Rates of opportunistic infection have not increased
Surgeons at the University of Pittsburgh School of Medicine have reduced the number of anti-rejection pills that some lung transplant patients receive — and the patients seem to be tolerating the change well.
Standard treatment for lung transplant patients involves a three-drug combination given twice a day. The therapy is intended to ward off an immune system attack on the donor organ.
The new approach, however, focuses on pretreatment of the patient and the administration of as little immunosuppression as possible after transplantation. More specifically, the clinical protocol involves a one-time dose of a T-cell-depleting drug that is given just before transplantation. Following transplantation, patients are treated with just one anti-rejection drug, tacrolimus (Prograf), which is administered at reduced levels. Prednisone usually is continued after the transplant but at a negligible dose, 5 mg compared to 20 mg. Under the protocol, some lung transplant patients are taking just one anti-rejection pill daily and others just the one pill four or five times a week.
The results, so far, show that this has been a good approach, says Kenneth R. McCurry, MD, assistant professor of surgery at the school’s division of cardiothoracic surgery, and director of the University of Pittsburgh Medical Center’s Lung and Heart-Lung Transplantation Program. "Anecdotally, many of our patients have done extremely well and have a better quality of life than we would otherwise anticipate two-to-four months post-transplant. They are not taking high doses of prednisone and other types of agents that may impact their quality of life." He presented his results at the American Transplant Congress in Boston in May.
More than 80 patients have been treated under the protocol since June 2002. The first 38 patients were given anti-thymocyte globulin (rabbit) (Thymoglobulin) pre-transplant. The one-year survival for these patients is 87%. The other patients received alemtuzumab (CamPath), which appeared to deplete T cells more broadly and for a longer period of time.
Acute rejection episodes have been fewer in the alemtuzumab patients reported in the presentation compared to those who received anti-thymocyte globulin. Twenty-five of the 38 anti-thymocyte globulin patients had rejection episodes greater or equal to Grade 2, compared to two of the first 10 alemtuzumab-treated patients.
Since alemtuzumab significantly depletes T cells, the physicians were concerned that they may be trading a greater incidence of bacterial infections on standard triple immunosuppression for a greater incidence of opportunistic infections such as viral infections.
That did not happen, although the physicians made rigorous attempts to identify them. For example, there were no opportunistic infections or related complications in the patients treated with alemtuzumab; a small percentage of the anti-thymocyte globulin patients developed cytomegalovirus (8%), the bacterial infection Nocardia (8%), or post-transplant lymphoproliferative disorder (3%), rates that were comparable to patients treated conventionally.
"We have not seen any increased incidence in infection in these patients and certainly no increased incidence of opportunistic infections compared to [those] utilizing standard triple immunosuppression," McCurry says. They attribute these in part to using prophylactic agents to prevent infection for several months post-transplant.
One-year follow-up results are not yet available to compare survival between the anti-thymocyte globulin-treated and alemtuzumab-treated groups. However, the overall patient survival for anti-thymocyte globulin-treated patients is 84%, compared to 98% in the alemtuzumab-treated patients.
Good record with other transplants
Some physicians have been reluctant to change the drug therapy for lung transplant patients since these donor organ recipients have the greatest incidence of immunosuppression-related complications. "The most common cause of death in the first three years after transplantation is infectious-related complications," McCurry says.
Instead, the fact that lung transplant recipients are plagued by poorer outcomes in general following transplantation was one reason for trying the approach, he explains. "Five-year survival is about 45%-50% and has remained that for the past 10 years of more. I thought that by altering our strategy to utilize agents that were more specific to the cells that cause rejection and utilizing less of nonspecific immunosuppressants, perhaps the result could be improved outcomes and fewer complications."
McCurry, however, also has seen the approach used with positive outcomes in kidney, liver, and intestinal transplant patients. "By the time I had initiated this in our lung transplant population, there was already substantial experience at this institution utilizing the strategy in numerous organs below the diaphragm, with a good safety record and good evidence for control of alloimmune responses," he says. "It appeared to be safe and efficacious. And you could run patients on lower-maintenance immunosuppression."
There had been no experience with thoracic organs, including lung transplants, but the basic way the immune system responds against an allograft, via any organ — the kidney, the liver, the intestine, the lung, the heart — is really no different, he says. "We felt that based on the efficacy and safety data in our organs that this was a reasonable approach in our lung transplant recipients."
Ultimately, McCurry doesn’t think it is likely that patients using this approach are going to come off immunosuppressant medications altogether. Placing patients on lower doses of maintenance immunosuppression drugs may increase compliance, however, since patients will be taking fewer maintenance medications. "We hope we can decrease the morbidity associated with [the drugs] as well," he says.
The limitations of the approach have been that the study took place at a single center and that the results still are short term. "Our survival has been excellent, but we have yet to follow these patients for a long period of time to determine the impact of this on chronic rejection."
McCurry is interested in seeing the protocol tested in a large trial. "We have presented some of our preliminary work with the Campath population, and have received some interest from some other centers and colleagues. Certainly, a multicenter trail that would evaluate this in a prospective randomized fashion would provide stronger data," he says.
Surgeons at the University of Pittsburgh School of Medicine have reduced the number of anti-rejection pills that some lung transplant patients receive and the patients seem to be tolerating the change well.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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