guide next steps of how to safely readminister the chemotherapy agent. This is especially important when the specific offending agent is part of first line treatment for the patient’s cancer diagnosis
Risk stratification and subsequent planning for a drug challenge, slowed infusion, or desensitization are the optimal approach to a patient after an HSR to a chemotherapeutic
With appropriate management, nearly all patients can continue to receive the same chemotherapy again despite an HSR. This requires close collaboration between the oncologist and the allergist

Introduction

Chemotherapy HSRs (hypersensitivity reactions) are systemic allergic reactions to chemotherapeutic agents that can range in severity from cutaneous-only to severe high-grade anaphylaxis
- These reactions can be IgE or non-IgE mediated and can represent significant hurdles to continuing treatment with highly preferred first line chemotherapeutic agents (as determined by known efficacy and/or adverse effect profile)
- Platins (eg, cisplatin, carboplatin, oxaliplatin) and taxanes (eg, paclitaxel, docetaxel) are among the most commonly implicated classes of chemotherapy known to cause HSRs, though theoretically any agent can cause an HSR
- Biologics represent a growing class of drugs that can cause HSRs

Epidemiology

Prevalence of chemotherapy HSRs varies according to the drug; the overall incidence of chemotherapy HSR is not well-established¹
- Platin-based drugs are the most common class of chemotherapy that can lead to IgE-mediated allergic reactions. Most reactions occur after the eight lifetime exposure²
  - Prevalence of carboplatin HSR is 1% to 2% with initial treatment but increases to approximately 22% to 40% in patients who have 8 or more lifetime exposures²
  - Prevalence of cisplatin allergy is 5% to 20%³
  - Oxaliplatin allergy prevalence is about 20% with most reactions that occur after the sixth lifetime dose⁴
- HSRs to other chemotherapy drugs, including taxanes, frequently occur with the first or second exposure⁵⁶

Etiology and Risk Factors

For platins, repeated exposure can lead to IgE sensitization, resulting in reproducible and persistent HSRs via generation of drug-specific IgE antibodies.⁷ IgE antibodies mediate mast cell activation, resulting in degranulation and release of inflammatory mediators
- Carboplatin HSRs are typically IgE mediated²
- For cisplatin, concomitant radiation therapy seems to increase the risk of developing an IgE-mediated HSR³
HSRs to other chemotherapy drugs, such as taxanes, are thought to be non-IgE mediated because they often occur with the first or second exposure, typically too early for IgE sensitization to occur unless sensitized via exposure to a cross-reactive substrate. These reactions do have the potential to resolve with subsequent exposures⁵⁶
- Paclitaxel reactions are thought to be because of direct mast cell activation⁵
  - Taxol is paclitaxel solubilized into solution with Cremophor (polyethoxylated castor oil), which can directly activate mast cells possibly via classical complement pathway activation and generation of anaphylatoxins such as C3a and C5a. Paclitaxel solubilized using albumin nanoparticles (Abraxane) has a much lower incidence of HSR, likely due to the absence of Cremaphor⁸
- Taxotere and a number of biologics contain the surfactant polysorbate 80, which can also activate mast cells directly, possibly via the generation of peroxide radicals. Peroxide radical generation can be enhanced by unnecessary exposure of the drug to heat and/or light⁹

