Re-Visiting Hypersensitivity Reactions to Taxanes: a Comprehensive Review

Clinic Rev Allerg Immunol DOI 10.1007/s12016-014-8416-0

Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review

Matthieu Picard & Mariana C. Castells

# Springer Science+Business Media New York 2014

Abstract Taxanes (a class of chemotherapeutic agents) Keywords Taxane . Paclitaxel . Taxol . Docetaxel . are an important cause of hypersensitivity reactions Taxotere . Nab-paclitaxel . Abraxane . Cabazitaxel . (HSRs) in cancer patients. During the last decade, the Chemotherapy . Hypersensitivity . Allergy . Skin test . development of rapid drug desensitization has been key Desensitization . Challenge . Diagnosis . Review . IgE . to allow patients with HSRs to taxanes to be safely re- Complement . Mechanism treated although the mechanisms of these HSRs are not fully understood. Earlier studies suggested that solvents, such as Cremophor EL used to solubilize paclitaxel, Introduction were responsible for HSRs through complement activation, but recent findings have raised the possibility that Hypersensitivity reactions (HSRs) to chemotherapy are in- some of these HSRs are IgE-mediated. Taxane skin creasingly common and represent an important impediment testing, which identifies patients with an IgE-mediated to the care of cancer patients as they may entail serious sensitivity, appears as a promising diagnostic and risk consequences and prevent patients from being treated with stratification tool in the management of patients with the most efficacious agent against their cancer [1]. During the HSRs to taxanes. The management of patients following last decade, different groups have developed rapid drug de- a HSR involves risk stratification and re-exposure could sensitization (RDD) protocols that allow the safe re- be performed either through rapid drug desensitization introduction of a chemotherapeutic agent to which a patient or graded challenge based on the severity of the initial is allergic, and their use have recently been endorsed by the HSR and the skin test result. Rapid drug desensitization National Comprehensive Cancer Network (NCCN) [2]. hasbeenshowntobeaneffectiveandsafemethodto Two classes of chemotherapeutic agents cause the vast re-introduce taxanes in hundreds of patients, including majority of chemotherapy-related HSRs: platins and taxanes those with life-threatening HSRs. Patients with non- [3]. Although it has now been well described that HSRs to severe delayed skin HSRs may benefit from rapid drug platins are IgE-mediated [4], the mechanism(s) of HSRs to desensitization since they may be at increased risk for taxanes remain to be established. This lack of a clear under- an immediate HSR upon re-exposure. This review fo- standing of what causes HSRs to taxanes has led in practice to cuses on the clinical presentation, diagnosis, and novel a greater diversity of management strategies for taxanes com- mechanisms of immediate HSRs to taxanes. A new pared with platins’ HSRs [5]. However, the possibility that an managementstrategyforHSRstotaxanesbasedonskin IgE-mediated mechanism might be implicated in some pa- testing and rapid drug desensitization is proposed. tients with HSRs to taxanes has recently been raised, and skin testing has emerged as a new diagnostic and risk stratification tool [6, 7]. Therefore, the need arose to re-visit the knowledge : acquired on HSRs to taxanes since the first use of the drug in M. Picard M. C. Castells (*) the late 1980s. Division of Rheumatology, Immunology and Allergy, Department of This review provides a general overview of the different Medicine, Brigham and Women’s Hospital, Harvard Medical School, 1 Jimmy Fund Way, Smith Building, Boston, MA 02115, USA taxanes currently used in practice as well as a presentation of e-mail: [email protected] the different types of HSRs encountered with these agents Clinic Rev Allerg Immunol

(with a focus on immediate HSRs). This is followed by a discussion of the different mechanisms that could account for these HSRs. Finally, the different strategies used in the management of HSRs to taxanes (with an emphasis on rapid drug desensitization) are reviewed.

