Chemotherapy hypersensitivity.pdf

Chemotherapy
Hypersensitivity
Natasorn Lekuthai,MD.
Allergy Fellowship Year 1

Chemotherapy
• Chemotherapy (CHT) still represents the gold standard for the treatment of the majority of cancers,
alone or in combination with the so-called more selective targeted therapies, namely monoclonal
antibodies or other biologicals.
• However, CHT can induce hypersensitivity reactions (HSRs) and remains the third leading cause of
fatal drug-induced anaphylaxis in the United States.
• Despite their prevalence and relevance, the ideal pathways for diagnosis, treatment and prevention
of these reactions are still unclear, and practice remains considerably heterogeneous with vast
differences from center to center.
Pagani M, Bavbek S, Alvarez-Cuesta E, et al. Hypersensitivity reactions to
chemotherapy: an EAACI Position Paper. Allergy. 2022;77:388–403.

Pathophysiology
Tsao, Lulu R., et al. "Hypersensitivity reactions to platinum agents and
taxanes." Clinical Reviews in Allergy & Immunology 62.3 (2022): 432-448.

A novel model of drug hypersensitivity
Jakubovic, Baruch D., et al. "Drug hypersensitivity in the fast lane: what clinicians should know
about phenotypes, endotypes, and biomarkers." Annals of Allergy, Asthma & Immunology 124.6
(2020): 566-572.

Endotype and Phenotype
(2020): 566-572.

Biomarker
(2020): 566-572.

Chemotherapy Hypersensitivity grading
https://ctep.cancer.gov/protocoldevel
opment/electronic_applications/docs
/CTCAE_v5_Quick_Reference_8.5x11.
pdf

Clinical presentation
• HSRs usually occur during or within a few hours after the end of drug infusion, although it is
possible to observe nonimmediate reactions that appear afterward by hours or days after the end of
CHT administration.

Skin test
• Skin prick test and intradermal tests performed to detect drug-specific IgE are useful only for a few
chemotherapeutic drugs, in particular platinum compounds and probably for taxanes.
• It can be used for
Ø Diagnosis
Ø Prevention
Ø Risk stratification
Ø Evaluation of cross-reactivity

• The best results are obtained when skin test are performed in the interval ranging from 6 weeks to
6 months after the allergic reaction.
• Regarding other chemotherapeutic drugs, skin testing tested positive in some patients with HSRs to
other chemotherapeutic drugs such as cyclophosphamide, procarbazine, gemcitabine,
methotrexate, and L- asparaginase but the diagnostic and predictive value of these results remains
uncertain.
Skin test

Drug provocation test
• The Drug Provocation Test (DPT) is the gold standard diagnostic technique used in the study of drug
hypersensitivity reactions and involves the controlled administration of a drug.
• DPT is a helpful tool in diagnosing HSRs to CHT to rule out hypersensitivity in some patients, to
study patients who receive more than one drug simultaneously, and as a gold standard to validate
other diagnostic tests.
• DPT could prevent non- hypersensitive patients from unnecessary rapid drug desensitization (RDD)
procedures when systematically applied before RDD.
• Careful patient selection and locally adapted risk management strategies are of the essence. DPT is
potentially indicated in patients with immediate reactions, including some cases of milder
anaphylaxis ( provided the risk assessment is favorable), and delayed reactions (provided they are
non-SCARs).
• A DPT may be performed if the skin test results are negative and the risk assessment is favorable. If
there is no reaction during the DPT, the patient can be sent back to regular infusion.

Drug provocation test
• Contraindications should include the lack of access to adequate installations, personnel with
expertise in drug allergy, or specific resources that ensure appropriate risk management plans.
• Additionally, we should consider the particular characteristics of these drugs and avoid DPT in
patients who do not need any further treatment with the culprit antineoplastic drug or who are
going to change to an alternative (and equally effective) CHT schedule.
• In the largest report, the majority of 188 patients with platin HSRs had mild-to-moderate initial
HSRs:
• 42% grade 1, 34% grade 2, and 24% grade 3, using the Brown system .
• After further risk stratification, 93 of 188 (49%) underwent DPTs
• 50 (54%) were positive and 7 (14%) of those were grade 3.
• A prior observational study found that patients with a history of paclitaxel HSR were more likely to
tolerate rechallenge than those with platin HSRs.

Specific IgE, basophil activation test, and other
biomarkers
• The authors concluded that both positive ST and oxaliplatin-specific IgE are good tools to confirm
oxaliplatin hypersensitivity, but negative results are less useful.
• There is only one case of reported specific IgE for taxanes.
• Basophil activation testing (BAT) as a diagnostic tool in chemotherapy has only been used in a
limited number of cases with platins.
• Total IgE was found to be predictive of a drug hypersensitivity reaction to platins in two different
populations.

Oxaliplatin and
Carboplatin
Specific IgE

Premedication for prevention
• Premedication is said to be effective and has been recommended for the prevention of
hypersensitivity reactions to different chemotherapeutics, such as epipodophillotoxins and
asparaginase.
• In addition, this procedure has dramatically decreased the incidence of HSRs to taxanes to 2–4% of
cases, even if in last few years the incidence of reactions has increased to 10%
• Premedication resulted ineffective in preventing true, IgE-mediated allergic reactions to platinum
salts.
• Moreover, administering systematic premedication with corticosteroids and antihistamines had no
significant effect on the effectiveness or safety of RDD in patients with confirmed hypersensitivity
to paclitaxel.
• Drugs used in the premedication can produce hypersensitivity reactions and should be investigated
when a chemotherapy hypersensitivity is suspected.