Diagnosis

Approach to Diagnosis

History is typically the most important tool in evaluating a chemotherapy HSR (hypersensitivity reaction) and begins with an assessment of the specific symptoms, the time of onset relative to the start of the infusion, and response to interventions
- Typical symptoms due to release of mast cell mediators include flushing, pruritus, urticaria, angioedema, dyspnea, and/or anaphylaxis. Acute nausea, vomiting, and/or diarrhea can occur in this setting
- Because mast cell mediators are released from preformed granules within the mast cell, symptoms usually occur and progress rapidly
- HSRs will usually respond promptly to interventions such as epinephrine and antihistamines
A serum tryptase level obtained within 2 hours of an HSR can be helpful in confirming a mast cell–mediated reaction when elevated.¹⁰¹¹ A normal tryptase level would not rule out an HSR
In some cases, skin testing can provide evidence of IgE sensitization, which can affect management decision-making¹²
Preliminary evidence suggests that interleukin-6 can be a novel biomarker for certain types of chemotherapy HSRs; further studies are needed to define the role of this assay in management¹³
Other tests, such as histamine, urine metabolite assays, and specific IgE, are not used to assess chemotherapy HSR
- Histamine is not typically used for hypersensitivity evaluation given its short half-life, and clinically relevant reference ranges for urine metabolite assays are not well-established
- Specific IgE assays for evaluation of chemotherapy HSR are yet to be approved by the FDA for use in the United States
A comprehensive discussion of the evaluation of allergic hypersensitivity is beyond the scope of this Clinical Overview, which focuses on aspects relevant to chemotherapy HSR

Diagnostic Criteria

Chemotherapy HSR
- There are no standardized diagnostic criteria for chemotherapy HSR
- Primarily a clinical diagnosis made on the basis of compatible history and presentation, with systemic allergic reactions to chemotherapy which are typically rapid in onset (seconds to minutes), and can range from cutaneous only to life-threatening (ie, high-grade anaphylaxis)¹⁰
Anaphylaxis
- Various criteria for defining anaphylaxis exist that acknowledge a wide spectrum of presentation
- One of the first attempts to define criteria that would aid the diagnosis of anaphylaxis led to the widely cited NIAID/FAAN (National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network) criteria which state that anaphylaxis is highly likely when 1 or more of the following are met:¹⁴
  - Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and at least 1 of the following:
    - Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
    - Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, incontinence)
  - 2 or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):
    - Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula)
    - Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
    - Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
    - Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
  - Reduced blood pressure after exposure to a known allergen for that patient (minutes to several hours)
    - Infants and children: low systolic blood pressure (age specific) or greater than 30% decrease in systolic blood pressure from baseline
    - Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from that person’s baseline
- In 2020, the World Allergy Organization updated their diagnostic criteria for anaphylaxis, simplifying the NIAID/FAAN criteria by combining the first 2 NIAID/FAAN criteria and modifying the third¹⁵
  - Acute onset (minutes to several hours) of typical mucocutaneous symptoms and significant symptoms from at least 1 other organ system after exposure to a known or probable allergen or
  - Acute onset (minutes to several hours) of respiratory and/or cardiovascular compromise after exposure to a known or probable allergen

Staging or Classification

Classification

Drug HSRs are traditionally classified into 4 pathophysiological types based on a system developed by Gell and Coombs in the 1960s;¹⁶ although immunologic understanding has advanced, this system is still widely used to provide a basic framework for classifying different types of HSRs¹⁷
- Gell and Coombs classification¹⁶
  - Type I: IgE mediated, immediate type
  - Type II: antibody-dependent cytotoxicity
  - Type III: immune complex disease
  - Type IV: cell mediated, delayed hypersensitivity
Isabwe et al¹⁸ recently proposed an updated classification system for HSRs to monoclonal antibodies based on the allergy workup, separating patients into different endophenotypes and comparing their outcomes; this is potentially a promising approach to classifying chemotherapeutic reactions more generally
- 4 phenotypes are identified with this system
  - Type I (IgE or non-IgE)
  - Cytokine release
  - Mixed (type I or cytokine release)
  - Type IV

