Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy

INTRODUCTION — Humanized monoclonal antibodies (MoAbs) represent a significant addition to therapeutic armamentarium for a variety of malignancies. Many of the agents that are used for cancer therapy share a risk for infusion reactions, most of which occur with the first dose. Although the majority of reactions are mild and not life threatening, serious reactions can occur and may be fatal if not managed appropriately.

After an introductory section summarizing the characteristics of infusion-related reactions (IRRs) and the general principles underlying prevention and treatment of these reactions, this review will discuss the reactions that occur with individual MoAbs used for cancer treatment and the prevention and management of these reactions. A discussion of infusion reactions to conventional cytotoxic agents is presented separately, as is a more in depth discussion of cutaneous adverse effects associated with both cytotoxic agents and the therapeutic MoAbs. (See "Infusion reactions to systemic chemotherapy" and "Cutaneous adverse effects of conventional chemotherapy agents" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

TYPES OF REACTIONS

Standard infusion reactions — The most common type of reaction to intravenously-administered MoAbs are referred to in this review as "standard infusion reactions" (SIRs).

Timing — SIRs to intravenously administered MoAbs typically develop within 30 minutes to two hours after the initiation of drug infusion, although symptoms may be delayed for up to 24 hours. Reactions tend to be delayed after subcutaneous administration. (See 'Subcutaneous daratumumab' below.)

The majority of reactions occur after the first or second exposure to the agent, but between 10 and 30 percent occur during subsequent treatments [1]. In general, the likelihood of an infusion reaction declines with each subsequent course of therapy.

The incidence of an infusion reaction during the first drug administration varies among individual agents and is highest for rituximab (both intravenous and subcutaneous) and alemtuzumab (≥50 percent each), and also significant for trastuzumab (up to 40 percent) and cetuximab (up to 20 percent, depending on the geographic area of residence).

Signs and symptoms — Intravenous infusion reactions may affect any organ system in the body. Most are mild in severity, although severe and even fatal reactions occur. The most common signs and symptoms of infusion reactions are:

●Fever and/or shaking chills

●Flushing and/or itching

●Alterations in heart rate and blood pressure

●Dyspnea or chest discomfort

●Back or abdominal pain

●Nausea, vomiting, and/or diarrhea

●Various types of skin rashes

Proposed mechanisms — The exact mechanism responsible for infusion reactions caused by any of the MoAbs is unclear, although understanding of the pathophysiology is an area of active research. Several different types of reactions to MoAbs have been identified, which may have overlapping clinical features and pathophysiology [2-4].

Most reactions appear to be the result of antibody-antigen interactions resulting in cytokine release. The most predictable reaction occurs with rituximab and is thought to be caused by the interaction of the drug with the target antigen (CD20) on circulating lymphocytes, followed by cytokine release from these cells as they are destroyed. Evidence for this mechanism includes the observation that severe and fatal reactions have typically occurred in patients with high numbers of circulating lymphocytes bearing the target antigen [5]. However, rituximab can also cause type I reactions involving activation of mast cells and basophils, illustrating the point that one drug may be capable of eliciting multiple types of reaction [2].

One group analyzed a series of 104 patients and proposed that reactions to MoAbs could be divided into five types, based on clinical signs and symptoms, timing, and biomarkers (figure 1) [2]:

●Type I-like reactions (mediated by mast cells and basophils) (see 'Anaphylaxis' below)

●Cytokine release reactions (mediated by T cells)

●Mixed type I and cytokine release

●Delayed type IV reactions (mediated by T cells and macrophages)

●SIRs

The first four types were amenable to desensitization, while SIRs do not require desensitization. (See 'Overview of desensitization' below.)

Other groups have categorized the reactions slightly differently, but also concluded that desensitization was useful in managing multiple types of reactions, and should be used to allow the patient to continue therapy with the drug of choice for their disease [3].

The mechanism underlying infusion reactions with therapeutic MoAbs might also be related to their ability to elicit human antichimeric antibodies (HACAs), human antihuman (HAHAs), or human antimouse (HAMAs) antibodies. However, a correlation between infusion reactions and HACAs or HAHAs has not been convincingly demonstrated for any drug. Furthermore, the development of antibodies to most of these drugs is far less common (one percent in one study [6]) than the incidence of infusion reactions [6,7]. (See 'Rituximab' below.)

Anaphylaxis — Anaphylaxis (a type 1 reaction) is rare with most MoAbs, although it has been described with rituximab, cetuximab, and trastuzumab. In addition, it is important to understand that all drugs have the potential to cause anaphylaxis in a small number of individuals. It is critical that clinicians be vigilant for signs and symptoms consistent with anaphylaxis, because readministration of the drug could result in a fatal reaction.

Signs and symptoms — Anaphylaxis caused by intravenously administered medications most often presents with the following signs and symptoms:

●Cutaneous symptoms – Flushing, itching, urticaria, and/or angioedema (usually of face, eyelids, or lips). Urticaria can be easily missed if the patient is fully dressed. The neck, trunk, abdomen, and axillae are the sites at which urticaria often appear first.

●Respiratory symptoms – Repetitive cough, sudden nasal congestion, shortness of breath, chest tightness, wheeze, sensation of throat closure or choking, and or change in voice quality (due to laryngeal edema).

●Cardiovascular symptoms – Faintness, tachycardia (or less often bradycardia), tunnel vision, chest pain, hypotension, sense of impending doom, and/or loss of consciousness.

●Gastrointestinal symptoms – Such as nausea, vomiting, abdominal cramping, and diarrhea.

The diagnosis is made clinically based on combinations of signs and symptoms (table 1). A common diagnostic mistake is equating anaphylaxis with anaphylactic shock and failing to recognize milder presentations. Anaphylactic shock is the extreme end of a spectrum, but the goal should be recognition and appropriate management of anaphylaxis in its milder forms, when it is more amenable to treatment and interventions can be undertaken to prevent subsequent, more severe reactions. Specifically, a patient who develops limited urticaria and mild wheezing after receiving a monoclonal antibody meets diagnostic criteria for anaphylaxis. Administration of the drug should be stopped immediately. The patient should not be considered a candidate for premedication or drug readministration at a slower rate of infusion [8]. Instead, referral to an allergist should be arranged. In the future, the patient will either need to be changed to a different and non-cross-reacting drug or receive the drug that caused the reaction through a desensitization procedure.

Mechanism of anaphylaxis — Anaphylaxis was traditionally defined as a constellation of signs and symptoms that arose from an IgE-mediated allergic reaction which resulted in explosive release of vasoactive mediators from mast cells and basophils throughout the body. However, the definition of anaphylaxis has been expanded in recent years to include any immune or non-immune reaction that leads to widespread activation of mast cells and/or basophils [9]. This more inclusive definition emphasizes the common endpoint of mast cell/basophil activation and the severity of the reactions that can result and places less importance on the mechanism by which the cells are activated.

All reactions with features of anaphylaxis should be considered potentially severe because of the tendency of anaphylaxis to recur and worsen with re-exposure to the causative agent. As an example, a patient who develops limited urticaria and mild wheezing after receiving a medication should be presumed to have anaphylaxis and should not be considered a candidate for premedication and drug readministration at a slower rate of infusion. Instead, referral to an allergist and/or use of a desensitization protocol should be pursued. (See 'Agents that can cause anaphylaxis' below.)

Evaluation of anaphylaxis — Evidence that a reaction was anaphylaxis can be obtained from blood tests collected at the time of the reaction and from skin testing, a technique employed by allergy specialists to identify drugs which are capable of causing mast cell activation, especially through IgE-mediated immune mechanisms. These two diagnostic tools are discussed in this section.

●An elevation in serum tryptase supports the diagnosis of anaphylaxis – Mast cells and basophils contain various chemical mediators that are transiently released into the circulation during anaphylaxis. Some of these are unique to these cell types and, if elevated, can help confirm that the reaction resulted from widespread activation of mast cells and basophils. The finding of an elevated serum total tryptase level suggests that the reaction was anaphylaxis, rather than a severe SIR.

The laboratory test that is most useful in this setting is a serum total tryptase level. Tryptase levels usually peak within three hours of the onset of symptoms, so blood should be drawn one to two hours after a reaction begins. Blood can be collected in a standard red top tube and serum should be frozen if it cannot be assayed promptly. Tryptase in frozen serum is stable for up to one year.

The upper limit of normal for serum total tryptase is 11.4 ng/mL in most laboratories. Any elevation in serum tryptase is consistent with anaphylaxis, although a normal tryptase level does not exclude anaphylaxis because tryptase elevations are not seen in mild anaphylactic reactions. A clinically significant elevation is defined as baseline tryptase x 1.2 + 2 ng/mL. Elevations in anaphylaxis can range from marginally elevated to greater than 100 ng/mL. In addition, if a patient's baseline tryptase is low (eg, 3 ng/mL), a rise to 8 ng/mL would be clinically significant, even though the higher level is still within normal limits. Thus, if a tryptase level is obtained immediately after a reaction, it is important to determine that individual's baseline by obtaining another value once symptoms have resolved for at least 24 hours. The interpretation of tryptase levels in anaphylaxis is discussed separately. (See "Laboratory tests to support the clinical diagnosis of anaphylaxis".)

If a patient's reaction was suggestive of anaphylaxis but tryptase levels were not elevated, skin testing may still be informative.

●Skin testing to evaluate anaphylaxis – Skin testing is a technique used by allergy specialists to determine if a drug is capable of activating mast cells in the skin and therefore potentially able to cause anaphylaxis if administered systemically.

Skin testing for drug allergy is generally performed by specialists with specific training in the technique, proper interpretation of results, and management of the rare allergic reactions that occur in response to the testing itself. Despite this, a few oncology centers perform this testing and have acquired some experience with testing for specific drugs, although this is not a widespread practice. The technique of skin testing is discussed in detail separately. (See "Overview of skin testing for IgE-mediated allergic disease".)

Agents that can cause anaphylaxis — Some MoAbs (cetuximab, rituximab, and trastuzumab) are believed to be capable of causing true IgE-mediated anaphylaxis. The best characterized is cetuximab, which has been associated with immediate and severe bronchospasm and hypotension requiring epinephrine and admission to the intensive care unit despite premedication with antihistamines with or without a glucocorticoid. These reactions are much more prevalent in some areas of the southeastern United States, and due to preexisting IgE antibodies from tick bites that are specific for galactose-alpha-1,3 galactose [alpha-gal], which is present on the Fab portion of the cetuximab heavy chain [10]. (See 'Cetuximab' below.)

MoAbs with a high frequency of infusion reactions on first exposure (eg, rituximab) have been presumed to be non-IgE dependent because of the lack of prior exposure and the low immunogenicity of humanized MoAbs. However, the demonstration of preexisting IgE anti-polysaccharide antibodies in patients with cetuximab reactions (discussed above) raises questions about whether similar mechanisms may underlie other MoAb-associated infusion reactions.