Premedication for prevention
• Premedication with steroids and antihistamines (eg, dexametasone 20 mg and chlorpheniramine 10
mg intravenous 1 h before chemotherapy) is effective for preventing moderate and severe infusion
reactions to taxanes, hence that premedication is usually included in local guidelines or the
manufacturer's recommendations (GRADE B).
• Premedication with steroids and antihistamines is effective for preventing infusion reactions to
epipodophyllotoxins, asparaginase and doxorubicin, hence that premedication is usually inluded in
local guidelines or the manufacturer's recommendations (GRADE D).

Treatment of breakthrough reactions

Desensitization
• RDD is a therapeutic approach delivered through protocols to patients in need of first-line drug
therapy.
• It safely administers the needed medication and provides a temporary tolerance to drugs to which
patients have presented immediate reactions, including anaphylaxis and selected non-severe delayed
reactions.

Desensitization
• Low-risk patients usually include those who have presented a Grade I or II HSR with
positive/negative ST. These patients do not have comorbidities and are not treated with β-blockers
or/and angiotensin-converting enzyme inhibitors (ACEI).
• High-risk patients usually include those who have presented a Grade III HSR and positive ST if
available. High-risk patients include patients that are being treated with β-blockers or/and
angiotensin- converting enzyme inhibitors, as well as those patients who have mastocytosis,
respiratory pathologies as cystic fibrosis, and cardiac pathologies, such as coronary disease.
• Pregnant patients are classified as high-risk.

Desensitization
• Candidate patients for RDD will include patients who have had a type I, cytokine-release syndrome,
mixed reactions or a Type IV HSR, excluding SCARs, such as Steven-Johnson syndrome, toxic
epidermal necrolysis, drug-related eosinophilia with systemic symptoms, acute generalized
exanthematous pustolosis. Serum sickness is not an indication for RDD.
• It should be emphasized that RDD should only be performed when there is no alternative therapy.
• RDD should always be performed in patients with positive ST, regardless of the grade of the initial
HSRs, since IgE and mast cells are involved in the reaction, and the risk of anaphylaxis is present at
each re-exposure.
• However, RDD is also indicated if the skin test results are negative, but the risk assessment is
unfavorable (i.e., undergoing DPT is not possible or would involve an unacceptable risk).

(2020): 566-572.

Desensitization
• If the clinical assessment is consistent with an HSR, then empiric desensitization is a reasonable and safe
approach to care and can be performed even when skin testing is not possible (ie, outpatient clinic without
access to chemotherapy drugs for skin testing)
• While 3-bag desensitization protocols have been most commonly used for intravenous medications,
increasing evidence suggests similar safety and efficacy by using a 1-bag protocol, resulting in a simpler and
more time-efficient desensitization; however, more data are needed, especially in patients with severe initial
HSR
• Patients without a convincing clinical history of an HSR do not require desensitization and typically respond
well to readministration of the chemotherapeutic agent. Examples include subjective symptoms of pruritus
or lip swelling without any objective skin findings during the infusion
• If symptoms are mild in nature (ie, flushing or pruritus alone without hives, back pain alone) or there is
heightened patient concern around readministration, then premedications, such as H1-antihistamines, and a
slowed infusion rate have been used successfully without the need for desensitization.
Khan, David A., et al. "Drug allergy: a 2022 practice parameter update." Journal of Allergy and
Clinical Immunology (2022).

Desensitization

Chemotherapy Desensitization

Desensitization
• Premedication for RDD is usually based on the patient's symptoms during the initial HSR
Ø antihistamines in case of cutaneous symptoms,
Ø aspirin and montelukast to prevent bronchospasm,
Ø COX-1 inhibitors, steroids and opioids for systemic symptoms including chills, rigors, fever and pain.
Ø Some authors have used omalizumab in recalcitrant patients, but data are insufficient to recommend this.
• Most RDD to chemotherapies (platins/taxanes) are uneventful.
• However, if a reaction were to occur, it would be during the 1st or the 2nd RDD.
• When a standard 3-bag protocol is performed, 75% of the reactions occur within the last bag, with
50% of the reactions during the last step. Additionally, these reactions are generally less severe than
the initial HSR.

Platinum-base agents
• Platinum compounds (cisplatin, carboplatin, oxaliplatin) can frequently determine HSRs and are
typically observed after multiple administrations.
• The development of hypersensitivity to several platinum agents is not well-understood but
is thought to be related to type I IgE-mediated hypersensitivity.
Ø The clinical pictures are similar to those of type I reactions;
Ø Prior exposure is necessary
Ø Retreatment with the same platinum drug is the trigger to the immunological stimulation necessary for the
reaction
Ø Skin test are often positive
Ø Skin test. reactivity correlates with the risk of reaction during desensitization
Ø Skin test conversion from negative to positive is seen following re-exposure and after the development of
the reaction.
• Only anecdotal cases of delayed HSRs that are likely due to T-cell–mediated mechanisms
are described after platinum salts administration. Therefore, their clinical importance is
unclear.

