Withdrawal from sirolimus may be feasible in liver transplant recipients

WASHINGTON — About half of patients who underwent liver transplantation were successfully weaned from m-TOR inhibitor therapy, showing that withdrawal is possible in this patient population, according to findings presented at The Liver Meeting 2017.

“We’ve decided to look at m-TOR inhibitors because most of the trials, or nearly all of them, of calcineurin inhibitors, which are known in the laboratory and in some clinical trials to be anti-tolerogenic, and have negative effect on regulatory T-cells and other tolerance mechanisms,” Josh Levitsky, MD, of Northwestern University in Chicago, said. “The idea behind our study using m-TOR inhibitors as a pathway to tolerance is that m-TOR inhibitors have been shown to have pro-regulatory tolerogenic effects which may lead to a better result when you try to withdraw therapy.”

Levitsky aimed to determine genetic factors that predict successful conversion from calcineurin inhibitors (CNI) to sirolimus (Rapamune, Pfizer) in patients who have undergone liver transplantation can also predict sirolimus withdrawal success.

The initial cohort in the prospective trial included 21 non-immune, non-viremic patients more than 3 years after transplantation. Weaning from sirolimus occurred over the course of about 6 months, with biopsies performed either at 12 months after weaning or in cases of attributable risk. The final analysis included 15 patients who met eligibility criteria, of whom eight met operational tolerance.

“There are very few biomarkers in control groups in these trials that have been shown to predict tolerance,” Levitsky said.

Mild adverse reactions near the end of weaning was reported in three of the non-tolerant patients, three more had mild attributable risk at the final biopsy, while one experienced a cancer recurrence.

Patients in the tolerant and non-tolerant groups were not different regarding age, time on sirolimus monotherapy, or time from transplantation to weaning, according to Levitsky.

Baseline data indicated that patients in the tolerant group had statistically higher tolerogenic dendritic cell and regulatory B cell percentages than their non-tolerant counterparts. “We did not find any difference between baseline CD4, CD8, memory B cells, naive B cells, memory CKT cells,” Levitsky said.

Gene expression analysis indicated that 153 probe sets in the blood distinguished the tolerant and non-tolerant groups at baseline. “This was at a high prediction,” Levitsky said.

This 153-gene signature carried an 82% sensitivity and a 100% specificity in predicting tolerance at end of study (AUC = 0.88). Additionally, 93 completely different probe sets in biopsy also distinguished the two arms at baseline.

A biopsy gene signature that was previously identified accurately predicted tolerance in 12 of 14 patients who underwent transplantation. The researchers in the current study used this as a validation.

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“In this pilot study, we were able to withdraw more than 50% of select liver transplant recipients,” Levitsky said. “We have blood and biopsy gene expression that might be used in monitoring long-term tolerance.” —by Rob Volansky

Reference:

Levitsky J, et al. Abstract 6. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Levitsky reports acting as a consultant for Transplant Genomics Incorporated; speaking and teaching for Novartis, Salix and Gilead; and receiving grant or research support from Novartis.