Prophylaxis with Sirolimus and Tacrolimus ± Antithymocyte Globulin Reduces the Risk of Acute Graft-versus-Host Disease without an Overall Survival Benefit Following Allogeneic Stem Cell Transplantation

Abstract

Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival.

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

“…These results are in agreement with a retrospective study in which the incidence of TA-TMA in patients who were given TAC/SIR ± ATG was not significantly different from that in patients who received MTX with TAC or CYA (10.2% vs 4.3%), 23 or with those of a recently randomized phase II trial comparing TAC/SIR with TAC/MTX, 24 although the high incidence of TA-TMA reported in this latter trial (24.3% with TAC/SIR and 18.9% with TAC/MTX) should be noted. 24 Endothelial cells can be activated and damaged by several factors after HSCT.…”

“…[17][18][19]21,22 In a recent phase II multicenter prospective trial conducted by our group, including some of the patients in this study, no differences were observed in the incidence of TA-TMA when TAC/SIR was compared with patients included in a prior prospective trial using CYA-mycophenolate (the overall incidences of TA-TMA were 10% and 6%, respectively). 25 In addition, very few studies 23,24 have evaluated the risk of TA-TMA among patients receiving the TAC/SIR combination in comparison with other TAC-based regimens. To shed further light on this matter, we performed a retrospective analysis in 102 allogeneic HSCT recipients who consecutively received TAC/SIR (n ¼ 68) or TAC/MTX ± ATG (n ¼ 34) for GVHD prophylaxis.…”

“…In fact, two recent studies suggest that TA-TMA incidence does not differ significantly between patients who received TAC/SIR and those who received TAC/MTX for GVHD prophylaxis. 23,24 However, these two studies were not focused on TA-TMA and only described the incidence of TA-TMA without analyzing risk factors for TA-TMA, management or clinical outcome.…”

Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

“…The administration of rapamycin has recently been shown to possibly decrease the severity of GVHD. 31 This observation tallies with our gene expression analysis.…”

The addition of sirolimus to the graft‐versus‐host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial

“…The mTOR [mechanistic target of rapamycin (serine/threonine kinase)] inhibitor sirolimus has been used extensively for the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT)(Alyea, et al 2008, Antin, et al 2003, Benito, et al 2001, Couriel, et al 2005, Cutler, et al 2004, Cutler, et al 2007, Furlong, et al 2008, Ho, et al 2009, Johnston, et al 2005, Jurado, et al 2007, Perez-Simon, et al 2013, Rodriguez, et al 2010, Rosenbeck, et al 2011). A randomized phase II trial in patients receiving mostly myeloablative HSCT suggested a benefit to tacrolimus/sirolimus (Tac/Sir) over tacrolimus/methotrexate (Tax/Mtx)(Pidala, et al 2012) in terms of acute GVHD prevention; however, a phase III randomized trial (Blood and Marrow Transplantation Clinical Trial Network [BMT CTN] 0402) comparing those 2 regimens in patients undergoing myeloablative HSCT from matched related donors for acute myeloid leukaemia, myelodysplastic syndromes or acute lymphoblastic leukaemia (ALL) showed no significant difference in acute GVHD (aGVHD)-free survival (Cutler, et al 2012), despite a trend towards lower rates of aGVHD.…”