Review

published: 08 November 2017

doi: 10.3389/fimmu.2017.01472

Drug Hypersensitivity and

Anaphylaxis in Cancer and
Chronic Inflammatory Diseases:
The Role of Desensitizations
Mariana Castells*

Allergy and Immunology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Drug allergy is a rising problem in the twenty-first century which affects all populations
and races, children, and adults, and for which the recognition, diagnosis, management,
and treatment is still not well standardized. Classical and new chemotherapy drugs,
monoclonal antibodies (MoAbs), and small molecules to treat cancer and chronic inflam-
matory diseases are aimed at improving quality of life and life expectancy of patients, but
an increasing number of reactions including anaphylaxis precludes their use in targeted
populations. Women are more affected by drug allergy and up to 27% of women with
ovarian and breast cancer develop carboplatin allergy after multiple cycles of treatment.
Carriers of BRCA genes develop drug allergy after fewer exposures and can present
Edited by:
with severe reactions, including anaphylaxis. Atopic patients are at increased risk for
Vanesa Esteban,
Instituto de Investigación Sanitaria de chemotherapy and MoAbs drug allergy and the current patterns of treatment with
la Fundación Jiménez Díaz, Spain recurrent and intermittent drug exposures may favor the development of drug allergies.
Reviewed by: To overcome drug allergy, desensitization has been developed, a novel approach which
Michael Breitenbach,
University of Salzburg, Austria
provides a unique opportunity to protect against anaphylaxis and to improve clinical
Sinisa Savic, outcomes. There is evidence that inhibitory mechanisms blocking IgE/antigen mast cell
University of Leeds, United Kingdom activation are active during desensitization, enhancing safety. Whether desensitization
*Correspondence: modulates drug allergic and anaphylactic responses facilitating tolerance is currently
Mariana Castells
[email protected] being investigated. This review provides insight into the current knowledge of drug allergy
and anaphylaxis to cancer and chronic inflammatory diseases drugs, the mechanisms of
Specialty section: drug desensitization and its applications to personalized medicine.
This article was submitted to
Inflammation, Keywords: desensitization, monoclonal antibodies in cancer, platins, drug allergy, taxanes
a section of the journal
Frontiers in Immunology
INTRODUCTION
Received: 31 May 2017
Accepted: 20 October 2017 With the unprecedented use of chemotherapies drugs and targeted monoclonal antibodies (MoAbs)
Published: 08 November 2017
and small molecules in the twenty-first century, increased hypersensitivity reactions (HSRs) have
Citation: emerged worldwide (1, 2). Drug allergic reactions are unexpected, can be severe including anaphylaxis
Castells M (2017) Drug and prevent the use of first-line therapies, with consequent impact in patient’s survival and quality
Hypersensitivity and Anaphylaxis in
of life (3, 4). These reactions range from mild cutaneous manifestations such as pruritus and hives to
Cancer and Chronic Inflammatory
Diseases: The Role of
life-threatening anaphylaxis with hypotension, oxygen desaturation and cardiovascular collapse, and
Desensitizations. deaths have been reported after re-exposure to allergic drugs (5, 6). The presentation of symptoms
Front. Immunol. 8:1472. can be atypical such as pain, which has been associated with taxenes reactions, and chills and fever
doi: 10.3389/fimmu.2017.01472 which have been seen with oxaliplatin and MoAbs reactions (7, 8). Delayed reactions occurring

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Castells Drug Anaphylaxis Role of Desensitization