Grading

Grading of reactions to chemotherapeutic agents is not standardized, and several different grading systems are used in the literature
- Grading the severity of reactions is important for considering various treatment approach options such as desensitization
- An anaphylaxis classification system by Brown¹⁹ has been widely used, whereas others in the field have used Ring and Messmer²⁰
  - Brown grading¹⁹
    - Grade 1: mild (skin or subcutaneous involvement only)
    - Grade 2: moderate (respiratory, cardiovascular, or gastrointestinal involvement, not meeting criteria for severe)
    - Grade 3: severe (hypoxia, hypotension, or neurologic compromise)
  - Ring and Messmer grading²⁰
    - Grade I: mucocutaneous involvement only
    - Grade II: moderate, non–life-threatening organ involvement (respiratory, cardiovascular, or gastrointestinal)
    - Grade III: severe, life-threatening organ involvement
    - Grade IV: cardiopulmonary arrest
In addition, the National Cancer Institute has published standardized definitions for adverse events, known as CTCAE (Common Terminology Criteria for Adverse Events), and this scale is also commonly used to grade and report reactions²¹
- Severity for each adverse event is graded on a scale of 1 to 5
  - Grade 1: mild
  - Grade 2: moderate
  - Grade 3: severe but not life-threatening
  - Grade 4: life-threatening
  - Grade 5: death related to adverse event
Chemotherapeutic reactions add additional complexity with additional clinical symptoms not incorporated into standard grading systems
Finding an optimal and universal grading system for drug reactions remains an unmet need

Workup

History

Symptoms
- Mast cell–mediated symptoms typically occur on a timescale of seconds to minutes of exposure (as opposed to hours to days) and most often include cutaneous symptoms of flushing, pruritus, and urticaria or angioedema
- More severe presentations would also include cardiopulmonary symptoms such as dyspnea, lightheadedness, and syncope. Gastrointestinal symptoms such as nausea, emesis, and diarrhea can also occur due to mast cell presence in gut tissue
Onset or response to interventions
- Mast cell–mediated reactions typically occur at the time of exposure to the culprit drug and rarely more than an hour after the exposure has occurred, especially if the drug is given IV
- Rapid response to medical therapy is typical of chemotherapy hypersensitivity
  - Anaphylaxis typically responds within seconds to minutes of epinephrine administration
  - Cutaneous-only reactions generally respond well to antihistamines
Vital sign changes
- Severe reactions featuring changes in vitals more strongly suggest cardiopulmonary involvement that can affect the management approach and the pretest probability of skin testing (if applicable)
Prior exposure
- This is useful mainly in the setting of reactions to platin-based drugs because this type of drug allergy tends to be IgE mediated, usually requiring prior exposures for IgE sensitization to occur

Physical Examination

Examination should begin with a quick assessment of the patient’s overall status, because syncope or presyncope is an immediate cause for concern of high-grade anaphylaxis requiring immediate administration of epinephrine
Next, assess vital signs including pulse, blood pressure, and O₂ saturation to determine if the patient is unstable and/or if there has been a change from the preinfusion baseline values
Perform a careful oropharyngeal, heart, lung, and skin examination looking specifically for signs of angioedema, tachycardia, wheeze, stridor, flushing, and/or urticaria

Laboratory Tests

Tryptase
- Released from mast cell granules in parallel with other vasoactive mediators of anaphylaxis such as histamine
- Serum tryptase level should ideally be obtained within 2 hours of symptom onset when a chemotherapy HSR (hypersensitivity reaction) occurs¹⁰¹¹
- A more stable serum marker of anaphylaxis than histamine, typically peaking within 1 to 2 hours of the onset of symptoms which is the ideal time window to check this laboratory test. Serum tryptase levels gradually decrease over several hours¹¹
- Interpretation
  - Most baseline tryptase levels are less than 11.0 ng/mL, and levels greater than 20 ng/mL are usually indicative of anaphylaxis or an underlying mast cell disorder such as systemic mastocytosis or hereditary alpha tryptasemia²²
  - Even if a tryptase level is found to be less than 11.0 ng/mL in a patient who had clinical anaphylaxis, it is useful to check the baseline tryptase level in the nonacute setting as a more accurate comparison reference to interpret the test drawn in the acute setting
    - European Union and US experts participating in the 2010 Working Conference on Mast Cell Disorders recommended using an acute serum tryptase level of at least 1.2× baseline tryptase level plus 2 ng/mL as indicative of clinically significant mast cell activation²³
      - For example, if baseline tryptase level is 10 ng/mL, an acute tryptase level of at least 14 ng/mL ([1.2× baseline level of 10 is 12] + 2 = 14) would be consistent with mast cell activation
    - Because baseline tryptase levels can vary widely among people, defining absolute cutoffs for the diagnosis of anaphylaxis is difficult. Multiple studies have shown clinical validation for using the “1.2x + 2” consensus formula in interpreting tryptase level in the context of anaphylaxis²⁴
Other tests
- A phenotype of cytokine release reactions may be responsible for some HSRs to oxaliplatin as well as to monoclonal antibodies. Preliminary studies have found cytokine release reactions consistently associated with increased serum interleukin-6 levels, suggesting that interleukin-6 can be a novel biomarker in distinguishing among different types of HSRs¹³
- Although European guidelines describe potential use of other in vitro tests such as basophil activation testing and drug-specific IgE in the diagnosis of HSR to platinum drugs, these assays are not FDA-approved for use in the United States¹⁰

