Sirolimus for Graft-Versus-Host-Diseases Prophylaxis in Non-Myeloablative Matched Related Transplantation: Safety and Efficacy.

Abstract 4329

The use of sirolimus (rapamycin) as an immunosuppressive agent after allogeneic hematopoietic transplantation is appealing given its antitumor and tolerance-inducing properties. Its safety and efficacy have been studied but are not completely understood in this patient population. We have compared GVHD prophylaxis with sirolimus together with early withdrawal of concomitant tacrolimus to standard tacrolimus in 49 patients receiving non-myeloablative transplant from matched related donors. All patients received identical conditioning with Cyclophosphamide 1g/m² days –7 and –6 and Fludarabine 25mg/m² days –7 through –3. Twenty-three patients received standard GVHD prophylaxis with methotrexate and tacrolimus. Twenty-six patients received methotrexate, sirolimus, with tacrolimus tapering over 15 days beginning day 20 or 30. Overall survival (OS) was similar in sirolimus and no sirolimus groups (median 526 vs 723 days, p=0.77). Similarly progression-free survival (PFS) was comparable (median 300 vs 382days p=0.78). Full chimerism was achieved in 73% patients received sirolimus vs. 58%patients received no sirolimus by day 100 (p=0.46). Chimerism was similar in the two groups at all time points examined. Toxicities including microangiopathy (MA), hypertriglyceremia and nephrotoxicity were analyzed. In patients receiving sirolimus MA developed in 2/26(8%) vs. in 1/23(4%) patients receiving no sirolimus (p=0.28). Creatinine >3mg/dl was seen in 6/26 (23%) patients receiving sirolimus vs. 6/23 (26%) patients receiving no sirolimus (p=0.47). In contrast the incidence of hypertriglyceremia (>500mg/dl) was significantly higher in the sirolimus group (10/26, 38% vs 2/23, 9% p<0.01). Hypertriglyceremia was however easily treated with anti-lipid agents, and no patient developed significant pancreatitis or other complications. The incidence of grade II-IV acute Graft versus host disease (GVHD) was modestly higher in the sirolimus (9/26, 35%) vs no sirolimus group (2/23, 9%), (p=0.0418). This acute GVHD occurred late at 60-100 days, more than 2 weeks after discontinuation of tacrolimus. Chronic GVHD was similar between patients receiving sirolimus and no sirolimus (15/26, 58%, vs. 9/23, 39%; p=0.25), as was transplant related mortality (3/26, 12%, vs. 4/23, 17%; p=0.69). Although sample size is limited, our data suggest that replacing tacrolimus early with continued sirolimus may be associated with modest increases in aGVHD. In our patients there is however little to suggest a negative impact on survival and engraftment. Other toxicities of sirolimus are minimal. Whether the early substitution of sirolimus for tacrolimus post transplant yields improved tumor control must await results of larger studies in specific tumor types.