Carboplatin
• In particular, the incidence of hypersensitivity reactions increases from 1% after the first dose of
carboplatin to 27% after 7 doses and <_46% in patients who have received >15 infusions.
• Recent data show that inherited mutations in BRCA1/BRCA2 appear to be associated with a higher
risk for carboplatin HSRs.
• The peak rate of hypersensitivity reactions occurs with the eighth or ninth dose, which often
corresponds with the second or third cycle after restarting treatment for malignancy recurrence.
• Standard carboplatin skin testing protocols use step-wise skin prick testing (10 mg/ mL) and 3-step
intradermal testing (0.1, 1, and either 3 or 5 mg/ mL) with 0.02 mL, in addition to a positive control
(0.1 mg/mL histamine base) and a negative control (saline).
• In Carboplatin hypersensitivity, skin test is
Ø Negative predictive value between 81% and 98.5% and a positive predictive value of 86%.
Ø Positive up to 100% of patients in case of severe reactions.
• However, the false-negative rate of carboplatin skin testing (ie, the development of HSR with next
exposure after a negative skin test) is reported to be as high as 8%-8.5% in the literature.
Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug hypersensitivity: introduction."
The Journal of Allergy and Clinical Immunology: In Practice 8.9 (2020): S1-S2.
Pagani M, Bavbek S, Alvarez-Cuesta E, et al. Hypersensitivity reactions to chemotherapy: an EAACI Position
Paper. Allergy. 2022;77:388–403.

• Patients with a recent history of anaphylaxis (within 4-6 weeks of skin testing) with maybe false-
negative skin test ,repeat skin testing is recommended for patients whose clinical history is
consistent with a hypersensitivity reaction and who have a negative initial skin test result on
evaluation. These patients’ condition can be managed with desensitization while they are awaiting
repeat skin testing.
• Patients undergoing evaluation with repeat skin testing, because of a history of hypersensitivity
reactions but with a negative initial skin test result, have also been able to safely receive their
chemotherapeutic dose using a modified 8-step desensitization protocol Antihistamine pre-
medication is recommended before the use of these desensitization protocols.
Carboplatin
Pagani M, Bavbek S, Alvarez-Cuesta E, et al. Hypersensitivity reactions to chemotherapy: an EAACI Position
Paper. Allergy. 2022;77:388–403.

Carboplatin
• Low-risk patients who have a history of nonpruritic, non- blistering delayed rash or those who have
a negative skin test result between 6 weeks and 6 months after their initial hypersensitivity reactions
and who are therefore at a lower risk of having a falsely negative skin test result may be candidates
to receive carboplatin by infusion at 50% of the standard infusion rate in an outpatient infusion
center setting.
• In addition, before the start of the desensitization protocol, patients with initial skin symptoms such
as pruritus or urticaria can be given oral or intravenous diphenhydramine 25 mg and oral ranitidine
150 mg (intravenous ranitidine 50 mg or famotidine can be substituted).
• Patients with mild cutaneous symptoms (flushing, erythema) as part of their hypersensitivity
reactions may also benefit from premedication with oral aspirin 325 mg on the night before their
desensitization and again 1 hour before their desensitization protocol begins.
Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug
hypersensitivity: introduction." The Journal of Allergy and Clinical Immunology: In Practice 8.9
(2020): S1-S2.

Oxaliplatin
• Oxaliplatin is a third-generation platinum-based chemotherapeutic agent most commonly used to
treat metastatic colon cancer in combination with leucovorin and fluorouracil (FOLFOX regimen).
• Most patients develop reactions after the sixth treatment cycle, with the incidence being as high as
20%, comparable to that of carboplatin (incidence 27% after the sixth dose).
• Oxaliplatin specifically, HSRs are more heterogeneous and include cytokine release reactions
presenting with fevers, chills, rigors, headache, chest pain, and/or back pain along with elevated
levels of IL-6 and TNF-α .
• Oxaliplatin can also induce mixed reactions with symptoms of both type 1 hypersensitivity and
cytokine release reactions.
• Cases of immune- mediated hemolytic anemia and thrombocytopenia complicated by bleeding have
also been reported for oxaliplatin. Delayed rashes have been reported hours to days after
carboplatin infusion, ranging in severity from mild reactions to skin desquamation.

• Most protocols premedicate patients with antihistamines to minimize the risk and/or severity of
breakthrough reactions with desensitization. Additional premedication with a combination of aspirin
and montelukast appears to be helpful for those patients whose reactions have prominently included
flushing.
• The literature describing idiosyncratic/cytokine storm like reaction is quite limited, but management
seems to revolve around intense premedication regimens of steroids with or without
antihistamines.
(2020): S1-S2.
Oxaliplatin

Platinum-base agents : skin test
• In any case, ST for carboplatin and possibly oxaliplatin seem predictive of allergic reaction to these
drugs.
• In Carboplatin hypersensitivity, skin test is
Ø Positive up to 100% of patients in case of severe reactions.
Ø Predictive tool for developing HSRs in patients with recurrent gynecological cancer who required re-
treatment with carboplatin.
Ø Negative predictive value between 81% and 98.5% and a positive predictive value of 86%.
• In oxaliplatin hypersensitivity
Ø Positive test ranges from 26% to 100%.
Ø a study demonstrated a negative predictive value of 95%.This may depend on the population, as some
authors found negative predictive value of 56%, with a
Ø positive predictive value of 92%.

