Abstract
AbstractThis trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.
Highlights
With the development of nonmyeloablative regimens, allogeneic hematopoietic cell transplantation (HCT) with related or unrelated donors has become a viable treatment option for older or medically unfit patients with hematologic malignancies.[1,2,3] A fully HLA-matched donor is considered ideal for the best possible outcome after allogeneic HCT.[4]
The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute Graft-versus-host disease (GVHD) could be reduced to less than the historical rate of 70% with the combination of cyclosporine, sirolimus, and mycophenolate mofetil in HLA class I or HLA class II mismatched related or unrelated HCT using nonmyeloablative conditioning
The current trial achieved its primary end point by successfully showing that the addition of sirolimus to cyclosporine and mycophenolate mofetil reduced the incidence of grade 2 to 4 acute GVHD after HLA-mismatched HCT from a historical incidence of 69% to 34%; the study cohort included HLA class I mismatches as well as class II mismatches that traditionally are associated with very high GVHD rates
Summary
With the development of nonmyeloablative regimens, allogeneic hematopoietic cell transplantation (HCT) with related or unrelated donors has become a viable treatment option for older or medically unfit patients with hematologic malignancies.[1,2,3] A fully HLA-matched donor is considered ideal for the best possible outcome after allogeneic HCT.[4]. All but 2 patients achieved sustained engraftment, and the relapse incidence was encouragingly low at 26% at 2 years. The cumulative incidence of grade 2 to 4 acute GVHD and grade 3 to 4 acute GVHD was high at 69% and 26%, respectively. This resulted in a high cumulative incidence of nonrelapse mortality (NRM) of 47% by 2 years after transplantation. The overall survival was 29% at 2 years after transplantation
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