Endeavors magazine: A Mysterious Allergy Afflicts the South

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A Mysterious Allergy Afflicts the South

by Sheila Read

[filed under: health & medicine; article date: january 2008]

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When Bert O’Neil began giving Erbitux to colon-cancer patients in clinical trials, he had no reason to be wary. After all, the drug had already been tested and was FDA-approved for use in colon cancer.

But at Carolina’s Lineberger Comprehensive Cancer Center, the first three patients who received the drug had potentially life-threatening allergic reactions. They collapsed to the floor, O’Neil says. “They had lost their blood pressure; they had become hypotensive.” He didn’t realize it at the time, but these patients’ reactions were O’Neil’s first clue to a baffling regional pattern of hypersensitivity to Erbitux.

The medical team quickly gave the patients epinephrine and high doses of steroids to help their blood pressure return to normal. The patients had to stay in the hospital’s intensive care unit for a day, just in case they had another reaction.

What had happened to the patients was an anaphylactic reaction, similar to what happens when a bee stings someone who’s allergic to bee venom. Anaphylaxis, which is sometimes fatal, is a type of allergic reaction. Symptoms may include itching, hives, swelling throat, shortness of breath, or a drop in blood pressure.

O’Neil, a medical oncologist who runs clinical trials for the gastrointestinal cancers group at Lineberger, was surprised. In large studies both in the United States and in Europe, the rate of serious allergic reactions to Erbitux was quoted at two to three percent, he says.

At first, O’Neil and his team thought they had gotten a bad batch of Erbitux. But when Bristol-Myers Squibb sent staff to investigate, they found that the doses had come from different batches.

“At that point,” O’Neil says, “we decided to carefully move forward and hope it was just a fluke that we had these three patients in a row.” For a while, the team didn’t see any more anaphylactic reactions in patients.

Then the reactions began again.

“It was obvious there was something strange going on that had nothing to do with the way we were doing things,” O’Neil says.

O’Neil’s team created guidelines for dealing with potential reactions. Rule number one was that an advanced care practitioner always had to be present when an Erbitux infusion began, so the team could immediately administer epinephrine and steroids if the patient had an allergic reaction.

The story got stranger as O’Neil talked to more oncologists. He heard that a colleague in Nashville, Tennessee, was finding the same problem. But when O’Neil spoke to oncologists from other areas of the country, they didn’t know what he was talking about. A prominent colorectal oncologist in New York “thought we were lying or crazy,” O’Neil recalls.

Erbitux, also known by its generic name cetuximab, is used in conjunction with chemotherapy and is useful in shrinking tumors, O’Neil says. Erbitux is a genetically engineered version of an antibody that combines mouse and human components. The Erbitux antibody works by sticking to the outside of a molecule called the epidermal growth factor receptor, and blocking it from functioning. This causes some cancer cells to die because the growth factor receptor can no longer transmit signals from outside the cancer cell telling the cell to grow.

Eventually O’Neil and his colleagues decided to pursue a study to confirm his suspicion: that patients in North Carolina and Tennessee were experiencing abnormal hypersensitivity to Erbitux. Carolina researchers pooled data from patients treated here with Erbitux with data from patients in clinical trials at Vanderbilt’s Ingram Comprehensive Cancer Center and the Sarah Cannon Cancer Research Institute, both in Tennessee.

The findings showed an “alarming frequency” of hypersensitivity to Erbitux at the three sites, according to a study published in the September 2007 issue of the Journal of Clinical Oncology. Of the 88 patients treated as part of trials in North Carolina and Tennessee, 22 percent experienced a serious hypersensitive reaction. In a European clinical trial, only 1.2 percent of 329 patients experienced a serious hypersensitive reaction to Erbitux.

The mystery remains as to why patients are more prone to allergic reactions to Erbitux in the middle South. (O’Neil says he’s heard of hypersensitive reactions to Erbitux in Arkansas.) Among the speculations are that the reaction is caused by an antibody that people in the region have developed after exposure to a certain kind of mouse, plant, or tree pollen.

“The idea is that, by coincidence, they’re allergic to something, and the antibody that’s created as part of that allergic reaction happens to also stick to Erbitux,” O’Neil says. “Antibodies are very specific in what they stick to, so that’s a fairly unusual kind of problem.”

The study also showed that a history of allergies can partially predict whether a person might have a reaction to Erbitux. “The chance of having an allergic reaction was about three times as high in the people who already had some other kind of allergies,” O’Neil says.

Although the allergic reactions can usually be countered with drugs, they can still be fatal. One patient died of a reaction at Sarah Cannon Cancer Research Institute. Later, Sarah Cannon discontinued all clinical trials of Erbitux.

Lineberger, though, is pressing forward with studies of Erbitux. Carolina had committed to clinical trials of the drug to determine if it’s effective in treating other types of cancer, including breast cancer and lung cancer.

Despite the high incidence of serious reactions to Erbitux in the region, O’Neil believes the drug has a place in cancer treatment. “We’re treating people here who have terminal colon cancer, and most of them have no other treatment option,” he says. “That’s the thing you have to weigh. Yes, there’s that risk, but on the other hand, most of these patients getting this drug are in a bad situation.”

Meanwhile, researchers have moved one step closer to solving the mystery. Thomas Platts-Mills, an allergist at the University of Virginia, collected serum samples from healthy volunteers in Tennessee and found the antibody that appears to cause the reaction to Erbitux, O’Neil says. Platts-Mills discovered that the antibody was almost always present in people who reacted to Erbitux and was not present in those who did not react to the drug.

Next, researchers will attempt to develop a clinical test to screen for people who have the antibody. Scientists at Carolina plan to collaborate with Platts-Mills and colleagues in Tennessee to determine whether such testing is accurate enough to be used in the clinic. Such a test could eventually be used in the middle South to guide treatment decisions, O’Neil says. Still, the main puzzle remains — just what is the allergen to which people are developing antibodies?

Sheila Read is a master’s student in medical journalism at Carolina.