Origins and Clinical Use of Taxanes

Paclitaxel

Paclitaxel (taxol) is a natural compound, originally isolated from the bark of the Pacific yew tree (Taxus brevifolia)inthe 1960s, with potent anticancer properties [8]. It exerts its antineoplastic effects by interfering with the dynamics of microtubules (components of the cell cytoskeleton) thereby causing mitotic block and cell death [9, 10].Taxolrarityin nature (the extraction of a single therapeutic dose necessitates the sacrifice of a 100-year-old Pacific yew tree) and its insol- ubility in water significantly hindered its development as a chemotherapeutic agent [11]. In the 1980s, a drug formulation suitable for intravenous injection was devised using Cremophor EL (polyoxyethylated castor oil), a solubilizer and emulsifying agent, and ethanol allowing clinical trials to proceed [12]. Following demonstration of its efficacy against notably ovarian and breast cancer, the need arose for a more sustainable and efficient mean of production. Total (synthetic) synthesis of paclitaxel was accomplished in 1994, but its complexity made it not commercially viable [11, 13]. A first solution came from the presence of paclitaxel precursors (10- Fig. 1 a Taxus baccata tree. b Taxus baccata needles and fruit. Pictures taken at Arnold Arboretum, Boston, MA deacetylbaccatin III and baccatin III), which can be trans- formed via a semisynthetic process into paclitaxel, in the emulsifying agent, and further diluted in an ethanol/water needles of the European yew tree (Taxus baccata)(Fig.1) solution for intravenous administration [15]. It is used in the [12]. European yew trees are more abundant than Pacific yew treatment of breast, ovarian, prostate, head and neck, and non- trees, and the needles can be harvested without killing the tree small cell lung cancers and gastric adenocarcinoma [15]. [12]. In recent years, plant cell cultures isolated from different Docetaxel is usually administered as a 1-h infusion every Taxus species and grown in large bioreactors have become the 3weeks[15]. method of choice for paclitaxel production [12]. Paclitaxel is used for the treatment of ovarian, breast, non-small cell lung cancers, and AIDS-related Kaposi’ssarcoma.Itiseitherin- Nab-Paclitaxel fused weekly, typically over 1 h, or every 3 weeks, typically over 3 h [14]. Nanoparticule albumin-bound paclitaxel (nab-paclitaxel; Abraxane) is a novel paclitaxel formulation, which does not Docetaxel contain Cremophor EL [16, 17]. It uses human serum albumin to encapsulate hydrophobic paclitaxel molecules in particles Docetaxel (taxotere) was discovered in 1986 in the search for of around 130 nm [18]. In addition, albumin is thought to a more soluble and easier to produce alternative to paclitaxel increase paclitaxel tumor uptake by, among other mecha- [12]. It was obtained from a semisynthetic process using the nisms, binding to gp60 (albondin) receptor thereby enhancing paclitaxel precursor 10-deacetylbaccatin III extracted from the the transendothelial transport of the drug [18, 19]. Abraxane needles of T. baccata [12]. Its structure is therefore highly was approved by the US FDA for the treatment of metastatic similar to paclitaxel. Despite a higher solubility than paclitax- breast cancer in 2005 and is now also approved for the el, the molecule remains insoluble in water [12]. Docetaxel is treatment of non-small cell lung cancer and adenocarcinoma formulated in polysorbate 80 (Tween 80), a solubilizer and of the pancreas [20, 21]. It is infused over 30 min and, in Clinic Rev Allerg Immunol contrast to the other taxanes, does not require the use of severe) versus 17.3 % (7.3 % severe) [34]. Also, at least one premedication to prevent HSR [21]. Many other nanoparticule death from a severe HSR has been reported in a patient delivery systems for paclitaxel are currently in development premedicated with the simplified regimen [39]. In [20]. premedicated patients, the duration of the paclitaxel infusion (3 versus 24 h) and the dose administered (175 versus 135 mg/ Cabazitaxel m2) do not influence the rate of HSRs [37, 40, 41]. Also, there is no indication that weekly paclitaxel regimens, which con- Cabazitaxel (Jevtana) is a semisynthetic taxane derived from tain lower doses and are administered as 1-h infusions, in- the precursor 10-deacetyl baccatin III contained in yew tree crease the rate of HSRs, and some groups have even success- needles that was developed to overcome tumor drug resistance fully withdrawn corticosteroid premedication in patients that to paclitaxel and docetaxel [22]. Tumor cells can overexpress had not reacted during the initial cycles [42–46]. ATP-dependant membrane transporter proteins, such as P- glycoprotein, that decrease intracellular drug concentrations Docetaxel by pumping out of the cell drugs with affinity for the transporter [10]. Paclitaxel and docetaxel have a high affinity for P- Several unexpected adverse events were uncovered during glycoprotein whereas cabazitaxel has a poor affinity providing phase II trials of docetaxel. A majority of patients (>50 %) the rationale for its use in certain taxane-resistant neoplasia experienced immediate HSRs that were not prevented by the [22]. Similarly to docetaxel, it is formulated in polysorbate 80 addition of premedication with antihistamines or intravenous and diluted in an ethanol/water solution before intravenous corticosteroid 30 min prior to the infusion [47–50]. Fluid administration [23]. In 2010, it was approved by the US FDA retention, which was later found to be caused by capillary in combination with prednisone for the treatment of hormone- protein leak induced by docetaxel [51], was an important resistant metastatic prostate cancer in patients previously treat- cause for treatment withdrawal in phase II studies and ap- ed with docetaxel [22]. It is usually infused every 3 weeks peared to be related to the cumulative docetaxel dose [52]. over 1 h [23]. Finally, many patients experienced a variety of toxic skin reactions presenting as desquamative rash, hand-foot syndrome, and plaque-like erythrodysesthesia [52]. Hypersensitivity Reactions to Taxanes Premedication with oral dexamethasone 8 mg twice daily for 3 days starting the day before the infusion was thereafter Incidence of Immediate Hypersensitivity Reactions adopted as the standard premedication regimen and found to and Impact of Premedication greatly reduce the prevalence of fluid retention and immediate HSRs to between 3.5–16.5 % and to around 5 %, respectively Paclitaxel [53–55]. The impact of premedication on toxic skin reactions is less clear as its prevalence has been found to vary greatly Early phase I clinical trials of paclitaxel were complicated by a between different trials [56, 57]. In an effort to minimize the high incidence of HSRs occurring during the drug infusion adverse effects of corticosteroids, different protocols have (immediate HSR) [24, 25]. Premedication with corticosteroids been used to reduce the duration of dexamethasone treatment (oral dexamethasone 20 mg 12 and 6 h pretaxol) and antihis- in patients receiving weekly docetaxel regimens without a tamines (histamine (H)-1 (dyphendydramine 50 mg or equiv- deleterious impact on the rate of HSRs, fluid retention, and alents) and H2 (cimetidine 300 mg or ranitidine 50 mg) re- skin toxicity [58, 59]. ceptor blockers) administered intravenously 30 to 60 min pretaxol allowed for a dramatic reduction in their incidence Nab-Paclitaxel [14, 24, 26]. Immediate HSRs to paclitaxel occur in around 10 % of premedicated patients and are severe in around 10 % Since nab-paclitaxel is devoid of Cremophor EL, the of patients who react [27–38]. A simplified premedication suspected cause of taxol HSRs, it is administered without regimen consisting of a single intravenous or oral dexameth- any premedication and as a 30-min infusion [21]. In a phase asone dose (10 mg) given 30–60 min before paclitaxel has III trial, a direct comparison between nab-paclitaxel and taxol been used with success by various groups without an obvious (administered with premedication) revealed that the rate of rise in immediate HSRs and has since gained wide acceptance HSRs was higher in the taxol arm;12 versus 4 %, severe as a reasonable alternative to the two-dose dexamethasone HSRs; 4 versus 0 % [60, 61]. However, postmarketing sur- protocol [27–30, 33, 36]. However, at least one retrospective veillance has revealed cases of severe and even fatal HSRs study reported a statistically significant lower rate of immedi- with nab-paclitaxel [21]. Its use in patients with a history of ate HSRs with the two-dose dexamethasone regimen com- mild to severe HSR to taxol and/or docetaxel has been report- pared to the simplified regimen (p=0.047); 7.5 % (0.9 % ed to be safe in a few case reports [62–65]. Clinic Rev Allerg Immunol