Even humanized (>90 percent) and "fully" humanized (>99 percent) MoAbs can cause anaphylaxis, albeit uncommonly, because the transgenic cell lines used to generate the drugs cannot produce human carbohydrate side chains, and these side chains can act as allergens [11]. This is the case with cetuximab-induced anaphylaxis.

NCI classification of infusion reactions — The most recent version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) for grading adverse reactions during chemotherapy administration has a scale for grading the severity of infusion reactions (table 2) as well as separate grading scales for allergic reactions from non-infusional drugs and anaphylaxis (table 3). There is also a separate grading scale for cytokine release syndrome (CRS), a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies (eg, blinatumomab) and following adoptive T-cell therapies for cancer (table 4). (See 'Blinatumomab' below and "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'CAR-T'.)

Allergists/immunologists have a different approach to classifying infusion reactions, which divides them into reactions with features of mast cell or basophil activation (signifying potential progression to anaphylaxis) and those without such features (ie, SIRs). The severity of the reaction is considered separately. This approach is intended to identify patients at risk for anaphylaxis on re-exposure, regardless of the severity of the initial reaction. (See 'Anaphylaxis' above.)

Patients with even mild symptoms of mast cell/basophil activation (eg, urticaria and dyspnea) must be treated with caution, because re-exposure to the causative agent could result in a fulminant and severe anaphylaxis. One of the authors (MC) is aware of unpublished cases in which failure to recognize anaphylaxis and manage it appropriately led to fatalities upon re-exposure to the causative drug, despite the premedications and reduced infusion rates that would have adequately managed most SIRs.

Thus, oncology specialists should be familiar with the characteristics of anaphylactic reactions and manage these rare reactions differently from SIRs. We recommend that patients with even mild signs or symptoms of anaphylaxis not be re-exposed to the causative agent until they have been evaluated by an allergy specialist with experience in drug allergy and desensitization [12]. In particular, these patients should not be considered candidates for additional premedication and an attempt at drug readministration using a slower rate of infusion.

USE OF PREMEDICATION TO PREVENT INFUSION REACTIONS — Premedication can help prevent and/or reduce the severity of infusion reactions, particularly standard infusion reactions (SIRs). By contrast, anaphylaxis is generally not prevented by premedication, although the severity of the reaction may be reduced in some cases. Attempts to identify patients who are likely to develop infusion reactions have met with limited success.

Pharmacologic prophylaxis with antihistamines and acetaminophen, with or without glucocorticoids, is recommended for certain drugs that are associated with a high incidence of infusion reactions (ie, rituximab, alemtuzumab, gemtuzumab ozogamicin, and cetuximab [in patients who reside in the Southeastern United States]). However, these regimens have been empirically derived rather than established through randomized trials. Furthermore, they are not completely protective, even for SIRs. Therefore, despite the use of premedication, patients must be monitored closely during and immediately following all infusions.

Because infusion reactions are most common during the first or second exposures, many clinicians eliminate premedication after the first two courses if there has not been a reaction. However, as noted above, between 10 and 30 percent of infusion reactions with these agents occur after the first two courses of therapy. In some institutions, diphenhydramine, a sedating antihistamine, is replaced by the nonsedating antihistamine cetirizine in patients who do not experience an infusion reaction during the first drug infusion [1].

GENERAL PRINCIPLES OF TREATMENT AND RECHALLENGE — Clinicians should be prepared for a reaction to occur during each drug administration, and standing orders should be in place to allow immediate intervention if an infusion reaction occurs, without waiting for the clinician to arrive [5]. Medical equipment and supplies needed for resuscitation (pharmacologic agents such as epinephrine, antihistamines, intravenous fluids, and aerosolized bronchodilators as well as oxygen, intubation and tracheostomy equipment, and a defibrillator) should be readily available in any area where chemotherapy is administered.

Treatment of an infusion reaction and possible rechallenge depend upon the type and severity or the reaction.

Treatment of mild to moderate SIRs — Mild to moderate standard infusion reactions (SIRs (table 2)) that do not involve symptoms of anaphylaxis are the most commonly encountered reactions. These can usually be managed with temporary interruption of the infusion and symptom management. (See 'Types of reactions' above.)

Rechallenge — After all symptoms have resolved, rechallenge with a reduced infusion rate and additional premedication is often successful.

For patients who have recurrent SIRs despite premedication, desensitization protocols have allowed for continued use of the drug in some cases [13]. Referral to an allergy specialist with experience in drug desensitization is an option for such patients [12].

Treatment of severe SIRs and anaphylaxis — Severe (grade 3 or 4 (table 2)) SIRs and reactions with any features of anaphylaxis require discontinuation of the drug infusion, and immediate treatment with epinephrine and antihistamines.

Prompt recognition and treatment are critical in anaphylaxis. In series of fatal anaphylaxis from all causes, death typically ensues within 30 minutes from exposure to the trigger. Detailed guidelines for the management of anaphylaxis are available from the Joint Council of Allergy, Asthma, and Immunology, which are summarized in a rapid overview table for adults (table 5) and children (table 6) [14]. (See "Anaphylaxis: Emergency treatment".)

The initial management of anaphylaxis includes the following:

●Stop the infusion of the suspect medication

●Intramuscular injection of epinephrine (table 5 and table 6)

●Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)

●Placement of the patient in the supine position (if tolerated) to maintain blood flow to vital organs

●Supplemental oxygen

●Volume resuscitation

●Intravenous antihistamines (table 5 and table 6)

Rechallenge after a severe SIR — Following a severe SIR, rechallenge is usually discouraged. However, the decision depends on whether the risk for a serious recurrent reaction is felt to be outweighed by mitigating clinical factors (ie, the potential clinical benefit of further treatment and no other reasonable alternatives). Examples at either end of the spectrum might include:

●The benefits of continued drug treatment probably outweigh the risks of rechallenge for a woman receiving adjuvant trastuzumab for a human epidermal growth factor receptor 2 (HER2)-positive early breast cancer.

●By contrast, drug substitution rather than rechallenge would be more appropriate for a patient who develops an SIR while receiving cetuximab as a second-line agent for metastatic colorectal cancer.

If a patient is felt to be a candidate for continuation of therapy because of the potential for clinical benefit and no other reasonable alternatives exist, then rechallenge may be pursued. In most cases, the mechanism of severe SIRs is not known, and so it is difficult to predict the best technique for preventing recurrence. However, we suggest the use of a "desensitization" protocol, in which the drug is readministered in a highly controlled manner, in sequential steps of gradually increasing dose. At the author's institution (MC), these reactions are managed in the same manner as anaphylaxis, with uniformly good outcomes [13,15].

Management after anaphylaxis — Rechallenge should not be attempted for suspected anaphylaxis. Instead, we suggest referral to an allergy specialist or an oncology center with experience in drug desensitization [12].

Although this is not recommended, there may be instances in which a patient with an apparent episode of anaphylaxis was rechallenged shortly after the reaction (eg, 30 minutes after symptoms have resolved) and appeared to tolerate the reinfusion. This situation can be misinterpreted as evidence that the reaction was not anaphylaxis or as an indication that the patient can receive additional courses safely in the future using standard administration. However, we urge caution in this situation. Mast cells and basophils, the cells involved in anaphylaxis, can be temporarily desensitized immediately after a reaction and may be unable to be activated further. However, the patient is at high risk for a recurrence of anaphylaxis as soon as the cells have recovered their sensitivity, a process which takes days to weeks. This phenomenon has probably contributed to the confusion that currently exists in the medical literature about the safety of rechallenge following a severe infusion reaction.

Overview of desensitization — Desensitization is indicated for allergic infusion reactions that have features of anaphylaxis [2]. The technique can also be applied to severe SIRs that recur despite slower rates of infusion and premedications. Important points regarding this technique include:

●Desensitization is absolutely contraindicated in patients with a history of a blistering dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis to a MoAb or other biologic modifier. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Other cutaneous effects'.)

●Desensitization was traditionally not applied to the management of other idiosyncratic immunologic reactions, such as serum sickness, hemolytic anemia, or drug fever, although there are reports of exceptions, such as desensitization in combination with glucocorticoids for serum sickness caused by rituximab. This is reviewed in more detail elsewhere. (See "Serum sickness and serum sickness-like reactions", section on 'Retreatment protocols'.)

●Desensitization should only be carried out under close medical supervision by experienced individuals who are comfortable with emergency management of anaphylaxis. At some institutions, all desensitization protocols are performed by allergists.

●Protocols for desensitization are personalized, and risk stratification is required to maximize safety in patients who have presented with anaphylactic reactions. Allergists should be involved in the initial evaluation and qualification of patients for desensitization.

Drug desensitization protocols are based upon administering increasing doses of medication in a stepwise manner, such that exposure is continuous, begins at very low doses, and increases gradually. The protocols presented herein have been performed successfully in published reports, although modifications may be needed in individual cases and experience with the technique is essential. Clinicians should avoid altering successful protocols to render them faster or significantly change the time interval between doses.

Drug desensitization induces a state of temporary tolerance that is dependent on continuous drug exposure. Once the drug is cleared from the system, the state of tolerance is lost. Therefore, patients must be carefully counseled that they remain allergic to the drug and must be desensitized for each subsequent administration. At some institutions, initial desensitizations are carried out in the medical intensive care unit. If the procedure is well tolerated, subsequent desensitizations are performed on standard hospital floors or in hospital-associated infusion units.

Successful desensitizations to trastuzumab [15,16], infliximab [17], and rituximab have been reported [13]. In theory, any patient with an IgE-dependent drug reaction can be successfully desensitized.

ALEMTUZUMAB — Alemtuzumab (Campath) is a recombinant humanized MoAb directed against the CD52 antigen, which is found on the surface of most T and B lymphocytes. It is used for treatment of lymphoid malignancies and is sometimes used for induction immunotherapy prior to solid organ transplants. (See "Treatment of T cell prolymphocytic leukemia", section on 'Alemtuzumab' and "Kidney transplantation in adults: Induction immunosuppressive therapy", section on 'Alemtuzumab'.)

Infusion reactions associated with alemtuzumab are frequent because T lymphocytes are so rich in cytokines and normal CD52+ T cells are more numerous than normal B cells. Infusion-related symptoms occur in the majority of patients despite premedication, and include rigors, hypotension, fever, fatigue, dyspnea, rash, urticaria, and pruritus. Most of the data on infusion reactions are derived from a clinical trial of 93 patients with chronic lymphocytic leukemia [18]. All of these reactions were most common in the first week of therapy and declined with continued administration:

●Rigors – 90 percent (41 percent grade 3)

●Fever – 85 percent (20 percent grade 3 or 4)

●Rash – 33 percent (all grade 1 or 2)

●Nausea – 54 percent

●Vomiting – 38 percent

●Dyspnea – 28 percent

●Hypotension – 17 percent

Prevention — Premedication with diphenhydramine (50 mg orally) and acetaminophen (650 mg orally) 30 minutes prior to dosing is recommended by the manufacturer.

