Sirolimus and mycophenolate mofetil as GVHD prophylaxis in myeloablative, matched-related donor hematopoietic cell transplantation

Abstract

We investigated sirolimus and mycophenolate mofetil (MMF) as graft-versus-host disease (GVHD) prophylaxis in patients with advanced hematologic malignancies receiving myeloablative hematopoietic cell transplantation (HCT) from HLA-identical sibling donors. Based on pre-study stopping rules, the trial was closed to accrual after enrollment of 11 adult patients. Seven of the 11 patients received busulfan-containing preparative regimens. Sirolimus was discontinued in 3 patients due to toxicity-related events of severe sinusoidal obstructive syndrome, portal vein thrombosis, altered mental status and in 1 patient due to risk of poor wound healing. Six of the 11 patients developed grade II-IV acute GVHD (AGVHD) a median of 15.5 days post-HCT. Two of 3 patients with grade IV AGVHD had sirolimus discontinued by 9 days post-HCT. All patients responded to AGVHD therapy without GVHD-related deaths. There were 2 nonrelapse- and 2 relapse-related deaths. At a median follow-up of 38 months (2–47 months), 7 of 11 patients were alive without disease. MMF and sirolimus GVHD prophylaxis did not reduce the risk of acute GVHD, however, there were no GVHD-related deaths. The severe toxicities in the patients receiving the busulfan-containing preparative regimens limited the continued use of sirolimus and MMF for the prevention of AGVHD.

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

“…Although a calcineurin inhibitor-free regimen would be most attractive, current evidence does not support the feasibility of this approach for GVHD prophylaxis after adult stem cell grafts. 32 Second, we acknowledge the risk of a biased classification. Although this was a randomized clinical trial with acute and chronic GVHD graded prospectively by treating physicians, blinding was not possible.…”

Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models

“…Although effective, these drugs result in significant toxicity and risk for opportunistic infections. 4,5 An alternative approach is to engineer the graft including T-cell depletion or administration of various subsets of T cells, such as regulatory T cells (Tregs). [6][7][8] Despite the knowledge of the impact of host APCs on GVHD induction, only a few preclinical studies have focused on targeting APCs to prevent GVHD induction.…”

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease

“…Unfortunately, currently available evidence does not support the safety of this approach. 42 We also acknowledge a more complete model of functional tolerance would include preservation of graft-versus-malignancy effects and immune competence for control of infection. The study was not designed to address these aspects of functional tolerance, and further investigation is needed.…”