Diagnostic Procedures

Skin testing
- A very useful diagnostic tool for evaluation of patients after a reaction, but it should be used with an understanding of its limitations
- Positive skin testing may support diagnosis of IgE-mediated HSRs, but negative results are not used to exclude diagnosis of chemotherapy HSR (which is primarily clinical)¹⁰¹²
- Most widely used diagnostic tool in the evaluation and risk stratification of platin HSRs;¹² high positive and negative predictive values have been reported in the literature¹⁰
- Procedure¹²
  - Various testing protocols have been developed and vary depending on the specific drug of interest and institutional or center protocols
  - Generally performed with epicutaneous skin testing followed by intradermal injections of escalating doses of drug until a reaction has been elicited, or a predefined maximum dose of the drug has been reached
  - Positive skin test result is defined by the diameter of resulting wheal or flare compared with negative control
  - Risk of severe reactions with skin testing is minimal, but skin testing should be performed under the guidance of an experienced practitioner familiar with the management of HSRs and anaphylaxis
- Interpretation
  - Skin testing has primarily been used as a risk stratification tool to guide choice of desensitization protocol after platin HSR
    - Positive skin testing for platins suggests IgE sensitization to these agents and is predictive of HSRs on reexposure; these patients are more likely to experience HSRs during desensitization¹⁰
    - Though negative skin testing does not rule out risk of future HSR, reactions in this setting are generally milder;¹² negative skin testing during the right time frame after an HSR can provide reassurance that patients can transition to faster desensitization protocols for subsequent infusions²⁵
  - Length of time between skin testing and prior platin exposure or HSR is also important in the interpretation. Based on data from Hymenoptera venom skin testing data and the risk of false negatives due to anergy, it is generally recommended that skin testing be performed at least 4 to 6 weeks after the initial HSR¹²
  - There are also higher rates of false-negative skin testing when performed more than 6 months after initial platin HSR, which suggests waning of skin test reactivity over time
  - Negative predictive value of a single intradermal test for carboplatin has been estimated at 81% to 92%¹²
- There are limited data to support use of skin testing for other classes of chemotherapeutics, though positive skin tests in patients with suspected HSRs to other drugs, such as taxanes, have been reported¹⁰
  - Skin testing has not been as routinely performed for taxanes, because the mechanism of hypersensitivity is thought, in most cases, to be non-IgE mediated⁵⁶
  - Diagnostic value of skin tests with other chemotherapy agents is uncertain¹⁰
- There is a need for additional studies and rigorous study designs to assess predictive values of skin testing to chemotherapeutics
- Other reasons to avoid unnecessary skin testing: certain chemotherapy drugs can cause nonspecific skin irritant effects or, as is the case with many newer biologics, may be cost prohibitive due to the cost of obtaining even a small aliquot of drug for testing

Differential Diagnosis

Table 1. Differential Diagnosis: Chemotherapy hypersensitivity.