Intravenous infusion rate — Gradual escalation to the recommended maintenance dose, usually over three to seven days, is required at initiation and after interruption of therapy for ≥7 days to minimize IRRs. In patients with lymphoid malignancies, the initial dose (3 mg) is given over two hours on the first day. Subsequent doses are increased to 10 mg daily then to the final maintenance dose of 30 mg/day three times per week every other day, as tolerated. Most clinicians administer the first three infusions over two hours until most of the B and T lymphocytes have been eliminated from the circulation [5].

Subcutaneous administration — Subcutaneous administration of alemtuzumab is associated with a less frequent, milder initial systemic reaction [19,20]. Because of sustained blood levels, infusion reactions do not recur with the same or higher intensity with subsequent doses, as often happens with the slow dose escalations from 3 to 30 mg during the first week of intravenous therapy. Another advantage is that the entire dose can be given safely from the outset of therapy, without the need for a gradual dose escalation. However, the subcutaneous route of administration is associated with a high frequency of local site reactions (pain and erythema) [20], and inferior antitumor efficacy, at least in the setting of T-cell prolymphocytic leukemia [21]. As a result, intravenous rather than subcutaneous administration is the standard approach.

Management — Patients who develop a standard immune reaction can usually be retreated after premedication with glucocorticoids (which may be administered as a component of the antiemetic regimen) with or without meperidine in addition to diphenhydramine and acetaminophen. Patients with reactions suggestive of anaphylaxis should not be rechallenged but instead referred to an allergist with experience in drug desensitization [12].

AMIVANTAMAB — Amivantamab is a bispecific antibody directed against epidermal growth factor and MET receptors, which is approved for adult patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'EGFR exon 20 insertion mutations'.)

IRRs including dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting have occurred in up to two-thirds of patients treated with this agent, and are most common after the first infusion [22]. The cumulative risk with subsequent infusions is 1.1 percent.

The United States prescribing information for amivantamab recommends premedication with acetaminophen 650 to 1000 mg plus an oral or IV H1 blocker prior to each dose of the drug; premedication with a glucocorticoid (dexamethasone 10 mg IV or equivalent) is recommended prior to the initial dose on week 1 (which is administered as a split dose on days 1 and 2), and only as necessary for subsequent infusions (week 2 and beyond, which are given on day 1 only).

BEVACIZUMAB — Infusion reactions are much less common with bevacizumab than with the MoAbs discussed above. Bevacizumab is a partially humanized MoAb that binds vascular endothelial growth factor (VEGF). It contains less than 10 percent murine protein. Infusion reactions of any grade are reported in <3 percent of cases, most of which are mild to moderate in severity (table 2). However, anaphylactic reactions have been reported [23].

The approved administration schedule uses a 90-minute infusion with the first dose, 60 minutes with the second dose, and 30 minutes with subsequent doses. However, some institutions use a 10-minute infusion (0.5 mg/kg per minute) for bevacizumab dosed at 5 mg/kg, and a more rapid rate of infusion does not appear to increase the incidence of reactions [24]. In a series of over 2300 courses of therapy in 370 patients, the incidence of mild infusion reactions was 1.6 percent, and no serious reactions were observed.

There is no standard premedication regimen for prevention or prophylaxis of infusion reactions. There is also no information on rechallenge.

BLINATUMOMAB — Blinatumomab is a bispecific T cell engager MoAb directed at both CD19 on precursor B cell ALL tumor cells and CD3 on cytotoxic T cells that has activity in the treatment of Philadelphia chromosome (Ph) negative residual, relapsed, or refractory B cell precursor ALL. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Blinatumomab'.)

Blinatumomab is administered by continuous intravenous infusion using an infusion pump over four weeks followed by a two-week treatment-free interval. Cytokine release syndrome (CRS), which may be life-threatening or fatal, has occurred in patients treated with blinatumomab. CRS has a specific definition and grading schema that are separate from standard immune reactions in the most recent National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (table 4). However, the symptoms overlap, and CRS may be mild, low-grade, and clinically indistinguishable from other types of infusion reactions. Serious adverse events that may be associated with CRS include pyrexia, headache, nausea, asthenia, hypotension, and elevations in serum aminotransferases and bilirubin. In some cases, disseminated intravascular coagulation, capillary leak syndrome, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) have been reported in the setting of CRS [25]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

The United States Prescribing Information for blinatumomab suggests that patients be hospitalized for the first three or nine days of the first cycle (depending on the indication for therapy) as well as the first two days of the second cycle (regardless of indication) to monitor for signs and symptoms of CRS and neurologic toxicities, including seizures. For all subsequent cycle starts and reinitiation (eg, if treatment is interrupted for four or more hours), supervision by a health care professional or hospitalization is recommended. Pretreatment with dexamethasone 20 mg intravenously is recommended prior to the first dose of each cycle, prior to each intracycle dose increase (eg, as occurs on cycle 1 day 8) or when restarting an infusion after an interruption of four or more hours.

Severe CRS (ie, grade 3 or worse (table 4)) appears to be rare, but pyrexia and headache are frequent. In an early phase II trial of 36 patients treated with blinatumomab, pyrexia developed in 81 percent (grade 1 or 2 in 75 percent, grade 3 in 6 percent), and headache developed in 47 percent; two patients had grade 4 CRS (graded the same as an infusion-related reaction (table 2)). One permanently discontinued treatment, while the other was successfully re-exposed after treatment interruption. Notably, both patients had a high leukemic burden with a high percentage of marrow blasts. A treatment pre-phase consisting of dexamethasone 10 mg/m² per day (up to five days) and cyclophosphamide 200 mg/m² per day (up to three days) was recommended thereafter for patients with a high tumor load, and no subsequently treated patient developed grade 3 or worse CRS during blinatumomab therapy. The United States Prescribing Information suggests administration of glucocorticoids for severe or life-threatening CRS.

Neuropsychiatric symptoms (including seizures, encephalopathy, tremor, dizziness, aphasia, confusion) are commonly seen with this agent, but it is not clear whether these neurologic symptoms are independent of CRS, part of the syndrome, or both. Symptoms most commonly occurred during the first week of a cycle. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".)

BRENTUXIMAB — Brentuximab vedotin is a CD30-directed antibody-drug conjugate that is used for treatment of certain CD30-positive lymphomas. (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on 'Brentuximab' and "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

In a phase I study of 45 patients with refractory or relapsed CD30-positive hematologic malignancies, brentuximab was administered intravenously once every three weeks. One patient developed an infusion-related reaction, which resolved after symptomatic treatment and did not recur with restarting the infusion, and a second patient developed anaphylaxis during administration of the second dose three weeks after the first dose [26]. Other cases of anaphylaxis have been reported [27].

Routine premedication is not recommended in the US Food and Drug Administration (FDA)-approved manufacturer's labeling [28]. By contrast, patients who have experienced a prior infusion-related event should be premedicated with acetaminophen, an antihistamine, and a corticosteroid prior to subsequent infusions. Anaphylaxis should prompt immediate and permanent discontinuation, unless a desensitization procedure is carried out under the supervision of an allergy expert.

Successful rapid desensitization with brentuximab vedotin was reported in a patient with repeated anaphylactic reactions that were refractory to multiple premedications [29]. Symptoms during these reactions included pruritus, flushing, tachycardia, and hypotension, although immediate skin testing was negative. The patient had minor symptoms during desensitization, but these resolved with additional medications and temporary interruption of the protocol. With repeated desensitizations, the patient was able to receive nine additional cycles of brentuximab, which resulted in a durable disease remission.

CETUXIMAB — Cetuximab is a human/mouse chimeric antibody directed against the epidermal growth factor receptor (EGFR). It is composed of the Fc regions of a murine anti-EGFR antibody with human immunoglobulin G subclass 1 (IgG1)-heavy and kappa light chain-constant regions [30]. Infusion reactions can occur in up to 25 percent of patients, but only 3 to 4 percent are severe. Cetuximab can also cause IgE-mediated anaphylaxis, so any reaction with features of anaphylaxis should be managed with extreme caution (table 1).

Grade 1 or 2 (table 2) reactions occur in approximately 20 percent of patients, typically during the first exposure, although they can occur during subsequent doses. Severe reactions (grade 3 or 4) are characterized by the rapid onset of bronchospasm, stridor, hoarseness, nausea and vomiting, urticaria, and/or hypotension. These symptoms are consistent with anaphylaxis. Most reactions (>90 percent) occur with the first dose, although some occur after several doses, underscoring the need to monitor patients for one hour after each drug infusion [31].

Incidence — The incidence of infusion reactions has been variable in different geographic areas. In Europe, rates of severe grade 3 or 4 infusion reactions in two trials of cetuximab in patients with metastatic colorectal cancer were 2.5 and 3.5 percent, respectively [32,33]. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Adverse effects'.)

Markedly higher rates have been reported in the middle southeastern region of the United States (North Carolina, Arkansas, Missouri, Virginia, Florida, and Tennessee), where the incidence of severe (grade 3 or 4) reactions with cetuximab was over 20 percent (table 2) [34]. All of the observed reactions occurred during the first 30 minutes of the first dose of cetuximab. Patients with a history of allergic disorders (asthma, drug reactions, etc) were significantly more likely to experience a severe infusion reaction (29 versus 8 percent for those with no history of atopy).

There is evidence that a significant proportion of these severe infusion reactions to cetuximab, although probably not all [35,36], are caused by IgE-mediated anaphylaxis. In a series of patients living in the southeast US who experienced severe reactions to cetuximab, 17/25 were found to have IgE antibodies in pretreatment serum that were specific for galactose-alpha-1,3 galactose, an oligosaccharide present on the Fab portion of the cetuximab heavy chain [10]. By contrast, only 1 of 51 patients who tolerated cetuximab had these antibodies. Tests for IgE specific to this allergen are commercially available [37,38]. There is some evidence to suggest that patients develop IgE antibodies to galactose-alpha-1,3 galactose as a result of tick bites, as the distribution of patients with cetuximab reactions is similar to that of the Lone Star species of tick found in the southeastern US, and many patients have reported reactions following a series of tick bites [39]. The same allergen is also found in meats, and some patients with cetuximab reactions report allergic reactions to meat ingestion. (See "Allergy to meats", section on 'Meats and monoclonal antibodies (cetuximab)'.)

Not all anti-EGFR MoAbs contain galactose-alpha-1,3 galactose. The presence of this oligosaccharide is related to the production of cetuximab in a murine cell line. Panitumumab, a fully humanized MoAb against EGFR, is produced using different cell culture techniques and does not contain galactose-alpha-1,3 galactose, a fact that may explain the lack of cross reactivity between these two agents and the lower rate of severe infusion reactions with panitumumab. (See 'Panitumumab' below.)

