ATG prevents severe acute graft-versus-host disease in mismatched unrelated donor hematopoietic cell transplantation.

Severe acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following mismatched unrelated donor hematopoietic cell transplantation (HCT). Through a retrospective analysis, we investigated the efficacy of GVHD prophylaxis with rabbit anti-thymocyte globulin (ATG) 7.5 mg/kg (1 mg/kg given on day -3, then 3.25 mg/kg/day on days -2 and -1 before stem cell infusion) followed by standard tacrolimus plus methotrexate in a consecutive series of 45 HLA partially matched unrelated donor HCT recipients. The cumulative incidence of grade III-IV aGVHD was 11% by 100 days (95% confidence interval [CI] 5%-25%). Moderate to severe chronic GVHD (per NIH consensus criteria) was 19% (95% CI 10%-36%) at 1 year, and 28% (95% CI 16%-48%) at 2 years. With a median follow-up time for surviving patients of 12 months (range: 5-39 months), overall survival was 55% (95% CI 39%-71%) at 1 year, and 45% (95% CI 27%-63%) at 2 years. Nonrelapse mortality was 11% (95% CI 5%-25%) by 100 days post-HCT, 26% (95% CI 16%-44%) by 1 year, and 30% (95% CI 18%-50%) by 2 years. The cumulative incidence of primary disease relapse was 23% (95% CI 13%-41%) at 1 year, and 33% (95% CI 20%-56%) by 2 years after HCT. Cytomegalovirus (CMV) infection or reactivation varied according to recipient and donor CMV serostatus. Epstein-Barr Virus (EBV) reactivation occurred in 54% (95% CI 40%-71%) of patients. Preemptive rituximab therapy was administered for EBV reactivation, however, posttransplant lymphoproliferative disorder was diagnosed in 5 (11%) cases, and was fatal in 1. A regimen of ATG 7.5 mg/kg total ending on day -1 effectively decreased the occurrence of grade III-IV aGVHD and severe chronic GVHD.

Sirolimus demonstrates activity in the primary therapy of acute graft-versus-host disease without systemic glucocorticoids.

BACKGROUND: Advances in acute graft-versus-host disease therapy are needed. DESIGN AND METHODS: We examined the efficacy of sirolimus as primary therapy for acute graft-versus-host disease in 32 patients. RESULTS: Acute graft-versus-host disease involved the skin in 53% of cases, gastrointestinal tract in 66%, liver in 16%. The syndrome was overall grade 1 in 12% cases, grade 2 in 75%, and grade 3 in 13%. Sirolimus was targeted to achieve serum trough levels of 5-14 ng/mL. Sixteen (50%) patients achieved sustained, complete resolution of acute graft-versus-host disease with sirolimus alone. In contrast, 19 of 32 (59%) matched historical controls treated with standard 1 mg/kg steroids achieved complete response (P=0.47). With median follow-up time for surviving patients of 16 (range 6-26) months, one year overall survival was 56% (95% CI 38-74%). The cumulative incidence of relapse at one year was 37% (95% CI 23-60%), and mortality in remission was 20% (95% CI 10-42%). The cumulative incidence of chronic graft-versus-host disease was 55% (95% CI 39-79%). Thrombotic microangiopathy occurred in 3 cases (grade 1 n=1; grade 2 n=2), and responded to dose reduction of calcineurin inhibitor. CONCLUSIONS: In this retrospective series, sirolimus demonstrates activity comparable to that of high-dose glucocorticoids in the primary therapy of acute graft-versus-host disease. Confirmation of this activity requires prospective clinical trials.