mTOR-Inhibitor-Attributed Events: Review of 2-Year Safety Data in Heart Transplant Recipients Receiving Everolimus Vs MMF in the Randomised Multi-Centre 2310 Study

Introduction: Everolimus (EVR), an mTOR inhibitor, allows reduction in cyclosporine exposure without affecting the efficacy in heart transplant recipients (HTxR). However, the use of mTOR inhibitors (sirolimus and EVR) is associated with complications comprising wound healing events, proteinuria and hyperlipidaemia and data beyond 12 months (M) of treatment is sparse. Methods: A2310 (NCT00300274) is a 24M, phase III, multi-centre, open-label study in 721 HTxR, randomised (1:1:1) to receive either EVR 1.5mg or 3mg/day (C0 3-8 or 6-12ng/mL) + reduced dose cyclosporine or mycophenolate mofetil (MMF) 3mg/day + standard CsA. All patients received steroids. Induction therapy was centre specific (basiliximab/thymoglobulin/no induction). The enrolment in EVR 3mg arm was prematurely terminated due to higher rate of mortality. At 24M, assessment of incidence of adverse events (AEs) was performed. Considering the safety profile of EVR at 12M, here we present comparison with 24M results on selected AEs of interest for mTOR inhibitors. Results: As expected, incidences of AEs were higher with EVR 1.5mg arm compared to MMF at 24M (table). The difference in incidence of events between EVR 1.5mg and MMF was < 10% except for pericardial effusions and hyperlipidaemia at M24. No patient in either group reported new occurrence of proteinuria after M12. Between M12 to M24, pleural and pericardial effusion was reported in few new patients in either arm, while new occurrence of hyperlipidaemia was more frequent with EVR 1.5mg arm and peripheral oedema with MMF arm. In the 24M analysis, neutropenia (≤1×109/L) was more frequent with MMF (EVR 1.5mg 2.5% vs MMF 7.9%). Incidences of any infection were similar in both the treatment arms (EVR 1.5mg 70% vs MMF 67%); bacterial infections were more frequent with EVR arm (31% vs 25% in MMF) and viral infections were twice more frequent with MMF (15% in EVR vs 32%).Conclusion: The overall pattern of AEs was consistent with the known safety profile of EVR and MMF with majority of mTOR inhibitor associated AEs occurring during the first year of treatment with EVR.