defibrotide and Hematologic-Neoplasms

Endothelial dysfunction and damage play important roles in the pathophysiology of graft versus host disease (GvHD) and hepatic venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS). Preliminary evidence suggests that defibrotide (DF) may decrease the risk of GvHD. We speculated that DF prophylaxis may have a synergistic effect with other immunosupressive agents by decreasing the incidence of GvHD and retrospectively evaluated the impact of a DF prophylaxis on the development of GvHD. Thirty-eight adult patients with various hematological neoplasms who underwent peripheral blood allogeneic hematopoietic stem cell transplantation from all donor types were included. All patients received DF for prevention of VOD/SOS. GvHD prophylaxis included rabbit anti-T lymphocyte globulin (rATLG), posttransplant cyclophosphamide (PTCy) and cyclosporine (CsA). The median follow-up of the surviving patients was 484 (365-814) days. The cumulative incidence of grade III-IV acute GvHD and moderate/severe chronic GvHD requiring systemic immunosupression at 1 year were 20.6 % and 5.3 %, respectively. Non-relapse mortality, GvHD-relapse-free survival, and overall survival of the study cohort at 1-year were 21.1 %, 44.7 % and 57.9 %, respectively. Our preliminary results suggest that DF may act as a global endothelial protectant and decrease the risk of GvHD in combination with rATLG, PTCy and CsA.

Topics: Adult; Aged; Animals; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Middle Aged; Peripheral Blood Stem Cell Transplantation; Polydeoxyribonucleotides; Rabbits; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Hepatic veno-occlusive disease (VOD) is a serious complication of high-dose chemotherapy regimens, such as those used in hematopoietic cell transplantation recipients. Defibrotide is considered a safe and effective treatment when dosed at 25 mg/kg/day. However, patients who develop VOD still have increased mortality despite the use of defibrotide. Data are limited on the use of doses above 60 mg/kg/day for persistent VOD. In this prospective clinical trial 34 patients received escalating doses of defibrotide. For patients with persistent VOD despite doses of 60 mg/kg/day, doses were increased to a maximum of 110 mg/kg/day. Increased toxicity was not observed until doses rose beyond 100 mg/kg/day. Patients receiving doses between 10 and 100 mg/kg/day experienced an average of 3 bleeding episodes per 100 days of treatment, whereas those receiving doses >100 mg/kg/day experienced 13.2 bleeding episodes per 100 days (P = .008). Moreover, dose reductions due to toxicity were needed at doses of 110 mg/kg/day more often than at lower doses. Defibrotide may be safely escalated to doses well above the current standard without an increase in bleeding risk. However, the efficacy of this dose-escalation strategy remains unclear, because outcomes were similar to published cohorts of patients receiving standard doses of defibrotide for VOD.

Topics: Adolescent; Adult; Child; Child, Preschool; Drug Administration Schedule; Drug Dosage Calculations; Female; Fibrinolytic Agents; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hepatic Veno-Occlusive Disease; Humans; Infant; Male; Myeloablative Agonists; Polydeoxyribonucleotides; Prospective Studies; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Topics: Adult; Aged; Disease Management; Female; Fibrinolytic Agents; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Male; Middle Aged; Polydeoxyribonucleotides; Survival Analysis

Topics: Adult; Aged; Diagnosis, Differential; Disease-Free Survival; Female; Fibrinolytic Agents; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Liver Diseases; Male; Middle Aged; Polydeoxyribonucleotides; Time Factors; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Vascular Diseases