Prevention — Consensus is lacking about how best to prevent IgE-mediated allergic reactions to cetuximab. Skin testing patients with cetuximab before initial administration has not been demonstrated to reliably identify patients who will have a severe reaction [40]. An immunoassay for the presence of IgE antibodies to cetuximab has been developed, but it is available from only a small number of commercial laboratories [41] and had a positive predictive value of only approximately 30 percent for identifying patients with moderate to severe reactions cetuximab in one study [42]. On the other hand, others report no anaphylactic reactions among a group of 60 patients who screened negative for the presence of preformed alpha-gal specific IgE antibodies (a negative predictive value of 100 percent) prior to receiving cetuximab [43]. Nevertheless, the optimal cutoff to define a positive test is not established, and the available data are currently insufficient to mandate testing for preformed IgE antibodies as a standard of care prior to cetuximab administration.

One option for patients in high-risk areas is to begin the drug infusion at a lower rate initially (eg, 2.5 to 3 mL/minute) under close observation by an advanced practitioner (clinician, clinician assistant, nurse practitioner) familiar with the immediate management of anaphylaxis and physically present during at least the first 30 minutes of the initial infusion. In addition, the patient could be questioned in advance about characteristics that have been identified as possible risk factors for reactions to cetuximab. These are:

●A history of other allergic disorders (medication or food allergies, venom allergy, asthma, atopic dermatitis, or allergic rhinitis) [34]

●Allergic reactions within a few hours of eating beef, pork, or lamb [10]

●Local reactions to tick bites lasting for weeks or longer [39]

We would suggest that patients with any of these possible risk factors be observed especially closely during their first and second exposure to cetuximab, particularly in high-risk areas. Although these approaches may not eliminate reactions in highly sensitized patients who react to low doses of the drug, close observation will ensure that the infusion is stopped at the earliest sign of allergic symptoms. In the absence of a reaction during the initial 30 minutes, the rate of infusion could be increased and the remainder of the dose administered over 90 minutes. Patients with pruritus, hives, or any allergic symptom during the initial 30 minutes should have the infusion stopped, have their skin tested within two weeks, and if positive, can be candidates for rapid desensitization [44].

The US Food and Drug Administration (FDA)-approved manufacturer's package insert recommends premedication with an H1 antagonist 30 to 60 minutes prior to the first dose. The benefit of glucocorticoid premedication, in addition to an antihistamine, was suggested by the MABEL (Monoclonal Antibody Erbitux in A European Pre-Licensure) registry database of over 1000 patients treated with cetuximab plus irinotecan for metastatic colorectal cancer [45]. Cetuximab-related infusion reactions were recorded in 16 percent of the population. Rates of any infusion reaction were significantly lower among those pretreated with an antihistamine plus a glucocorticoid as compared with an antihistamine alone (9.6 versus 26 percent) and for grade 3 or 4 reactions (1.0 versus 4.7 percent).

An important point is that premedication would not be expected to prevent true IgE-mediated anaphylaxis, so clinicians must remain vigilant for signs of this type of reaction. (See 'Anaphylaxis' above.)

In practice, most patients receiving cetuximab are also receiving irinotecan, for which premedication with both a glucocorticoid and antihistamine is recommended. For patients receiving cetuximab alone, pretreatment with an antihistamine alone is acceptable, although the addition of a glucocorticoid (with or without an H2 receptor antagonist) is reasonable for those living in high-incidence areas. (See 'Incidence' above.)

Patients should be monitored for at least one hour following completion of infusion or longer if a reaction occurs.

Following the initial dose, premedication with diphenhydramine is optional and should be based on clinical judgment. In some institutions, diphenhydramine is replaced by the nonsedating antihistamine cetirizine if there is no reaction during the first infusion of cetuximab [1].

As an alternative to cetuximab, patients in high-risk areas have been preferentially treated with panitumumab rather than cetuximab. Both MoAbs appear to be therapeutically interchangeable. There are data supporting the use of panitumumab in combination chemotherapy regimens, but no data directly comparing panitumumab versus cetuximab in this setting. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Are cetuximab and panitumumab interchangeable?'.)

Management and rechallenge — Mild to moderate infusion reactions (table 2) without features of anaphylaxis may be managed by temporarily halting the drug infusion and additional diphenhydramine. Most patients will tolerate readministration using a slower infusion rate (2.5 mL/minute) with additional premedication after all symptoms have resolved. Patients should be observed for one hour after the end of each infusion.

In the case of a severe standard infusion reaction (table 2) or anaphylaxis, drug infusion should be discontinued immediately. Appropriate medical therapy during the reaction includes epinephrine, intravenous fluids, intravenous antihistamines, glucocorticoids, and if needed, bronchodilators and oxygen (table 5). Patients should be carefully observed until the resolution of all symptoms and signs.

The manufacturer recommends that cetuximab be permanently discontinued if there is a severe infusion reaction. Although the addition of steroids may not block the anaphylactic reaction, at least three case reports note successful retreatment with glucocorticoid premedication and close monitoring in an intensive care unit setting [46,47]. In addition, successful desensitization to cetuximab has been reported and a protocol is available [48]. Therefore, management of a patient with suspected cetuximab anaphylaxis depends upon the expertise and resources available to the supervising clinician.

Panitumumab, another MoAb directed against the EGFR, has comparable antitumor efficacy and a lack of cross-reactivity with cetuximab. Patients with a severe infusion reaction or anaphylaxis to cetuximab can be safely be switched to panitumumab [49-51]. There are data supporting the use of panitumumab in combination chemotherapy regimens, but no data directly comparing panitumumab versus cetuximab in this setting. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'Are cetuximab and panitumumab interchangeable?'.)

DARATUMUMAB — Daratumumab is a human CD38-directed MoAb indicated for the treatment of refractory multiple myeloma. (See "Multiple myeloma: Treatment of first or second relapse", section on 'Daratumumab, bortezomib, dexamethasone (DVd)'.)

IRRs to daratumumab are common (up to 56 percent [52]), predominantly occur during the first infusion, and are mostly mild (grade 1 or 2 (table 2)) [53,54]. Symptoms may include bronchospasm, hypoxia, dyspnea, hypertension, cough, throat tightness, laryngeal edema, pulmonary edema, nasal congestion, and rhinitis. Less common symptoms include hypotension, headache, rash, urticaria, pruritus, nausea, vomiting, and chills.

The United States Prescribing Information recommends the following to diminish the risk of IRRs:

●Premedication with antihistamines (diphenhydramine 25 to 50 mg or equivalent), oral acetaminophen (650 to 1000 mg) and a glucocorticoid (methylprednisolone 100 mg or equivalent dose of an intermediate or long-acting agent) before all infusions.

●A slower initial infusion rate with the first dose, with incremental increases in the rate in the absence of IRRs. For patients who develop a grade 1, 2, or 3 infusion-related reaction, the infusion should be stopped and, once symptoms have resolved, restarted at a reduced rate.

●Post-infusion medication with an oral glucocorticoid (20 mg methylprednisolone or equivalent dose) on the first and second days after all infusions.

●For patients with a history of chronic respiratory disease (eg, chronic obstructive pulmonary disease [COPD] or asthma), consider prescribing post-infusion medications such as short- and long-acting bronchodilators, and inhaled corticosteroids. If the patient experiences no major infusion reactions after the first four doses, these additional inhaled post-infusion medications may be discontinued.

However, whether these maneuvers reduce the risk of reactions is not clear. In at least three trials, infusion reactions occurred in 42 to 48 percent despite premedication (as described above) and incremental escalation of the infusion rate [54-56]. The United States Prescribing Information recommends permanent discontinuation of daratumumab after a grade 4 (life-threatening) infusion reaction or after the third occurrence of a grade 3 reaction.

A modified premedication plan has been proposed that additionally includes a single dose of montelukast, a leukotriene receptor antagonist, prior to the first infusion, but the benefit of this strategy is not clear [52,53]. In one report of 94 patients, 41 percent of those who received prophylactic montelukast still had an infusion-related reaction with the first dose, although the rate was higher (57 percent) in those who did not receive prophylactic montelukast [52]. There was also a suggestion of fewer respiratory symptoms as a component of the infusion reaction when prophylactic montelukast was used (46 versus 67 percent). Despite the paucity of data and the lack of a specific recommendation from the US Food and Drug Administration (FDA) on this issue, we suggest the addition of montelukast to the premedication regimen of corticosteroids, antipyretics, and an antihistamine prior to the first infusion of daratumumab.

Others have proposed a split-dose strategy for the first dose of daratumumab, in which the initial dose of 16 mg/kg is divided into two doses of 8 mg/kg, each administered with the same premedication once daily over two consecutive days [57]. Largely based on experience with this infusion schedule from the phase Ib EQUULEUS trial, which has not yet been published [58], the FDA approved this infusion schedule in February 2019.

Following the first infusion, subsequent doses can be given over shorter durations. The United States Prescribing Information suggests infusion times of 6.5, 4.5, and 3.5 hours for the first, second, and third infusions, respectively. Even faster infusion times have been well tolerated beginning with the third dose of daratumumab [59].

Subcutaneous daratumumab — A formulation of fixed-dose, subcutaneously (SC) administered daratumumab in combination with hyaluronidase (daratumumab-hyaluronidase) demonstrates a similar pharmacokinetic and efficacy profile to intravenous (IV) daratumumab in multiple myeloma, but lower rates of IRRs [60,61]. In one trial comparing IV versus SC administration, fewer patients receiving daratumumab-hyaluronidase infused SC over a three- to five-minute period developed an infusion-related reaction (13 versus 34 percent with daratumumab IV over seven hours), and rate of grade 3 reactions was also lower (2 versus 5 percent). Symptoms were similar (mainly chills, fever, dyspnea, and nasal congestion); injection site reactions (erythema, bruising, pruritus) occurred in ≤2 percent [61]. All but one of the 33 IRRs developed after the first dose of daratumumab-hyaluronidase, and the median time to onset after administration was longer with SC than with IV administration (3.4 hours [interquartile range 1.5 to 4.4, range 1 to 47.8] versus 1.5 hours [interquartile range 1 to 1.8, range 0 to 24.5]). All patients receiving SC daratumumab-hyaluronidase should be observed for at least six hours after the first dose.

As with the IV formulation, the United States Prescribing Information for daratumumab-hyaluronidase recommends premedication with antihistamines (diphenhydramine 25 to 50 mg or equivalent), oral acetaminophen (650 to 1000 mg) and a glucocorticoid (methylprednisolone 100 mg or equivalent dose of an intermediate or long-acting agent) prior to each infusion. Post-infusion medication with an oral glucocorticoid (20 mg methylprednisolone or equivalent dose) on the first and second days is also recommended, which can be discontinued if the patient does not experience a major systemic administration-related reaction after the first three doses. As with IV daratumumab, for patients with a history of chronic respiratory illness (COPD, asthma), consider prescribing short and long-acting bronchodilators and inhaled corticosteroids, which can be discontinued after the first four doses in the absence of a major systemic infusion reaction.