Condition	Description	Differentiated by
Mastocytosis	Abnormal accumulation and activation of mast cells	Elevated baseline tryptase level, genetic studies for c-kit variant, skin and/or bone marrow biopsy
Systemic capillary leak syndrome	Episodic leakage of plasma into surrounding tissue causing hypovolemic shock and tissue edema	Much longer duration than a typical anaphylactic reaction (days versus minutes to hours). Normal tryptase level
Anxiety or panic attack	Psychosomatic	Response to anxiolytic or other anxiety intervention; normal tryptase level
Carcinoid syndrome	Overproduction and release of serotonin metabolites by neuroendocrine tumor which can cause flushing, diarrhea, and wheezing	Elevated urine 5-HIAA level
Pheochromocytoma	Overproduction and release of catecholamines by neuroendocrine tumor causing tachycardia, anxiety, and flushing	Elevated urine catecholamines level
Vocal cord dysfunction	Paradoxical vocal cord closure during inhalation resulting in hoarseness, stridor, and dyspnea	Can be diagnosed by laryngoscopy while symptomatic. Lack of response to bronchodilators

Caption: 5-HIAA, 5-hydroxyindoleacetic acid.

Treatment

Approach to Treatment

When a reaction occurs, immediate treatment depends on the severity of symptoms and can include stopping the infusion, oxygen, IV fluids, antihistamines, corticosteroids, bronchodilators, and/or epinephrine²⁶²⁷
- If the reaction is mild (eg, cutaneous only) and symptoms resolve quickly, using shared decision-making, infusion can be restarted the same day under close monitoring
- If the reaction is severe (eg, anaphylaxis), it is reasonable to stop any further treatment and refer to an allergist for further management planning
- A comprehensive discussion of anaphylaxis management is beyond the scope of this Clinical Overview; potential anaphylaxis should be managed according to institution-specific procedures and protocols
- A tryptase level within 2 hours of the reaction offers additional clinical value if elevated¹⁰¹¹
History of HSR (hypersensitivity reaction) to a chemotherapeutic should not lead to use of second line agents, because allergic patients can safely receive chemotherapy through desensitization²⁸
Risk stratification and subsequent planning for a drug challenge, slowed infusion, or desensitization are the optimal approach to a patient after an HSR to a chemotherapeutic²⁸
Knowledge of these tools can identify nonallergic patients, allowing first line therapy and returning patients to an outpatient setting for infusions

Nondrug and Supportive Care²⁶²⁷

When a reaction occurs, the first step is to stop the infusion and assess the patient including vital signs and physical examination
While assessing the patient, oxygen can be placed if any respiratory symptoms¹⁵
- High-flow oxygen via nonrebreather facemask is preferred if available
IV fluid is used for blood pressure support and anaphylaxis management¹⁵
- Boluses of isotonic crystalloid, up to 30 mL/kg for adults or 20 mL/kg for children, can be given and repeated as necessary to maintain adequate perfusion²⁹
Explanation of symptoms, treatment, and reassurance during the reaction are an important part of patient care during the reaction

Drug Therapy

If the symptoms are cutaneous only without systemic symptoms, use of nonsedating newer-generation antihistamine treatment (eg, cetirizine 10 mg or fexofenadine 180 mg) is reasonable³⁰
If reaction is severe or higher grade, including hypotension or concern for anaphylaxis, intramuscular epinephrine is first line therapy¹⁵²⁹
- Standard dosing
  - Pediatrics: 0.01 mg/kg (max 0.3 mg in infants/children, 0.5 mg in adolescents)
  - Adults: 0.3 to 0.5 mg
- Dosing should be repeated every 5 to 15 minutes if symptoms are ongoing
Antihistamines and glucocorticoids are second line treatments in anaphylaxis; they have no role in primary management and should not be given before or instead of epinephrine¹⁵²⁹
- H1 and H2 antihistamines may help with management of cutaneous and gastrointestinal symptoms but are not effective for life-threatening anaphylaxis manifestations
- Glucocorticoids are commonly administered in anaphylaxis, but robust evidence of benefit is lacking; routine use is controversial
If cough or wheezing is present, inhaled bronchodilators such as albuterol can be considered as part of the initial treatment strategy; bronchodilators are also second line treatment and not an alternative to epinephrine¹⁵²⁹
Common initial dosing for second line anaphylaxis therapies is summarized in Table 2
Evidence supporting use of antihistamines and glucocorticoids as premedication to prevent chemotherapy HSRs is mixed, and there is significant variation in guideline recommendations and expert or center practice patterns^10313233