Skin test : Platinum agents

• When initial skin testing is negative, the time elapsed since the platin HSR occurred (<6 weeks or >6
months) should be taken into consideration and repeat skin testing has been used to identify
individuals that are truly allergic.
• A risk-stratification protocol using 3 serial skin tests has been shown to be safe and effective in
evaluating and managing patients with carboplatin-induced HSR. This protocol has been reported to
safely differentiate patients who are allergic from those who are nonallergic and helps prevent
unnecessary desensitization.
• One potential approach sought to simplify the platin skin testing/risk-stratification process while
maintaining safety and efficacy by studying a modified 1-step platin intradermal skin testing protocol
(using highest platin skin test concentration only) in patients with a history of platin HSR who have
tolerated an initial desensitization.
• Empiric desensitization without skin testing allows the patient to proceed with first-line therapy.

Skin test : Platinum agents
• In one of these studies, 5/37 (13.5%) ST-negative patients who had been tested within 10 days of an
immediate HSR to platinum agents developed recurrent reactions and subsequently converted to
ST-positive.
• There are also higher rates of false-negative ST if performed more than 6 months after initial
carboplatin and oxaliplatin HSR, which suggests waning of ST reactivity over time.
• In early studies, 12/23 (52%) of carboplatin initial ST-negative patients and 2/21 (10%) of oxaliplatin
initial ST-negative patients were found to convert to ST- positive on serial ST [14, 36], and repeat
skin testing protocols for risk stratification were developed to identify “ST converters.”

• They all underwent platin challenge and 7 of 12 tolerated the challenge and did not require
desensitization. In another study, 1 of 21 patients with positive platin challenge had anaphylaxis
(hives, hypoxemia, hypotension, dyspnea, and wheezing) that required epinephrine and resolved
within 30 minutes. The study concluded that platin challenges can reduce desensitization
requirements (32% of platin challenges were negative) but still have an inherent risk.
• The most experienced published approach has used a 12-step desensitization protocol for a variety
of chemotherapeutic agents, including platinum compounds, has been reported to be successful in
413 procedures, with 94% of procedures having only a mild or no reaction and 6% had moderate
to severe reactions.
• 1-bag desensitization protocol while these still require multiple steps, no carboplatin drug dilutions
were required, significantly simplifying the burden of resources (ie, skilled pharmacist, preparation
time) needed to proceed safely and shortening the time required for desensitization.

Risk stratification in carboplatin HSR by ST

8 and 12-step carboplatin desensitisation protocol
Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug hypersensitivity:
introduction." The Journal of Allergy and Clinical Immunology: In Practice 8.9 (2020): S1-S2.

1-bag carboplatin desensitization protocol

12-step oxalipaltin desensitization
(2020): S1-S2.

Breakthrough reactions in platin
desensitization

Cytoskeletal disruptors (Taxanes)
• Taxane agents are used in the treatment of breast, gynecologic, prostate, head and neck, and lung
cancers, and include paclitaxel, docetaxel, nab-paclitaxel, and cabazitaxel .
• Paclitaxel (Taxol) was originally isolated from the bark of the Pacific yew tree, while docetaxel (Taxo-
tere) was made from a semisynthetic process.
• Taxanes share a highly similar structure (docetaxel and cabazitaxel come from a common paclitaxel
precursor), but they may differ in the solubilizer used (eg, Cremophor EL for paclitaxel, or
polysorbate 80 (tween) for docetaxel and cabazitaxel). Nanoparticle albumin-bound (nab-paclitaxel),
devoid of Cremophor EL, seems to have a lower rate of HSRs.
• Taxanes can provoke HSRs in about 30% of patients, but the incidence declines to less than 5% with
the premedication with steroids and antihistamines.

• Paclitaxel (including solvent-free formulation nab-paclitaxel), docetaxel and cabazitaxel cause HSRs
that usually (95%) develop during the first or second infusion, with the most severe reactions
occurring within the first few minutes.
• The appearance of reactions to the first exposure could be explained by the fact that taxanes
molecules can be isolated from yew tree pollen, as well as from hazelnut trees and its nuts, providing
potential sources of environmental exposure.
• Taxanes may cause mast cell and/or basophil activation through IgE- mediated mechanisms, direct
action on basophils, or IgG- mediated mechanisms that cause complement activation and release of
anaphylatoxins (C3a, C5a).Therefore, the role of skin testing after a taxane HSR remains unclear.
Pagani M, Bavbek S, Alvarez-Cuesta E, et al. Hypersensitivity reactions to chemotherapy: an EAACI
Position Paper. Allergy. 2022;77:388–403.
Tsao, Lulu R., et al. "Hypersensitivity reactions to platinum agents and taxanes." Clinical Reviews
in Allergy & Immunology 62.3 (2022): 432-448.

• Although initial data indicated that a majority of patients were allergic and cross-reactivity with tree
pollen allergens was suggested.
• Cremophor EL in paclitaxel and polysorbate 80 in docetaxel and cabazitaxel are solubilizing and
emulsifying agents that can cause complement activation with anaphylatoxin production and mast
cell activation in vitro.
• Polysorbate 80 may also cause direct mast cell activation via peroxide formation. Data supporting
the role of Cremophor includes the decreased rate of immediate HSRs with nanoparticle albumin-
bound paclitaxel (nab-paclitaxel), with no reactions seen in phase I, II, or III studies despite omitting
premedication. Nevertheless, severe immediate HSRs have still been reported with nab-paclitaxel in
post-marketing surveillance.
Pagani M, Bavbek S, Alvarez-Cuesta E, et al. Hypersensitivity reactions to chemotherapy: an EAACI
Position Paper. Allergy. 2022;77:388–403.