ELOTUZUMAB — Elotuzumab is a humanized MoAb targeted against SLAMF7, a glycoprotein expressed on multiple myeloma and natural killer cells. It is approved, in combination with lenalidomide or pomalidomide plus dexamethasone, for treatment of relapsed multiple myeloma.

Infusion reactions were initially reported in approximately 60 percent of patients [62,63], but in subsequent studies in which premedication was routinely administered, this rate decreased to approximately 10 percent [64-66]. Seventy percent of reactions occur with the first dose. The majority of reactions are grade 1 or 2 (table 2), and the most common symptoms are fever, chills, and hypertension, but bradycardia and hypotension may also occur.

The United States Prescribing Information recommends pretreatment with acetaminophen, dexamethasone, and an H1 as well as an H2 receptor blocker prior to each infusion of elotuzumab.

GEMTUZUMAB OZOGAMICIN — Gemtuzumab ozogamicin (GO, Mylotarg) is a recombinant humanized MoAb that binds to the CD33 antigen, which is expressed on myeloblasts in over 70 percent of patients with acute myeloid leukemia [67].

Infusion-related events (fever, chills, hypotension, tachycardia, hypoxia, respiratory failure) can occur during or within 24 hours following infusion of gemtuzumab ozogamicin [68-70]. Rarely, severe and potentially fatal IRRs develop, including anaphylaxis and pulmonary events (such as pulmonary edema and acute respiratory distress syndrome). Symptomatic intrinsic lung disease and high peripheral blast counts appear to increase the risk of a severe reaction.

Prevention — The manufacturer recommends routine premedication with acetaminophen (650 mg orally) and diphenhydramine (50 mg orally or intravenously) one hour prior to administration of each infusion, and 1 mg/kg methylprednisolone (or an equivalent dose of an alternative glucocorticoid) 30 minutes prior to infusion. Additional doses of acetaminophen and diphenhydramine may be administered every four hours after the initial pretreatment dose.

Management — Management depends on the severity of the reaction. For patients with mild to moderate symptoms, temporarily halting drug infusion and symptomatic treatment with additional diphenhydramine and acetaminophen as well as intravenous fluids are appropriate. For patients with signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension, discontinue the drug.

IBRITUMOMAB — 90-Yttrium-ibritumomab tiuxetan (90Y-ibritumomab, Zevalin) is a radioimmunoconjugate in which a murine MoAb against CD20 is conjugated to a radioisotope. It is used for the treatment of relapsed indolent lymphomas. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Radioimmunotherapy'.)

Potentially fatal infusion reactions with features of anaphylaxis (angioedema, bronchospasm, hypotension, hypoxia) have been reported with 90Y-ibritumomab. Most of these occur during or within 30 to 120 minutes after the first infusion.

The manufacturer recommends that patients be screened for human antimouse antibodies (HAMA) because they may be at increased risk of allergic or serious hypersensitivity reactions. However, the number of patients who develop HAMA after receiving an initial dose of ibritumomab is low (2 percent in one study [71]), and there is no evidence that the presence of HAMA identifies patients at an increased risk for an infusion reaction. Known type I hypersensitivity or anaphylactic reactions to yttrium chloride, murine proteins, or rituximab are contraindications to treatment with ibritumomab. Patients should be referred to an allergist with experience in drug desensitization if the use of this agent is desired in a high-risk patient [12].

Treatment is generally given in conjunction with rituximab, for which it is standard practice to premedicate patients with acetaminophen (650 mg orally) and diphenhydramine (50 mg orally) before the first and second infusions; at some institutions, routine premedication also includes an H2 receptor blocker (eg, famotidine 20 mg intravenously).

ISATUXIMAB — Isatuximab is an anti-CD-38 monoclonal antibody that is approved in combination with pomalidomide and dexamethasone for treatment of refractory multiple myeloma. (See "Multiple myeloma: Treatment of first or second relapse", section on 'Refractory to lenalidomide and bortezomib'.)

In a pivotal phase III trial, IRRs occurred in approximately 38 percent of patients despite premedication; all were observed during the first infusion, and the vast majority were grade 1 to 2 [72]. The most common symptoms were dyspnea, cough, chills, and nausea, and the most common signs were hypertension and dyspnea. However, anaphylactic reactions have also occurred. The United States Prescribing Information recommends premedication with acetaminophen, H2 antagonists, diphenhydramine, and dexamethasone 15 to 60 minutes prior to each dose [73]. Reactions of grade 3 or greater severity should prompt permanent discontinuation of the drug.

MOGAMULIZUMAB — Mogamulizumab is a humanized antibody directed against CC chemokine receptor 4 (CCR4), which is overexpressed on malignant T cells; it is approved for treatment of adults with relapsed or refractory mycosis fungoides or Sézary syndrome. (See "Treatment of Sézary syndrome".)

Fatal and life-threatening infusion reactions are reported with mogamulizumab, 90 percent of which occur during the first infusion. In one study, infusion reactions occurred in 35 percent of patients treated with this agent, with 8 percent of the reactions being severe [74]. The most common symptoms were chills, nausea, fever, tachycardia, rigors, headache, and vomiting.

The United States Prescribing Information for mogamulizumab suggests premedication with diphenhydramine and acetaminophen prior to the first infusion. However, whether premedication reduces the risk or severity of reactions is not clear. In the phase III trial cited above [74], infusion reactions occurred in 42 percent of patients without premedication and in 32 percent of those who were premedicated. Patients should be monitored closely for symptoms or signs of an infusion reaction, and the infusion should be interrupted for an infusion reaction of any grade.

OBINUTUZUMAB — Obinutuzumab is a type II anti-CD20 MoAb that is approved, in combination with chlorambucil, for initial treatment of chronic lymphocytic leukemia. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Chemoimmunotherapy'.)

IRRs are more common and severe than seen with rituximab, a second anti-CD-20 MoAb, and occur almost exclusively during the first infusion. In a pivotal phase III trial comparing chlorambucil alone versus chlorambucil plus either obinutuzumab or rituximab, premedication with oral acetaminophen (650 to 1000 mg) and diphenhydramine (50 to 100 mg) was administered approximately 30 minutes prior to the start of the first infusion; glucocorticoids were recommended for patients with a high circulating white blood cell count. Overall, 67 percent of patients had an infusion-related reaction during the first infusion of obinutuzumab, despite premedication [75,76]. Twenty-one percent had a grade 3 or 4 reaction (table 2). Symptoms included hypotension, tachycardia, dyspnea, nausea, vomiting, diarrhea, hypertension, flushing, and chills. However, there were no fatalities, rates of IRRs on cycle 1 days 8 and 15 were markedly lower and milder (3 and 1 percent respectively, all grade 1 or 2), and there were no IRRs during subsequent cycles.

The mechanism underlying the infusion reactions appears related to release of proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, IL-10, and monocyte chemoattractant protein (MCP)-1, among others [77,78]. Pretreatment with the immunomodulatory agent ibrutinib, which is sometimes used in combination with obinutuzumab, reduces cytokine release and lowers the risk of obinutuzumab-related IRRs [77]. (See "Selection of initial therapy for symptomatic or advanced chronic lymphocytic leukemia/small lymphocytic lymphoma", section on 'Immunoglobulin heavy chain variable unmutated (high risk)'.)

The US Food and Drug Administration (FDA)-approved manufacturer’s drug information recommends that all patients be premedicated with acetaminophen, an antihistamine, and a glucocorticoid prior to the first infusion. For cycle 1 days 8 and 15, and all subsequent cycles, acetaminophen premedication is recommended for all patients; an antihistamine is recommended only for those patients with an infusion-related reaction ≥grade 1 during the prior treatment; intravenous glucocorticoid is recommended only for patients with a grade 3 reaction during the prior infusion, or with a lymphocyte count >25 x 10⁹/L at the time of treatment. Patients with any grade 4 reactions (table 2) (including but not limited to anaphylaxis) should permanently discontinue therapy.

OFATUMUMAB — Ofatumumab is a fully human anti-CD20 MoAb that is used for relapsed chronic lymphocytic leukemia (CLL). Treatment is administered weekly for seven weeks (initial dose 300 mg, and each subsequent dose 2000 mg), followed by a four week rest, then 2000 mg weekly for four weeks.

Ofatumumab is associated with a high frequency of infusion reactions (which are potentially fatal [79]) during the first two weekly doses, despite premedication with acetaminophen and an antihistamine prior to each dose, and an intravenous glucocorticoid (equivalent to 50 mg of prednisolone) 30 to 60 minutes before the first and second doses [80,81]. In a summary of unpublished data from a phase II trial of 154 patients receiving ofatumumab for CLL, infusion reactions occurred in 44 percent on the day of the first infusion (300 mg), and in 29 percent of the day of the second infusion (2000 mg) [81]. Reactions were less frequent and less severe during subsequent cycles.

The most common symptoms were transient rigors, pyrexia, fatigue, rash, and increased sweating. Reactions usually occurred within the first few hours after starting the infusion and were categorized as mild; only two patients had grade 3 or 4 (severe) pyrexia [82]. Other reported manifestations of an infusion reaction included bronchospasm, dyspnea, laryngeal and pulmonary edema, hypertension and hypotension, syncope, back pain, urticaria and angioedema [81].

Prevention — The manufacturer recommends premedication prior to each dose of ofatumumab with acetaminophen 1000 mg and an oral or intravenous antihistamine. They also recommend intravenous glucocorticoid (prednisolone 100 mg or its equivalent) for doses 1, 2, and 9, with a gradual reduction in the glucocorticoid dose for infusions 3 through 8 and 10 through 12 in the absence of a grade 3 or worse reaction during the prior infusion.

Management — For patients who develop a reaction during treatment with ofatumumab, the infusion should be interrupted immediately. The following guidelines for resuming treatment are available from the manufacturer [81]:

●Grade 4 (table 2) reaction – Discontinue permanently.

●Grade 1, 2, or 3 reaction – Resume if the reaction resolves or remains no worse than grade 2 with the following modifications based on the initial grade of the reaction:

•Grade 1 or 2 – Infuse at one-half the prior infusion rate.

•Grade 3 – Infuse at a rate of 12 mL/hour.

OLARATUMAB — Olaratumab is a human immunoglobulin G subclass 1 (IgG1) MoAb that binds to the platelet-derived growth factor alpha receptor (PDGFRA) and blocks PDGF ligands from binding; it had been approved, in combination with doxorubicin, for treatment of advanced soft tissue sarcoma in 2016 based on an open-label randomized phase II trial showing a survival benefit over doxorubicin alone. However, the survival benefit could not be confirmed in a larger randomized phase III trial, and in January 2018, the US Food and Drug Administration (FDA) and European Medicines Agency both recommended against initiating therapy with olaratumab plus doxorubicin in patients with newly diagnosed advanced soft tissue sarcoma. While the company is working to withdraw the drug from the market, patients who are currently receiving olaratumab and receiving clinical benefit may, in consultation with their physician, continue therapy through drug access programs.

