Some of the equipment required for Desferal infusion.
Karim is smiling because the night-long Desferal treatments are now a thing of the past, thanks to Exjade.
Children’s clinical trials confirm a pain-free, non-invasive way to combat iron overload in kids with genetic blood disorders.
Iron overload happens rarely in humans, so the body is ill-equipped to remedy it. In fact, not too much but too little iron, anemia, is a worldwide health problem, especially among women. That is why the body has evolved a system to prevent eliminating too much iron, maintaining a healthy balance.
But there are cases when this balance is upset, leading to potentially lethal consequences. For example, treating some genetic blood disorders, such as thalassemia and sickle cell anemia, requires regular blood transfusions. If patients receive blood regularly, they can live relatively normal lives. Here’s the rub: every drop of blood contains 1 mg of iron. Regular blood transfusions mean regular flow of iron, which the body has no way of releasing. The result is iron overload.
“What happens is these milligrams of iron get stored in the organs and then, like a bumper on a car, the organs get rusted,” explains Elliott Vichinsky, MD, chief of the Hematology/ Oncology division at Children’s Hospital & Research Center Oakland. “Iron oxidizes, or basically rusts the membranes or tissues in the body, destroying them. Just what you’ve seen happen on a bumper of a car is what happens internally. Eventually they destroy the pancreas, the patient gets diabetes, or it destroys the hormone-making organs that guide gonadal functions, and eventually they destroy the heart and the patient dies of heart disease. So a great deal of effort has gone into figuring out ways to get rid of the iron.”
Desferal to the rescue
The first breakthrough came in the 1970s with the approval of the iron chelator desferrioxamine, marketed as Desferal. Desferal is very successful at removing iron from the blood and organs. However, it has two major drawbacks. First, it’s a big molecule and can’t be swallowed and absorbed. Second, if you inject it as a shot, 99 percent of it is excreted unused. Therefore, to be effective, Desferal must be administered by infusion, or the pumping of a constant stream of the chelator into the blood, so it can circulate and stay active. The process takes 12 hours daily.
Starting in 1978, there has been a dramatic change in survival rates of thalassemia and sickle cell patients because of this treatment. Patients are now living fully into their 40s and 50s, something unheard of before Desferal. But some young patients are still dying of heart failure from iron overload because the treatment is so odious that compliance can be low.
Clearly, something else was needed, something simpler to use, less invasive.
“The Holy Grail for these patients is an oral chelator,” Dr. Vichinsky says.
Cut to 2003, when Children’s Hospital became host to phase 2 trials of the oral iron chelator deferasirox (aka ICL670), commercially known as Exjade. Exjade, made by Novartis, is a pill that dissolves in water and, when ingested, binds with iron and not with other essential elements such as copper and zinc. Its chalky flavor isn’t beloved by patients, but the alternative, 12-hour daily shifts on Desferal pumps, is even less popular. The question is: does it work as well?
Internationally, more than 1,000 patients participated in the largest study ever undertaken for an iron chelator. About 40 patients who had thalassemia or sickle cell were followed at Children’s in a series of phase 2 and, later, phase 3 clinical trials. One of them was Karim Zamani.
Karim, 21, has been coming to Children’s since he was 10 years old to be treated for thalassemia. (Sickle cell and thalassemia adults still receive care at Children’s because for generations these patients rarely survived to adulthood, and only pediatricians were trained to manage their conditions.) About five years ago, Karim began using Desferal.
“I wasn’t really that compliant,” he admits. “It’s hard at night, you’re already tired, on top of that you have to stay up an extra hour. In the morning you wake up, you’re swollen and hurt for a long time.”
When he was invited to join the Exjade study, he had to be compliant with Desferal for a year to compare the two treatments. Enduring that year meant many sleepless nights and discomfort, but Karim says it more than paid off.
“Trying Exjade was great, it was a life-changing experience,” he acknowledges. “All you have to do is take some pills. Takes two minutes max. It doesn’t taste good but taste doesn’t matter, it’s a hundred times better than poking yourself at night. Now they let us take it with orange juice.”
The groundbreaking treatment worked not only for Karim. In October 2005, Dr. Vichinsky, who was the lead investigator and first author on studies that compare Desferal (IV infusions) to Exjade (oral chelation), testified in front of the Food and Drug Administration panel empowered to approve Exjade for use. The medication was approved unanimously.