Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies

Abstract

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to drug-induced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab.

Keywords::

• allergy
• anaphylaxis
• cetuximab
• drug desensitization
• etanercept
• infliximab
• monoclonal antibody
• rituximab
• trastuzumab

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Release date: 9 December 2011; Expiration date: 9 December 2012

Learning objectives

Upon completion of this activity, participants should be able to:

• • Distinguish infusion-related reactions amenable to desensitization

• • Analyze infusion-related reactions to rituximab and their management

• • Analyze infusion-related reactions to infliximab and their management

• • Analyze infusion-related reactions to cetuximab and their management

Financial & competing interests disclosure

EDITOR

Elisa Manzotti, Editorial Director, Future Science Group

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P. Vega,MD, Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine

Disclosure: Charles P. Vega, MD, has disclosed no relevant financial relationships.

AUTHORS

David I. Hong,MD, Harvard Medical School, Boston, MA, USA

Disclosure: David I. Hong, MD, has disclosed no relevant financial relationships.

Lora Bankova,MD, Harvard Medical School, Boston, MA, USA

Disclosure: Lora Bankova, MD, has disclosed no relevant financial relationships.

Katherine N. Cahill,MD, Harvard Medical School, Boston, MA, USA

Disclosure: Katherine N. Cahill, MD, has disclosed no relevant financial relationships.

Timothy Kyin,MD, Harvard Medical School, Boston, MA, USA

Disclosure: Timothy Kyin, MD, has disclosed no relevant financial relationships.

Mariana C. Castells,MD, PhD, Harvard Medical School, Boston, MA, USA

Disclosure: Mariana C. Castells, MD, PhD, has disclosed no relevant financial relationships.

Figure 1. The prevalence of hypersensitivity reactions is reduced with rapid desensitization.

(A) Breakdown of initial presenting reactions for which patients were referred for desensitization. (B) Prevalence of reactions with desensitization.

CUT: Cutaneous; CVR: Cardiovascular; F/C: Fever/chills; GI: Gastrointestinal; N-M: Neurologic/muscular; RESP: Respiratory; THROAT: Throat tightness.

Adapted with permission from [5].

The use of monoclonal antibodies (mAbs) in modern medicine is a technological advance that has revolutionized our approach to treating and thinking about a number of human diseases. By targeting specific proteins, mAbs provide an efficient means of exploiting our understanding of disease mechanisms to maximize therapeutic efficacy and, hopefully, minimize harm to the patient. The collective experience of using various mAbs over the years has uncovered data on hypersensitivity reactions to these drugs. Most reactions to mAbs occur acutely during the infusion, with symptoms ranging from mild rigors to systemic anaphylaxis. An extensive review of reactions to monoclonal treatments is beyond the scope of this review but can be found in the recently published review by Maggi et al.[1]. Reactions have been documented to occur with initial or repeated exposure, and skin testing to the offending agent can be negative, suggesting the mechanism of reaction is not necessarily IgE-dependent. The timing and type of symptoms patients experience during a reaction strongly suggest involvement by cells containing preformed inflammatory mediators (i.e., mast cells and basophils) since most reactions are responsive to immediate interventions such as stopping the infusion and treating symptoms of mast cell or basophil degranulation with epinephrine, antihistamine and/or albuterol.

Hypersensitivity reactions, including most acute infusion reactions, represent a treatment impediment that in many cases can be circumvented by desensitization in which a patient is temporarily ‘tolerized’ to a medication that previously induced a hypersensitivity reaction. Since the first desensitization protocols to penicillins were conceived in the 1940s [2,3], desensitizations have since been successfully performed against a variety of other medications eliciting acute hypersensitivity reactions. Our group’s experience desensitizing ovarian cancer patients to carboplatin and paclitaxel demonstrated that acute IgE-dependent (carboplatin) or -independent (paclitaxel) reactions are both amenable to desensitization protocols using serial log dilutions and careful step-wise dosing advancement [4].

While there is risk to re-administering a drug to which a patient has had a hypersensitivity reaction, this risk should be weighed against the benefit of using that drug when the offending agent is the best or only treatment option. Desensitization is contraindicated in patients whose reaction suggests a history of Stevens–Johnson syndrome or toxic epidermal necrolysis. Nor is desensitization appropriate for reactions of serum sickness or hemolytic anemia [101]. Re-administration of the suspected offending agent in these patients is absolutely contraindicated. Other syndromes for which desensitization should be avoided include hypersensitivity pneumonitis, cytokine-release syndromes and direct adverse drug effects that are dose dependent.

Desensitization is generally effective for IgE-dependent or -independent hypersensitivity reactions, including anaphylaxis [4]. Some reactions to mAbs occur on first exposure, and skin test data is generally not helpful [5]. While desensitization protocols may vary slightly from group to group, all start by giving the patient an extremely small dose, often 10²–10³-fold lower than the full dose, and gradually increasing the rate of infusion in a step-wise fashion over fixed time intervals until the patient is ‘tolerized’ to the offending agent. The step-wise nature of desensitization protocols makes it unlikely that the patient will suffer a reaction as severe in magnitude as the initial reaction since the drug is typically infused in a slow, highly controlled fashion, and there are multiple built-in breakpoints for medical intervention if needed.