IRRs occurred in 70 of 485 patients (14 percent) who received at least one dose across several clinical trials of olaratumab, as reported in the FDA drug safety database [83]. In 68 cases, the first occurrence was during the first or second course of therapy. Symptoms included flushing, dyspnea, bronchospasm, or fever/chills; in severe cases, the reaction included severe hypotension, anaphylactic shock, or cardiac arrest.

Although the incidence of overall infusion reactions was not significantly different among patients who did versus did not receive premedication (18 versus 12 percent) in the drug safety database, the United States Prescribing Information recommends premedication with diphenhydramine (25 to 50 mg intravenously) and dexamethasone (10 to 20 mg intravenously) prior to treatment on cycle 1, day 1 only. They also recommend that the drug be permanently discontinued for grade 3 or 4 IRRs (table 2). For less-severe reactions, temporarily stop the infusion, and once symptoms are resolved, restart the infusion at one-half of the initial infusion rate.

PANITUMUMAB — Panitumumab is a MoAb directed against the EGFR that is produced using a different cell culture technique than that for cetuximab. It is a fully human IgG2 MoAb. Since it contains no murine component, it was predicted to cause fewer infusion reactions. As noted above, the significantly lower incidence of infusion reactions with panitumumab compared with cetuximab may also be related to the absence of galactose 1,3-alpha galactose on the Fab fragment. (See 'Cetuximab' above.)

In single agent treatment trials and during postmarketing surveillance, the rate of any infusion reaction was 4 percent, and 1 percent were severe (anaphylaxis, bronchospasm, fever, chills, hypotension, some fatal) [84-86]. However, in light of this low rate of infusion reactions, routine premedication is not recommended prior to panitumumab infusion.

Patients who develop a grade 1 or 2 infusion reaction without symptoms of anaphylaxis should have the drug temporarily withheld, and after symptoms have resolved, restarted at 50 percent of the infusion rate. Permanent discontinuation of panitumumab is recommended in the setting of anaphylaxis or a grade 3 or 4 reaction. Due to the rarity of such reactions, there are no data on rechallenge or desensitization. However, successful treatment with cetuximab has been reported [87].

There is one unpublished report of delayed-onset angioedema occurring several days after a third panitumumab dose, which was initially attributed to an antibiotic [88]. However, a subsequent panitumumab dose caused recurrent angioedema and respiratory arrest.

POLATUZUMAB — Polatuzumab vedotin is an antibody-drug conjugate indicated in combination with bendamustine and rituximab for treatment of relapsed or refractory diffuse large B cell lymphoma. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Polatuzumab/bendamustine/rituximab'.)

Polatuzumab can cause severe IRRs even after premedication, some occurring as late as 24 hours after receiving the drug. The United States Prescribing Information recommends administering an antihistamine and antipyretic prior to each dose, even in the absence of a reaction. (See 'Rituximab' below.)

RAMUCIRUMAB — Ramucirumab is a recombinant MoAb of the immunoglobulin G subclass 1 (IgG1) class that binds to the vascular endothelial growth factor receptor 2 (VEGFR-2), blocking receptor activation. It is approved for advanced stomach cancer. (See "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'Ramucirumab with or without paclitaxel'.)

Prior to the institution of premedication recommendations in clinical trials of ramucirumab, IRRs occurred in 7 of 37 patients (16 percent), including two severe events [89]. The majority occurred during or following the first infusion of the drug. Symptoms included rigors, back pain, chest discomfort, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. Severe cases included bronchospasm, hypotension, and supraventricular tachycardia. The US Food and Drug Administration (FDA)-approved manufacturer’s labeling recommends premedication with an intravenous histamine H1 receptor antagonist (eg, diphenhydramine) prior to each ramucirumab infusion [89]. For patients who develop a grade 1 or 2 infusion-related reaction (table 2), premedication with dexamethasone and acetaminophen prior to each subsequent infusion is recommended. Using this approach, there was only one infusion-related reaction among 236 patients treated with ramucirumab on a phase III trial [90].

RITUXIMAB — Rituximab is a mouse/human chimeric MoAb targeting the CD20 antigen. Dose, schedule, and route of administration vary according to the indication. (See "Initial treatment of stage I follicular lymphoma" and "Overview of biologic agents in the rheumatic diseases" and "Initial treatment of stage II to IV follicular lymphoma", section on 'Immunotherapy-based treatment'.)

Intravenous administration — Over 50 percent of first infusions of rituximab are accompanied by an infusion reaction.

One of the most predictable side effects of rituximab is a constellation of symptoms/signs that occurs within the initial 30 to 120 minutes of the first exposure in over 50 percent of patients [91,92]. The most common are headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, nausea, rhinitis, urticaria, pruritus, asthenia, and a sensation of tongue and throat swelling (angioedema) [6,91,92]. Bronchospasm and/or severe hypotension are present in less than 10 percent of cases, and fewer than 5 percent of reactions are severe (grade 3 or 4) or suggestive of anaphylaxis [6]. Severe reactions are most likely in patients with high circulating levels of tumor cells (particularly in chronic lymphocytic leukemia [CLL] and mantle cell lymphoma); in these cases, fractionation of the rituximab dose is recommended in addition to premedication. (See 'Dose fractionation' below.)

For most patients, the reaction complex is brief and resolves completely when the infusion is stopped. In a review of the experience in almost 300 patients receiving rituximab for lymphoma, the mean duration of infusion-related symptoms was less than one hour for chills, angioedema, and nausea, 1.5 hours for headache and hypotension, and approximately three hours for fever [6]. Guidance about resuming the infusion after symptoms have resolved is provided below. (See 'Management of SIRs and rechallenge' below.)

Infusion reactions are markedly less common after the initial infusion [7]. The manufacturer reports a frequency of 77, 30, and 14 percent during the first, fourth, and eighth infusions of rituximab, respectively.

Mechanism — The majority of these infusion reactions are thought to be related to an antibody-antigen interaction between rituximab (the antibody) and CD20 (the antigen) on lymphocytes, resulting in cytokine release from these cells [91]. Severe symptoms (pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and even death) have typically occurred in patients with high numbers of circulating cells bearing the target antigen (eg, as in CLL), and underlying comorbid conditions [5,93]. Reactions such as these can be minimized by fractionating the rituximab dose over several days. (See 'Dose fractionation' below.)

Prophylaxis of infusion reactions — Because of the high incidence of infusion reactions, it is standard practice to premedicate patients with acetaminophen (650 mg orally) and an H1 receptor blocker (eg, diphenhydramine 50 mg orally) 30 minutes before the first and second infusions; at some institutions, routine premedication also includes an H2 receptor blocker (eg, famotidine 20 mg intravenously). Standard premedications can be eliminated during subsequent infusions if reactions are not evident.

Premedication with acetaminophen and diphenhydramine attenuates but does not prevent infusion reactions [5]. The addition of a single pretreatment dose of a glucocorticoid (which is typically given for emesis prophylaxis just prior to chemotherapy in conjunction with rituximab) does not appear to further reduce the rate of severe reactions; in one report grade 3 or 4 infusion reactions (table 2) still occurred in 10 percent of patients [94]. There are no reports evaluating the efficacy of a more extensive approach to prophylaxis, such as the addition of a glucocorticoid beginning ≥12 hours prior to treatment, as is used for taxanes [5]. However, we have used this approach successfully in several patients with severe recurrent reactions. (See "Infusion reactions to systemic chemotherapy", section on 'Taxanes'.)

Infusion rate — The high incidence of infusion reactions has also led to the general practice of starting the first dose slowly and gradually increasing the speed of infusion. The first infusion is usually administered over approximately four hours, with later infusions over less time in the absence of a reaction.

The first rituximab infusion is typically initiated at a rate of 50 mg/hour; in the absence of an infusion reaction, it is increased by 50 mg/hour every 30 minutes to a maximum of 400 mg/hour. Subsequent infusions can be started at a rate of 100 mg/hour if the initial infusion was well tolerated and the rate increased by 100 mg/hour every 30 minutes to a maximum of 400 mg/hour if there is no evidence of an infusion reaction.

For patients receiving a concurrent chemotherapy regimen for which glucocorticoids are included for emesis prophylaxis, an accelerated infusion schedule may be used after the first dose of rituximab [95]. The first treatment is given according to the standard schedule, beginning at 50 mg/hour, and gradually increasing thereafter. All subsequent cycles of rituximab can be administered over 90 minutes, with 20 percent of the dose given in the first 30 minutes, and the remainder over the next 60 minutes. The safety of this approach was shown in the phase III RATE trial, in which 363 previously untreated patients with non-Hodgkin lymphoma (NHL) who did not experience a grade 3 or 4 infusion-related reaction to rituximab (in combination with one of two different chemotherapy regimens, CHOP versus CVP) during cycle 1 all received a faster infusion in cycle 2, and if well-tolerated, all subsequent cycles [96]. Twenty percent of the total dose was administered in the first 30 minutes, and if tolerated, the remainder was administered over 60 minutes. The incidence of grade 3 IRRs during cycle 2 was 1.1 percent (95% CI 0.3-2.8). Based upon these results, the US Food and Drug Administration (FDA) approved a 90-minute infusion for rituximab starting at cycle 2 for patients with NHL who did not experience a grade 3 or 4 infusion-related adverse reaction during cycle 1. Patients with clinically significant cardiovascular disease and high circulating lymphocyte counts (>5000/microL) are not recommended to receive the faster infusion, even in the absence of a severe infusion reaction.

Dose fractionation — As noted above, the likelihood of an infusion reaction is higher in patients who have a very elevated white blood cell (WBC) count. Many protocols fractionate the rituximab dose during cycle one in all patients in order to minimize the potential for a serious adverse reaction, particularly if the patient has CLL and a high WBC count. A typical administration schedule is 50 mg/m² on day 1, followed by the remainder of the dose (325 mg/m²) on day 3. For patients whose WBC count is >100,000/microL, rituximab may be withheld for the first cycle of therapy. (See 'Mechanism' above.)

Management of SIRs and rechallenge — Patients who develop a non-life-threatening mild to moderate standard infusion reaction (SIR) can usually be managed by temporary discontinuation of drug infusion alone. Once all symptoms have resolved, most patients will tolerate a slower infusion rate (one-half the rate at which the reaction occurred) with additional antihistamines plus acetaminophen. If the infusion reaction does not recur, the infusion rate may then be increased by 50 mg/hour to the maximum of 400 mg/hour.

