Safety and Efficacy of the mTOR Inhibitor Everolimus As Early Interventional Replacement for Calcineurin Inhibitors (CNI) in Graft-Versus-Host Disease (GVHD) Prophylaxis After Allogeneic Stem Cell Transplantation

ORLANDO, Fla.The use of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is feasible and efficacious for the prevention of graft-versus-host disease (GVHD) in a series of patients after allogeneic stem cell transplantation (SCT).

The use of CNI agents like cyclosporine (CSA) or tacrolimus in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) has been the standard prophylaxis regimen for GVHD. Everolimus is a novel immunosuppressive drug that inhibits mTOR. The use of mTOR inhibitors in combination with CNI has recently been reported to have clinical efficacy in the prevention of acute GVHD after allogeneic SCT. Everolimus as a replacement for CNI in GVHD prophylaxis after allogeneic SCT was studied by Herbert G. Sayer, MD, and colleagues at University Hospital in Jena, Germany. Findings from this study were presented during the 52nd American Society of Hematology Meeting and Exposition.

This study was a single-center, retrospective analysis of patients treated with everolimus due to severe toxicity induced by CNI-based GVHD prophylaxis. A total of 10 patients (3 acute myeloid leukemias [AML], 1 myelodysplastic syndrome [MDS], 1 acute lymphoblastic leukemia [ALL], 4 non-Hodgkin's lymphoma [NHL]) with a median age of 51 years (range, 24-64) who underwent allogeneic blood SCT were enrolled. Myeloablative conditioning was used in 3 patients, and reduced-intensity conditioning was used in 7 patients. Four patients had HLA-matched family donors and 6 patients had unrelated donors. Prophylaxis for GVHD consisted of the following: standard CSA+MTX (3 patients), CSA+MMF (6 patients), and CNI+MMF+MTX (1 patient).

After a median of 14 days following SCT (range, 6-16), everolimus 0.75 mg twice daily orally was given as an interventional treatment to replace the CNI. Reasons for stopping CNI primarily included nephrotoxicity (CTC ≥ grade 3) in 7 patients and neurotoxicity (CTC ≥ grade 3) in 3 patients. In addition to interventional treatment with everolimus, 2 patients received steroids, 5 patients received MMF, and 3 patients received steroids+MMF. All patients showed neutrophil engraftment on median day +18 (range, 8-20) and platelet engraftment on day +21 (range, 10-88). Three patients experienced acute GVHD ≥ grade II (Glucksberg/Consensus NIH). An additional 3 patients experienced chronic GVHD (grade I; Consensus NIH). Seven patients were considered high risk for CMV reactivation, of which 2 patients experienced activation of the virus.

The average time period for everolimus treatment was 140 days (range, 19-509). As per November 2010, 6 patients are alive, resulting in a cumulative overall survival of 60%. One patient experienced AML-relapse on day +312. Causes of death in 4 patients were as follows: multiorgan failure (MOD) (day +19), pneumonia (day +103), questionable pulmonary embolism (day +211), and MOD and limited chronic GVHD (day +411).

The use of everolimus in GVHD prophylaxis after allogeneic SCT is efficacious with a manageable toxicity profile. However, further evaluation of everolimus after SCT is warranted. A prospective, multicenter, phase 2 trial to evaluate the safety and efficacy of everolimus for early replacement of CNI after SCT is currently being developed and is scheduled to start soon.

Off Label Use: Everolimus is only approved as a immunosuppressive drug in solid organ transplantation.