Cabazitaxel nab-paclitaxel [79–81]. Drug discontinuation usually leads to acompleteresolution[80]. Cabazitaxel has mostly been studied in patients with metastatic castration-resistant prostate cancer (mCRPC) previ- Clinical Features of Immediate Hypersensitivity Reactions ously treated with docetaxel and in combination with a to Taxanes daily oral prednisone regimen [66]. Premedication with an intravenous corticosteroid (dexamethasone 8 mg) and The majority of immediate HSRs to taxanes occurs during the H1 (dyphendydramine 25 mg) and H2 (ranitidine first or second infusion of the drug and usually develops 50 mg) blockers at least 30 min before the infusion is within minutes of starting the infusion [26, 33, 82]. The signs recommended given its potential to cause HSRs [23]. and symptoms of these reactions are thought to be the result of However, no HSR were reported in at least two trials cumu- basophil/mast cell degranulation (Fig. 2) and are similar in lating 656 patients treated with cabazitaxel for mCRPC [67, premedicated and non-premedicated patients [3, 26, 33, 82]. 68]. Interestingly, a large phase III trial in which 662 men with Patients commonly complain of localized or generalized mCRPC were treated with docetaxel in combination with flushing, and a significant percentage report chest, back, daily prednisone also did not report any HSR [69]. In contrast, and/or abdominal pain [3, 26, 82]. Respiratory and throat a phase II study of 71 patients with metastatic breast cancer symptoms (dyspnea, chest tightness, wheezing, throat tight- resistant to taxanes (docetaxel and paclitaxael) found that 6 % ness) can be prominent and associated with a significant drop of patients suffered a HSR to cabazitaxel [70]. Gender differ- in oxygen saturation [3, 26, 82]. Cardiovascular involvement ences and/or a higher and more prolonged intake of cortico- range from acute hypertension to hypotension, and patients steroids in men with mCRPC could possibly account for this may report a sense of impending doom [3, 26, 82]. Finally, discrepancy. gastrointestinal symptoms (nausea, vomiting, diarrhea) often accompany these HSRs [3, 26, 82]. Following the discontin- Non-Immediate Hypersensitivity Reactions to Taxanes uation of the infusion, rapid resolution is the norm although patients with protracted courses (sometimes unresponsive to Although less common than immediate HSRs, a range of epinephrine) and biphasic reactions have been seen [26, 33, delayed, possibly immune-mediated, reactions have been de- 83, 84]. As of 2009, mortality from severe anaphylactic reac- scribed with taxanes. Importantly, delayed onset skin eruptions had been reported in 54 % of 290 docetaxel cases and in tions (most commonly a benign maculopapular rash) can be 29 % of 683 paclitaxel cases recorded by the US FDA [83]. the prelude to an immediate HSR during the next infusion [7]. In one case, a 37-year-old woman that had presented with Mechanisms of Immediate Hypersensitivity Reactions urticaria, lip swelling, and fever 10 days after her first pacli- to Taxanes taxel infusion suffered a fatal anaphylactic reaction shortly after the start of the second infusion despite premedication Three different mechanisms may account for immediate [71]. Stevens-Johnson syndrome (SJS) and toxic epidermal HSRs to taxanes: (1) complement activation induced by necrolysis (TEN) have also been described in case reports and Cremophor EL (compounded with paclitaxel) and poly- picked up in postmarketing surveillance with paclitaxel, do- sorbate 80 (compounded with docetaxel) which generates cetaxel, and nab-paclitaxel [21, 72, 73]. Acute interstitial pneumonitis has been reported with paclitaxel, docetaxel, and more recently nab-paclitaxel and usually presents with fever, dry cough, dyspnea, bilateral interstitial lung infiltrates, and leukocytosis [74–77]. Around half of patients described in case reports required mechanical ventilation, and the mortality rate was high [75]. Patients are usually treated with high-dose corticosteroids for several weeks as the pneumonitis is thought to be T-cell mediated [78]. In a recent trial of nab-paclitaxel and gemcitabine in pancreatic cancer, 4 % of patients in the nab-paclitaxel/gemcitabine arm developed pneumonitis whereas only 1 % did in the gemcitabine arm [77]. Moreover, two patients in the nab-paclitaxel/gemcitabine arm died as a result [21]. Subacute cutaneous lupus erythematosus (SCLE), which presents as a photodistributed skin Fig. 2 Clinical features of immediate HSRs to taxanes. Created with data eruption often accompanied by the presence of antiRo/SSA from J Allergy Clin Immunol. 2008;122:574–80 and Gynecol Oncol. antibodies, has been associated with paclitaxel, docetaxel, and 2005;99:393–9 Clinic Rev Allerg Immunol anaphylatoxins triggering basophil/mast cell activation [85, Essayan et al. reported the case of an ovarian cancer patient 86]; (2) histamine release through a direct but undefined effect that had suffered repeated immediate HSRs to paclitaxel of paclitaxel on basophils [87]; (3) an IgE/IgG-mediated starting with the first infusion [87]. Premedication and a mechanism directed against either the taxane moiety (pacli- significant reduction in the infusion rate did not prevent re- taxel, docetaxel) or the solvent (Cremophor EL, polysorbate currences, and she received subsequent infusions through a 80) (Fig. 3)[6, 88–92]. desensitization protocol. Basophil activation tests on purified Paclitaxel (compounded with Cremophor EL) has been basophils were performed on the patient and three healthy shown to cause a marked complement activation in vitro in controls with paclitaxel alone and Cremophor EL alone [87]. 4/10 healthy subjects and 5/10 cancer patients at a concentra- They found that paclitaxel without Cremophor EL induced tion of 100 μg/ml, which translates into a Cremophor EL histamine release from basophils in the patient and the three concentration of 8.8 mg/ml [85]. In comparison, the maximal healthy controls at a concentration 10- to 100-fold higher than serum concentration of Cremophor EL reached with a 3-h the expected paclitaxel serum concentration. In this study, paclitaxel infusion at a dose of 175 mg/m2 averages 3 mg/ml Cremophor EL did not induce any histamine release, which [93]. Furthermore, Cremophor EL alone was found to trigger might be explained by the fact that experiments were likely complement activation to the same extent that paclitaxel/ conducted in a decomplemented medium [85]. Also, paclitax- Cremophor EL did at equivalent concentrations suggesting el did not induce any histamine release from purified human that Cremophor EL is solely responsible for this effect [85]. skin mast cells [87]. The authors therefore hypothesize that Similarly, docetaxel (compounded with polysorbate 80) and paclitaxel and not Cremophor EL might cause immediate polysorbate 80 alone have been shown to cause complement HSRs by triggering basophil activation through a non-IgE- activation in vitro [86]. These findings support the role of mediated mechanism. However, these findings also fail to these emulsifying agents in triggering complement activation identify a mechanism that differentiates highly reactive pain a high proportion of healthy subjects and thereby to cause tients from healthy controls, which are likely to tolerate immediate HSRs through anaphylatoxin production. taxanes if given premedication. However, it remains to be demonstrated that complement More recently, Prieto-Garcia and Pineda de la Losa de- activation occurs in vivo in humans who react to taxanes scribed a patient that had suffered a severe anaphylactic reac- and that this mechanism accounts for patients who react tion within seconds of her second lifetime paclitaxel infusion despite premedication and a slower infusion rate. [6]. The patient had a positive intradermal skin test (IDT) to

