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Reuters Health Information (2012-02-10): In small pilot study, some pediatric liver recipients come off immunosuppression

Drug & Device Development

In small pilot study, some pediatric liver recipients come off immunosuppression

Last Updated: 2012-02-10 17:55:24 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Immunosuppressant drugs can be safely withdrawn for a "surprising" percentage of pediatric liver recipients whose grafts came from a parent, according to a report January 18th in the Journal of the American Medical Association.

In a small pilot study, the authors of the report tested a protocol for weaning the children from their immunosuppressant medications.

Twelve of 20 healthy young patients (60%) maintained normal allograft function for at least one year without immunosuppression, Dr. Sandy Feng of the University of California, San Francisco and her colleagues found.

At follow-up, these patients had been off immunosuppressant drugs while sustaining normal liver function for a median of 35.7 months (interquartile range 28.1 to 39.7 months).

Biopsies performed more than two years after immunosuppression withdrawal in the tolerant patients demonstrated normal allograft histology. Among the nontolerant patients, liver function returned quickly to normal after immunosuppression was reinitiated.

"These outcomes demonstrate that immunosuppression withdrawal in this clinical trial setting appears to be feasible for both tolerant and nontolerant patients," Dr. Feng and her colleagues write.

"The 60% is really quite intriguing and exciting and needs to be explored further in a larger study," Dr. Feng told Reuters Health. "We don't want to be cavalier about these findings and suggest that this is ready for everyone to do on their own."

There have been isolated reports of children and adults either stopping medication on their own or needing to come off the medication due to serious illness, Dr. Feng said, but these findings are clearly not generalizable to well transplant patients.

In Japan, she added, where deceased donor transplants are infrequently done, approximately 15% of children were successfully weaned off of immunosuppression after living donor transplants, but this experience did not include systematic biopsies to assess the graft before and after withdrawing immunosuppression.

In the current study, Dr. Feng and her team investigated the feasibility of withdrawing immunosuppression in 20 stable patients, who were a median age of 6.9 months when they underwent a parental living donor transplant, in most cases due to biliary atresia. The patients' median age at study enrollment was 8 years, 6 months. All had stable allograft function, and were on a single immunosuppressant drug (13 were on tacrolimus, and 7 were taking cyclosporine).

The investigators gradually withdrew the immunosuppressant medication over at least 36 weeks. Patients in the study underwent liver function tests every two weeks and had clinic visits every three months as immunosuppression was withdrawn. If allograft function remained normal, they had monthly liver function tests and twice-yearly clinic visits for another two years, and then liver tests every two months and annual clinic visits for two more years.

Children had biopsies at study entry, at four to eight weeks, and at four years after their last dose of immunosuppressant medication, unless they did not meet the primary endpoint of normal liver function for one year after withdrawal of immunosuppression.

While 12 patients met the study's primary endpoint, eight patients did not because they developed indeterminate rejection (5 patients); acute rejection (2 patients); and violation of exclusion criteria (1 patient). The median time to not meeting the primary end point was 5.68 months after withdrawal of immunosuppressant medication had been initiated.

Time after transplantation was the most important factor in whether or not a patient was operationally tolerant, the authors said; it was a median of 100.6 months for the patients who met the primary end point, and 73.0 months for those who did not (p=.03). These patients also had less portal inflammation and lower total C4d scores on liver biopsy.

"The keys are incredibly close monitoring and follow-up," Dr. Feng said in an interview. "We feel that close monitoring is absolutely essential to minimize the downsides of developing rejection as a result of the immunosuppressant withdrawal."

In comments to Reuters Health, Dr. Charles Miller, a liver transplant surgeon at the Cleveland Clinic in Ohio who was not involved in Dr. Feng's study, said transplant doctors have been trying for years to wean patients off immunosuppression.

Dr. Feng said she and her colleagues are now planning a larger study that will investigate immunosuppression withdrawal in patients with deceased donors. They are also hoping to find a biomarker for early identification of patients that will do well after immunosuppression is withdrawn.

In the meantime, Dr. Miller said, "There's no good test for tolerance. It's a little bit like, 'We'll stop the drugs and see what happens.'"


JAMA 2012;307:283-293.

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