• A common finding in many studies on taxane- induced HSRs is the decreasing risk of reaction with
repeated exposures.
• Patients with immediate moderate to severe HSRs were significantly more likely to have positive
skin tests (ST) than patients with a nonimmediate or mild immediate HSRs.
• However, cross-reactivity between nab-paclitaxel and other taxanes in case of confirmed
hypersensitivity (confirmed with skin testing or drug provocation testing) is yet to be adequately
studied.
• Docetaxel and paclitaxel have a cross-reactivity rate of 90%, suggesting that the taxane moiety or
the solvent (cremophor EL, polysorbate 80) may be both responsible for cross-reactivity.

• Patients with negative ST and patients with a nonimmediate or mild immediate index reaction were
significantly more likely to resume regular infusion eventually.
• Immediate HSRs to paclitaxel and docetaxel occur in approximately 10% of patients despite
premedication and are severe in 1%.
• Delayed rashes have also been reported hours to weeks after infusion. Severe reactions such as
SJS/TEN, acute interstitial pneumonitis, and subacute cutaneous lupus erythematous have been
described in case reports with paclitaxel, docetaxel, and nab-paclitaxel.

• Concentrations used for paclitaxel skin testing range from 1 to 6 mg/ mL (SPT) and from 0.001 to 6
mg/mL (IDT). False- positive results can occur at 6 mg/mL (IDT).
• Concentrations used for docetaxel skin testing range from 4 to 10 mg/mL (SPT) and from 0.04 to 10
mg/mL (IDT).
• Skin testing with cabazitaxel and nab-paclitaxel has not been reported.
• Patients with a delayed skin reaction and a positive skin test response may be at risk of an
immediate hypersensitivity reaction on reexposure and may require desensitization. The risk of a
recurrent delayed reaction also decreases with repeated exposures, and many can eventually
tolerate regular infusions.
• In contrast, patients with severe nonimmediate hypersensitivity reactions (eg, SJS) should not be
reexposed to taxanes.
(2020): S1-S2.

Skin test :taxanes
Sensitivity of 16.7% (95% CI, 8.7–24.6%)
Specificity of 100% for taxane skin test.

• Patients who develop immediate reactions despite pretreatment can be successfully managed using
a 3-bag desensitization protocol similar to platin desensitization.
• To address this, a 1-bag protocol was recently shown to be noninferior to a multibag rapid
desensitization protocol with 98% success and could offer a safe, effective, less labor-intensive
option for paclitaxel desensitization.
• In addition, the literature shows that the majority of patients with mild taxane reactions (ie, without
respiratory symptoms or hypotension) can safely resume regular or slowed infusions without
desensitization.
• Another option for patients who react to paclitaxel is to switch to a noncremophor paclitaxel such
as paclitaxel formulated as albumin-bound particles, which is not used routinely due to cost.
• Severe delayed reactions that are often T-cell–mediated such as SJS/TEN, cutaneous vasculitis,
acute interstitial pneumonitis, and subacute cutaneous lupus erythematosus have been described in
case reports in association with paclitaxel, and these are not amenable to desensitization.

Risk stratification after paclitaxel HSR

Reintroduction
in Taxanes HSR
(2020): S1-S2.

12-step paclitaxel protocol
(2020): S1-S2.

16-step paclitaxel protocol
(2020): S1-S2.

Breakthrough reactions in taxane
desensitization

Bacterial enzyme (Asparaginase)
• Asparaginase is derived from a bacterial polypeptide protease available in three forms.
• Asparaginase is a critically important treatment for specific cancers including acute lymphoblastic
leukemia and lymphoblastic lymphoma. Immediate-type reactions to asparaginase occur in 3%-45%
of patients.
• The incidence of HSRs to asparaginase ranges from 6% to 43% of cases, increasing after the fourth
dose.
• Intravenous administration, a prolonged interval between different chemotherapy administrations,
and the association with HLA DRB1 07:01 allele are the most important risk factors for developing
HSRs.
• Evidence suggests that HSR to asparaginase may be an IgE-mediated type I reaction, based on the
positivity of ST. Complement activation mediated by IgG or IgM may also be implicated.
• Most HSRs occur during the first hour of administration, even if delayed reactions have been
reported.

Asparaginase
• Three formulations of asparaginase that are FDA- approved for use in the United States.
Ø Native Escherichia coli asparaginase and
Ø Pegylated (PEG) form of asparaginase, also derived from E coli.
Ø Asparaginase, which is derived from an alternate bacterial source, Erwinia chrysanthemi.
• Data show that in patients who switch to asparaginase E. chrysanthemi, after hypersensitivity to E
coli–derived asparaginase, leukemia outcomes are similar to patients who never developed clinical
hypersensitivity.
• In patients who react to E coli asparaginase, substitution of either Echrysanthemi asparaginase or
pegylated asparaginase may be better tolerated.