Given the growing importance and utilization of monoclonal therapy in treating human diseases, the need to circumvent hypersensitivity reactions to deliver essential treatments is answered by desensitization techniques. This article covers the existing literature on monoclonal desensitizations focusing on four widely used agents: rituximab, infliximab, cetuximab and trastuzamab.

Rituximab

Rituximab is a chimeric mouse–human anti-CD20 monoclonal antibody used in the treatment of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic lymphoma (CLL) and in combination therapy for rheumatoid arthritis (RA), Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) [6]. Infusion-related reactions described in the prescribing insert include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events,or death, which can occur within 30–120 min of infusion [6]. The majority of these infusion reactions were shown to occur during the first infusion and decrease with each subsequent exposure. The rate of occurrence of infusion reactions on first exposure also varies depending on the treatment indication (12% for WG/MPA, 27% for RA, 77% for NHL) for reasons that are unknown [6].

The first reported series of rapid desensitization for hypersensitivity reactions to rituximab was described by Castells et al. as part of a case series of 413 desensitizations in 98 patients [4]. The paper described the efficacy of a three-solution, 12-step, rapid desensitization protocol for cancer patients who experienced hypersensitivity reactions to their first-line chemotherapy agent. Desensitizations were performed for reactions to carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin or rituximab. Three of the 98 patients had seven desensitizations performed for reactions to rituximab: two patients with severe pruritis and rash, and a third patient who had syncope. A complete list of presenting symptoms can be found in Figure 1.

Just prior to desensitization, all patients received premedication with H1-receptor blockers (diphenhydramine or hydroxyzine) and H2 blockers (famotidine or ranitidine). The predominant reason for substituting oral hydroxyzine for intravenous (iv.) diphenhydramine was a history of restless leg syndrome with iv. diphenhydramine. Acetaminophen and/or glucocorticoids were also administered at the discretion of the referring physician. An example of the desensitization protocol for rituximab is shown in Table 1. Three 250-ml solutions with different concentrations were used in a 12-step protocol in which the dose was advanced over 15-min intervals by increasing the rate and/or the concentration of drug being administered. Solutions #1 and #2 were 100- and ten-fold dilutions, respectively, of the original drug concentration and were used for steps #1–4 and #5–8 of the protocol. The concentration of solution #3 was calculated based on the remaining dose of rituximab to be delivered after the completion of step #8, diluted in 250 ml of buffer solution. Steps #9–11 continued the incremental dose increase after which the patient was considered ‘desensitized’. The remainder of the dose to be infused was given in step #12 at a rate of 80 ml/h. This final step constituted approximately half of the total desensitization time and approximately 92% of the total dose administered. Most reactions, if any, occurred during this last step. Most reactions were mild and treated with iv. diphenhydramine or oral hydroxyzine after pausing the infusion. Severe infusions were treated with methylprednisolone and parenteral albuterol, oxygen or epinephrine, all of which were available at the patient bedside. The infusion was then resumed once symptoms subsided.

All patients receiving rituximab via desensitization were able to receive their full treatment dose over seven desensitizations with no severe reactions. Some patients did experience mild reaction (defined as any non-life-threatening reaction). It is notable that of all 413 desensitizations studied, the majority of desensitizations (67%) had no reaction and severe reactions occurred in only 6% of cases. Also, no patient experienced any reaction during desensitization that was more severe than the initial presenting reaction.

Brennan et al. described a group of 14 additional patients who experienced hypersensitivity reactions to rituximab as part of a review of 105 desensitizations to mAbs in 23 patients who had reactions to mAbs [5]. The protocol for infusions and treatment of reactions was identical to that described in Castells et al. but adapted to dosing of mAbs (rituximab, infliximab and trastuzumab) [4]. Eleven out of 14 rituximab-sensitive patients developed a reaction on their first exposure and had no known prior exposure to any other mAb [5]. Data on rituximab skin testing were collected, but the sensitivity and specificity could not be validated on a larger scale and a negative skin test did not preclude desensitization over a strong clinical history of hypersensitivity reaction. Interestingly, one patient in the study converted from a positive to a negative skin test and was able to tolerate a subsequent rituximab infusion without desensitization. To date, there are no published reports of detectable IgE specific to rituximab.

Consistent with the findings of Castells et al., the majority of reactions that occurred to rituximab desensitization occurred during the last step (#12) with the majority of reactions consisting of mild cutaneous symptoms (i.e., flushing, hives) [4]. Again, all reactions were less severe than the initial presenting hypersensitivity reaction. When reactions did occur, the infusion would be paused and the symptoms treated with additional diphenhydramine or hydroxyzine. For severe or refractory symptoms, methylprednisolone was usually administered as well.

