The mTOR inhibitor sirolimus has been used in the prevention and treatment of GVHD after allogeneic hematopoietic stem cell transplantation (HSCT). In parallel, mTOR inhibitors have demonstrated clinical activity against various lymphoma histologies. In a retrospective study, we found that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received a sirolimus-containing GVHD prophylaxis regimen had a lower rate of relapse (Armand et al, J Clin Oncol. 2008;26(35):5767). We therefore performed a multicenter, phase III, open label randomized trial comparing tacrolimus, sirolimus and methotrexate (Tac/Sir/Mtx, with sirolimus starting on day -3 of HSCT) for GVHD prophylaxis to conventional sirolimus-free regimens (tacrolimus + methotrexate (Tac/Mtx) or cyclosporine + MMF (Csa/MMF), pre-specified by center), in patients undergoing RIC HSCT for any lymphoma except Burkitt lymphoma. The primary endpoint was 2-year overall survival (OS); progression-free survival (PFS), acute and chronic GVHD were among the secondary endpoints. 139 patients were enrolled at five institutions between June 2009 and September 2012. The median age was 57 years (range, 23-70). 42 patients had aggressive B-NHL, 31 indolent B-NHL, 28 CLL, 19 T-NHL and 19 Hodgkin lymphoma. 66 were assigned to the Tac/Sir/Mtx arm, and 73 to the control arm (67 to Tac/Mtx and 7 to Csa/MMF). All patients but 1 received the allocated intervention, and all received peripheral blood stem cell products, as mandated by the protocol. Based on a planned interim analysis, the DSMB recommended reporting of the interim results at this time. Median follow-up for survivors is 22 months, and only 12% of living patients have less than 12 months of follow-up. There was no evidence of increased toxicity in the Tac/Sir/Mtx arm. At the time of this analysis, the Kaplan-Meier estimate of 2-year OS by intent to treat (
Figure 1A) is 66% (95CI, 51-77) in the Tac/Sir/Mtx arm vs. 71% (95CI, 58-81) in the control arm (
p=0.7); the corresponding 2-y PFS (
Figure 1B) is 62% (95CI, 48-73) vs. 56% (95CI, 43-68) (
p=0.9). The conditional power for finding a significant difference in the primary endpoint of 2y OS is <1%, prompting the current report. There was no significant difference in non-relapse mortality (2y cumulative incidence 14% in both groups,
p=0.9) or cumulative incidence of relapse (2y incidence 25% vs. 30%,
p=0.8). However, the addition of sirolimus resulted in a significant decrease in the cumulative incidence of grade 2-4 acute GVHD (6-month cumulative incidence 9% vs. 25%,
p=0.014;
Figure 1C), even after excluding patients who received Csa/MMF. This was apparent in both patients receiving matched related and those receiving matched unrelated grafts. There was no significant difference in the incidence of grade 3-4 acute GVHD (3% vs. 4% at 6 months,
p=0.7) or chronic GVHD (2-year cumulative incidence 59% vs. 55%,
p=0.5;
Figure 1D).
In conclusion, the addition of sirolimus to the GVHD prophylaxis regimen in patients with lymphoma undergoing RIC HSCT is associated with a significant decrease in grade 2-4 acute GVHD after transplantation, without impacting toxicity, severe acute GVHD, chronic GVHD, progression-free or overall survival. These results should be broadly applicable to all recipients of RIC HSCT using T-cell-replete peripheral blood stem cells, and suggest that tacrolimus, sirolimus and methotrexate could be a preferred regimen in this patient population. Pre-specified subgroup analyses by histology and correlative studies will be performed when follow-up is complete in late 2014.