more than 24 h after chemotherapy infusions can be due to the non-IgE involvement, cytokine storm, and mixed patterns. The
prolonged half-life of MoAbs and the presence of premedications, endotypes responsible for the expression of symptoms include
which may mask the acute phase of the reactions (9, 10). mast cell and basophil activation through known receptors
The traditional classification of drug hypersensitivity and (FceRI, FcgR, MRGPRX2) and directly through known recep-
allergy into the classical types I–IV does not encompass the tors: complement, kinin and bradykinin activation and COX-1
current spectrum of reactions and symptoms occurring in inhibition. Associated biomarkers include serum tryptase, skin
cancer patients and patients with chronic inflammatory diseases testing, basophil activation test, specific IgE and patch testing
(11, 12). Some of the reactions have no known underlying among others (13, 25–28).
mechanism, others have a known mechanism which is not part Patients presenting with reactions compatible with pheno-
of the four described types and some drugs can induce mixed types consistent with acute and delayed IgE and non-IgE, mast
reactions with two or more proposed mechanisms (13, 14). cell/basophil activation, and T cell activation endoptypes may be
Hypersensitivity to rituximab, a chimeric anti-CD20 MoAb, prevented from the use of first-line therapies for fear of inducing
can induce cytokine-like reactions with chills, fevers, hypoten- anaphylaxis or more severe delayed reactions upon re-exposure
sion, and oxygen desaturation, which have been attributed to to the allergenic drug. A groundbreaking procedure, desensitiza-
the release of cytokines such as IL-6, IL-1β, and TNF-α and are tion, has emerged in the last 15 years as a proven effective and safe
named cytokine release syndrome or cytokine storm, which is procedure to maintain patients on their first-line medications.
not contemplated in the Gell and Coombs classification (15). In
contrast, some patients have classical IgE-mediated reactions to CLINICAL VIGNETTE
rituximab and have presented positive skin testing demonstrat-
ing that IgE and mast cells are part of the underlying mechanism Mrs. MFF is a 49-year-old healthy female who was discovered
(16). Some patients reactive to oxaliplatin present mixed reac- to have ovarian cancer after a routine gynecology ultrasound
tions with Type I features such as hives and hypotension, along and was initially treated with surgery and chemotherapy with
with fever and chills as seen in cytokine storm-like reactions, six courses of carboplatin and paclitaxel and entered remission.
presenting a complex mixed pattern of reactivity which provides Two years later, the CA125 is increased and new masses are
challenges to management and treatment (17). During mixed found in her abdomen, a diagnosis of recurrent stage 4 ovarian
reactions tryptase, the major mast cell protease, and IL-6 can be cancer is made and carboplatin and paclitaxel restarted. After the
elevated in serum indicating mast cell activation and cytokine second course of carboplatin, the patient feels her hands itchy
release from unknown cellular sources. Reactions to taxenes but finished the infusion and did not have any further symptoms.
can trigger direct mast cell/basophil activation with elevation of On the day of her third infusion, the patient presented flushing,
serum tryptase with or without evidence of IgE, indicating that generalized pruritus, shortness of breath, and sudden dizziness.
more than one mechanism can explain taxane hypersensitivity. The blood pressure drops below normal range as well as the oxy-
A different receptor than FceRI, such as the recently described gen saturation and the patient has a syncopal episode and needs
MrgprX2 for drugs with THIQ motifs such as quinolones and to be resuscitated with epinephrine, fluids, anti-histamines, and
paralyzing agents such as atracuronium could be activated dur- steroids. She recovers and her diagnosis is of anaphylaxis, a serum
ing non-IgE taxane reactions (13, 18–20). tryptase level during the episode is elevated at 52 ng/ml (normal
Patients presenting with delayed cutaneous reactions are at a range 11.4  ng/ml). The patient is evaluated for carboplatin
great concern for Stevens–Johnson syndrome and toxic epider- allergy and skin testing is positive. Her options are to change to
mal necrolysis, two life-threatening conditions which can lead a second-line agent which is likely to reduce her life expectancy
to permanent disability, blindness, and dramatic decrease in or to remain on first-line therapy with carboplatin but because
the quality of life for survivors (16, 21). The underlying mecha- of her anaphylactic reaction this option is not considered safe
nisms of the reactions are poorly understood and up to now no unless carboplatin can be introduced through desensitization,
predictive markers have been available. Genetic susceptibility a powerful and novel intervention which has shown to protect
and defined HLA haplotypes are thought to be risk factors for patients against anaphylaxis and permit re-introduction of
some of the reactions, such as HLA-B 5701 in HIV patients allergy drugs.
reactive to abacavir. In patients with targeted haplotypes, a new
role for viral reactivation of HHV6 and other virus have been DRUG DESENSITIZATION
demonstrated, and the pathogenic role of the virus is under
study (22–24). The term drug desensitization is currently used to define a process
To provide an operational classification which can adapt to by which a patient’s immune response to a drug is modified to
the increasing knowledge of the mechanisms of reactions and to generate temporary tolerance, taking advantage of well character-
the symptoms and clinical presentations, a recent initiative has ized inhibitory pathways (6). In the case of IgE-mediated drug
provided a new terminology, applicable to precision medicine. In allergy, positive skin testing and specific serum IgE can be used
the new categorization drug allergy phenotypes are defined by the as biomarkers along with elevated serum tryptase level during
underlying endotypes and associated biomarkers and can be used the acute reaction (8, 11, 17). Patients without evidence of IgE
in personalized medicine, with each patient being categorized mechanism are good candidates for desensitization provided the
according to her/his symptoms complex presentation. Current phenotype of the drug reaction is a type I or a type IV like reaction
phenotypes include acute and delayed reactions with IgE and without features of SJS/TEN (16, 21, 29) (Table 1).