Because rapid desensitization is temporary, repeat desensitizations took into account the patient’s previous history with desensitizations by prescribing additional premedication(s), either pre-infusion or at specific steps during the protocol depending on the timing and type of reaction(s) encountered. In addition to antihistamines, supplementary premedications also included montelukast alone (for bronchospasm), montelukast plus aspirin (for flushing), and acetaminophen with or without glucocorticoids (for fever/chills). For example, a patient who experienced hives, bronchospasm and flushing at the beginning of step 12 would receive premedication with diphenhydramine, ranitidine, montelukast and aspirin before the infusion and additional iv. diphenhydramine just prior to step 12. Of all the rituximab desensitizations studied in this series, only one severe reaction (hypotension) occurred, but like all the other desensitizations performed in the study the reaction was treated to resolution and the patient was able to receive the full prescribed dose.

Infliximab

Infliximab is a chimeric mouse–human IgG1 mAb that binds TNF-α with high affinity and specificity, and is used primarily in the treatment of inflammatory bowel disease and rheumatoid arthritis. Other TNF-α inhibitors include etanercept, a TNF receptor–IgG fusion protein; certolizumab, a humanized antibody; and two fully human anti-TNF-α monoclonals, adalimumab and golimumab. Infliximab is administered via iv. infusion while etanercept, adalimumab, golimumab and certolizumab are administered subcutaneously.

Acute reactions constitute the most common type of reaction observed with TNF-α inhibitors. The majority of reports define acute reactions as reactions occurring in the first 24 h after infusion and range from headache, dizziness, nausea, flushing and pruritus to more systemic symptoms of hypersensitivity reaction like chest pain, dyspnea and sometimes full anaphylaxis [7,8].

Patients who develop antibodies against infliximab (human antichimeric antibodies) have an increased risk of having an acute infusion reaction than patients who did not develop antibodies against infliximab. In a study by Hanauer et al., 38% of patients who had an acute infusion reaction, defined as a reaction occurring within 1 h of infusion initiation, were found to have positive IgG antibodies to infliximab [7]. Similarly, Baert et al. showed a strong association between the concentration of antibodies against infliximab and the occurrence of an infusion reaction [9]. Other reports describe antibodies to infliximab belonging to both the IgE and IgM classes, and a high index of correlation with infusion reactions [10]. The use of concomitant immunosuppressive agents such as methotrexate [9] or daily oral steroids [11] has been reported to reduce the incidence of infusion reactions by inhibiting the development of antibodies to infliximab, suggesting this is an important mechanism behind the development of acute reactions to monoclonals in general.

In addition to blocking antibody formation to infliximab, some groups suggest that slowing the infusion rate can be helpful in some instances of acute infusion reactions [12]. Several groups have also developed protocols for infliximab administration with routine premedication with steroids, antihistamines and acetaminophen [12,13]. However, at least two open studies on adverse drug reactions to infliximab suggest that there is no advantage of a routine premedication for patients who do not have a prior history of infusion reactions [14,15].

For acute infusion reactions, several desensitization protocols have been successfully applied. Puchner et al. first reported successful desensitization to TNF-α inhibitors for anaphylactic reactions in 2001 [16]. They described two patients who were desensitized to infliximab in an intensive care unit setting using an 11-step protocol with a twofold increase at each step starting at 1/100,000 of the final dose [16]. The dose was increased every 15 min and the infusion was completed in 4 h. Both desensitizations were successful with the patients able to receive the necessary dose of medication.

Chiefetz et al. summarized their group’s experience for managing acute infusion reactions to infliximab based on the severity (mild, moderate or severe) of a patient’s infusion reaction [8]. The specific categorizations of reactions within the mild, moderate and severe subcategories are too lengthy to describe for this review but correlated to the mortality risk of the respective reactions. The study was a retrospective analysis of 165 patients who received a total of 479 infusions over a 2.5-year window. All patients received initial infusions starting at 10 ml/h for 15 min. The rate of infusion was then doubled every 15 min to 20, 40, 80 and 100 ml/h, after which the patient was continued at 150 ml/h for 30 min. If there was no reaction during this interval, the rate was increased to a top rate of 250 ml/h. If, and only if, patients suffered a reaction, they were given subsequent infliximab infusions by modified infusion protocols including desensitization for a history of moderate-to-severe reactions. In the study, there were 26 acute reactions of which 15 (58%) were mild, six (23%) were moderate and five (19%) were severe. Patients with mild reactions received standard premedication (diphenhydramine and acetaminophen) before a test dose of 10 ml/h was given prior to uptitration of the rate over 3 h. Six patients who had moderate reactions received standard premedication with uptitration of the rate from 10 ml/h to 125 ml/h over six steps of 15-min intervals. Patients with severe reactions received standard premedication with the addition of steroids prior to infusion uptitration from 10 ml/h to 100 ml/h over five steps of 15-min intervals. All patients with mild or moderate reactions were able to continue infliximab treatment. Of the four patients who had severe reactions, two were able to continue treatment with desensitization, one had a breakthrough severe reaction and one withdrew from further treatments.