Table 2. Second line therapies for anaphylaxis with adult and pediatric initial dosing.

Second line agents	Adult dosing	Pediatric dosing
Corticosteroids*
Dexamethasone	8-16 mg IV/IM/PO	0.3 mg/kg PO/IV/IM (max 8 mg)
Prednisone	1 mg/kg (max 50 mg) PO	1-2 mg/kg (max 50 mg) PO
Methylprednisolone	1-2 mg/kg (max 125 mg) IV	1-2 mg/kg (max 125 mg) IV
Hydrocortisone	200-500 mg IM or IV	5-10 mg/kg (max 500 mg) IM or IV
H₁ antagonists†
Diphenhydramine	25-50 mg IV/IM/PO over 5 minutes	1 mg/kg IM/IV/PO (max 50 mg) over 5 minutes
Cetirizine	10 mg PO over 1-2 minutes	Younger than 6 years 2.5 mg PO 6-11 years 5-10 mg PO
H₂ antagonist†
Famotidine	20 mg IV/PO	0.25 mg/kg (max 20 mg) IV/PO
Bronchodilators
Albuterol	2.5-5 mg nebulized every 20 minutes 3 times 4-8 puffs MDI every 20 minutes 3 times 15 mg/hour continuously nebulized	2.5-5 mg nebulized every 20 minutes 3 times 2-8 puffs MDI every 20 minutes 3 times 5-15 mg/hour continuously nebulized
Ipratropium	500 mcg nebulized	250-500 mcg nebulized

Caption: IM, intramuscular; max, maximum; MDI, metered-dose inhaler.

*Given lack of evidence that prolonged steroid course is effective in preventing recurrence, a 1-time dose of dexamethasone is recommended for patients with uncomplicated presentation.

†No proved benefit of IV over oral antihistamines; consider PO unless severe nausea and/or vomiting, and airway and/or respiratory compromise.

From McHugh K et al. Anaphylaxis: emergency department treatment. Emerg Med Clin North Am. 2022;40(1):19-32, Table 2.