Fig. 3 Mechanisms of immediate HSRs to taxanes. The taxane moiety different mechanisms: (1) an IgE-mediated mechanism or (2) direct may cause mast cell and/or basophil activation through three different complement activation that leads to the production of anaphylatoxins. mechanisms: (1) a direct but undefined action on basophils but not mast Following activation, mast cells and basophils release a variety of medi- cells; (2) an IgE-mediated mechanism, or (3) an IgG-mediated mecha- ators that can be measured (serum tryptase or 24-h urinary nism that causes complement activation through immune complex for- methylhistamine), and the actions of which can be pharmaceutically mation leading to the production of anaphylatoxins (C3a and C5a) that blocked (histamine antihistamines; LTC4 montelukast; PGD2 aspirin). can activate basophils and mast cells through their surface receptors. LTC4 leukotriene C4. PGD2 prostaglandin D2 Solvents may cause mast cell and/or basophil activation through two Clinic Rev Allerg Immunol paclitaxel at a concentration of 0.1 μg/ml (0.0001 mg/ml). In suffer an immediate HSR upon their first taxane exposure contrast, 15 patients with adverse reactions to paclitaxel were requires further investigation. Nonetheless, it provides a skin-test negative to paclitaxel up to a concentration of rationale for the use of taxane skin testing in the evalua- 6 mg/ml (SPT) and 1 mg/ml (IDT) [6]. Furthermore, an IgE tion of patients with HSRs to taxanes. dot-blot assay performed with the patient’sserumwas positive to paclitaxel and negative to Cremophor EL [6]. The assay performed with serum from a non-allergic Management of Hypersensitivity Reactions to Taxanes control was negative to paclitaxel and Cremophor EL [6]. Other groups have also reported positive skin test As previously described, there are different types of HSRs to results to paclitaxel and docetaxel performed at non- taxanes (immediate and non-immediate reactions), each of irritating concentrations [7, 88, 89]. Also, cases of IgE- which may vary in severity. These factors along with the mediated reactions to Cremophor EL and polysorbate 80 benefits expected from this treatment and the availability, (based on positive skin test results to these molecules and effectiveness, and toxicity of alternative agents for a particular not the active drug) have been reported upon the admin- patient will together influence the decision to discontinue or istration of non-taxane drugs raising the possibility that re-introduce the medication. As a general rule, severe non- this may also happen in some cases of immediate HSRs to immediate HSRs (SJS/TEN; pneumonitis) should lead to drug taxanes [90–92]. Altogether, these findings strongly sup- discontinuation however compelling the indication to pursue port that at least in some patients, an IgE-mediated mech- treatment [100]. On the other hand, the management of anism may mediate immediate HSRs to taxanes. non-severe delayed onset skin eruptions is less clear It seems difficult to reconcile the fact that most patients although data suggest that safe re-introduction can be react upon the first or second exposure (leaving a little achieved [7]. Importantly, since in some patients these opportunity for sensitization) with an IgE-mediated delayed reactions can be the prelude to potentially se- mechanism. This conundrum could potentially be ex- vere immediate HSRs [71], precautions (such as the use plained by the fact that sensitivity to taxanes can develop of a rapid desensitization protocol) may be necessary in without exposure to the drug, possibly via pollen expo- certain circumstances. sure [94]. Paclitaxel and the precursors for docetaxel Since paclitaxel first clinical use in the 1980s, different (baccatin III and 3-deacetylbaccatin III) have been isolat- approaches have been put forward to safely re-introduce ed from different species of yew trees and from different taxanes in patients who suffered immediate HSRs and for parts of the plant including its pollen [94]. Interestingly, which the causal agent was considered the best therapeu- paclitaxel-specific IgG were found in the serum of 8.8 % tic option. In this section, we will review the data of 63 healthy blood donors from Belgium (where supporting each approach as well as their potential short- T. baccata is widespread) despite having never been ex- comings before proposing a management strategy for posed to the drug [94]. Among atopic blood donors (de- immediate and non-severe delayed HSRs based on the fined as sensitive to Betula species), this percentage in- currently available evidence. The severity of immediate creased to 21.4 %. In contrast, paclitaxel-specific IgGs HSRs will be graded according to the classification pro- were not detected in 50 healthy blood donors from the posed by Brown et al. (Table 1)[101]. southern hemisphere (where yew trees do not grow) [94]. There is evidence in some patients reactive to the heparin antidote, protamine, that drug-specific IgGs (in combination with complement) can mediate immediate HSRs Table 1 Severity grading system of immediate HSRs – [95 97]. Although this mechanism has not been explored Grade Severity Description in taxane HSRs, it may turn out to be relevant. Another possibility is that paclitaxel-specific IgE are produced in 1 Mild Symptoms are limited to the skin (e.g., flushing) patients exposed to yew tree pollen. In this regard, the or involve a single organ/system and are mild (e.g., mild back pain). allergenic potential of yew tree pollen has been shown in 2 Moderate Symptoms involve at least two organs/systems two different populations. In a study from Japan, 5/18 (e.g., flushing and dyspnea), but there is no patients with springtime allergic rhinitis showed sensitiv- significant drop in blood pressure or in itytotheTaxus cuspidata pollen as demonstrated by IgE oxygen saturation. immunoblotting and, in a study from Italy, 27 % of 562 3 Severe Symptoms typically involve at least two organs/ patients allergic to the Cupressacea (cypress) pollen had a systems, and there is a significant drop in ≤ positive prick test to a T. baccata pollen extract [98, 99]. blood pressure (systolic 90 mmHg and/or syncope) and/or oxygen saturation (≤92 %). The possibility that patients may develop IgE and/or IgG sensitivity to taxanes through pollen exposure and then Adapted from Brown et al. [101] Clinic Rev Allerg Immunol