In 2006, Duburque et al. reported their experience with desensitization in 14 patients with Crohn’s disease who had developed infusion reactions despite prophylactic administration of hydrocortisone [17]. The protocol was specifically for patients with severe infusion reactions for whom the continuation of infliximab therapy was considered as the only therapeutic option. The authors used an 11-step protocol in which the final target dose was 5 mg/kg. The first four steps of the protocol represented dose escalations using a solution of infliximab diluted to 2 × 10^-3 mg/ml/kg in which the rate was increased in a step-wise manner every 15 min. Steps #5–11 further increased the dosage using a solution of 0.2 mg/ml/kg. The rate of dose escalation is unfortunately not specified, but the total infusion time was 2 h and 45 min in each case. Of the 14 patients studied, all were able to receive at least one full infliximab treatment. Three patients had mild reactions which were easily managed during the desensitization, one patient had angioedema necessitating stoppage of the protocol, and one patient had a delayed reaction consisting of generalized arthralgias, myalgias, fever and headache requiring treatment with corticosteroids.

Brennan et al. reported the experience from our center with six patients who had immediate-type hypersensitivity reactions to infliximab [5]. The patients were assessed for infliximab hypersensitivity by an allergist and offered desensitization if the patient had a mild or severe acute reaction defined by Brown’s criteria [18] and/or a positive skin test to infliximab. Four patients (67%) had a positive intradermal skin test at either 0.1 or 1.0 mg/ml concentration and all patients undergoing desensitization had reactions after several exposures to infliximab. The same protocol used for rituximab desensitization was used successfully for infliximab desensitization with the majority of reactions occurring during the last step and consisting of mainly cutaneous symptoms of flushing, pruritis and/or hives. In addition to the premedication algorithm used to treat and prevent reactions in patients undergoing repeat desensitizations, another protocol modification that was occasionally employed was the insertion of one or more additional steps in the protocol to decrease the slope of the dose–time curve at certain points in the protocol where reactions occurred despite additional premedication. An example of an infliximab desensitization protocol for a patient who required a 13-step protocol, as opposed to a standard 12-step protocol, is shown in Table 2. All patients who underwent infliximab desensitization were able to receive their full treatment dose.

Other monoclonal TNF-α inhibitors

Although local reactions with hives, local swelling and pruritus are the most common allergic reaction with the injectable TNF-α inhibitors [19], systemic reactions after adalimumab administration have also been reported [20–22]. Skin testing has been used to document the IgE-mediated mechanism of reactions to both etanercept and adalimumab [19,21,23]. Rodriguez-Jimenez et al. performed a successful desensitization in a patient with plaque psoriasis who had poor responses to methotrexate and etancercept [21]. Infliximab was also tried but discontinued secondary to a cardiac dysrhythmia associated with its use. Adalimumab was very effective but induced generalized urticaria and rhinitis after six doses. The patient was skin-test positive to full strength adalimumab (50 mg/ml) as compared with ten negative control patients. In their protocol, no premedications were given and the adalimumab was given over six injections spaced 60 min apart starting with a 0.5-mg dose. Each subsequent injection was a rough doubling of the prior step. By the end of the 6-h desensitization, the patient had received her full dose of 44.25 mg. The administration of the early doses was made possible by 1:10 and 1:100 dilutions of full strength adalimumab in sterile water.

Bavbek et al. very recently reported a successful desensitization to etanercept in a patient with ankylosing spondylitis who became sensitized to both adalimumab and etanercept [23]. The patient had developed local swelling, diffuse pruritus and shortness of breath after his 26th adalimumab injection and was then switched to etanercept. He developed a local reaction followed by a disseminated urticarial rash after his 22nd etanercept injection. The patient was positive on intradermal skin test to 1:100 dilution of etanercept as compared with two negative control patients. An attempt to prevent a reaction with antihistamines was unsuccessful secondary to a breakthrough disseminated urticarial rash. The patient was then desensitized following a 3-day protocol as shown in Table 3. The patient was premedicated with aspirin, montelukast, H1 and H2 blockers, and received six to seven consecutive injections of gradually increasing etanercept doses on days one through three. Each injection was spaced by 30- to 150-min intervals starting at 1/100 dilution of the final dose and doubling the dose with each step. The cumulative dose on the first and second day was identical and equal to approximately half of the target dose (12.25 mg). On day three, the patient achieved the full target dose (25 mg) and desensitization was maintained by twice-weekly administrations of full-dose etanercept. Only small (<3 cm in diameter) local injection site reactions were reported.

Cetuximab

Cetuximab is a human–murine chimerized IgG1 mAb that targets the extracellular ligand-binding domain of the EGF receptor (EGFR). It was the first US FDA-approved mAb directed against EGFR and is approved for metastatic colorectal cancer and squamous cell carcinoma of the head and neck [102]. It carries a black-box warning of severe infusion reactions that have been reported to occur in 3% of patients with 90% of those reactions occurring during the first infusion with rare fatalities (<1:1000). These reactions occurred despite the use of prophylactic antihistamines, and the reactions that developed were consistent with a type I IgE-mediated hypersensitivity reaction with bronchospasm, hypotension and/or urticaria. The current manufacturer guidelines require discontinuation from further treatment once a severe infusion reaction has occurred [102].