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Castells Drug Anaphylaxis Role of Desensitization

Table 1 | Indications, contraindications and risk factors for drug desensitization. The mechanisms underlying drug desensitization are based
Indications High-risk patients Contraindications on in  vitro and in  vivo models which have proposed that mast
cells and basophils can be induced to predominantly inhibitory
Reactions type I (mast Severe anaphylaxis Severe cutaneous adverse pathways by small incremental antigen doses, deactivating signal
cells/IgE/basofills) (intubation) reactions (SCARs) (SJS/TEN,
Reaction type IV (except DIHS/DRESS, AGEP)
transduction and mediators release (13) (Figure 1).
SCARs) Negative skin test is seen following desensitization in patients
No alternative drug Severe respiratory Immunocytotoxic reactions with IgE-mediated reactions, providing evidence of the powerful
disease (type II reactions) mechanisms which turn off skin mast cells (30–32). Partitioning of
Drug is more effective Severe cardiac Vasculitis an optimal dose into 11–16 incremental doses starting at 1/1,000
and/or associated with disease the target dose and delivering them with sufficient time interval
less side effects to mast cells; inhibits the acute release of beta-hexosaminidase, a
Drug has a unique Severe systemic Serum sickness-like (type III mast cell granule mediator, prevents the generation of arachidonic
mechanism of action diseases reactions)
acid and products such as leukotrienes and prostaglandins and
Use of beta-blockers,
ACE inhibitors
the late generation of inflammatory cytokines (Figure 1) (13).
Pregnancy During desensitization, calcium influx is abolished and
actin polymerization impaired, providing stability to intracel-
SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis; DIHS, drug-induced
hypersensitivity syndrome; DRESS, drug reaction (rash) with eosinophilia and systemic
lular granules in an antigen-specific fashion (Figure  1) (13).
symptoms; AGEP, acute generalized exanthematous. Membrane events that prevent internalization or modify its

Figure 1 | In vitro IgE/antigen mouse mast cells activation and desensitization (13). (A) Desensitization of in vitro DNP-IgE sensitized mouse mast cells with DNP
inhibits the release of granule mediators such as beta-hexosaminidase. Instead of one single optimal dose, 11 suboptimal sequential doses are given until reaching
the optimal dose. (B) Desensitization of in vitro OVA-IgE sensitized mouse mast cells with OVA inhibits the release of granule mediators such as
beta-hexosaminidase. Instead of one single optimal dose, 11 suboptimal sequential doses are given until reaching the optimal dose. (C) Desensitization of in vitro
DNP-IgE sensitized mouse mast cell mediators with DNP inhibits the de novo generation of cytokines TNF alpha and IL-6 (D). (E) Calcium entry (blue line) occurs
after activation of DNP-IgE sensitized mouse mast cells with DNP but not when cells have been desensitized to DNP (red line, * DNP). Desensitization is specific
since cells that were DNP desensitized and OVA-IgE sensitized presented calcium entry after OVA activation (red line, * OVA). (F) Membrane events are modified
during desensitization with lack of internalization of desensitized antigens: left panels indicate that OVA desensitization does not present internalization of antigen
(upper panel) as opposed to activation (lower panel with green labeled OVA internalized) and right panels indicate that after OVA desensitization another non
desensitizing antigen such as DNP can be internalized (upper panel) as seen with activation (lower panel).