If the reaction is severe, additional treatment, such as saline infusion, bronchodilators, oxygen, epinephrine, and hydrocortisone may be required. In these cases, rechallenge on the same day is generally discouraged. For severe SIRs that do not have features of anaphylaxis, subsequent rechallenge is usually successful with an intensified premedication regimen (a glucocorticoid such as hydrocortisone 100 mg or dexamethasone 12 mg plus H1- and H2-receptor blockers the night before and one hour prior to rechallenge) and splitting of the dose, as is typically done for CLL (eg, 50 mg/m² on day 1 and the remainder of the dose on day 3).

For patients who have recurrent infusion reactions despite premedication, referral to an allergist for desensitization may allow for continued use of the drug in some cases [12].

Management of anaphylaxis — Patients with signs or symptoms of possible anaphylaxis should be referred to an allergist or an oncology center with experience in drug desensitization [2,12]. Successful desensitization protocols for rituximab have been published (table 7) [17,97].

Other reactions — Other less common infusion reactions associated with rituximab include mucocutaneous reactions (Stevens-Johnson syndrome, vesiculobullous dermatitis, and toxic epidermal necrolysis), which typically present 1 to 13 weeks after therapy. Patients who develop these blistering reactions should never be re-exposed to the drug because of the risk of a fatal recurrence. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

Serum sickness (a delayed type III allergic reaction in the Gell and Coombs classification (table 8)) has been reported with rituximab, mainly in patients receiving the drug for an autoimmune condition [98-101]. The most common clinical presentation is fever, followed by arthralgia and rash [101]. Other symptoms include myalgia, malaise, fatigue, conjunctival hyperemia, and purpura. The severity can range from mild to moderate joint aches, rash, and headache to life-threatening angioedema (table 9). Patients generally respond to pulse methylprednisolone therapy with resolution of symptoms within 48 hours. In one case, antibodies to the mouse F(ab')(2) fragments of rituximab were identified. (See "Serum sickness and serum sickness-like reactions".)

Subcutaneous administration — A subcutaneous (SC) formulation (rituximab-hyaluronidase) has been developed that includes hyaluronidase as a permeation enhancer. It can be administered over five minutes and is an option for patients with certain lymphoma subtypes who have tolerated at least one full dose of intravenous rituximab. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Immunotherapy-based treatment'.)

Administration-related reactions have occurred in approximately 45 to 50 percent of individuals treated with SC rituximab, despite premedication with acetaminophen and an antihistamine [102,103]. In contrast to intravenous rituximab, most reactions after SC administration are grade 1 or 2 injection site reactions (table 10) with erythema, pruritus, rash, induration, edema, and injection site pain. Some of these reactions have occurred more than 24 hours after administration. However, systemic reactions have also occurred, including chills, fever, nausea and vomiting, dyspnea, bronchospasm, urticaria, hypotension, angioedema, and anaphylaxis. (See 'Management of anaphylaxis' above.)

In general, both local and systemic reactions are most common with the first injection, and the proportion of patients reporting local cutaneous effects and the intensity of local reactions both decrease over subsequent treatment cycles.

The manufacturer recommends premedication with acetaminophen and an antihistamine prior to each dose, with consideration of glucocorticoid premedication as well.

SACITUZUMAB GOVITECAN — Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan (SN-38). It is approved for treatment of triple-negative breast cancer. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Sacituzumab govitecan'.)

This drug can cause severe and life-threatening hypersensitivity reactions. Infusion reactions within 24 hours of drug administration occur in over one-third of patients; the severe (grade 3 or 4) infusion reaction rate is two percent [104]. The United States Prescribing Information recommends pretreatment with antipyretics, an H1- and an H2-receptor antagonists prior to each infusion, with the addition of a glucocorticoid for patients with a prior infusion reaction.

TAFASITAMAB — Tafasitamab is a CD19-directed cytolytic antibody that is approved, in combination with lenalidomide, for treatment of refractory, transplant-ineligible, diffuse large B cell lymphoma. (See "Diffuse large B cell lymphoma (DLBCL): Second or later relapse or patients who are medically unfit", section on 'Tafasitamab'.)

In a phase II trial, IRRs of any grade developed in 12 percent of treated patients, mostly during the first two cycles [105]. Signs and symptoms included chills, flushing, dyspnea, and hypertension. The United States Prescribing Information recommends premedication prior to starting tafasitamab, which may include acetaminophen, an H1 receptor antagonist, an H2 receptor antagonist, and/or glucocorticoids. Premedication is optional for subsequent infusions if there are no reactions during the first three infusions.

TRASTUZUMAB AND OTHER HER2-TARGETED THERAPIES

Trastuzumab — Trastuzumab is a humanized MoAb that binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2); it mediates antibody-dependent cellular cytotoxicity against cells that overexpress this protein. Trastuzumab is an important agent for the treatment of HER2-overexpressing metastatic breast cancer and for adjuvant treatment of high-risk HER2-overexpressing primary breast cancer. (See "Adjuvant systemic therapy for HER2-positive breast cancer" and "Systemic treatment for HER2-positive metastatic breast cancer".)

Trastuzumab treatment is usually initiated with a loading dose of 4 mg/kg, followed by 2 mg/kg weekly, although some data support the safety and efficacy of every three week dosing (loading dose 8 mg/kg followed by 6 mg/kg intravenously [IV] every three weeks) [106]. The first dose is generally administered over 90 to 120 minutes, with subsequent infusions shortened to 30 to 45 minutes if no reactions occur.

The vast majority of infusion reactions occur with the first infusion, are mild in severity, and easily managed. Between 20 and 40 percent of women have an infusion reaction during the initial infusion. Somewhat higher rates (47 to 62 percent) are reported with combinations of trastuzumab and cytotoxic agents [107,108]. The most common symptoms are fever, chills, nausea, headache, abdominal pain, and dyspnea, and less often include vomiting, dizziness, rash, rhinitis, or hypotension. Most infusion reactions are mild, and they begin shortly after the initiation of drug infusion [108-112]. In a summary of the postmarketing experience with trastuzumab in over 25,000 women with metastatic breast cancer, only 0.3 percent of patients had infusion reactions that were described as serious and had features of anaphylaxis (bronchospasm, hypotension, angioedema) [111].

Prevention — Most clinicians do not routinely premedicate prior to the first trastuzumab dose. However, patients may be instructed to self-administer acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) if flu-like symptoms develop in the first 24 hours after drug administration.

Management and rechallenge

Mild to moderate symptoms — Most mild to moderate standard infusion reactions (SIRs; grade 1 or 2 (table 2)) are resolved by simply slowing the infusion rate. In some cases, temporary discontinuation of drug infusion with symptomatic treatment (acetaminophen and/or diphenhydramine) is needed for persistent mild to moderate symptoms. Meperidine is rarely indicated for chills/rigors.

Once symptoms resolve, retreatment is usually possible. Fever and chills generally do not recur with subsequent infusions; in one study, they were present in 40 and 3 percent of initial versus subsequent infusions, respectively [109]. Despite the unclear benefit of pretreatment (and the markedly lower risk of an infusion reaction for the second and subsequent doses), many clinicians use acetaminophen and diphenhydramine pretreatment as well as a slower infusion rate for the second infusion if there was a reaction to the first exposure, eliminating pretreatment for subsequent treatments if the drug is well tolerated.

More severe reactions — The US Food and Drug Administration (FDA)-approved package labeling suggests interruption of the infusion for any patient who develops dyspnea, clinically significant hypotension during administration. A severe SIR does not preclude rechallenge, provided there are no symptoms to suggest anaphylaxis. A rechallenge might be considered after complete resolution of symptoms if the risk for a serious recurrent reaction is felt to be outweighed by mitigating clinical factors (ie, the potential clinical benefit of further treatment and the lack of other reasonable alternatives). In such cases, premedication with both an H1 and H2 histamine receptor blocker (eg, diphenhydramine plus famotidine) and a glucocorticoid is generally recommended.

Management of anaphylaxis — Drug infusion should be stopped immediately in patients who have signs of anaphylaxis such as urticaria, angioedema, hypotension, or severe respiratory distress. These patients should be treated for anaphylaxis.

Rapid desensitization protocols have been developed for patients in whom continued trastuzumab treatment is limited by recurrent infusion reactions [2,16,17]. However, experience with this regimen is limited to a small number of patients. Referral to an allergy specialist with experience in drug desensitization is recommended for patients with persistent reactions despite premedication [12].

Subcutaneous (SC) preparations of trastuzumab are discussed below. (See 'Subcutaneous preparations' below.)

Ado-trastuzumab emtansine and fam-trastuzumab deruxtecan — Ado-trastuzumab emtansine (also known as T-DM1) is a HER2-directed antibody-drug conjugate composed of trastuzumab, a thioether linker, and DM1, a derivative of the antimitotic agent, maytansine. It is approved for advanced breast cancer in patients previously exposed to trastuzumab and taxanes. (See "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Treatment-free interval of less than six months'.)

Fam-trastuzumab deruxtecan is a different drug-antibody conjugate that links trastuzumab to a topoisomerase-I inhibitor; it is approved for previously treated advanced HER2-overexpressing breast cancer and advanced HER2-positive gastric adenocarcinoma. (See "Second and later-line systemic therapy for advanced unresectable and metastatic esophageal and gastric cancer", section on 'HER2-positive adenocarcinoma' and "Systemic treatment for HER2-positive metastatic breast cancer", section on 'Fam-trastuzumab deruxtecan'.)

In contrast to trastuzumab, infusion-related adverse events with both of these drugs occur rarely and are typically grade 1 or 2 (table 2). Symptoms have included flushing, chills, fever, dyspnea, hypotension, wheezing, bronchospasm, and tachycardia; in the case of ado-trastuzumab emtansine, only one case of a serious allergic/anaphylactic-like reaction has been reported [113].

Routine premedication is not indicated for either drug.

Pertuzumab — Pertuzumab is a MoAb that binds a different epitope of the HER2 extracellular domain than trastuzumab, and prevents HER2 homo- and heterodimerization with other HER-family receptors. It is typically used in combination with trastuzumab.

IV pertuzumab has been associated with infusion and hypersensitivity reactions. In a randomized trial of trastuzumab and docetaxel plus either pertuzumab or placebo conducted in 808 patients with HER2-positive breast cancer, the initial dose of IV pertuzumab or placebo was administered the day before trastuzumab and docetaxel to assess the frequency and severity of pertuzumab-associated infusion reactions [114]. The overall frequency of infusion reactions with pertuzumab was 13.0 percent (versus 9.8 percent with placebo); most reactions were mild, and fewer than 1 percent were grade 3 or 4 (table 2). The most common symptoms were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. The overall frequency of infusion/hypersensitivity reactions throughout the trial was 10.8 versus 9.1 percent in the pertuzumab and placebo groups, respectively, and four patients experienced anaphylaxis with pertuzumab (versus two in the placebo group).

Routine premedication is not indicated. The FDA-approved labeling information suggests that patients be observed closely for 60 minutes after the first infusion and for at least 30 minutes after subsequent infusions. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions.

