Ultra-short course sirolimus contributes to effective GVHD prophylaxis after reduced-intensity allogeneic hematopoietic cell transplantation

Abstract

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day þ 100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Sirolimus as long-term graft-versus-host-disease prophylaxis in haploidentical hematopoietic stem cell transplant recipients for non-malignant disorders is associated with high incidence of acneiform lesions

“…Immunosuppressive drugs are used for protracted periods in solid organ transplants and for a few months to years in HSCT depending on the disease and post-transplant complications. [ 7 8 9 ] Sirolimus promotes induction of regulatory T cells which hastens tolerance,[ 10 ] which in malignant diseases might affect the graft-versus-leukemia effect. [ 11 ] However, this is not the primary concern in HSCT for non-malignant diseases and we opted to introduce sirolimus as GVHD prophylaxis in our protocol for non-malignant diseases and in malignant diseases, when CNI could not be administered.…”

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

“… a Excludes studies in alloHCT recipients where sirolimus was used as treatment of GVHD 212–214 ; or where sirolimus doses were personalized to a trough concentration of 3–12 ng/mL without a pharmacodynamic analysis 83–85,90,94,95,97,99,114,215,216 , 5–10 ng/mL 86,88,89 , 5–12 ng/mL 217 , 5–15 ng/mL 218 , 6–14 ng/mL 98 , 10–15 ng/mL 219 ; or where a short course of sirolimus was given without dose personalization 220 . b Authors did not conduct these pharmacodynamic analyses because they determined that they had insufficient sirolimus pharmacokinetic data. c Tacrolimus start day and methods for calculating summative sirolimus concentrations were not included in the manuscript. d One patient also received ATG. Abbreviations: alloHCT: allogeneic hematopoietic cell transplantation; BU: busulfan; C 0 : trough plasma concentration; CI: confidence interval; Cl/F: apparent oral clearance; CY: cyclophosphamide; FLU: fludarabine monophosphate; GVHD: graft-versus-host disease; HPLC: high-performance liquid chromatography; HR: hazard ratio; IQR: inter-quartile range; IS: immunosuppression; IV: intravenous(ly); MA: myeloablative; Mel: melphalan; MS: mass spectrometry; PBSC: peripheral blood stem cell; RIC: Reduced-intensity conditioning; TBI: total body irradiation; TMA: Thrombotic microangiopathy; UCB: umbilical cord blood; URD: unrelated donor; V d /F: volume of distribution …”

“… a Excludes studies in alloHCT recipients where sirolimus was used as treatment of GVHD 212–214 ; or where sirolimus doses were personalized to a trough concentration of 3–12 ng/mL without a pharmacodynamic analysis 83–85,90,94,95,97,99,114,215,216 , 5–10 ng/mL 86,88,89 , 5–12 ng/mL 217 , 5–15 ng/mL 218 , 6–14 ng/mL 98 , 10–15 ng/mL 219 ; or where a short course of sirolimus was given without dose personalization 220 . …”

Rapamycin‐resistant effector T‐cell therapy

“…The goal of this intervention was to control GVHD initiated by the unmanipulated T cells contained in the G-CSF-mobilized peripheral blood allograft. In collaboration, we have piloted a short-course sirolimus GVHD prophylaxis approach (130). The typical use of sirolimus after transplantation consists of prolonged drug administration, which has been associated with effective prevention of acute GVHD (131) and improved anti-tumor outcome in lymphoma patients (132).…”