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Castells Drug Anaphylaxis Role of Desensitization

Figure 2 | Model of in vitro mouse mast cells activation and desensitization. The left side cartoons provide the steps of antigen/IgE/FceRI activation starting from
antigen cross-linking, internalization, calcium entry and release of granule mediators, generation of lipd mediators such as prostaglandins and leukotrienes, and
production of late phase cytokines. The right sided panel provides the hypothetical membrane capping and rearrangement occurring during the delivery of
sequential suboptimal doses of allergen in desensitization preventing internalization of antigen, calcium entry, and mediators release.

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Castells Drug Anaphylaxis Role of Desensitization

Figure 3 | In vitro and in vivo protocols for induction of IgE/antigen desensitization. In the left panel in black, increasing single doses of antigen induce a dose
response release of beta-hexosaminidase in vitro mouse mast cells. In white, the same doses given sequentially induce a profound inhibition of the beta
-hexosaminidase release. In the right panel, a model of desensitization protocol used for human desensitization in which 3 bags and 12 steps (4 steps per bag) are
used to administer sequential doubling doses every 15 min which provides the target dose of 300 mg after 5.66 h when the last step is completed.

response to subthreshold doses of antigen occur during desen-

sitization and are associated with incremental unresponsiveness
to specific antigen (Figure  2) (13). Association of the FceRI
to ITIM containing receptors, capable of dephosphorylating
ITAMs receptors has been postulated as one of the mechanisms
of desensitization. Mast cells desensitized to one antigen are
responsive to a second non desensitizing antigen, providing
evidence of compartimentalization and highly specialized and
regulated intracellular processes (Figure 1) (13).
The protocols used for in  vitro desensitization have been
adapted in  vivo and further adaptations have produced safe
protocols for human use (Figure 3) with similar dose increments
and interval times (25–28). These human protocols have now
been used in thousands of cases with remarkable safety since Figure 4 | Putative mechanism of protection against anaphylaxis
the inhibitory mechanisms of desensitization protect against during human desensitizations. By delivering the target dose of the drug
by small incremental doubling doses (Figure 3), the threshold for anaphylaxis
anaphylaxis (Figure 4) (33, 34). is re-established at each step and never reaches that of the initial
Whether after multiple desensitizations neutralizing antibod- triggering dose.
ies can be generated which may block allergenic drug epitopes
has been hypothesized (6). Maintaining drug desensitization state
depends upon continued drug exposure and desensitized drugs
require administration at regular intervals to maintain a stable chest, or abdominal pain (such as seen with taxanes, oxaliplatin,
pharmacokinetics state. Desensitization needs to be repeated if MoAbs such as rituximab) (33, 35).
several half-lives of the medication have elapsed (6, 33). Delayed reactions are attributed to type IV reactions and can
Protocols for drug desensitization have been successfully used occur several days after the infusion and are typically limited
for antibiotics, chemotherapy drugs, and MoAbs among other to the skin with maculopapular rashes (36). Reactions that
drugs in patients with IgE and non-IgE-mediated HSRs (Figure 5) involve mucosal membranes and/or are associated with systemic
(6, 14, 33, 35). The phenotypes of reactions amendable to desensi- symptoms are not amenable to desensitization due to the risk of
tization include immediate and delayed reactions. Typical type I inducing a severe systemic reaction with small amounts of drug
reactions usually begin within minutes of initiation of the infusion antigen (16, 21, 29).
to few hours after the infusion due to anti-histamine and steroid Desensitization should be considered in patients with reaction
premedication. The signs and symptoms include puritus, flush- phenotypes consistent with type I and type IV reactions who have
ing, urticaria, angioedema, throat tightening, wheezing, nausea, no alternative therapy or for whom alternative therapies are of
diarrhea, hypotension, syncope, seizures, and cardiovascular col- less value or can induce more side effects. The algorithm for the
lapse which can lead to death. Atypical symptoms include back, evaluation of these patients is seen in Figure 6 (6, 34, 37). The