Most reactions to cetuximab occur with the first infusion. An unusually high rate of severe infusion reactions in North Carolina (USA) and Tennessee (USA) [24] prompted an investigation that led to the discovery of a relatively high prevalence of preformed anticetuximab IgE directed against galactose-α-1,3-galactose in patients who had first-time infusion reactions [25]. Unlike most other mAbs, cetuximab is generated in a mouse cell line (SP2/0) that expresses α-1,3-galactosyl transferase, which is present on the Fab’ portion of the cetuximab heavy chain. There was a surprising degree of regional variation in the prevalence of anticetuximab IgE expression with high prevalence in patients from North Carolina, Tennessee and Arkansas (USA) and low prevalence in patients from northern California (USA) and Massachusetts (USA). The reason for this variation is unknown.

The first published desensitization to cetuximab was a case report describing a female with metastatic breast cancer and pre-existing anticetuximab-specific IgE [26]. A five-solution, 20-step protocol was used with premedications of prednisone at 12 and 1 h before infusion and diphenhydramine 30 min pre-infusion. Four tenfold serial dilutions were used in succession starting from the most dilute (0.0002 mg/ml) to the final, most concentrated solution (2 mg/ml), and each step represented a rough doubling of the prior step’s dose starting with 0.001 mg administered in step 1 and 325 mg administered in the final step, #20. The patient developed an erythematous, pruritic, maculopapular rash and subjective shortness of breath at the start of the final solution (step #17), which was managed with diphenhydramine, famotidine and solumedrol. Her symptoms recurred shortly after restarting the infusion necessitating additional treatment, but she was able to complete the infusion at half the planned infusion rate without further reaction.

Saif et al. attempted empiric desensitization in two patients who had acute reactions to panitumumab, a humanized mAb against EGFR, and were switched to cetuximab therapy using an empiric desensitization protocol [27]. It is, however, unclear if either patient described in the study had hypersensitivity to cetuximab to begin with since neither patient had received cetuximab previously nor was either patient evaluated for the presence of preformed anticetuximab IgE. In addition,, the primary authors were based in northeast USA, a region with low prevalence of preformed anticetuximab IgE [24]. In any case, patients received a test dose of full-strength cetuximab followed by careful uptitration of the infusion rate until the full dose was administered. One patient developed an acneiform rash after the third cetuximab treatment of unclear acuity while the second patient was able to receive eight treatments without event.

Our group has successfully managed hypersensitivity reactions to cetuximab using a one-solution, five-step desensitization protocol as opposed to our standard three-solution, 12-step protocol. Cetuximab is distributed at a fixed concentration in a proprietary buffer solution and, because the buffer is not available as a stand-alone product, dilutions were not made. Table 4 shows a successful desensitization protocol (previously unpublished) for a 49-year-old female with metastatic colon cancer who experienced a hypersensitivity reaction during her first infusion of cetuximab. Her symptoms began 30 min into the infusion with nausea, vomiting, full body urticaria, a sensation of throat closing and she subsequently became nonresponsive. Skin testing to cetuximab was positive on intradermal testing at a 1:10 dilution but negative on prick, and 1:1000 and 1:100 intradermal dilutions. The one-bag, five-step protocol was carried out seven times for this patient without any reactions during desensitization.

Alternative options to reduce or eliminate transfusion reactions include switching from cetuximab to panitumumab, which is a fully humanized IgG2 mAb targeting [28–30]. Use of premedication with antihistamines and corticosteroids has been shown in post-hoc analysis to reduce rates of grade 3 or 4 reactions to 1.0 versus 4.7% with antihistamine premedication alone during first administrations [31]. There have even been reports of successful readministration of cetuximab after a hypersensitivity reaction during the first administration using a premedication regimen of H1 and H2 antihistamines, steroids and a test dose [28]. However, caution needs to be exercised in the interpretation of these case reports as the underlying mechanism for the initial reactions are not described.

Trastuzumab

Trastuzumab is a humanized mouse IgG1 mAb with selective affinity for the human EGF2 protein, HER2. Traztuzumab is approved for the treatment of HER2-overexpressing metastatic breast cancer. Rates of severe hypersensitivity reaction to trastuzumab range from 0.6 to 5% [32,103], with the bulk of reports in the literature reporting mild-to-moderate infusion reactions characterized by fevers or chills in 40% of patients [33,103]. The current recommendation of the manufacturer is to permanently discontinue trastuzumab in those who develop anaphylaxis, angioedema or acute respiratory distress syndrome [103].