• Anti–PEG asparaginase IgG has shown utility in predicting and confirming clinical reactions to
pegylated asparaginase as well as in identifying patients who are most likely to experience failure
with rechallenge.
• Premedication with steroids reduces the rate of HSRs when studied across trials comparing patients
premedicated with steroids and those not given steroids, it is unknown whether the development of
antiasparaginase antibodies is similarly reduced.
Asparaginase

Risk factors

Alkylating agents : Cyclophosphamide
• Adverse reactions to cyclophosphamide (CYC) are most commonly due to drug toxicity.
• Type I hypersensitivity reactions to CYC are relatively rare, but case reports can be found in the
literature. Visitsunthorn et al described a pediatric patient treated with CYC for systemic lupus
erythematosus who developed urticaria on the first exposure to the agent.
• Type I hypersensitivity reaction to CYC is diagnosed on the basis of clinical history with or without
skin testing.
• Signs and symptoms consistent with IgE-mediated hypersensitivity, such as hives, flushing,
angioedema, pruritus, wheezing, and hypotension occurring during or shortly after receiving a dose
of CYC, are highly suggestive of a type I hypersensitivity reaction
(2020): S1-S2.

• Skin testing can be used to confirm the clinical history; providers perform percutaneous prick testing
with 10 mg/mL and intradermal testing with 1 mg/mL (1:10) and 10 mg/mL (1:1).
• In the case report by Visitsunthorn et al, prick and intradermal testing was performed with 0.02 mL
of the following dilutions of CYC: 1:100, 1:10, and 1:1. Rosas et al also performed prick testing with
10 mg/mL and intradermal testing with 1 mg/ mL. In all cases, prick and intradermal tests with CYC
were compared with a histamine-positive control and a diluent- negative control, and results were
determined on the basis of this comparison. Neither of these published studies included controls to
determine optimal nonirritating skin testing concentrations for CYC.
• Equivocal history and negative skin testing result may be subjected to graded challenge.
(2020): S1-S2.
Alkylating agents : Cyclophosphamide

12-step CYC desensitization
(2020): S1-S2.

• Doxorubicin is an inhibitor of DNA and RNA synthesis that intercalates between DNA base pairs,
inhibits topo- isomerase II, and leads to production of free radicals.
• Doxorubicin is available without liposomal encapsulation (trade name Adriamycin), in liposomal
form (trade name Myocet), and in pegylated liposomal form (trade name Doxil). Liposomal
encapsulation allows for preferential concentration in tumor tissue.
• The non-liposomal form of doxorubicin is very rarely associated with hypersensitivity reactions. In
contrast, the incidence of hypersensitivity reactions to pegylated liposomal doxorubicin is
approximately 8%, with some series reporting up to a 25% incidence.
• Reactions usually occur during the first cycle. The mechanism of hypersensitivity on first exposure
may be explained at least in part by complement activation, which has been demonstrated in vivo
during infusion of pegylated liposomal doxorubicin and may lead to mast cell activation.
• Interestingly, in the setting of carboplatin hypersensitivity, combining carboplatin with pegylated
liposomal doxorubicin appears to have a protective effect and is associated with reduced incidence
of hypersensitivity reactions compared with carboplatin as a single agent or in combination with
paclitaxel. Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug
(2020): S1-S2.
Anthracyclines : Doxorubicin

• Doxorubicin may also cause adverse effects that mimic, but are not, hypersensitivity reactions.
Liposomal doxorubicin is associated with palmar-plantar erythrodysesthesia, also called hand-foot
syndrome, which is a relatively common dermatologic toxic reaction associated with cytotoxic
chemotherapy that can limit the use of such drugs. This typically occurs in the first 3 cycles of
treatment.
• The ability to perform skin testing in the evaluation of doxorubicin hypersensitivity is limited by
cutaneous toxicity. Doxorubicin hypersensitivity is therefore generally diagnosed clinically, and
there are no published skin testing protocols at this time.
• In a report of 413 cases of rapid desensitization, desensitization to doxorubicin was successfully
completed in a total of 29 patients. A 12-step rapid desensitization protocol may be used in cases
with mild or moderate symptoms. In the case of severe reactions including hypoxemia or
hypotension
• 16-step rapid desensitization protocol should be used for the patient’s first lifetime desensitization.
If this is tolerated, a 12-step rapid desensitization protocol may be considered for subsequent
infusions. Standard pretreatment includes a histamine H2-receptor antagonist and a long-acting
histamine H1-receptor antagonist, with optional additional premedications tailored to the patient’s
initial reaction. Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug
(2020): S1-S2.
Anthracyclines : Doxorubicin

12-step doxorubicin desensitization
(2020): S1-S2.

Antifolate agents : Methotrexate
• Methotrexate (MTX) is an antifolate chemotherapy and immunosuppressant agent that is used for the
management of osteosarcoma, acute lymphocytic leukemia, and rheumatoid arthritis, along with other
autoimmune diseases in adults and children.
• It inhibits the activity of dihydrofolate reductase, which is needed for de novo purine synthesis.
• Adverse effects, more commonly seen with high doses used in cancer therapy, include abdominal cramping,
malaise, mucositis, myelosuppression, and renal and hepatic toxicity. MTX pneumonitis that can progress to
interstitial fibrosis has also been reported.
• Although the incidence of hypersensitivity reaction is unknown, it is likely rare, and case reports of
anaphylactic or anaphylactoid reactions have been described.
• However, the following concentrations have been used for prick testing (10 mg/mL) and intradermal testing
(0.1 mg/mL and 1 mg/mL).Other skin testing concentrations with IDT (2.5 mg/mL),
• In the pediatric population, a recent retrospective review of a single-center experience with MTX showed
that only 1 of 4 patients tested positive on skin testing. This may suggest immediate type I hypersensitivity as
part of the pathogenesis in some patients.
(2020): S1-S2.

