Improved Survival in Lymphoma Patients Receiving Sirolimus for Graft-Versus-Host Disease Prophylaxis After Allogeneic Hematopoietic Stem-Cell Transplantation With Reduced-Intensity Conditioning

Abstract

A B S T R A C T PurposeInhibitors of the mammalian target of rapamycin (mTOR) kinase have shown clinical activity in several lymphoma subtypes. Sirolimus, an mTOR inhibitor, also has activity in the treatment and prophylaxis of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem-cell transplantation (HSCT). We hypothesized that the use of sirolimus for GVHD prophylaxis in patients with lymphoma might lead to improved survival after transplantation through a decreased incidence of disease progression. Patients and MethodsWe retrospectively analyzed 190 patients who underwent transplantation for lymphoma. We compared the outcomes of patients who received sirolimus for GVHD prophylaxis with those of patients who received transplantation with a combination of a calcineurin inhibitor and methotrexate without sirolimus. ResultsOverall survival (OS) after transplantation was significantly superior in the sirolimus group, which was confirmed in multivariable analysis. The benefit was restricted to patients undergoing reduced-intensity conditioning (RIC) HSCT (3-year OS, 66% for sirolimus group v 38% for no-sirolimus group; P ϭ .007; hazard ratio [HR] for mortality in multivariable analysis ϭ 0.5, P ϭ .042). Patients who received sirolimus had a similar incidence of nonrelapse mortality but a decreased incidence of disease progression compared with patients who did not receive sirolimus (3-year cumulative incidence of progression, 42% v 74%, respectively; P Ͻ .001; HR for progression in multivariable analysis ϭ 0.4, P ϭ .01). The effect of sirolimus persisted after adjusting for the occurrence of GVHD. No such survival advantage was apparent in a similar comparison of patients who underwent transplantation for diseases other than lymphoma. ConclusionThis study suggests that sirolimus can independently decrease the risk of lymphoma progression after RIC HSCT, paving the way for prospective clinical trials.

The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

“…16 The favorable ECOG performance status reported after 1 year of transplantation (ECOG=0-1 in more than 90% of evaluable patients), the low incidence of CMV infection, the small number of invasive fungal infections observed and the low rate of infection-related mortality (6% at 2 years post-transplant) in the Si-Tac group can be attributed to the lower incidence of chronic GVHD. Remarkably, sirolimus has direct antineoplastic, antifungal and anti-cytomegalovirus activities with possible clinical implications, as recently suggested in two large studies by Marty et al 36 and Armand et al 38 In the current comparison, the lower incidence of GVHD in the Si-Tac group was not associated with a lower response or a higher relapse rate compared with that in patients receiving CsA-MMF. Considering that both subgroups received the same RIC, these data indicate that sirolimus allows the reduction of GVHD without hampering the efficacy of the procedure.…”

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

“…There was no increase in DLI use, relapse incidence or relapse-related mortality, even though donor T-cell chimerism developed significantly slower in the sirolimus-treated patients. Reports indicating that sirolimus has specific anti-neoplastic activity against lymphomas 23 could not be confirmed. However, it cannot be ruled out that a potential anti-neoplastic effect of sirolimus was offset by an attenuated GvT response due to slower development of donor chimerism.…”

Does peritransplantation use of rituximab reduce the risk of EBV reactivation and PTLPD?

“…9,10 A recent report describes 2 patients with PTLPD successfully treated with rituximab and rapamycin after renal transplantation. 11 Rapamycin has been shown to be effective GVHD prophylaxis after allo-SCT 12 ; however, the prevalence of PTLPD was not reported. These observations suggest consideration of a clinical trial using a conditioning regimen incorporating rapamycin and lower doses of rituximab for GVHD prophylaxis in high risk patients for PTLPD and GVHD, especially older patients receiving unrelated or mismatched transplantation with ATG.…”