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Castells Drug Anaphylaxis Role of Desensitization

100
Cutaneous
Cardiovascular
90
Respiratory
Throat Tightness
80
Gastrointestinal
Neurological/Muscular
70
Percentage of Patients (%)

60

50

40

30

20

10

Carboplatin Paclitaxel Doxorubicin/Adriamycin Rituximab

Chemotherapeutic Agents

Figure 5 | Symptoms and signs of hypersensitivity reactions amendable to desensitization. Carboplatin and other paltins such as cisplatin and oxaliplatin reactions
include classical symptoms of anaphylaxis with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms. Reactions to taxenes including paclitaxel and
docetaxel present with pain as a neuromuscular symptoms in up to 4% of the patients. Doxorubicin/adriamycin and other chemotherapies present with sudden
onset hypo or hypertension in up to 60% of patients and rituximab and other monoclonal antibodies present with cutaneous and cardiovascular symptoms in 70%
of the patients.

Figure 6 | Algorithm for the evaluation of drug hypersensitivity reactions and the role of desensitization for the re-introduction of the first-line medications, when no
alternative is available or the alternative does not provide the same benefits or life expectancy as the first line.

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Castells Drug Anaphylaxis Role of Desensitization

nature and symptoms of the initial reactions needs to be estab- and in second-line or salvage settings. Carboplatin is the most
lished and tryptase and skin test provide evidence of IgE and/ popular since it is less nephrotoxic and neurotoxic than cispl-
or mast cell involvement. BAT is a research tool and cannot be atin. Allergic reactions to platins are IgE-mediated and require
applied to current clinical practice. sensitization through multiple exposures, with 27% of women
Drug desensitization can be performed in patients of any becoming allergic after seven life time exposures (12, 43, 44).
age and in pregnant women when alternative therapies are not Allergic symptoms typically start at the second round of treat-
possible or when delaying therapy may incur a shortened life ment, when the cancer recurs and after 1–2 exposures sensitized
span. Anaphylaxis is the major risk during desensitization since patients present with flushing and pruritus which can progress
patients are exposed to their allergic drug. Large series have to shortness of breath with further exposure and can lead to
demonstrated that most breakthrough reactions during desensi- anaphylaxis, with hypotension and cardiovascular collapse (2, 4,
tization are mild and less severe than the patient’s initial HSR and 7, 33, 45). Patients bearing BRCA 1 and 2 gene mutations have
fatalities have not been reported, but all desensitizations can only an increased risk for carboplatin reactions, which can occur with
be performed by an expert allergist familiar with the personal- fewer exposures (46, 47). Most reactions to platins occur during
ized protocol and potential reactions (Table 1) (17, 33, 35). The or shortly after the drug infusion and the phenotype is that of
safety of desensitizations is paramount and patients with grade 3 type I reaction. In a study of 60 carboplatin sensitized patients,
severe initial reactions and anaphylaxis can be desensitized with 100% had cutaneous, 60% pulmonary, 40% respiratory, and 42%
minimal reactions as seen in Table 2. gastrointestinal symptoms (6).
Desensitization is not recommended for type II and type III The phenotype of reactions to oxaliplatin can be more com-
serum sickness-like reactions or in patients with reactions with plex with features including typical IgE-mediated symptoms and
skin desquamation, EM, Stevens–Johnson syndrome or toxic atypical symptoms such as back and pelvic pain and cytokine-
epidermal necrolysis, because small amounts of drug can induce mediated fever and chills (7, 11, 17, 48, 49). Antibody-mediated