Re-challenge re-challenge procedure allowed completing the paclitaxel infusion in 93 % of HSRs (65/70). Weiss et al. reported the first cohort of patients with immediate The experience with docetaxel is more limited. Schrijvers HSRs to paclitaxel to undergo re-treatment with the drug [26]. et al. showed that premedication with corticosteroids starting These patients were enrolled in different phase I trials of 12 h before the infusion along with antihistamines could paclitaxel sponsored by the National Cancer Institute and were successfully prevent grade 1 or 2 HSRs to docetaxel in 13/ thus not premedicated. Among twenty-seven patients with 14 patients [47]. Markman et al. used a rapid re-challenge definite immediate HSRs to paclitaxel (of which at least approach (similar to the one described above for paclitaxel) in 41 % had been severe), all underwent re-challenge with 17 patients with HSRs to docetaxel [103]. All were able to premedication [26]. Eleven patients (41 %) had a recurrent complete every docetaxel infusion although one patient opted HSR (one of which died as result), and seven of these patients to discontinue treatment since she had reacted during each of that had reacted despite premedication tolerated subsequent the first three infusions. In contrast, a more recent study paclitaxel infusions without additional precautions [26]. In showed that 16/43 patients (34 %) re-challenged to docetaxel 1993, Peereboom et al. described a re-challenge procedure had a recurrent HSR, and other groups have also reported for patients with immediate HSRs despite premedication in a failures of the rapid re-treatment strategy or of the progressive case series of eight patients [102]. Patients, which had expe- 24-h infusions creating the need for alternative methods to rienced grade 2 to 3 HSRs to paclitaxel, were re-challenged safely re-introduce taxanes in reactive patients [55, 104–106]. within 24 h of their initial HSR following additional doses of dexamethasone and antihistamines, and the rate of the pacli- Changing to a Different Taxane taxel infusion was progressively increased so that the infusion extended over 24 h. Three patients experienced minor symp- Paclitaxel and Docetaxel Cross-Reactivity toms during the re-challenge procedure although, surprisingly, all seven tolerated a subsequent paclitaxel infusion despite In 1998 and 2000, two case series described a total of seven using the same premedication regimen and infusion rate as patients with immediate HSRs to paclitaxel that did not react during the original infusion that had triggered the HSR [102]. when treated with docetaxel suggesting that cross-reactivity Other groups have also reported a high success rate using a between taxanes was low or even non-existent [107, 108]. progressive 24-h paclitaxel infusion starting at 1–2mg/hand However, one of the case series did not include any severe slowly increasing the rate so as to complete the infusion over a HSR to paclitaxel, [108] and in the other, the severity of the period of 24 h [28, 31, 34]. Most groups administer an reactions was not described [107]. Dizon et al. reviewed all additional dose of dexamethasone following the initial HSR cases of severe HSRs to taxanes (defined as severe enough to and before the first re-infusion and perform subsequent pacli- justify withdrawing the medication) at their institution over a taxel infusions using a standard premedication regimen and a period of 5 years [109]. They identified 16 patients with a progressive 24-h infusion [28, 31, 34]. Whether this protocol severe HSR to paclitaxel of which 10 were treated with is effective because it induces a certain degree of desensitiza- docetaxel. Among those 10 patients, three had experienced a tion or because the maximal serum concentration of paclitaxel grade 3 HSR and seven a grade 2 HSR to paclitaxel. Upon and/or Cremophor EL reached is below the threshold for their first docetaxel infusion, 9/10 patients suffered a HSR basophil/mast cell activation remains unknown. However, (grade 2—8andgrade1—1) indicating a 90 % cross- for practical reasons and because they carry a higher risk of reactivity rate in their population. In this cohort, no patient febrile neutropenia, 24-h infusions are rarely performed that had not had a prior HSR to paclitaxel had a severe HSR to nowadays [40]. docetaxel. More recently, Sanchez-Munoz et al. performed a Markman et al. developed a slightly different strategy for similar study and found that 3/8 patients switched from pac- re-treating patients with immediate HSRs to paclitaxel [33]. litaxel to docetaxel and 4/9 patients switched from docetaxel Following an immediate HSR, the infusion was stopped and to paclitaxel because of a severe HSR had a recurrent reaction the patient treated with intravenous corticosteroids and anti- [110]. It appears that the cross-reactivity rate between pacli- histamines. Upon complete resolution (usually within taxel and docetaxel varies among different populations and 30 min), the infusion was resumed at the previous rate. that the severity of the initial HSR may influence this rate. Subsequent infusions were given without any modification of the premedication or the infusion rate. Among 44 patients Paclitaxel, Docetaxel, and nab-Paclitaxel Cross-Reactivity with mostly grades 1 and 2 HSRs, 43 agreed to the re- challenge procedure and one patient with a grade 3 reaction Fader et al. published a case series of five patients with grade 3 refused. These 43 patients experienced a total of 70 HSRs HSRs to paclitaxel that all tolerated nab-paclitaxel [64]. Four since some patients reacted on subsequent infusions despite other patients with HSRs to paclitaxel and/or docetaxel (two having tolerated the rapid re-challenge procedure. The rapid of which with grade 3 HSRs) have been reported to tolerate Clinic Rev Allerg Immunol nab-paclitaxel in the literature [62, 63, 65]. To our knowledge, following the treatment of the reaction. In comparison, the some patients have reacted to nab-paclitaxel following a HSR protocol used by Markman et al. administered a higher initial to paclitaxel, and caution should be exercised if such a switch dose of paclitaxel, increased the dose more abruptly, and is desired. Finally, it should be mentioned that taxanes are not reached a much higher final rate than the protocol of necessarily equivalent to one another from an oncologic stand- Robinson et al. and yet seemed more effective at preventing point and regarding their general adverse effect profile HSRs. Other small cohorts of ≤10 patients desensitized to [54, 60]. Therefore, the decision to change from one taxanes have been described using a variety of protocols with taxane to another should not be based solely on the risk a generally good success rate [55, 88, 89]. The diversity and of cross-reactivity. sometimes-conflicting nature of the data show the need to validate desensitization protocols in a large number of patients Desensitization Protocols that includes patients with severe HSRs and ideally in different populations to reliably establish their safety and efficacy. Essayan et al. performed the first desensitization to paclitaxel on a patient with a grade 3 HSR who had failed re-challenge Rapid Drug Desensitization with a progressive 24-h infusion [87]. The desensitization