The first reports of desensitization to trastuzumab in 2002 were in two females with metastatic breast cancer [34]. The first patient developed urticaria and palmar pruritus after her third infusion. 1 week later, 5 mg into her infusion, she developed flushing, severe vaginal itching, nausea, vomiting, rigors and angioedema of the face, lips and tongue. She had positive intradermal skin testing (0.5 mg/ml). The second patient developed diffuse pruritis after 10 months of therapy with trastuzumab, which was managed with antihistamines. The following month she had throat tightness in the first minute of her infusion. Her skin testing on prick and intradermal was negative. Desensitization protocols consisted of premedication with diphenhydramine and ranitidine 1 h before a 15-step protocol. The first five steps involved dose escalation starting with a 5 µg/ml solution and the final ten steps used a 1 mg/ml solution. Both patients experienced hypersensitivity symptoms, the first with angioedema of the tongue and urticaria, and the second with diffuse pruritis during the desensitization protocol.

Unlike rituximab, most hypersensitivity reactions to trastuzumab occurred after multiple exposures to trastuzumab [5]. Skin testing was positive in three patients tested, one on epicutaneous testing, and two on intradermal testing. All three patients underwent successful desensitization protocols a total of 29 times. Table 5 is representative of a successful desensitization protocol for trastuzumab employing the three-solution, 12-step protocol previously described (Castells et al.[4], Brennan et al.[5]). One patient experienced a severe respiratory reaction during her tenth lifetime desensitization to trastuzumab after completing seven previous uneventful desensitizations. In addition,, one mild delayed reaction was experienced after trastuzumab desensitization.

In addition to successful desensitization, Melamad and Stahlman reported the induction of tolerance in their first case report by performing weekly subcutaneous immunotherapy with trastuzumab [34]. The same two patients who underwent the 15-step desensitization were continued on subcutaneous immunotherapy injections with trastuzumab. During the first week, patients received daily injections of 15 mg and increased the frequency to three injections over the second week. During weeks 3 through to 10, 20-mg injections were given twice weekly followed by weekly 20-mg injections thereafter for as long as patients were on trastuzumab therapy. This protocol worked for one patient who endured postinfusion reactions of rigors, chills and occasional hives for several months, but by the time of publication had continued on trastuzumab infusions for 3 years with no further allergic symptoms. The second patient tolerated the immunotherapy protocol, but after her second and third infusions of trastuzumab, developed severe hypertension and the drug had to be discontinued. This approach suggests that the desensitized state can be maintained through immunotherapy as long as continuous exposure to the agent is not limited by its toxicity. Another potential downside to this approach may be the increased likelihood of antibody formation, which may limit the therapeutic efficacy of the mAb.

Expert commentary

This review provides evidence for the efficacy and safety of rapid desensitization to treat hypersensitivity reactions to mAbs. Patients who present with acute infusion reactions that are IgE or non-IgE mediated are candidates for rapid desensitization. Symptoms of hypersensitivity reactions include flushing, itching, hives, swelling, throat tightening, shortness of breath, wheezing, nausea, vomiting, diarrhea, acute neuromuscular pain, hypotension or cardiovascular collapse. Even with high severity symptoms, patients can be successfully desensitized with no or minimal symptoms when using the protocol described in Castells et al.[4] and Brennan et al.[5], which is amenable to modifications based on patient reactions. The experience of our group and others has demonstrated that desensitization to mAbs such as rituximab, infliximab, trastuzumab and cetuximab leads to significant attenuation of moderate and severe reactions with the majority of patients having no reactions during desensitization. Patients need to be desensitized for each drug exposure since rapid desensitization does not provide long-term tolerance unless the patient has continued exposure to the medication, which can sustain tolerization. Desensitization protocols need to be customized to the patient’s specific dose and should be produced and supervised by allergists who can predict the patient’s risk, select the appropriate protocol, and can recognize the early signs of anaphylaxis, its management and treatment. This is key to the success of the protocol, preventing early termination and permitting the delivery of the target dose. Application and use of these protocols requires strong collaboration between pharmacists, nurses and doctors. High-risk rapid desensitizations require intensive care unit admission but repeated desensitizations or low-risk desensitizations in centers with extensive desensitization experience can be performed in a step-down infusion center or in-hospital floor.

Patient safety is always the paramount consideration and the risks and benefits associated with rapid desensitization need to be weighed carefully. For this reason, we strongly believe that desensitizations should only be done under the supervision of specially trained allergy specialists and nurses. Our institution’s nursing policy requires 1:1 nursing care for desensitizations as a high level of vigilance is required throughout the entire procedure to minimize the risk of errors in following the protocol as well as monitoring the patient for immediate hypersensitivity reactions. When done correctly, rapid desensitization is a highly effective re-administration strategy in patients who need an agent to which they have hypersensitivity reactions.