irreversible and potentially fatal reactions (Table 1) (16, 21, 29). thrombocytopenia and immune complex-mediated syndromes
The most commonly used intravenous desensitization pro- with urticaria and proteinuria have also been observed (17, 50).
tocols are standardized 12- to 16-step protocols modeled after Skin testing to platins has been safely done (Table 3) and is
in vitro protocols and can be personalized to all drugs with adjust- diagnostic tool to demonstrate an IgE/mast cell mechanism in
ment of the target dose, time intervals between doses and starting patients with carboplatin and cisplatin reactions (7, 11, 17). For
dose (Figure 3) (33, 38). Protocols are available for intravenous patients exposed to six or more courses of carboplatin in the
desensitizations but also for oral, subcutaneous, intraperitoneal, last 6  months the positive predictive value is up to 86% (11).
or intravenous routes in the outpatient and inpatient settings Oxaliplatin skin testing is negative in up to 50% of patients pre-
(39–41). Desensitization for delayed reactions is also available senting type I reactions, indicating other than IgE mechanisms
and may take several days but recent data suggest that some or lack of skin test allergenic determinants (17). Circulating
of these reactions may be amenable to shorter time intervals serum specific IgE has been demonstrated and patients reac-
(8, 36, 42). The overall safety of desensitizations is similar for all tive to oxaliplatin with detectable serum-specific IgE have also
medications provided the mechanism of the initial reaction is of demonstrated IgE to carboplatin and cisplatin without exposure,
type I, IgE and non-IgE or type IV. As seen in Figure 7, the overall indicating broad cross-reactivity (51). IgE to platins can be
safety indicates that 93% of patients present with no reaction or short lived since a study has demonstrated that ST is negative
grade 1 reactions and all completed the desensitization. in a high proportion of patients with a remote history of HSR to
Platins, taxanes, and MoAbs are the most common chemo- carboplatin, but re-exposure leads to resensitization and severe
therapy currently used in desensitization and are described below. reactions (11). When platins are considered as first-line therapy,
desensitization is a safe option since increased premedications
Platin Hypersensitivity alone do not prevent anaphylaxis and cross-reactivity may pre-
Platinum compounds are used in ovarian, colorectal, endometrial, vent the use of other platins (51). Patients with severe cutanoues
glioblastoma, lung, and pancreatic cancer as initial chemotherapy reactions, SJS and TEN are currently not candidates since the
mechanism of the reactions is unknown and small amounts
of medications may induce severe symptoms (1, 16, 21, 29).
Table 2 | Safety of first desensitization in patients with grades 1, 2, and 3 initial Desensitization provides a similar life expectancy as non-allergic
reactions. non desensitized patients (Figure  8) without increased health
costs (33).
First desensitization reaction grade

Initial 0 1 2 3 Total Taxanes

hypersensitivity Taxanes are used in gynecologic, lung, breast, and prostate
reaction grade cancers and reactions to taxenes are among the most frequent
1 76 (61%) 38 (30%) 7 (6%) 4 (3%) 125 chemotherapy reactions and fatalities have been reported (52).
2 38 (58%) 22 (34%) 4 (6%) 1 (2%) 65 Paclitaxel and docetaxel have been the more frequently used and
3 122 (60%) 54 (26%) 10 (5%) 19 (9%) 205 more recently other taxenes such as cabacitaxel and abraxene
Total 236 114 21 24 396
have become popular (53). Paclitaxel is an insoluble compound
From Sloane et al. (33). originally isolated from the bark of the pacific yew tree, Taxus

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Castells Drug Anaphylaxis Role of Desensitization

Figure 7 | The overall safety of desensitization for common chemotherapy drugs and monoclonal antibodies.