protocol was based on the one used in penicillin-allergic Safety and Efficacy In 2005, Feldweg et al. (from Brigham patients and consisted of administering doubling doses of and Women’s Hospital/Dana-Farber Cancer Institute; BWH/ paclitaxel every 15 min starting with a 1-ml volume of a DFCI) reported on the use of a 6- to 7-h rapid drug desensi- solution diluted 100, 000-fold compared with the final solu- tization (RDD) protocol for patients with HSRs to paclitaxel tion. The protocol had 20 steps that preceded infusion of the and/or docetaxel [106]. Seventeen patients (eight with grade 3 undiluted final solution. The patient received three desensiti- HSRs to paclitaxel and nine with grade 2 HSRs to paclitaxel, zations and had minor symptoms that did not require any three of which also had a grade 2 HSR to docetaxel) were treatment during each of them starting with a dose as low as treated with the RDD protocol described in detail below. Five 2 ml of a 1,000-fold diluted solution. This report highlighted patients had failed a re-challenge with a slower infusion rate, the important role that desensitization could play in patients and one patient had failed a change from paclitaxel to doce- highly reactive to paclitaxel and that had failed other methods taxel prior to being referred to allergy for RDD. A total of 77 of drug re-introduction. desensitization procedures were performed, and four patients Markman et al. devised a desensitization protocol for pa- (24 %) had a breakthrough HSR most commonly during their tients that failed their rapid re-challenge procedure mentioned first desensitization. Three of them had a very minor HSR that above [33]. Patients treated with this protocol were given did not recur on subsequent desensitizations following adjust- doses of dexamethasone starting 36 h before the procedure ments to the protocol that included reducing the final infusion and received their paclitaxel infusion as follows: 2 mg/100 ml rate. The other patient had minor flushing during the proce- over 30 min followed by 10 mg/100 ml over 30 min and the dure, but 6 h after its completion, she had a severe HSR with remainder of the dose in 500 ml over 3 h. The first solution is hypotension that required epinephrine treatment. She decided approximately a 30-fold dilution of the final concentration not to receive paclitaxel thereafter. translating into a 5-fold increase in concentration between Two other studies have confirmed the safety and efficacy of bags. Nine patients were treated with this protocol, and eight the RDD protocol in patients reactive to paclitaxel and/or did not have any HSR. The patient that reacted was able to docetaxel [3, 111]. Lee et al. reported on the outcome of 114 complete the infusion following the treatment of the HSR and desensitization procedures to paclitaxel in 22 patients [111]. a 30-min pause in the infusion. It should be noted that in this Breakthrough HSRs occurred in six patients (27 %) in a total cohort, most patients had a non-severe HSR to paclitaxel and of nine procedures (8 %). Only one breakthrough HSR was that one patient with a grade 3 HSR was not offered re- severe being associated with hypotension, but all desensi- challenge and/or desensitization. tization procedures allowed the administration of the Robinson et al. proposed another desensitization protocol total dose. In addition, two desensitizations to docetaxel for paclitaxel in which the total dose is diluted in a 1-l bag were performed in one patient uneventfully. In a study infused at an initial rate of 3–6 ml/h that is gradually increased on 413 desensitizations to chemotherapy that mainly by 6 ml/h every 10–15 min until a final rate of 42 ml/h is involved platins and taxanes, 28 patients underwent reached [82]. The desensitization lasts around 24 h. Eight 140 intravenous and 12 intraperitoneal desensitization patients were treated with this protocol (seven of which had procedures to paclitaxel [3]. An important finding was had a severe HSR to paclitaxel) and four (50 %) had break- that most breakthrough reactions occurred during the through reactions, one of which was severe and led to defin- first desensitization and that their incidence dramatically itive paclitaxel discontinuation. The three other reactive pa- reduced thereafter. These reactions were all less severe tients were able to receive the remainder of the paclitaxel dose than the initial HSR, and only one required epinephrine Clinic Rev Allerg Immunol treatment. Importantly, all patients were able to safely remain below the saturation point of the drug (e.g., 1.2 mg/ml receive their full treatment. Further evidence of the for paclitaxel). The final rate is usually 80 ml/h, which makes safety and efficacy of this protocol has recently been a 12-step/3-bag desensitization and a 16-step/4-bag last provided among 62 patients that underwent 471 desen- around 6 and 7 h, respectively. Figure 4 depicts schematically sitization procedures of which 8 % were complicated by on a log scale the progressive increase in the cumulative dose breakthrough HSRs (none of them severe) [7]. infused over time during a 12-step/3-bag desensitization and compares it to a regular infusion. Interestingly, most break- Description of the Protocol The BWH/DFCI RDD protocol is through HSRs occur during step 12 of the protocol, which as follows (Table 2): 1/10th and 1/100th of the total dose to be may be explained by the fact that the dose administered during administered are prepared in 250-ml bags (bags 1 and 2, this step would have been sufficient to trigger a HSR in all respectively) [106]. Sometimes, an additional bag containing patients, if they had not received it through desensitization up 1/1000th the total dose in 250 ml is prepared if the patient had to this point [3]. a very severe initial HSR or is thought to be very sensitive [5]. The infusion of bag 1 is started at a rate of 2.5 ml/h, and the Setting and Patient Preparation for RDD At BWH/DFCI, rate is doubled every 15 min for three additional steps. The desensitization procedures are usually performed in the out- infusion then continues with the next bag, which has a 10-fold patient infusion unit with a one-to-one nurse/patient ratio. The higher concentration of the drug, and the rate is decreased 4- first desensitization might be performed in the intensive care fold so that the dose administered during this step is approx- unit if the initial HSR was severe (grade 3) and/or the patient imately twice that of the previous one. The rationale for presents important co-morbidities (e.g., severe cardiovascular doubling doses at each step to achieve desensitization is based or respiratory disease) that would put her/him at a higher risk on in vitro data from mouse and human mast cells and on the of having a severe or difficult to manage breakthrough HSR. experience with penicillin desensitization protocols [100, As the risk of a breakthrough HSR steadily decreases with 112–114]. The final bag (usually bag 3 if bag 1 is a 1/100th each desensitization, subsequent procedures can be performed dilution) contains the total dose to be administered (minus the in the outpatient setting provided no severe HSR occurred dose given with bags 1 and 2) in 250 ml or a larger volume to during the initial desensitization [3].

