Graft-versus-Host disease Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy: Results of the EVTAC Trial

Abstract

A calcineurin inhibitor combined with methotrexate is the standard prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus, a derivative of sirolimus, seems to mediate antileukemia effects. We report on a combination of everolimus and tacrolimus in 24 patients (median age, 62 years) with either myelodysplastic syndrome (MDS; n = 17) or acute myeloid leukemia (AML; n = 7) undergoing intensive conditioning followed by HSCT from related (n = 4) or unrelated (n = 20) donors. All patients engrafted, and only 1 patient experienced grade IV mucositis. Nine patients (37%) developed acute grade II-IV GVHD, and 11 of 17 evaluable patients (64%) developed chronic extensive GVHD. Transplantation-associated microangiopathy (TMA) occurred in 7 patients (29%), with 2 cases of acute renal failure. The study was terminated prematurely because an additional 6 patients (25%) developed sinusoidal obstruction syndrome (SOS), which was fatal in 2 cases. With a median follow-up of 26 months, the 2-year overall survival rate was 47%. Although this new combination appears to be effective as a prophylactic regimen for acute GVHD, the incidence of TMA and SOS is considerably higher than seen with other regimens.

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

“…In contrast to previously published evidence in the setting of busulfan/cyclophosphamide conditioning, 27 or that of largely intravenous busulfan/fludarabine but with the combination of TAC/everolimus, 29 we did not observe a significantly increased risk of hepatic VOD among patients treated with SIR/TAC and busulfan-based conditioning. However, the overall incidence of this complication was low and this risk was likely mitigated by avoiding cyclophosphamide, pharmacokinetic targeting of intravenous busulfan, initiation of SIR on day -1 after conditioning therapy was completed, and VOD prophylaxis with ursodeoxycholic acid in all patients.…”

Safety and efficacy of defibrotide for the treatment of severe hepatic veno-occlusive disease

“…Elevations of von Willebrand factor, thrombomodulin, E-selectin, and soluble ICAM-1 before and early after allogeneic transplantation may be useful in predicting VOD in patients receiving sirolimus [Cutler et al 2010] and could lead to pre-emptive trials based on biomarkers, leading to improved treatment strategies to reverse VOD pathophysiology earlier in specific high-risk groups [Platzbecker et al 2009]. …”

Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: A dual center retrospective analysis

“…Attempts to introduce everolimus for prophylaxis of acute GVHD (aGVHD) failed because of significant side effects such as sinusoidal obstruction syndrome and transplant-associated microangiopathy, again most likely as a result of combination with CNI. 32 Nevertheless, a single preliminary report from Jedlickova et al 33 in 21 patients suggests everolimus as a promising candidate for the treatment of sclerodermatous cGVHD.…”