• Case reports have described prolonged infusion ranging from 6 to 27 hours. However, at some institutions,
the current practice for both adults and children involves a desensitization protocol with 3 bags of different
concentrations that are administered via 12 steps, with the first bag consisting of 1/100th of the total dose,
the second bag 1/10th of the total dose, and the third bag containing the remainder of the dose.
• A 16-step protocol involving 4 bags has also been performed in cases with severe reactions. Each step
involves doubling of the concentrations every 15 minutes until the last step (step 12) is reached. The
premedications can include H1 and H2 antagonists in addition to leukotriene receptor antagonists and/or
corticosteroids.
(2020): S1-S2.
Antifolate agents : Methotrexate

(2020): S1-S2.
12 step and 16-step
MTX desensitization
protocol

Tyrosine kinase inhibitors
• TKIs are used in the treatment of numerous malignancies and myeloproliferative disorders, as well as
hypereosinophilic syndrome and aggressive systemic mastocytosis in the case of imatinib. As a
family, they are associated with significant cutaneous and systemic side effects that are important to
differentiate from true hypersensitivity.
• Tyrosine kinases are a large group of enzymes that participate in many cell functions, including cell
signaling, growth, and division. The challenge with using TKIs has been their association with
significant idiosyncratic or pharmacologic effects including cutaneous and systemic side effects
(including a recent FDA black box warning for serious heart-related events, cancer, blood clots, and
death).
• The mechanism of these adverse effects is pleotropic and may relate directly to tyrosine kinase
effects rather than immunologic hypersensitivity.
Fleisher, Thomas A. "Practical guidance for the evaluation and management of drug hypersensitivity:
introduction." The Journal of Allergy and Clinical Immunology: In Practice 8.9 (2020): S1-S2.
Khan, David A., et al. "Drug allergy: a 2022 practice parameter update." Journal of Allergy and Clinical
Immunology (2022).

(2020): S1-S2.
More than 50 TKIs
are approved by
FDA.

• EGFR-TKI’s most common adverse effect is skin toxicity, usually manifested as acneiform rash, skin
fissure, xerosis, and paronychia. More than one-half of patients taking these drugs experience an
acneiform eruption. It is usually mild or moderate but can be severe in a minority of cases. Because
EGFRs are highly expressed in sebaceous epithelium, eruptions are generally most concentrated in
seborrheic areas such as the scalp, face, neck, chest, and upper back. The periorbital region, palms,
and soles are usually spared. The acneiform eruption is often dose- dependent and begins within 1
week of treatment
• Hand-foot skin reactions, presenting with pain and blistering on the palms and soles, are reported
with sorafenib, sunitinib, and other EGFR inhibitors. EGFR inhibitors have also been associated with
hair changes, aphthous ulcerations of the oral and nasal mucosa, photosensitivity, and urticaria.
Cases of SJS and TEN have been reported with TKIs, but the incidence is low.
• In some cases, the dose of TKI is reduced or the TKI is discontinued and then reintroduced at a
lower dose once the cutaneous symptoms improve. Immediate discontinuation of the drug is
recommended if there is any sign of a bullous or exfoliative skin rash. NSAIDs, minocycline, or
doxycycline may be useful in preventing EGFR-TKI–related skin rash.

Imatinib
• Ten patients with imatinib hypersensitivity who underwent subsequent desensitization were
described by Nelson et al in 2006. These patients had predominantly cutaneous initial reactions,
though several had additional fever, blistering, edema, or diarrhea. One patient was skin tested by
skin prick testing at 0.01 and 0.1 mg/mL and intradermal testing at 0.001 mg/mL, 0.01 mg/mL, and
0.1 mg/mL. Erythema was reported on intradermal testing. Of these 10 patients who completed a 4-
hour rapid oral desensitization ,8 were subsequently able to tolerate daily imatinib without
hypersensitivity symptoms. The other 2 patients developed rash hours to days after desensitization.
• Subsequently, Paolo published a case report describing slow oral desensitization to imatinib over
23 days for a patient who developed eosinophilic dermatitis after 6 weeks . Skin testing result was
negative, using skin prick 0.1 mg/mL, and intradermal testing with 0.0001 mg/mL, 0.001 mg/mL,
0.01 mg/mL, and 0.1 mg/mL imatinib. Patch testing was also performed, and the result was negative
using 0.1 mg/mL imatinib in 5% petrolatum. For the rapid oral desensitization, same-day dose
increases were administered every 20 minutes. The patient initially failed rapid desensitization
twice but was able to tolerate imatinib after slow oral desensitization.
(2020): S1-S2.

Imatinib slow oral desensitization
(2020): S1-S2.

Imatinib rapid oral desensitization
(2020): S1-S2.
Every 20 minutes

Sorafenib
• Sorafenib is more commonly associated with hand- foot skin reaction and other symptoms related to
toxicity, but it can rarely (<1%) trigger allergic symptoms, including urticaria.
• In 2008, Bauer et al described a patient who developed a pruritic generalized maculopapular rash after
2 weeks of sorafenib therapy. The rash resolved with discontinuation of sorafenib and treatment with
oral antihistamines and topical steroids.
Ø They were able to restart sorafenib using premedication and a 6-day oral tolerance protocol, with day 1 doses
given every 15 minutes The patient developed erythema after the 11-step protocol, which was treated with 4
mg dimethindene maleate, with resolution. The patient was premedicated with methylprednisolone 24 mg on
day 1, and premedicated with methylprednisolone 24 mg and fexofenadine 180 mg on days 2 to 12.
Thereafter, fexofenadine was used only as needed.
(2020): S1-S2.