Table 2 Example of 12-step/3-bag desensitization protocol used at Brigham and Women’s Hospital and Dana-Farber Cancer Institute

Name of medication Paclitaxel

Target dose 300 mg (175 mg/m2; usually infused over 180 min) Standard volume per bag 250 ml Volume per bag Concentration (mg/ml) Total dose per bag (mg) Solution 1 250 0.012 3 Solution 2 250 0.2 30 Solution 3 250 1.19 297.6 300−2.3625 (cumulative dose received at step 8) Step Solution Rate (ml/h) Time per step (min) Dose administered Cumulative Fold increase per step (mg) dose (mg) per step 1 1 2.5 15 0.0075 0.0075 – 2 1 5 15 0.015 0.0225 3 3 1 10 15 0.03 0.0525 2.3 4 1 20 15 0.06 0.1125 2.1 5 2 5 15 0.15 0.2625 2.3 6 2 10 15 0.3 0.5625 2.1 7 2 20 15 0.6 1.1625 2.1 8 2 40 15 1.2 2.3625 2.0 9 3 10 15 2.98 5.3375 2.3 10 3 20 15 5.95 11.288 2.1 11 3 40 15 11.9 23.188 2.1 12 3 80 174 276.8 300 ≤2.0 Total time: 339 min=5.65 h Clinic Rev Allerg Immunol

are systematically given even if not part of the standard premedication regimen. It is recommended that patients with delayed HSRs following desensitization receive a short-term (3–7 days) treatment with antihistamines, aspirin, montelukast, and, rarely, corticosteroids. Zileuton, which blocks the synthesis of leukotrienes through 5- lipooxygenase inhibition [118] and used as a single dose 30–60 min before the procedure, may also be considered in some patients with refractory breakthrough HSRs.

Fig. 4 Log scale of the cumulative dose of paclitaxel administered over time during desensitization compared to a 3-h regular infusion of a 300-mg Management of Breakthrough HSRs During RDD If a HSR dose. The starting dose of a 12-step/3-bag protocol is around 40,000-fold occurs during a desensitization procedure, the infusion is less than the target dose and 3,000-fold less than the starting dose of a immediately paused; and depending on the severity of regular infusion. After 1 min of a regular infusion, around 1.7 mg of symptoms, treatment can vary from simple observation paclitaxel has already been administered. The desensitization protocol uses a very low starting dose to ensure that it is below the reaction threshold. The to epinephrine injection [3]. Once symptoms have subsi- dose is then increased by 2-fold increments every 15 min until a dose ded, the procedure is resumed from the exact point where around 10-fold less than the target dose is reached (step 11; 2.75 h). That it was stopped. The protocol may then be adjusted for dose is also roughly equivalent to the starting dose of a regular infusion, subsequent desensitizations to prevent recurrent break- which is often sufficient to trigger a HSR if not administered through desensitization. The rate of step 12 is kept constant at 80 ml/h allowing through HSRs by either prolonging a step (from 15 to the remainder of the dose to be delivered at a slower pace (<2-fold increase) 30 min), adding an extra step (with a rate at mid-point that is similar to the rate at which a regular infusion is delivered between the rate of the previous and the next step), and/or adding premedication before the step where the HSR has occurred [3]. Also, patients who react early during the Beta-blockers should be withheld 24 h before the pro- desensitization process (bag 1) may benefit from a 16- cedure in all patients, unless extenuating circumstances step/4-bag protocol [5]. Together, these precautions and are present, as they might interfere with epinephrine, strategies have contributed to make RDD a safe and should it be required to treat a HSR [115]. Also, high- effective mean of re-introducing taxanes even in patients risk patients should also preferentially avoid angiotensin- with life-threatening HSRs. converting enzyme inhibitors 24 h before desensitization as they may increase the risk of prolonged hypotension in Skin Testing the event of a HSR [116]. Patients are advised to report any symptom they may experience during the procedure Taxane skin testing was initially performed on two patients since rapid discontinuation of the infusion and treatment with severe HSRs to paclitaxel (administered without are keys to prevent severe HSRs. Following the end of the premedication during phase I trials) and four paclitaxel- infusion, patients are observed for 30 min and then tolerant controls [26]. SPT and IDT were performed with discharged home. They are advised to inform the desen- diluted and undiluted paclitaxel and were found to be negative sitization team of any delayed reaction. in all patients. This somewhat limited experience (combined Patients receive the same standard premedication regi- with the fact that most HSRs occurred with first exposure) led men that they would for a regular infusion, which in- to the assumption that taxane HSRs were not IgE-mediated. cludes dexamethasone as previously mentioned. This long-held view was recently challenged by Prieto-Garcia However, additional doses of corticosteroids are rarely and Pineda de la Losa who described a case of a patient with a used. Aspirin 325 mg (oral) and montelukast 10 mg severe paclitaxel HSR on her second lifetime exposure in (oral), which were shown to be more effective at mini- whom a positive IDT to paclitaxel was elicited at a concen- mizing breakthrough HSR compared with methylpredni- tration of 0.0001 mg/ml6. They also showed that a paclitaxel solone, are commonly given as a single dose 30–60 min concentration of 6 mg/ml (undiluted) in SPTand of 1 mg/ml in before the procedure along with the other premedication IDT were non-irritant as they did not induce a positive re- drugs [117]. Aspirin acts by inhibiting the synthesis of sponse in 15 patients that had adverse reactions to paclitaxel. prostaglandins and montelukast by blocking the receptor The experience with docetaxel skin testing is even more for cysteinyl leukotrienes; these are important mediators limited. Messaad et al. skin tested to docetaxel (SPT secreted by activated mast cells and basophils (Fig. 3) 10 mg/ml and IDT 1 mg/ml) a patient that had a severe [117]. H1 (cetirizine 10 mg (oral) or diphenhydramine immediate HSR to docetaxel on first exposure [119]. The 25–50 mg (IV) or hydroxyzine 25–50 mg (oral)) and H2 results were negative. To our knowledge, nab-paclitaxel and (famotidine 20 mg (IV) or ranitidine 50 mg (IV)) blockers cabazitaxel skin testing have not been performed. Clinic Rev Allerg Immunol