Treatment Procedures

If a reaction occurs, a referral to an allergist with experience in the evaluation and management of chemotherapy reactions can guide next steps of how to safely readminister the chemotherapy agent. This is especially important when the specific offending agent is part of first line treatment for the patient’s cancer diagnosis
NCCN guidelines (National Comprehensive Cancer Network) likewise recommend allergist consultation in the event of HSR; patients who have had mild reactions have the potential to develop more serious reactions, and patients who have had severe reactions should not receive the implicated drug again unless under specialist guidance³⁴
Risk stratification based on clinical history can be used to determine suitability for drug challenge, trial of a slowed infusion, or an attempt at drug desensitization³⁵³⁶
Factors considered in risk stratification can include clinical features of prior HSR (ie, severity, symptoms, onset or duration, interventions, response to interventions), results of tryptase and skin testing, medical comorbidities, other medications, and pregnancy status. Various risk stratification protocols and tools have been developed and can assist in management decision-making¹⁰³⁵³⁶³⁷
Drug challenge
- A drug challenge involves administering a full dose of the drug to a person who carries a label of an unconfirmed or low-risk allergy (eg, subjective symptoms that improve without treatment) to that drug and is felt to be an essential tool for effectively delabeling (ie, removing the “label,” or diagnosis, of drug allergy from the patient’s chart) patients in the field of drug allergy
- Decision to use a drug challenge must include shared decision-making with the patient balancing the need for optimal treatment in an experienced center against the potential risks of a reaction
- Drug challenge is usually performed under the guidance of an allergist, under close monitoring in the rare case that a reaction occurs
- For chemotherapy reactions specifically, the drug challenge (full dose) can be performed in the infusion center, where the patient normally receives chemotherapy, under the supervision of a physician trained in the recognition and treatment of anaphylaxis (usually an allergy/immunology specialist)
  - If challenge is tolerated, the patient is deemed not allergic; further treatment can proceed in the outpatient infusion center
  - If an HSR occurs during the challenge, the next step would likely be to empirically desensitize
Slowed infusion
- Chemotherapeutic agent can be infused at a slower rate but still administrating a full dose. This has been successful in patients with low-risk reactions to chemotherapeutics (eg, flushing, dizziness without blood pressure alterations, pruritus without rash, cough that improved without treatment). A slowed infusion is also less labor-intensive, because it does not require a pharmacy team to make dilutions of the chemotherapy, as would be necessary with desensitization
- Slowed infusion can be performed in the infusion center where the patient normally receives chemotherapy
- There are no standardized guidelines to guide ongoing management after a trial of slowed infusion; in general, patients can continue slowed infusions in their usual site of treatment if tolerated—if not, referral for desensitization can be considered
Desensitization
- This is the gradual introduction of increasing amounts of a drug over hours leading to induction of tolerance to a specific drug
- Drug desensitization allows patients to safely receive a drug to which they previously had an HSR including anaphylaxis
- Desensitization needs to be performed with each subsequent cycle of chemotherapy
- Desensitization is indicated when there is a severe reaction history, but there are no reasonable alternative treatment options³⁷
- Desensitization is preferred over other approaches (ie, drug challenge or slowed infusion) in certain situations, such as in severely ill patients with prior drug allergy who need urgent treatment with the implicated drug but are not able to give a clear history due to sedation, impaired cognition, or lack of consciousness. Empiric desensitization is appropriate in these patients³⁷
  - These patients are unable to alert their care teams of any subjective reaction symptoms that would precede objective findings such as vital sign changes such as hypoxia or hypotension (which would be essential to note with drug challenge)
- Patients with significant cardiac or pulmonary conditions should be carefully evaluated for decreased functional reserve that would render them unable to cope with the stress of an HSR or treatment with epinephrine if a reaction occurs³⁷
- 2 major approaches to desensitization are used—one bag and multibag
  - One-bag desensitization
    - A full dose of chemotherapy is given during a one-bag desensitization³⁸
      - Published protocols have ranged from 4 to 17 steps; typically, infusion is initiated at a very low rate (eg, 0.1 mL/hour) and the rate is increased with each step, at 15-minute intervals
      - Total duration of infusion in published protocols typically ranges from 3 to 5 hours
      - These protocols provide a safe and effective means of facilitating readministration of a chemotherapeutic agent after a mild to moderate reaction (eg, hives improved with antihistamines, chest tightness that improves quickly) while decreasing the burden of resources required
  - Multibag desensitization
    - This has been the traditional approach to chemotherapy desensitization using 3 bags at a concentration of 1:100, 1:10, and 1:1 given slowly over multiple hours
    - There is a high rate of success with these protocols, but they are resource-intensive³²
    - They are used to allow a patient to continue to receive chemotherapy safely after a moderate to severe HSR including anaphylaxis when there is no reasonable alternative drug
  - Comparing one-bag and multibag approaches
    - One-bag protocols can have shorter time to completion compared with multibag protocols. In addition to being less resource-intensive from a pharmacy perspective (no dilutions), one-bag protocols require less nursing support because there is only 1 bag to administer³⁸
    - Although one-bag desensitization is less resource-intensive in pharmacy preparation and nursing administration, it does require a high-precision automatic pump
    - Retrospective studies show comparable outcomes in efficacy, tolerability, and safety between one-bag desensitization and 3-bag or multibag desensitization protocols that have been used more commonly in the past decade³⁹
    - However, there is no true side-by-side data comparing one-bag protocols with multibag protocols
    - Most of the patients receiving one-bag protocols were low to medium risk in most studies
    - In addition, it is typically not possible to achieve the same small concentrations for the initial doses as a multibag desensitization protocol and this should be taken into consideration when deciding on the protocol, especially for higher-risk patients
- Resource considerations³⁷
  - Although chemotherapy desensitization is safe and effective, it is also resource-intensive
  - Desensitization requires prolonged infusions, dedicated infusion beds or chairs, pharmacy access to chemotherapy, trained staff, and space, which increase costs
  - Desensitization needs to be performed in settings with low nurse to patient ratio, with close observation and where resuscitation personnel and resources are readily available
  - Newer risk stratification protocols using variables such as initial HSR severity and skin testing in the context of shared decision-making can provide safe and effective means of avoiding unnecessary desensitization procedures³⁵³⁶
  - A better understanding of the clinical phenotypes of patients and the chemotherapeutic reactions is needed
  - Plan of care decision-making led by expert allergists in close collaboration with the patient, pharmacy, and oncology and infusion team staff is critically important in maintaining safety
Premedication before drug challenge or drug desensitization
- Data on use of premedications are conflicting, and premedication regimens before challenges and desensitization vary widely between countries and researchers in the field
- One study suggests administering systematic premedication with corticosteroids and antihistamines had no significant effect on the effectiveness or safety of desensitization in patients with confirmed hypersensitivity to paclitaxel³³
- Concern remains that premedications could mask early signs of hypersensitivity and delay treatment
- Another large review suggests that a combination of prevention strategies used judiciously reduces the occurrence and severity of HSRs and improves safety⁴⁰

