We have previously shown that the potent immunosuppressive agent, sirolimus, combined with tacrolimus and low-dose methotrexate results in low rates of grade II–IV acute GVHD for both related and unrelated donor RIC transplantation.[11
] In the current study, we demonstrated that the combination of tacrolimus and sirolimus alone, omitting the low dose methotrexate, is similarly effective in the prevention of acute GVHD. After adjusting for relapsed patients who had acute GVHD induced by rapid withdrawal of immune suppression, the cumulative incidence of grade II–IV acute GVHD was 17% for patients receiving tac/sir as GVHD prophylaxis. This result is also concordant with previously published results using this same prophylaxis regimen in myeloablative MRD PBSC transplantation, where the grade II–IV acute GVHD incidence was 10%, and treatment related mortality was minimal.[15
] A multi-center randomized trial testing the combination of tacrolimus and sirolimus versus tacrolimus and methotrexate in matched sibling donor myeloablative transplantation is on-going through the BMT Clinical Trials Network.
Considering the equivalence in GVHD control, the elimination post transplant methotrexate from the tac/sir combination may be associated with some potential benefits. The omission of methotrexate may have accounted for the significant reduction in patients from the tac/sir group who actually developed neutropenia (21%) or significant thrombocytopenia (21%), compared to 52% and 41% in the tac/sir/mtx group, respectively. The elimination of methotrexate may provide cost savings and added convenience for patients since it obviates the need for multiple clinic infusion visits during the first week after stem cell infusion.
The incidence of acute GVHD noted in this study compares favorably with other pharmacologic prophylactic strategies of GVHD after RIC transplantation. In RIC related donor transplantation, the incidence of grade II–IV acute GVHD ranges from 16–47% with tacrolimus or cyclosporine and mycophenolate mofetil (MMF)[16
], and 12–36% with tacrolimus or cyclosporine and methotrexate.[18
] Incorporation of alemtuzumab or antithymocyte globulin as GVHD prophylaxis is associated with a low incidence of acute and chronic GVHD after RIC transplantation. However, these in-vivo T cell depletion approaches are associated with an increased risk of infection and disease relapse, often necessitating the use of donor lymphocyte infusion to restore the GVL effect. [4
In addition to its immune suppressive properties, sirolimus may have additional benefits in allogeneic transplantation beyond GVHD prevention. Along with other mTOR inhibitors, sirolimus has been shown to have direct anti-cancer activity in several hematologic malignancies. [20
] The anti-cancer activity of sirolimus appears to be mediated through inhibition of the mTOR pathway and inhibits immature cells by blockade in G0/G1 phase of the cell cycle. While it is unclear if the doses used to prevent acute GVHD are sufficient to mediate anti-cancer activity, results of a recent retrospective study on lymphoma patients receiving RIC transplant with Bu/Flu conditioning demonstrated that those transplanted using tacrolimus/sirolimus based GVHD prophylaxis enjoy superior disease free survival than those receiving non-sirolimus containing GVHD prophylaxis. [21
] Preliminary results incorporating sirolimus into a RIC regimen in a group of patients with high risk leukemia also suggested improved disease control after transplant.[22
] Larger series will be needed to assess the impact of sirolimus on disease control. Interestingly, there has also been recent data suggesting that the combination of mTOR inhibitors with methotrexate can provide a synergistic effect against acute lymphoblastic leukemia in cell lines and animal models.[23
As true in many single institution non-randomized phase II studies, our data are limited by the fact that the study populations for the 2 trials are small, and there is insufficient power to detect small differences in GVHD outcomes. Furthermore, the tac/sir/mtx trial was conducted a few years earlier than the tac/sir trial. This could have impacted the transplant related mortality comparisons because supportive care and antifungal therapy have improved in recent years, although this difference should not influence the development of GVHD. Definitive confirmation of acute GVHD rates with tac/sir vs. tac/sir/mtx will require a prospective randomized phase III trial.
In summary, our study demonstrates that the combination of tacrolimus and sirolimus alone is associated with good acute GVHD control and little toxicity after RIC transplantation from matched sibling donors. The use of low dose intravenous busulfan with sirolimus in this RIC setting does not appear to increase the risk of hepatic VOD or TMA. While the incidence of chronic GVHD remains high, long-term survival outcomes are encouraging, suggesting that the graft-versus-malignancy effect is preserved. Sirolimus containing GVHD prophylaxis regimens are worthy of further investigation in reduced intensity transplantation.