March 13, 2008 — Members of a study team led by Dr. Thomas Platts-Mills of the University of Virginia Health System knew they had a medical mystery on their hands.
When treated with the widely-used cancer drug, cetuximab, patients in several states — mostly in the Southeast — were experiencing allergic reactions more frequently and more severely than those living elsewhere. Reactions typically occurred during initial treatment and sometimes included anaphylaxis, a life-threatening condition characterized by a rapid drop in blood pressure, fainting, difficulty breathing and wheezing.
Previous research had shown that 22 percent of patients in Tennessee and North Carolina had severe allergic reactions to the drug. Even higher reaction rates and clusters of cases had been reported in Arkansas, Missouri and Virginia. This data contrasted sharply with the drug's label, which states that 3 percent of patients experienced severe allergic reactions, as well as with results in the Northeast, where less than 1 percent of patients receiving cetuximab had allergic reactions.
"There seemed to be a link between geographic location and allergic response, and we wanted to know why," said Platts-Mills, a U.Va. professor of medicine, allergy and clinical immunology. The team's findings, published in the March 13 edition of the New England Journal of Medicine, offer a key clue to solving this mystery.
The study found that most patients who proved severely hypersensitive to cetuximab had certain IgE antibodies in their blood serum before being treated. Those antibodies attack a type of sugar molecule (galactose--1,3-galactose) found in cetuximab. Researchers now believe these antibodies cause patients' allergic reactions to the drug.
Antibodies are proteins produced by the immune system to identify and combat invading organisms such as bacteria and viruses. IgE is the key antibody unleashed during allergic reactions. Every individual has different IgE antibodies and produces a specific IgE for each foreign substance detected.
Although study data did not explain why patients in certain geographic areas develop IgE antibodies against galactose--1,3-galactose, researchers suggest the cause may lie in different regional exposures. Exposures may include infections caused by fungi, microscopic parasites, tick bites and tapeworms.
The study analyzed blood serum samples from 76 patients who had been treated with cetuximab at multiple centers, predominantly in Tennessee, Arkansas and North Carolina. Twenty-five (33 percent) of these patients had an allergic reaction to the drug. Assessment of pretreatment serum samples showed that 17 of the patients who had allergic reactions had antibodies against cetuximab; only one of the 51 patients who did not have an allergic reaction had the antibodies.
The control group for the study included 72 subjects in Tennessee, 49 in northern California and 341 in Boston. IgE antibodies against cetuximab were found in 20.8 percent of the Tennessee control group, 6.1 percent of the northern California control group and 0.6 percent of the Boston control group.
"Our findings indicate it may be useful to pre-screen patients to determine if they have specific IgE antibodies to cetuximab and, therefore, are at risk for serious adverse reactions. Over the long term, our findings could help medical researchers and drug developers understand the allergic reactions and risks associated with other antibody-based therapeutics," Platts-Mills said.
Cetuximab is given by intravenous injection for treatment of metastatic colorectal cancer and squamous-cell carcinoma of the head and neck. It belongs to a class of drugs known as recombinant monoclonal antibodies, immune-based therapies prescribed for cancers, inflammatory bowel disease, rheumatoid arthritis and asthma. Approved by the FDA in 2004, cetuximab works by slowing or stopping the growth of cancer cells.