Five-year view

In the next 5 years we predict the expansion and universal application of desensitization protocols allowing all patients with acute hypersensitivity reactions to be treated with first-line therapy mAbs to cure or modify diseases such as cancer and chronic inflammatory diseases. Minimizing the impact of hypersensitivity reactions on clinical management decisions should lead to improvements in overall survival and quality of life as more mAbs become available to treat a wider range of diseases. The wider adoption of rapid desensitization techniques will require strong collaboration between specially trained allergists and other medical and surgical specialists to provide successful protocols, including support and recommendations in the management of reactions. As awareness of the benefits of desensitization to mAbs and other therapeutics increases, we expect these procedures will become the standard of care worldwide for patients in which the offending agent is the preferred or only available treatment. Basic research to uncover the mechanism(s) behind rapid desensitization will identify its molecular and cellular targets, and will provide pharmacological interventions aimed at reducing the risk for patients and increasing efficacy of drug delivery.

Table 1. Rituximab desensitization protocol: standard three-solution, 12-step protocol.

Step	Solution	Rate (ml/h)	Time (min)	Volume infused per step (ml)	Dose administered with this step (mg)	Cumulative dose (mg)
1	1^†	2.0	15	0.50	0.0221	0.0221
2		5.0	15	1.25	0.0553	0.0774
3		10.0	15	2.50	0.1106	0.1880
4		20.0	15	5.00	0.2212	0.4092
5	2^‡	5.0	15	1.25	0.5530	0.9622
6		10.0	15	2.50	1.1060	2.0682
7		20.0	15	5.00	2.2120	4.2802
8		40.0	15	10.00	4.4240	8.7042
9	3^§	10.0	15	2.50	10.9730	19.6772
10		20.0	15	5.00	21.9459	41.6231
11		40.0	15	10.00	43.8918	85.5149
12		80.0	174.375	232.50	1020.4851	1106.0000

^†Solution 1: 250 ml of 0.044 mg/ml (total per bag: 11.060 mg).

^‡Solution 2: 250 ml of 0.442 mg/ml (total per bag: 110.600 mg).

^§Solution 3: 250 ml of 4.389 mg/ml (total per bag: 1097.296 mg).

Target dose: 1106.0 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final concentration: 4.424 mg/ml; standard time of infusion: 187 min; total time: 339.375 min (5.66 h). The total volume and dose dispensed are more than the final dose given to the patient because many of the solutions are not completely infused.

Adapted with permission from [5].

Table 2. Infliximab desensitization protocol for a patient who had recurrent urticaria at step 11 refractory to additional antihistamine^†.

Step	Solution	Rate (ml/h)	Time (min)	Volume infused per step (ml)	Dose administered with this step (mg)	Cumulative dose (mg)
1	1^‡	2.0	15	0.50	0.0118	0.0118
2		5.0	15	1.25	0.0296	0.0414
3		10.0	15	2.50	0.0591	0.1005
4		20.0	15	5.00	0.1182	0.2187
5	2^§	5.0	15	1.25	0.2956	0.5143
6		10.0	15	2.50	0.5912	1.1055
7		20.0	15	5.00	1.1824	2.2879
8		40.0	15	10.00	2.3648	4.6527
9	3^¶	10.0	15	2.50	5.8655	10.5182
10		20.0	15	5.00	11.7309	22.2492
11		40.0	15	10.00	23.4619	45.7111
11a		60.0	15	15.00	35.1928	80.9039
12		80.0	174.375	232.50	545.4889	591.2000

^†A three-solution, 13-step protocol was developed. Note the addition of step 11a.

^‡Solution 1: 250 ml of 0.024 mg/ml (total per bag: 5.912 mg).

^§Solution 2: 250 ml of 0.236 mg/ml (total per bag: 59.120 mg).

^¶Solution 3: 250 ml of 2.346 mg/ml (total per bag: 586.547 mg).

Target dose: 591.2 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final concentration: 2.3648 mg/ml; standard time of infusion: 187.5 min; total time: 354.375 min (5.91 h).

Adapted with permission from [5].

Table 3. Etanercept desensitization protocol for a patient with hypersensitivity to both adalimumab and etanercept.

Step	Time interval from previous step (min)	Dose (mg)	Dilution	Volume administered (ml)
Day 1^†
1	0	0.25	1:100	1
2	30	0.5	1:10	0.2
3	60	1	1:10	0.4
4	60	2	1:10	0.8
5	90	4	1:1	0.16
6	120	4.5	1:1	0.18
Day 2^‡
1	0	0.25	1:100	1
2	30	0.5	1:10	0.2
3	60	1	1:10	0.4
4	60	2	1:10	0.8
5	90	4	1:1	0.16
6	120	4.5	1:1	0.18
Day 3^§
1	0	0.25	1:100	1
2	30	0.5	1:10	0.2
3	60	1	1:10	0.4
4	60	2	1:10	0.8
5	90	4	1:1	0.16
6	120	8	1:1	0.32
7	150	8.75	1:1	0.35
Maintenance dosing (twice weekly)
1	NA	25	1:1	1

^†Total dose administered: 12.25 mg.

^‡Total dose administered: 12.25 mg.

^§Total dose administered: 25 mg.

Etranercept desensitization standard dilution: 25 mg/ml.

Data from [23].

