December 5, 2023
December 5, 2023

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Drug Allergies II: The Cetuximab Mystery

Last week we introduced the problem of allergic reactions in response to exposure to medications. As we noted, this can occur with almost any medication. The most common allergic reactions are IgE-mediated with the release of histamine and, if very severe, can result in the very dramatic and dangerous anaphylactic reaction.

Of course, allergic reactions can occur with chemotherapeutic drugs as well, and certain drugs have proven to be more allergenic than others. In the past two decades, antibodies against various antigens on tumor cells have become an increasingly prominent part of the antineoplastic armamentarium. Antibodies are proteins, and proteins are a particularly powerful antigenic stimulus for the immune system, i.e., it is common to find allergic reactions to antibody drugs.

Cetuximab (Erbitux) is an antibody that was made against the epidermal growth factor receptor (EGFR) present on the surface of certain tumor cells; it acts as an inhibitor and in doing so inhibits the tumor’s growth. It was approved by the FDA in 2009 for the treatment of colorectal cancer and has since proven effective as well for head and neck cancer. The drug is particularly useful because, while highly effective, it also has a limited array of side effects.

For our discussion of allergies, what is significant is that this particular antibody is a chimeric mouse-human antibody, i.e., it was produced by a combination of both mouse and human lymphocytes and thus the antibody has components that are human but also murine (mouse-derived) proteins. As a consequence, when the drug is infused, the body’s immune system has a stronger propensity to recognize the antibody as foreign because of the mouse proteins. This is in contrast to panitumumab (Vectibix), a competing EGFR inhibitor drug, which is a purely human antibody and thus less allergenic.

The hypersensitivity reaction associated with cetuximab is the usual IgE-mediated response, which can include hives, shortness of breath, fever, tachycardia, chills, bronchospasm and hypotension. In contrast to what we described in the last episode for oxaliplatin, the allergic reaction typically occurs on the first exposure to the medication. Mild reactions typically occur in 15-20% of patients, with more severe reactions (grade 3 or 4) in 2-3%. A national database described an overall rate of 8.4%. Typically, because of this high rate of allergic reactions, great care is taken in providing pre-treatment medications that include corticosteroids, Benadryl (diphenhydramine, an antihistamine), and acetaminophen (Tylenol) as prophylaxis. This is all considered a regular and normative part of the standard of care in the administration of cetuximab.

Here is where it gets interesting. Studies conducted in the Southeastern U.S. showed rates of allergic reactions that were dramatically higher than those that were seen elsewhere in the U.S. or the rest of the world. A 2006 study of 90 patients treated at the University of North Carolina with cetuximab found that 20% had an allergic reaction while 14% had severe allergic reactions (grade 3 or 4). Almost simultaneously another study found that 22% of 53 patients treated at two sites in Tennessee had grade 3-4 hypersensitivity reactions. A contemporaneous study from a Florida VA hospital found a rate of 27% of grade 3-4 reactions, and another North Carolina study found an overall hypersensitivity rate of 29%. Similarly high rates of allergic reactions were also observed in Missouri, Oklahoma and Arkansas.

All sorts of hypotheses were put forward to try to explain the reasons for these observations of extremely high rates of severe hypersensitivity reactions to cetuximab in this region, including tick exposure, cigarette smoking, and allergy histories, but none of the proposed hypotheses could adequately explain the geographic observations that were made. For a while, it was believed that there was some pollen or plant present in the swamps or other parts of the region that was cross-reacting with the drug, but ultimately this hypothesis did not bear out either.

The observation that the hypersensitivity reactions occurred during the initial infusion suggested that the antigen exposure pre-dated the infusion. It was discovered that the IgE antibodies that were formed were reactive to galactose-alpha-1,3-galactose, or alpha-gal, an oligosaccharide (a short-chain sugar) that is part of cetuximab. The presence of this antibody for alpha-gal has high sensitivity and specificity for predicting an allergic reaction to cetuximab.

But alpha-gal is also part of a tick known as the Lonestar tick (amblyomma americamum) which is widely present throughout southern Appalachia and the areas we have described. What clinched this issue was a study conducted at Johnson City Medical Center in Northeast Tennessee—this is actually northern Appalachia. The study looked at 71 cancer patients who were treated with cetuximab. In contrast to all the other studies done in that region, they found a rate of hypersensitivity reactions of 8.5% overall and of grade 3-4 reactions of 1.4%, consistent with the rest of the U.S. and the world. There are no Lonestar ticks in that part of Tennessee.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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