Management of Infusion Reactions in Clinical Trials and Beyond: The US and EU Perspectives

Rechallenge

In any circumstance, the decision to rechallenge with any agent should be based on several clinical factors, including the risk for a serious recurrent reaction and the potential clinical benefit of further treatment. For example, if the drug is given as salvage therapy or as palliative care, the long-term clinical benefits of continued treatment are likely to be small and may not warrant the risk for severe toxicity. In this case, switching to an alternative agent, if available, may be appropriate.

Continuing active treatment, however, should be a priority for patients who have mild-to-moderate reactions, and strategies that safely allow continuation should be considered, particularly if the goal of therapy is to prolong survival. The decision to continue or discontinue treatment must be made on a case-by-case basis after weighing all of the relevant clinical factors.

Challenge With Panitumumab in Patients Who Developed IRs to Cetuximab(Drug information on cetuximab)—Scarce data are available on the safety of panitumumab in patients who developed IRs to cetuximab.[ 40-42] One anecdotal report published in May 2007 described a 53-year-old male with metastatic colorectal cancer who was pretreated with diphenhydramine(Drug information on diphenhydramine) before receiving an infusion with cetuximab.[40] During the infusion, the patient developed an HSR, infusion was stopped, and the patient was treated with diphenhydramine at 50 mg and dexamethasone(Drug information on dexamethasone) at 4 mg. The patient was switched to panitumumab at 6 mg/kg and began treatment 5 weeks after his reaction to cetuximab. He received one dose every 2 weeks and completed six doses of panitumumab without premedication and without incident, before experiencing further disease progression. A decision was made by the patient and his family to cease active therapy and he was referred to hospice.

A similar case describes a 39-yearold white male with metastatic colorectal cancer who received cetuximab monotherapy as third-line treatment and experienced an IR with massive facial urticaria within 5 minutes, despite premedication with dexamethasone, clemastine(Drug information on clemastine) fumarate, and ranitidine(Drug information on ranitidine).[43] A second attempt was made at a reduced infusion rate 90 minutes later with the same response. No subsequent cetuximab was given. The patient was premedicated with cetirizine and given panitumumab. No IR occurred. The patient received a total of six infusions of panitumumab every 2 weeks. Personal experience shows a similar response, demonstrating a decrease in the incidence of severe IRs to panitumumab, but requiring no premedication, when switched to cetuximab. The most severe reaction to panitumumab presented as a grade 2 acneiform rash.

Recently a report was presented on three patients who underwent successful rechallenge with panitumumab following grade 3 hypersensitivity reactions to cetuximab.[44] These patients were challenged with a standard dose of panitumumab (6 mg/kg), after experiencing grade 3 IRs with prior cetuximab, under strict observation and no premedication. The first patient, a 58-year-old male with metastatic colorectal cancer, developed grade a 3 IR during his eighth dose of cetuximab. The second patient was a 58-year-old female with metastatic colorectal cancer who developed a grade 3 IR during her 12th dose of cetuximab. The third patient was a 61-year-old male with pancreatic cancer who experienced a grade 3 IR during administration of the loading dose of cetuximab. All patients were Caucasians with an average age of 59 years and no history of prior allergy. No patient received any premedication. The first patient received panitumumab for 2 months; the second patient was treated for 6 months; and the third patient, who was rechallenged 1 week after the IR to cetuximab, had a partial response following 6 months of therapy.

Desensitization

Often, a patient has limited therapeutic alternatives if standard treatments cause a hypersensitivity reaction. Therefore, the ability to safely retreat a patient with an agent that previously led to an adverse event could be clinically useful.[45] There are multiple anecdotal reports of successful uses of desensitization protocols after severe IRs from cetuximab in the literature. Graded challenge, which gradually increases the dose until the targeted dose is reached, may be appropriate to avoid repeat reaction that may be fatal.[46]

Although anecdotal reports suggest successful challenge with panitumumab following IR with cetuximab,[44] the safety of cetuximab after IR with panitumumab is not known. We recently reported two patients who were successfully desensitized after IR with cetuximab and safely retreated with panitumumab and cetuximab.[46] Both patients were premedicated with 50 mg of oral prednisone(Drug information on prednisone) 24, 12, and 3 hours prior to receiving cetuximab, and with 50 mg IV diphenhydramine and 20 mg IV famotidine(Drug information on famotidine) prior to cetuximab. They then received a desensitization protocol for cetuximab after a test dose of 20 mg IV over 10 minutes, followed by a slow infusion at 10% of the original rate for 2 hours, followed by 25% of the original rate in the interval between 2 and 2.5 hours, then a 50% reduced rate between 2.5 and 3 hours, and finally 100% of the infusion rate after 3 hours. The patients were observed for 4 hours after completion of infusion.