Different groups have since adopted the practice of taxane emphasized that desensitization protocols, despite their skin testing. Gastaminza et al. performed skin testing (SPT efficacy at preventing life-threatening immediate HSRs, 0.4 mg/ml and IDT 0.04 mg/ml) on three patients with HSRs are not efficacious at preventing severe delayed reac- to docetaxel and found one positive result [89]. All three tions. On the other hand, patients with non-severe de- patients tolerated docetaxel re-administration through a desen- layed onset HSRs such as a benign maculopapular rash sitization protocol. In another study, 17 patients with immedi- may be safely re-exposed to taxanes although the meth- ate HSRs to taxanes (14 with paclitaxel and three with doce- od of re-introduction will depend on skin testing results taxel) underwent skin testing [88]. Paclitaxel was used at up to [7]. We have noticed that these delayed reactions recur 6 mg/ml (SPT and IDT) and docetaxel at up to 10 mg/ml (SPT in only a minority of patients and that when they do, and IDT). Two patients had positive results although the drug they are rarely more severe than the initial reaction and and concentration to which they tested positive is not men- they tend to subside over repeated exposures. Another tioned. Among the 15 patients with negative skin tests, 12 concern is that such delayed reactions may be the pre- were challenged and eight reacted suggesting a poor negative lude to an immediate HSR thus providing the rationale predictive value in this population. Skin-test and challenge- for skin testing [7, 71]. positive patients were subsequently desensitized to taxanes, Patients with immediate HSRs should undergo skin testing and 5/10 (50 %) experienced a mild breakthrough HSR. In as the result can be used as a diagnostic and risk stratification contrast, paclitaxel skin testing (SPT 1 mg/ml; IDT tool [7, 88]. Although the majority of immediate HSRs usu- 0.001 mg/ml followed if negative by 0.01 mg/ml) was recent- ally occur within minutes of the start of the infusion, some ly performed on 64 patients with immediate and delayed reactions with features of immediate-type HSRs (e.g., flush- HSRs to taxanes [7]. Forty-four out of 56 patients (79 %) with ing, pruritus, angioedema, urticaria, bronchospasm, and even a paclitaxel HSR, 3/6 (50 %) with a docetaxel HSR, and 2/2 hypotension) may have a delayed onset of up to 24 h after the (100 %) with HSRs to both drugs had a positive result. infusion [106]. Such HSRs may represent a late-phase phe- Patients were most commonly positive at the lowest IDT nomenon of which the immediate phase would have been concentration (0.001 mg/ml), and two patients exhibited a blunted by the premedication given prior to the taxane infu- positive SPT. Patients with a negative skin test and either a sion [115]. In patients with severe immediate HSRs, it may be delayed or grade 1 or 2 immediate HSR were considered for helpful to measure mediators released by basophils/mast cells challenge. All 11 patients that were challenged had no HSR upon activation (e.g., serum tryptase and 24-h urinary and were able to resume regular infusions. Interestingly, one methylhistamine) so as to document their role in the HSR of those subsequently developed a grade 3 HSR and, on re- [106] and to detect rare patients with mast cell activation evaluation, was found to have converted from a negative to a disorders, which may represent a particular challenge for positive skin test. These preliminary data suggest that desensitization [120]. taxane skin testing could be used as a risk stratification Skin testing should be performed at least 2 weeks after tool in the decision to re-introduce taxane through a the event to minimize the possibility of a false-negative challenge or a desensitization procedure. However, experi- result due to the refractory period following a HSR [121]. ence with taxane skin testing is still limited, and as shown Drugs that may interfere with skin reactivity should also by these studies, its value may vary between different be withdrawn for the appropriate amount of time before populations, highlighting the need for further research on skin testing [121]. Paclitaxel skin testing is performed at this promising new diagnostic and risk stratification tool 1 mg/ml (SPT); and if negative, 0.001 mg/ml (IDT); and for taxane HSRs. if negative, 0.01 mg/ml (IDT) and docetaxel skin testing at 10 mg/ml (SPT); and if negative, 1 mg/ml (IDT). Proposed Management Strategy for HSRs to Taxanes Systemic reactions, although very rare, may be induced by skin testing, and emergency treatment should be avail- The management strategy proposed in this review aims to able to treat these reactions [121]. provide a general approach to taxane HSRs based on the We recommend taxane re-introduction through a rapid drug evidence currently available and our own experience. As the desensitization protocol in those with a positive skin test (even evidence on taxane skin testing is still fairly new and limited, if the initial reaction was consistent with a delayed onset this approach may be subject to change over the next few maculopapular rash) since it indicates mast cell sensitivity to years as new data emerge. The proposed management strategy taxanes and possibly an underlying IgE-mediated mechanism for HSRs to taxanes is summarized in Fig. 5. [7, 88]. RDD also appears to be the safest approach for There is a general agreement that patients with severe negative skin-test patients with a severe initial HSR, especial- delayed type HSRs such as SJS/TEN or pneumonitis should ly as the negative predictive value has not been established for not be re-exposed to the inciting agent and probably to this test in this population [7]. It seems reasonable to proceed potentially cross-reacting drugs [100]. It should be to a graded challenge in patients with grade 1 or delayed type Clinic Rev Allerg Immunol

Fig. 5 Algorithm for the management of HSRs to taxanes. See text for infusion. These reactions should be classified as immediate as they may details. Asterisk denotes that some patients may experience HSR that are represent a late-phase reaction of which the immediate phase could have consistent with basophil/mast cell activation up to 24 h following an been blunted by premedication

HSRs and a negative skin test, as their risk of recurrent severe grade 2 HSR (e.g., flushing, dyspnea, throat tightness, reaction appears to be low [7]. Prior to challenge, the standard back pain, and sense of impending doom without any changes premedication regimen for the taxane concerned should be in vital signs). administered as for a regular infusion. To minimize the risk of causing a severe HSR, it is advised to start the infusion at a relatively low rate (e.g., 2 mL/h) that can then be increased by Conclusions 10-fold increments so as to reach the rate of a regular infusion in around three steps [100]. If no HSR occurs with the graded The field of HSRs to chemotherapy is rapidly evolving, and challenge procedure, the patient can safely resume regular important achievements have been made over the years infusions; whereas in the event of an immediate HSR, RDD allowing many patients allergic to their chemotherapy to is recommended for future infusions [7]. The management of receive it safely. As highlighted in this review, the manage- skin-test negative grade 2 reactors is less clear as fewer of ment strategies for taxane HSRs are being progressively re- those patients have been challenged [7]. The decision to fined and will likely continue to evolve, especially as more is proceed with either a graded challenge or desensitization will discovered on the underlying mechanisms of those reactions. thus depend on the level of comfort of the allergist that Further research is thus needed on the mechanisms of HSRs to supervises the procedure and of the patient who undergoes it taxanes and on those of rapid drug desensitization as well as as well as on the severity of the initial HSR. Therefore, an on the clinical approach to patients suffering from HSRs to allergist experienced in drug allergy may feel comfortable to taxanes. perform a graded challenge in a patient with a moderate grade 2 HSR (e.g., flushing, dyspnea, and back pain) without significant co-morbidities and who wishes to resume regular Conflicts of Interest Matthieu Picard and Mariana C. Castells declare infusions whereas he may opt for RDD in patient with a more that they have no conflict of interest. Clinic Rev Allerg Immunol

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