Table 3 | Skin testing for the diagnosis of chemotherapy drug allergy including activation (55–57). Taxanes are used with premedications includ-
platins, monoclonal antibodies, and paclitaxel.
ing anti-histamines and steroids due to a high rate of reactions
Medication Prick (mg/ml) Intradermal (mg/ml) in early clinical studies (54). The rate of reaction has decreased
to less than 10% and typically occurs during the first or second
Carboplatin 10 0.1, 1, 5, and 10
Cisplatin 1 0.1 and 1
lifetime exposure in up to 80% of the patients (54). The phenotype
Oxaliplatin 5 0.5 and 5 of the reactions include type I symptoms such as throat tightness,
Rituximab 10 0.1, 1, and 10 flushing, hypotension, and dyspnea but atypical symptoms such
Infliximab 10 0.1, 1, and 10 as chest, back, or pelvic pain (8, 36, 54).
Tocilizumab 20 0.2, 2, and 20 Skin testing has uncovered IgE-mediated reactions to taxanes
Centuximab 20 0.2, 2, and 20
Traztuzmab 21 0.21, 2.1, and 21
and a recent study reported that 103 of 145 taxane reactive patients
Bevacizumab 25 0.25, 2.5, and 25 (71%) had positive results. Negative skin test patients who were
Cyclophosphamide 10 0.1, 1, and 10 challenged were likely to tolerated taxane infusions without
Methotrexate 25 0.2, 2.5, and 25 desensitization. Atopy was present in over 40% of the patients and
Paclitaxel 1–6 0.001 and 0.01
because patients react at first or second exposure suggested prior
sensitization or cross-reactivity with environmental allergens (8).
Risk stratification based on biomarkers such as skin testing can
Baccata tree and solubilized in cremophor and docetaxel is a safely guide the management to taxane reactions and allows a
semi-synthetic molecule derived from a precursor found in significant number of patients to resume regular infusions. For
European yew tree needles and solubilized in polysorbate 80 patients with positive skin test and significant initial reaction for
(36, 54). The solvents can cause complement activation, gen- whom taxanes are first-line therapy, desensitization should be
erating anaphylotoxins C3a and C5a and leading to mast cell considered (8).

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Castells Drug Anaphylaxis Role of Desensitization

Monoclonal Antibodies and ofatumumab can induce severe HSRs likely due to the gly-
There are over 45 MoAbs currently in use for the treatment of cosylation patterns in  vitro and the generation of neo antigens
cancer and inflammatory and autoimmune diseases. Reactions (58). This is best exemplified in reactions to cituximab which can
to MoAbs depend on their structure and vary from chimeric occur at first exposure in patients sensitized through tick bites
mouse-human, humanized, to fully human. Some of the most to the mammalian oligosaccharide epitope, galactose-alpha-
frequently used MoAbs are presented in Table 4, including their 1,3-galactose (alpha-gal) (59).
targets, incidence of overall injection/infusion site reactions, and The phenotypes of MoAbs reactions include limited infusion
HSRs (19, 34, 35). reactions, IgE-mediated reactions, serum sickness-like reactions,
Monoclonal antibodies immunogenicity depends on the cytokine storm-like reactions, and mixed reactions. Infusion
human content but fully human MoAbs, such as adalimumab reactions are characterized by nausea, chills, fever, and malaise
and for trastuzumab these reactions can occur in up to 40% of
patients (34, 35). Like cytokine storm-like reactions, which are
more severe, can associate with hypotension, oxygen desatura-
tion, and require treatment with steroids and COX-1 inhibitors,
proinflammatory cytokines (such as IL-6 and TNF-α) are thought
to be involved (60, 61).
Immediate and delayed HSRs can occur with MoAbs and
serum sickness-like reactions, such as seen with infliximab and
omalizumab, which can present with rash, myalgia, fever, polyar-
thralgias, pruritus, edema, and fatigue (35).
Monoclonal antibodies used subcutaneously can elicit injec-
tion-site reactions few hours after the injection and persisting for
several days. The phenotype of these reactions include local red-
ness, warmth, burning, itching, urticaria, pain, and induration,
varying in frequency from 0.8 to 4.5% with certolizumab to up to
45% with omalizumab (39).
Reactions to MoAbs can occur during the infusion and
should prompt interruption of the treatment and the evaluation
of tryptase and inflammatory cytokines to further understand
the mechanism of the reactions. Skin testing with the offending
agent can be done for type I and mixed reactions 2–4  weeks
after the reaction to avoid false negative results, in particular in
Figure 8 | Life expectancy for cancer patients allergic and desensitized to anaphylactic reactions in which natural desensitization can occur
carboplatin and non-allergic to carboplatin [from Sloane et al. (33)]. Allergic (35). An important consideration is cost of MoAbs; there are no
and non-allergic ovarian cancer patients treated with carboplatin or available reagents at the present time for the evaluation of MoAb
carboplatin desensitization presented a similar life expectancy with a non
reactions and using a treatment vial may exceed several thousand
significant advantage for the allergy desensitized patients.
dollars, precluding a diagnostic skin test evaluation. The negative

