A prospective single-center study on CNI-free GVHD prophylaxis with everolimus plus mycophenolate mofetil in allogeneic HCT

Abstract

We report a single-center phase I/II trial exploring the combination of everolimus (EVE) and mycophenolate mofetil (MMF) as calcineurin inhibitor (CNI)-free GVHD prophylaxis for 24 patients with hematologic malignancies and indication for allogeneic HCT after a high dose or reduced-intensity ablative conditioning. The study was registered as EudraCT-2007-001892-12 and Clinicaltrials.gov as NCT00856505. All patients received PBSC grafts and no graft failure occurred. 7/24 patients (29%) developed acute grades III and IV GVHD (aGVHD), 16/19 evaluable patients (84%) developed chronic GVHD (cGVHD) of all grades, and 6/19 (31.6%) of higher grades. No severe toxicities related to study medication were observed. The median follow-up of all surviving patients is 2177 days. The 3-year OS was 45.2% (95% CI: 27.4–61.4%), and the 3-year PFS was 38.7% (95% CI: 22.0–55.1%). The cumulative incidence of relapse at 1 year and 3 year was 25% (95% CI: 12.5–50.0%), and 33.3% (95% CI: 18.9–58.7%), the cumulative incidence of NRM at 1 year and 3 years was 20.8% (95%CI: 9.6–45.5%), and 29.2% (95%CI: 15.6–54.4%), respectively. The utilization of CNI-free GVHD prophylaxis with EVE+MMF resulted in high rates of acute and chronic GVHD. Therefore, we do not recommend a CNI-free combination of mTOR inhibitor EVE with MMF as the sole GVHD prophylaxis. In subsequent studies, this combination should be modified, e.g., with further components like post-transplant cyclophosphamide (PTCy) or anti-thymocyte globulin (ATG).

Everolimus and mycophenolate mofetil effectively prevent GvHD in children with severe acute kidney injury undergoing allogeneic HSCT

“…A single-center phase I/II trial investigated the combination of everolimus and MMF as calcineurin inhibitor-free GVHD prophylaxis for 24 patients with hematologic malignancies and resulted in high rates of acute and chronic GHVD rates. 34 The main difference to this study is that our patients converted from CNI-treatment to everolimus only after a median time of 22 days after HSCT. Only two patients received exclusively everolimus/MMF.…”

“…39 In contrast to these results, Schaefer et al showed a protracted overall, regulatory and naïve CD4 + T cell reconstitution of adult patients that received everolimus/MMF after HSCT in a prospective single-center study compared with historical CNI-receiving controls. 34 Furthermore, a beneficial effect could be explained by the direct anti-tumor efficacy of everolimus. 40,41 The phosphatidylinositol-3-kinase (PI3K)/Akt and the mTOR signaling pathway, are hyperactivated in 50-80 % of AML patients 42 and mTOR inhibition might be a possible therapeutic target.…”