• More recently, Linauskiene et al described a patient with sorafenib treatment complicated by fever
and generalized urticaria 10 days into treatment. The urticaria resolved 5 days after discontinuation
of sorafenib, systemic glucocorticoids, and oral antihistamines.
Ø The 8-day oral tolerance protocol was based on the Bauer et al study and was complicated by
antihistamine-responsive pruritus during the first several days of the protocol. This patient also
developed facial urticaria after reaching the maintenance dose of 400 mg twice daily, which was
managed with dose reduction to 400 mg in the morning and 200 mg in the evening.
Ø Premedication with prednisolone 30 mg and bilastine 20 mg was used on days 1 to 4, and
premedication with bilastine 20 mg on days 5 to 7.
Sorafenib
(2020): S1-S2.

(2020): S1-S2.
Sorafenib oral
tolerance induction

Regorafinib
• Regorafenib is an oral protein kinase inhibitor approved for the treatment of hepatocellular
carcinoma, metastatic colorectal cancer, and stromal tumors.
• Hand-foot skin reaction, mild rash, and mucositis are common mucocutaneous adverse effects
frequently requiring dose modification. Severe skin reactions such as erythema multiforme or
Steven-Johnson syndrome may preclude further administration.
• Case report
Ø A 58-year-old woman diagnosed with metastatic hepatocellular carcinoma, was treated with
sorafenib followed by nivolumab-ipilimumab.
Ø Given the progression of her disease, she started third-line therapy with regorafenib 160 mg/d,
decreasing to 120 mg/d on day 10 owing to oral mucositis.
Ø On day 12, she developed fever (39oC) and took acetaminophen and amoxicillin (for the fifth
time during the previous months owing to recurrent high fever of unknown origin, probably
neoplastic fever).
Ø On day 16, she was admitted to hospital with a pruritic generalized maculopapular rash , vaginal
and conjunctival erythema, and persistent high-grade fever.
Ø Regorafenib, acetaminophen, and amoxicillin were discontinued. Intravenous antihistamines
and corticosteroids were initiated. The fever subsided and the exanthema improved markedly in
24 hours, resolving within 1 week. García-Gutiérrez I, Acevedo M, Tornero P, et al. Severe Maculopapular Exanthema Induced by Regorafenib: Successful
Desensitization and Adaptation of a Dosage Regimen. J Investig Allergol Clin Immunol. 2019;29(4):300-302.
doi:10.18176/jiaci.0377

Ø Given the severity of the reaction, the dose of regorafenib was reduced to 80 mg/d for the first
desensitization. Based on a previous protocol for sorafenib , a 10-step protocol was followed,
reaching a cumulative dose of 80 mg on day 1.
Ø The patient was discharged and continued to take 80 mg/d for 3 weeks followed by 1 week off
treatment.
Ø A second desensitization was performed the following week. A dose of 80 mg was reached on
day 1 (same 10-step protocol). The doses reached on days 2 and 3 (single doses) were 100 mg
and 120 mg, respectively. All doses were well tolerated. The patient continued to take 120 mg
daily.
Ø In order to avoid monthly desensitization and hospitalization and after consultation with the
hepatologist, we decided to continue with 120 mg/d for 3 weeks, decreasing to 80 mg during
the resting week instead of discontinuation, in order to maintain desensitization. Potential drug
toxicity was closely monitored, and the dose was adjusted accordingly.
Regorafinib
García-Gutiérrez I, Acevedo M, Tornero P, et al. Severe Maculopapular Exanthema Induced by Regorafenib: Successful
doi:10.18176/jiaci.0377

García-Gutiérrez I, Acevedo M, Tornero P, et al. Severe Maculopapular Exanthema Induced by Regorafenib: Successful
doi:10.18176/jiaci.0377

• Case of a 59-year-old Japanese woman diagnosed with recurrence after curative operation for
sigmoid colon cancer (T3N2aM0, Stage IIIC) .Regorafenib was started as a late-line treatment.
• After 2 weeks, the patient experienced regorafenib-induced serious erythema multiforme with high
grade fever. thus, regorafenib was discontinued and oral prednisolone was started at 50 mg/day
orally for 2 weeks.
• Regorafenib 80 mg/day was resumed after 30 days since prednisolone was stopped but skin rash
rapidly reappeared. The drug was discontinued and start prednisolone 30 mg/day.
• Subsequently, treatment with regorafenib at a daily dose of 80 mg, in combination with continuous
oral PSL (30 mg/day) was reattempted 7 days after the EM disappeared. Afterward, there were no
more occurrences of rash, and the patient was able to tolerate the increase in the regorafenib dose
and reached a standard daily dose of 160 mg with PSL (10 mg/day)
Regorafinib
Tashiro K, Shinto E, Kajiwara Y, et al. Systemic steroid treatment can desensitize the skin
reaction due to regorafenib in a recurrence colorectal cancer patient. Int Cancer Conf J.
2019;8(4):164-169. Published 2019 May 24. doi:10.1007/s13691-019-00376-4

Regorafinib
Tashiro K, Shinto E, Kajiwara Y, et al. Systemic steroid treatment can desensitize the skin
reaction due to regorafenib in a recurrence colorectal cancer patient. Int Cancer Conf J.
2019;8(4):164-169. Published 2019 May 24. doi:10.1007/s13691-019-00376-4

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