Duke/UF researchers compare antirejection medicines in lung transplant patients
GAINESVILLE, Fla.—One of the latest drugs designed to keep the body’s immune system from attacking a life-saving organ transplant works no better than a 40-year-old mainstay in warding off short-lived bouts of rejection in lung transplant recipients, report researchers from Duke University and the University of Florida Shands Transplant Center.
The findings, published recently in the journal Transplantation, could have major cost implications for these patients, who each year pay thousands of dollars for the antirejection medicines aimed at keeping them alive. That’s because the old standby, azathioprine — known by the trade name Imuran – costs about one-fourth the amount of the newer drug, mycophenolate mofetil, which averages $300 a month for a standard supply.
The results, from one of the largest prospective trials in lung transplant patients to date, also contrast sharply with previous reports of mycophenolate mofetil’s success in curtailing rejection in kidney transplant patients. Doctors say their study points to the need for the development of highly specialized treatments for each type of organ transplant.
“This just highlights for us the need to look for new drugs and to conduct new clinical trials to see if we can decrease the amount of acute rejection lung transplant patients experience,” said transplant pulmonologist Dr. Maher A. Baz, an assistant professor of medicine at UF’s College of Medicine.
Last year, 956 patients received a lung transplant, according to the United Network for Organ Sharing. More than two-thirds of all patients battle temporary periods of rejection in the first hundred days after lung transplantation, Baz said. These spells usually persist for a few days and resolve when doctors administer increased doses of medication. Recurrent episodes, however, raise the risk of chronic rejection, a condition that occurs in about half of all recipients within five years after surgery. Patients stop responding to the drugs and lung function slowly declines, leading to death from respiratory failure.
“For a long time, we’ve had very limited options for immunosuppression for all solid organ transplant recipients,” said Dr. Scott M. Palmer, medical director of Duke’s lung transplant program. “In the past few years, we’ve seen a number of new drugs approved. Lung transplantation is an area where there’s been little industry interest in primary drug trials because the number of lung transplant recipients is relatively small compared with the number of kidney transplants, so most new drugs that are developed are initially studied in kidney transplant patients.
“But we’re finding that what’s true in one solid organ does not necessarily hold true in other solid organs,” he added. “Our goal has been to do trials in lung transplant patients that help guide us so we can make evidence-based decisions about which agent or combination of agents are best in our population of patients.”
In May 1995, the Food and Drug Administration approved mycophenolate mofetil, also known as Cellcept, for the prevention of rejection associated with kidney transplantation after studies showed it decreased the incidence of acute rejection from approximately 40 percent to 25 percent in the first six months after surgery; since that time it has become standard treatment for these patients. In recent years, researchers began testing the drug in heart and lung transplant recipients. Mycophenolate mofetil and azathioprine both interfere with white blood cells’ ability to multiply, but act in slightly different ways. These cells are the immune system’s first line of defense against foreign invaders and, likewise, cause organ rejection.
UF and Duke researchers randomly assigned 81 lung transplant patients to receive either the standard medication azathioprine or the newer drug mycophenolate mofetil as part of their medication regimen. Doctors found the drugs were comparable in their ability to hold acute rejection at bay.
“In the next year we’ll know whether there’s any significant difference between the two drugs and the incidence of chronic lung rejection three years after transplantation,” Baz said. “That’s the main question that’s still unanswered.”
Dr. Sangeeta Bhorade, a pulmonologist at Loyola University’s Stritch School of Medicine, welcomed the findings, saying too few controlled trials have been conducted in lung transplantation, limiting clinicians’ ability to determine optimal therapy for lung transplant recipients. Bhorade said there could be several reasons why mycophenolate mofetil did not reduce acute rejection rates, as has been reported in kidney transplantation.
Most clinicians agree that the immune system is more likely to recognize the lungs as foreign than other organ systems in the body, and lung transplants are associated with higher acute rejection rates than any other organ transplant, Bhorade said. In fact, in the first six months after surgery, only 15 percent to 20 percent of kidney recipients experience an episode of rejection, compared with 60 to 70 percent of lung transplant patients.
“Therefore, higher levels of immunosuppression and/or different types of immunosuppression may be more beneficial in lung transplantation,” she said.
Researchers also did not monitor how well patients metabolized the drugs, Bhorade said. Some, such as those with cystic fibrosis, may not have absorbed mycophenolate mofetil as well as others, affecting the results. In addition, the study may have had too few patients to pick up on small but important differences in rejection rates, she said.
Meanwhile, UF and Duke physicians plan to continue using azathioprine as the standard treatment for lung transplant recipients, although the newer drug is given to patients who cannot tolerate azathioprine because of side effects.
“In this era of cost-effective and evidence-based medicine, we really need long-term, compelling data that show a therapy is going to improve long-term survival or reduce chronic rejection and side effects for us to change practice,” Palmer said.