Table 4 | Common monoclonal antibodies in use and rate of overall reactions and hypersensitivity reactions (HSR).

Drug Target Overall reactions HSR

Rituximab (Rituxan®) IV CD20 77% (first infusion) (52) 5–10% (53)

Ofatumumab (Arzerra®) IV CD20 44% (first infusion) (54) 2% (55)
67% (combination therapy) (55)
Obinutuzumab (Gazyva®) IV CD20 66% (56,57) (58)*
Trastuzumab (Herceptin®) IV HER-2 40% (mild; first infusion) (59) 0.6–5% (60)
Cetuximab (Erbitux®) IV EGFR 15–21% (61) 1.1–5% (62–65)
14–27% (Southern USA) (43,66,67)
Tocilizumab (Actemra®) IV IL-6 receptor 7–8% (68) 0.1–0.7% (68)
Infliximab (Remicade®) IV TNF-α 5–18% (69) 1%* (69)
Etanercent (Enbrel®) SC TNF-α 15–37% (70) <2% (70)
Adalimumab (Humira®) SC TNF-α 20% (71) 1% (71)
Golimumab (Simponi®) SC TNF-α 4–20% (72,73) Not reported
Certolizumab (Cimzia®) SC TNF-α 0.8–4.5% (74,75) Not reported
Brentuximab (Adcetris®) IV CD30 12% (76) (77–79)*
Bevacizumab (Avastin®) IV VEGF-A <3% (80) Not reported
Omalizumab(Xolair®) SC lgE 45% (81) 00.9–0.2% (81,82)

*< p = 0.05

Frontiers in Immunology  |  www.frontiersin.org 9 November 2017 | Volume 8 | Article 1472

Castells Drug Anaphylaxis Role of Desensitization

predictive value of skin testing is not known and in a study of Serum tryptase, skin testing, BAT, and specific IgE are helpful
23 patients reactive to trastuzumab, infliximab, or rituximab, diagnostic tools which will be complemented in the future with
13 patients had positive skin test. Positive and negative skin test genotyping to identify patients at risk before reactions occur.
patient with significant initial reactions are candidates for desen- Appropriate treatment of the reactions including epinephrine
sitization and subcutaneous protocols are available. Successful use and management with personalized desensitization protocols
desensitizations to rituximab, ofatumumab, obinutuzumab, can enhance the quality of life, life expectancy, and safety of an
trastuzumab, cetuximab, tocilizumab, infliximab, etanercept, increasing at risk population of patients with cancer and inflam-
adalimumab, golimumab, certolizumab, brentuximab, bevaci- matory diseases allergic to their best medications. Most patients
zumab, and omalizumab have been reported (33–35). with reactions with phenotypes consistent with type I and type
IV reactions are candidates for desensitization, which can provide
CONCLUSION advancement of personalized treatments. Drug desensitization
protects against anaphylaxis and activates inhibitory mechanisms
Drug hypersensitivity is an increasing health hazard, which can which need further research to uncover cellular and molecular
compromise the quality of life and the life expectancy of cancer players amendable to pharmacological applications, which can
patients and patients with chronic inflammatory diseases with make desensitization safer and more effective.
reactions to their first-line therapy. Recognition of the mechanisms
of the reactions into phenotypes, understanding the underlying AUTHOR CONTRIBUTIONS
endotypes and evaluation of biomarkers is key to personalized
medicine and enhanced patient safety allowing for informed All authors listed have made a substantial, direct, and intellectual
decisions regarding drug re-exposure and desensitization. contribution to the work and approved it for publication.

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