Table 4. Cetuximab desensitization protocol: one-solution, five-step protocol.

Step	Solution	Rate (ml/h)	Time (min)	Volume infused per step (ml)	Dose administered with this step (mg)	Cumulative dose (mg)
1	1^†	5.0	30	2.50	5.0658	5.0658
2		10.0	30	5.00	10.1316	15.1974
3		20.0	30	10.00	20.2632	35.4606
4		40.0	30	20.00	40.5264	75.9870
5		80.0	256.87	342.49	694.0011	769.9881

^†Solution 1: 380 ml of 2.026 mg/ml (total per bag: 770.002 mg).

Target dose: 770.0 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final concentration: 3.08 mg/ml; standard time of infusion: 187.5 min; total time: 376.87 min (6.28 h).

Table 5. Trastuzumab desensitization protocol: standard three-solution, 12-step protocol.

Step	Solution	Rate (ml/h)	Time (min)	Volume infused per step (ml)	Dose administered with this step (mg)	Cumulative dose (mg)
1	1^†	2.0	15	0.50	0.0115	0.0115
2		5.0	15	1.25	0.0288	0.0403
3		10.0	15	2.50	0.0575	0.0978
4		20.0	15	5.00	0.1150	0.2128
5	2^‡	5.0	15	1.25	0.2875	0.5003
6		10.0	15	2.50	0.5750	1.0753
7		20.0	15	5.00	1.1500	2.2253
8		40.0	15	10.00	2.3000	4.5253
9	3^§	10.0	15	2.50	5.7047	10.2300
10		20.0	15	5.00	11.4095	21.6395
11		40.0	15	10.00	22.8190	44.4585
12		80.0	174.375	232.50	530.5415	575.0000

^†Solution 1: 250 ml of 0.023 mg/ml (total per bag: 5.750 mg).

^‡Solution 2: 250 ml of 0.230 mg/ml (total per bag: 57.500 mg).

^§Solution 3: 250 ml of 2.282 mg/ml (total per bag: 570.475 mg).

Target dose: 575.0 mg; standard volume per bag: 250 ml; final rate of infusion: 80 ml/h; calculated final concentration: 2.3 mg/ml; standard time of infusion: 187.5 min; total time: 339.375 min (5.66 h).

Adapted with permission from [5].

Key issues

• • The usefulness of monoclonal antibodies (mAbs) as therapeutic tools is limited in patients who experience acute infusion reactions.

• • Most reactions to mAbs occur acutely during the infusion with symptoms ranging from mild rigors to systemic anaphylaxis.

• • Hypersensitivity reactions, including most acute infusion reactions, represent a treatment impediment that in many cases can be circumvented by desensitization in which a patient is temporarily ‘tolerized’ to a medication that previously induced a hypersensitivity reaction.

• • While there is risk to re-administering a drug to which a patient has had a hypersensitivity reaction, this risk should be weighed against the benefit of using that drug when the offending agent is the best or only treatment option.

• • The experience of our group and others has demonstrated that desensitization to mAbs such as rituximab, infliximab, trastuzumab and cituximab leads to significant attenuation of moderate and severe reactions with the majority of patients having no reactions during desensitization.

• • Patient safety is always the paramount consideration and the risks and benefits associated with rapid desensitization need to be weighed carefully.

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Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

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1. Your patient is a 50-year-old woman with rheumatoid arthritis. She was recently started on rituximab and suffered a severe reaction to treatment. Desensitization to rituximab is appropriate for which of the following types of reaction?

• □ A Stevens-Johnson syndrome

• □ B Hemolytic anemia

• □ C Hypersensitivity pneumonitis

• □ D Anaphylaxis

2. What should you consider regarding infusion-related reactions and desensitization therapy to rituximab?

• □ A Infusion-related reactions occur at low but steady rates regardless of the indication for treatment with rituximab

• □ B Most reactions during desensitization occur during the final step

• □ C Most reactions during desensitization are severe and require treatment with epinephrine

• □ D The best candidates for desensitization lack the IgE antibody specific to rituximab

3. The patient is later treated with infliximab, which results in another infusion-related reaction. What should you consider regarding the prevention of reactions to infliximab?

• □ A Concomitant treatment with methotrexate or corticosteroids makes a reaction to infliximab more likely

• □ B Routine premedication prior to infliximab administration is unnecessary among patients without a previous reaction

• □ C Desensitization is rarely effective for patients with an infusion-related reaction to infliximab

• □ D Desensitization to infliximab uses a 6-step protocol

4. The patient’s rheumatologist is considering a change of therapy to cetuximab and wants your opinion. What can you tell the rheumatologist?

• □ A Prophylactic antihistamines and corticosteroids will not reduce the risk for severe infusion-related reactions to cetuximab

• □ B A 12-step desensitization protocol is required following infusion-related reactions

• □ C A 3-solution desensitization protocol is required following infusion-related reactions

• □ D Exchanging cetuximab for panitumumab may reduce the risk for infusion-related reactions