Our experience suggests that in cases where options are limited, such patients can be successfully retreated with cetuximab in a hospital setting with close monitoring after appropriate desensitization and premedication. Further studies focusing on desensitization and identifying hypersensitivity profiles of different anti–epidermal growth factor receptor antibodies are warranted.

How Should Patients Be Followed?

Biphasic reactions may occur in up to 20% of patients experiencing anaphylactic reactions. Therefore, an observation period with close monitoring is indicated even after symptoms re solve. The reported time intervals between the initial reaction and the second- phase reaction may extend up to 72 hours. Thus, close monitoring of patients who have experienced a severe infusionrelated reaction is advisable.[47]

Effect of Monoclonal Antibody IRs on Clinical Trials

Two potential conflicts arise when monoclonal antibodies are incorporated into clinical trials. The first is the potential dilemma in intent-to-treat efficacy results. This could create problems in evaluating phase III randomized trials after a number of patients demonstrate grade 3 or 4 IRs that preclude them from being rechallenged with a monoclonal antibody. Should patients be prescreened for hypersensitivity before trial enrollment using a test dose? Should these patients be excluded from final efficacy results? Certainly this is not a significant issue if IRs are either low in incidence or not severe and can be rechallenged. This problem has not been systematically evaluated, nor have consensus opinions for future trials been developed.

The second potential conflict concerns those geographic areas endemic to high rates of IRs. Should these regions be excluded, expecting that 20% to 25% of patients enrolled in trials in those areas will not complete therapy? Could future trials delay patient enrollment in these facilities until reliable assays could prescreen their patients for preformed IgE? Could a prior history of atopy in individual patients be acceptable for exclusion? Again, no consensus has been developed; at the present time clinicians must use their own experience and training to determine which patients are appropriate for any given trial incorporating monoclonal antibodies in the regimen.

Conclusions

Monoclonal antibodies are important new therapeutic tools for treating many different types of cancers; these agents are often used along with cytotoxic chemotherapy. It appears that humanized and fully human antibodies engender anaphylaxis less often than do agents that contain mouse derived sequences.

Clinicians, patients, and nurses should be alert to the early signs of anaphylaxis such as sneezing, tachypnea or tachycardia, dyspnea, or a sense of impending illness. Because of geographic variations in the incidence of severe IRs, patients who live in or have lived in the southeastern United States should be observed with special vigilance. When such severe adverse events occur, rapid use of epinephrine(Drug information on epinephrine) and discontinuation of the antibody infusion are vital. Patients should have blood and urine tests to determine if the reaction is IgE mediated. If the reaction is consistent with an IgE-mediated event, then rechallenge with the same agent should only be contemplated in a circumstance where immediate observation and intervention are available.

Some patients can be desensitized to allergens, including monoclonal antibodies. In the event that a patient reacts to cetuximab, there are anecdotal reports of subsequent safe use of the fully human monoclonal antibody panitumumab. In the near future, blood tests that will help to determine which patients are at high risk for these types of reactions may be available.

Financial Disclosure: Dr. Cmelak has received speaker honoraria from Bristol-Myers Squibb and ImClone; he has acted as a consultant and participated in steering committees for Amgen. Dr. Lordick has been a member of speakers bureaus and acted in a consultant/advisory role for Amgen. Dr. Goldberg has acted as a consultant for Bristol-Myers Squibb, ImClone, Amgen, Genentech, Pfizer, and sanofi-aventis. Dr. Saif has been a member of speakers bureaus for Amgen, Bristol-Myers Squibb, Roche, Pfizer, sanofi-aventis, and Onyx; he has received research funding from Roche, PhytoCeutica, Samyang, Biogen Idec, and Taiho.

This supplement and associated publication costs were funded by Amgen.

Acknowledgment: The authors wish to acknowledge William Fazzone, PhD, from MediTech-Media, Ltd., supported by Amgen, for editorial assistance including formatting the mansucript for submission.

Address all correspondence to:
Anthony J. Cmelak, MD
Department of Radiation Oncology
B-1003 The Vanderbilt Clinic
22nd Avenue at Pierce
Nashville, TN 37232-5671
e-mail: anthony.cmelak@vanderbilt.edu