Malignancies and Pediatric Liver Transplantation: Promising Management with the mTOR-inhibitor Everolimus

Abstract

Some malignancies such as hepatoblastoma may be an indication for liver transplantation (LT) or some, for example, post-transplant lymphoproliferative disease (PTLD) may develop after successful LT. An immunosuppressive therapy after LT can promote the recurrence of the primary malignancy. The mammalian target-of-rapamycin inhibitors (mTORi) are immunosuppressive agents with anti-tumor properties. We examined the impact of everolimus (EVL) together with calcineurin inhibitors on allograft outcome and patient survival in pediatric LT (PLT) with various tumors. This retrospective study included eleven liver-transplanted pediatric patients who received EVL after LT. The reason for adding an mTOR inhibitor was the neoplastic disease, either leading to LT (n = 7) or PTLD that developed after LT under immunosuppression (n = 3). The median age at the start of therapy was four years (range: seven months- 18 years); the median follow-up was 3 (range: 1 – 5) years). The primary endpoints were recurrence or metastasis of the primary tumor, uncontrolled PTLD, or death. Graft function and potential side effects were documented. Both patient survival and graft survival rates for the observation period were 100%. No patient developed recurrence or reported metastatic disease of the primary tumor. Liver function test results remained normal during the study period in 8 out of 11 patients. Three patients developed elevated liver enzymes that resolved over time. All the patients received EVL either as monotherapy (n = 2) or in combination with cyclosporine A (n = 7) or tacrolimus (n = 2). Typical side effects documented were recurrent infections (n = 8), stomatitis (n = 5), and cytopenia (n = 2), and medication was temporarily interrupted in one patient. Although the patient cohort was small, our results support the use of EVL in patients with tumor occurrence in the context of pediatric LT. No cases of recurrence or metastases were reported during the follow-up period after LT; sufficient immunosuppression was maintained. The side effect profile appeared acceptable. A longer follow-up in more number of patients is necessary to confirm these preliminary data.