Safety and Efficacy of the mTOR Inhibitor Everolimus as Early Interventional Replacement for Calcineurin Inhibitors In Graft-Versus-Host Disease (GvHD) Prophylaxis After Allogeneic Stem Cell Transplantation

The medical backbone of GvHD prophylaxis has been considered the use of a calcineurin inhibitor (CNI) like cyclosporine or tacrolimus in combination with methotrexate (MTX) or mycophenolate mofetil (MMF). The mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001, Certican®) is a novel immunosuppressive drug and beside sirolimus approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with CNI showed promising clinical effectiveness in innovative prevention strategies of acute GvHD after allogeneic stem cell transplantation (SCT). In this single centre retrospective analysis, we report the outcome on patients (pts), treated interventional with everolimus due to severe toxicity induced by CNI-based GvHD prophylaxis.

Ten pts (3 acute myeloid leukaemias, 1 myelodysplastic syndrome, 1 acute lymphoblastic leukaemia, 4 Non-Hodgkin-lymphomas) underwent allogeneic blood SCT between 7/2007 and 3/2010. The median age was 51 years [range: 24–64] with 6 pts in advanced stages of their disease. Myeloablative conditioning was used in 3 pts (12 G TBI/120mg/kg cyclophosphamide (cyclo)] and reduced-intensity conditioning in 7 pts [5× treosulfan/fludarabine (flu), 1× busulfan/flu and 1× amsacrine/cytarabine/flu followed by 4 G TBI/cyclo]. HLA-matched family donors in 4 pts and unrelated donors in 6 pts donated on day 0 a median of 4.73 × 10⁶ kg per bodyweight CD-34 positive stem cells. GvHD-prophylaxis consisted of standard CNI+MTX in 3 pts, CNI+MMF in 6 pts and CNI+MMF+MTX in 1 patient. Antithymocyte globulin as in vivo T-cell depletion was given in 7 pts as part of the reduced intensity conditioning regime.

Everolimus (0.75 mg Certican ® twice a day orally) was individual started after a median of 14 days [range: 6–16] after SCT. Primary reasons for stopping CNI (median day +10 [range 1–15]) were nephrotoxicity (CTC ≥ grade 3) in 7 pts and neurotoxicity (CTC ≥ grade 3) in 3 pts. Two pts received steroids in addition to everolimus temporally, 5 pts MMF and 3 pts steroids+MMF. The intended plasma therapeutic level of everolimus was 3–8 mg/l. All patients showed neutrophil engraftment on median day +18 [range: 8–20] and platelet engraftment on day +21 [range: 10–88]. Acute GvHD ≥ grade II (Glucksberg/Consensus NHI) occurred in 3pts (30%) (2× grade II, 1× grade III) or IBMTR-Index-Score ≥ B (2×B, 1×C). Chronic GvHD limited disease score grade I (Consensus NIH) was observed in 3 pts (n=1 overlap syndrome and n=2 de-novo cGvHD). Two out of 7 high risk pts for CMV reactivation developed viral activation. Until day +100 3 pts stopped interventional GvHD prophylaxis due to oral bleeding on day +46 (n=1) and assumed TMA on day +57/+64 (n=2). The period of everolimus administration was 140 days on average [range: 19–509]. As per August 2010 6 pts are alive resulting in a median cumulative overall survival of 58%. ALL-relapse had to be observed on day +312 in one patient. Fatal casualties occurred on day +19 by multiorgan failure (MOD), on day +103 by pneumonia, on day +211 by questionable pulmonary embolism and on day+ 411 by MOD and limited cGvHD.

A delayed CNI-free GvHD-prevention strategy with the m-TOR inhibitor everolimus is feasible and efficacious in a series of patients after allogeneic SCT. The manageable toxicity profile in our cohort with pre-existing organ dysfunction at treatment onset mandates further evaluation of everolimus after SCT. A prospective multicentre phase II trial of everolimus as intended early replacement for CNI after SCT with a focus on tolerability is scheduled to start soon.

Sayer: Novartis Pharma: Honoraria, Research Funding. Off Label Use: Everolimus -Certican (R)- is only approved as a immunosuppressive drug in solid organ transplantation. Hochhaus: Novartis: Consultancy, Research Funding.