Margetuximab — Margetuximab is an Fc-engineered anti-HER2-receptor monoclonal antibody that is FDA approved, in combination with chemotherapy, for treatment of metastatic HER2-positive breast cancer in patients who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. In the phase III SOPHIA study IRRs occurred in 13 percent of patients treated with margetuximab plus chemotherapy, they were grade 3 in 1.5 percent, and most occurred during the first cycle of therapy [115].

Routine premedication is not indicated. The FDA-approved labeling recommends that the drug be permanently discontinued for severe or life-threatening IRRs, and that clinicians consider premedication (antihistamines, glucocorticoids, antipyretics) for later cycles in patients who experience mild or moderate IRRs.

Subcutaneous preparations — SC preparations of trastuzumab (trastuzumab-hyaluronidase) and pertuzumab plus trastuzumab in a fixed-dose combination with hyaluronidase (pertuzumab-trastuzumab-hyaluronidase) for injection under the skin are commercially available, and may be more convenient for patients since they can be administered at home by a health care professional. (See "Neoadjuvant therapy for patients with HER2-positive breast cancer", section on 'Other agents'.)

These preparations do not appear to have a higher risk of administration-related systemic reactions as compared with the IV formulations of trastuzumab, though injection site reactions are more frequent:

●In a randomized trial comparing IV versus SC trastuzumab, efficacy was similar, although the percentage of patients receiving SC trastuzumab who developed mild, moderate, or severe injection site reactions was 8, 7, and 1 percent, respectively [116]. None of the patients undergoing IV treatment developed a local injection site reaction.

●The noninferiority randomized FeDeriCa study in patients with HER2-positive early breast cancer demonstrated comparable efficacy and safety of SC pertuzumab-trastuzumab-hyaluronidase versus IV pertuzumab plus trastuzumab, except for administration-related reactions, which were higher with SC administration; most of these were injection site reactions (13 versus 0 percent in the IV group with injection site pain or erythema being the most common symptoms [117]). Systemic reactions (hypersensitivity, anaphylaxis) only developed in 4 percent.

The United States Prescribing Information does not recommend routine pretreatment prophylaxis for IRRs for either SC trastuzumab or pertuzumab-trastuzumab-hyaluronidase.

AGENTS TARGETING THE PROGRAMMED CELL DEATH RECEPTOR — Mild infusion-related side effects (fever, chills, headaches, nausea) have been reported in patients treated with agents targeting the programmed cell death receptor 1 (PD-1) or its ligand (PD-L1; eg, nivolumab, durvalumab [118], atezolizumab, avelumab [119], pembrolizumab, and cemiplimab). The reported incidence of severe or life-threatening IRRs has been less than 2 percent with all agents. For patients with severe reactions, such as throat tightness, shortness of breath, or desaturation, desensitization has been successfully done by one of the authors (MC).

IRRs have occurred in a higher frequency overall (25 percent) with avelumab, although fewer than 1 percent are severe (grade 3 or worse (table 2)) [119]. The United States Prescribing Information for avelumab recommends premedication with acetaminophen, and an antihistamine is indicated during the first four cycles and subsequently as needed. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma" and "Treatment of recurrent and metastatic Merkel cell carcinoma", section on 'Avelumab'.)

Steroids, aspirin, and the leukotriene receptor antagonist montelukast have also been successfully used for severe reactions by one of the authors (MC).

SUMMARY AND RECOMMENDATIONS

●Frequency and types of reactions

•Virtually all of the therapeutic monoclonal antibodies (MoAbs) used for cancer treatment have the potential to cause infusion-related reactions (IRRs), but certain drugs (eg, daratumumab, rituximab, cetuximab alemtuzumab, ramucirumab, ofatumumab) are associated with a high enough risk to warrant special precautions. (See 'Introduction' above.)

•IRRs are most likely during the first or second infusion; however, between 10 and 30 percent of reactions occur during subsequent courses of therapy, so the clinician must remain vigilant with every administration. (See 'Types of reactions' above.)

•The mechanism underlying MoAb-related IRRs is unclear, but most are thought to be related to antigen-antibody interactions precipitating cytokine release. Anaphylaxis is uncommon, but has been reported primarily with rituximab, trastuzumab, and cetuximab. (See 'Types of reactions' above.)

•There is a wide spectrum of severity, ranging from mild fever and chills to life-threatening anaphylaxis with bronchospasm, and hypotension. Anaphylaxis (characteristic features being urticaria, wheezing, hypotension, and gastrointestinal symptoms but not fever) must be differentiated from all other types of IRRs (termed standard infusion reactions [SIRs]), regardless of severity.

Anaphylaxis is likely to recur despite premedication and typically becomes more severe upon re-exposure. For these reasons, patients with symptoms of anaphylaxis (even if mild) should not be re-exposed to the drug until they have been evaluated by an allergist or oncologist with experience in drug allergy. (See 'NCI classification of infusion reactions' above.)

●Prevention – For certain agents, specific prophylactic maneuvers can be helpful; however, despite premedication, clinicians must be prepared for an IRR to occur during each drug administration. Standing orders should be in place to allow immediate intervention without waiting for the clinician to arrive. (See 'General principles of treatment and rechallenge' above.)

Specific premedication regimens for individual agents are addressed in the sections that discuss these agents above, briefly:

•Pharmacologic prophylaxis with a histamine H1 receptor antagonist is recommended prior to each infusion of ramucirumab. (See 'Ramucirumab' above.)

•Pharmacologic prophylaxis with antihistamines plus acetaminophen with or without a glucocorticoid is suggested for other high-risk agents (ie, rituximab, gemtuzumab ozogamicin, first infusion of cetuximab in a patient who resides in a high-risk area, intravenous [IV] alemtuzumab, elotuzumab). Since IRRs are most likely during the first or second infusion, many clinicians eliminate routine premedication after the first two exposures if there has not been a reaction. However, as noted above, IRRs can also occur with later courses of therapy.

•For patients receiving rituximab who have high levels of circulating malignant cells (eg, chronic lymphocytic leukemia (CLL) or mantle cell lymphoma), dose fractionation (ie, 50 mg/m² on day 1, and the remainder of the dose administered on day 3) with premedication is advisable. For patients whose WBC count is >100,000/microL, rituximab may be withheld for the first cycle of therapy. (See 'Rituximab' above.)

•With alemtuzumab, subcutaneous rather than IV administration lowers the incidence and severity of IRRs, and is preferred where possible. (See 'Alemtuzumab' above.)

•With daratumumab, premedication with an antihistamine, acetaminophen, and a glucocorticoid is recommended prior to all doses, as is postmedication with a glucocorticoid on the first and second day after each dose. In addition, gradual escalation of the infusion rate with at least the first three doses is recommended in the absence of an IRR. (See 'Daratumumab' above.)

•Blinatumomab may cause a potentially fatal cytokine release syndrome (CRS) with pyrexia, headache, nausea, asthenia, hypotension, and elevations in serum aminotransferases and bilirubin (table 4). Patients are hospitalized for the first nine days of the first cycle and the first two days of the second cycle to monitor for signs and symptoms of CRS. Pretreatment with dexamethasone is recommended prior to the first dose of each cycle, prior to each intracycle dose increase (eg, as occurs on cycle 1 day 8), or when restarting an infusion after an interruption of four or more hours. (See 'Blinatumomab' above.)

●Immediate treatment – Immediate management of IRRs is tailored to the clinical situation. The following represent general guidelines for management of a patient who is suspected of having an infusion reaction during therapy with a therapeutic MoAb.

•Mild to moderate SIRs – If the reaction is limited to mild or moderate symptoms of SIR (grades 1 or 2 (table 2)), without features suggestive of anaphylaxis, drug infusion should be temporarily stopped and assessment of airway, breathing, circulation, and mentation accomplished rapidly. IV administration of 50 mg of diphenhydramine and 650 mg of acetaminophen may provide symptomatic relief. Once symptoms have resolved, resumption of the drug infusion at a slowed rate may permit treatment continuation with close monitoring. (See 'Treatment of mild to moderate SIRs' above.)

•Severe SIRs or anaphylaxis – Severe SIRs (grades 3 or 4 (table 2)) or reactions of any severity with any features of anaphylaxis (eg, generalized urticaria, wheezing, hypotension, and angioedema) require prompt recognition and treatment. In fatal anaphylaxis, death typically ensues within 30 minutes from exposure to the trigger. (See 'Treatment of severe SIRs and anaphylaxis' above.)

Detailed guidelines for the management of anaphylaxis are available from the Joint Council of Allergy, Asthma, and Immunology, and are summarized in a rapid overview table for adults (table 5) and children (table 6). These guidelines should be available to all practitioners who administer agents with the potential for an infusion reaction. They include the following:

-Immediately discontinue drug infusion

-Assess airway, breathing, circulation, and adequacy of mentation

-Call for help (summon a resuscitation team in the hospital setting, call 911 or an equivalent service in the community setting)

-Place the patient in the supine position with legs elevated (if tolerated)

-Administer intramuscular epinephrine into the anterolateral thigh (0.3 to 0.5 mg aqueous epinephrine, 1 mg/mL preparation)

-Establish IV access with two 14 to 16 gauge catheters

-Administer both an H1- (eg, 50 mg of diphenhydramine) and an H2- (eg, 20 mg of famotidine) histamine receptor blocker IV

-Systemic administration of a glucocorticoid (eg, 125 mg methylprednisolone IV) may not help acutely, although it may prevent a prolonged or recurrent reaction

The treatment of anaphylaxis is covered in more detail elsewhere. (See "Anaphylaxis: Emergency treatment".)

●Rechallenge and desensitization – Once the acute event has subsided, the issue of rechallenge must be addressed. The decision to attempt retreatment depends upon the drug, the severity of the reaction, the cancer being treated, and whether there are reasonable treatment alternatives (see 'General principles of treatment and rechallenge' above):

•If the reaction was mild to moderate and did not involve symptoms of anaphylaxis, rechallenge is usually possible with premedication (corticosteroids, antihistamines) and a slower rate of infusion after the symptoms have cleared.

-In the case of rituximab, fractionation of the dose over three days is recommended. (See 'Management of SIRs and rechallenge' above.)

-In the case of a patient with a severe reaction to the initial infusion of cetuximab, switching to the non-cross reacting alternative agent panitumumab is a reasonable alternative to rechallenge with cetuximab. (See 'Cetuximab' above.)

•If the reaction was severe or involved any symptoms of anaphylaxis, the patient should either be changed to an alternative drug (if one is available) or, if there are no reasonable alternatives and use of the drug is clinically necessary, referred for evaluation to an allergist or oncologist with experience in drug desensitization.

Desensitization protocols may allow for continued use of the drug in some patients with severe SIRs and anaphylaxis, but experience in patients receiving MoAbs is relatively limited. At some institutions, these are only performed by allergy specialists. (See 'Overview of desensitization' above and 'Rituximab' above and 'Trastuzumab and other HER2-targeted therapies' above.)