Follow-Up

Monitoring

Common practice for monitoring after a reaction depends on reaction severity
- Once acute reaction has improved (clinical symptoms of the reaction resolved and vital signs are baseline), patients who developed a grade 1 to 2 infusion reaction (Brown criteria) should be monitored closely (vital signs and clinical status) at least 1 hour in the infusion center before discharge home
- Patients who require epinephrine and/or experienced grade 3 anaphylaxis should be monitored closely (vital signs, respiratory and mental status) for 3 to 4 hours until symptoms of the initial reaction improve in the infusion center. This recommendation is based on data showing late-phase bronchoconstriction in severe asthma patients which can occur in this time frame⁴¹
No long-term monitoring is usually needed in these people, and no additional medications are indicated once symptoms have improved and the patient is discharged home
Oncologist will continue to guide the chemotherapy treatment and dosing, but referral to an allergist can guide how best to give the chemotherapy agent again after an HSR (hypersensitivity reaction) if there are no reasonable alternatives

Prognosis

Though about 5% of Americans have experienced anaphylaxis from any cause, fatal outcomes are rare and occur in less than 1% of cases; data specific to chemotherapy-specific anaphylaxis are not available⁴²
Rates of fatal drug anaphylaxis appear to be increasing. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with β-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers⁴²
A significant risk factor for poor clinical outcome from anaphylaxis is delayed administration of epinephrine, and the prognosis of patients who are rapidly treated with epinephrine for anaphylaxis is excellent⁴³
Data and experience from large academic centers described in this review show that nearly all patients can continue to receive the same chemotherapy again despite an HSR. This requires a close collaboration between the oncologist and the allergist

Referral

Patients who have experienced an acute infusion reaction should be referred to an allergy/immunology specialist who can offer recommendations on diagnostic testing and future infusion options as mentioned previously

References

1.Broyles AD et al. Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs. J Allergy Clin Immunol Pract. 2020;8(9S):S16-S116. Published correction appears in J Allergy Clin Immunol Pract. 2021;9(1):603; and J Allergy Clin Immunol Pract. 202;9(1):605.