defibrotide and Acute-Disease

Thrombotic thrombocytopenic purpura (TTP) has emerged as one of the main transplant-related complications over the last 15 years. The current study defines the incidence and the risk factors for the occurrence of TTP in 131 consecutive leukemic children who were transplanted between January 1994 and December 1997 at four Italian pediatric centers. Patients with ALL (101), AML (21), MDS (9), underwent an HLA-identical sibling BMT (82) or an HLA-identical unrelated BMT (49), receiving a conditioning regimen consisting of high-dose chemotherapy in 24 patients and of F-TBI combined with high-dose chemotherapy in 107 patients. The diagnosis of TTP was retrospectively evaluated on the basis of parallel criteria. TTP treatment varied according to the protocol of each treatment center. Twenty-eight of 131 patients (21.4%) developed TTP at a median of 46 days (range 21-80) after BMT. Multivariate analysis demonstrated that the risk of TTP was higher in patients who underwent unrelated BMT (P value = 0.02). Acute GVHD, stage of disease at BMT, conditioning with TBI, gender, age, did not appear to be associated with the occurrence of TTP. As to the outcome, TTP resolved in 19 patients while in nine it was the principal cause of death (32.1%). In patients with TTP, LDH peak value was the only statistically significant factor (P = 0.001) related to severe TTP. In conclusion, our experience demonstrates that leukemic children undergoing BMT, especially from an unrelated donor, should be carefully assessed for TTP which appears to be a severe and relatively common transplant-related complication when strict diagnostic criteria are applied.

Topics: Acute Disease; Bone Marrow Transplantation; Child; Child, Preschool; Combined Modality Therapy; Female; Fibrinolytic Agents; Graft vs Host Disease; Humans; Immunosuppressive Agents; Incidence; Infant; L-Lactate Dehydrogenase; Leukemia; Male; Plasma; Plasmapheresis; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Prognosis; Purpura, Thrombotic Thrombocytopenic; Remission Induction; Retrospective Studies; Risk Factors; Transplantation Conditioning; Treatment Outcome

Angiogenesis and endothelial activation and dysfunction have been associated with acute graft-vs.-host disease (aGVHD), pointing to the endothelium as a potential target for pharmacological intervention. Defibrotide (DF) is a drug with an endothelium-protective effect that has been approved for the treatment of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Clinical data suggest that DF also reduces the incidence of aGVHD; however, the mechanisms of DF-mediated aGVHD regulation have not been examined. To investigate possible DF-mediated prophylactic and therapeutic mechanisms in aGVHD, we performed

Topics: Acute Disease; Endothelium; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Human Umbilical Vein Endothelial Cells; Humans; Male; Polydeoxyribonucleotides

The efficacy of defibrotide in the treatment of acute thrombophlebitis of the legs has been investigated in 140 patients, randomized into two groups. All patients received defibrotide either alone or as an addition to conventional therapies. Two different schemes of administration were selected and carried out in each group, according to the time of onset of thrombophlebitis. Defibrotide demonstrated a good clinical efficacy in both groups, with a highly significant reduction in those patients receiving defibrotide and conventional therapies. The clinical result were outstanding in two subgroups: extensive thrombophlebitis and brachioaxillary phlebitis.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Drug Evaluation; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Polydeoxyribonucleotides; Random Allocation; Thrombophlebitis; Time Factors

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective therapy for the treatment of high-risk haematological malignant disorders and other life-threatening haematological and genetic diseases. Acute graft-versus-host disease (aGvHD) remains the most frequent cause of non-relapse mortality following allo-HCT and limits its extensive clinical application. Current pharmacologic agents used for prophylaxis and treatment of aGvHD are not uniformly successful and have serious secondary side effects. Therefore, more effective and safe prophylaxis and therapy for aGvHD are an unmet clinical need. Defibrotide is a multi-target drug successfully employed for prophylaxis and treatment of veno-occlusive disease/sinusoidal obstruction syndrome. Recent preliminary clinical data have suggested some efficacy of defibrotide in the prevention of aGvHD after allo-HCT. Using a fully MHC-mismatched murine model of allo-HCT, we report here that defibrotide, either in prophylaxis or treatment, is effective in preventing T cell and neutrophil infiltration and aGvHD-associated tissue injury, thus reducing aGvHD incidence and severity, with significantly improved survival after allo-HCT. Moreover, we performed in vitro mechanistic studies using human cells revealing that defibrotide inhibits leucocyte-endothelial interactions by down-regulating expression of key endothelial adhesion molecules involved in leucocyte trafficking. Together, these findings provide evidence that defibrotide may represent an effective and safe clinical alternative for both prophylaxis and treatment of aGvHD after allo-HCT, paving the way for new therapeutic approaches.

Topics: Acute Disease; Animals; Biomarkers; Biopsy; Cell Communication; Cell Line; Chemotaxis, Leukocyte; Cytokines; Disease Models, Animal; Endothelium; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Inflammation Mediators; Leukocytes; Mice; Polydeoxyribonucleotides; Tissue Donors; Transplantation, Homologous

Topics: Acute Disease; Aged; Aminoglycosides; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Female; Gemtuzumab; Hepatic Veno-Occlusive Disease; Humans; Leukemia, Myeloid; Platelet Aggregation Inhibitors; Polydeoxyribonucleotides; Time Factors

Severe hepatic veno-occlusive disease (VOD) is a recognized complication of autologous and allogeneic stem cell transplantation (SCT) that is often fatal. Defibrotide (DF) is a polydeoxyribonucleotide that has been found to have anti-thrombotic, anti-ischaemic and thrombolytic properties without causing significant anticoagulation. Preliminary studies have demonstrated activity for DF in the treatment of VOD, with minimal associated toxicity. In the present study, 40 patients who fulfilled established criteria for VOD were treated with DF on compassionate grounds in 19 European centres; 28 patients met risk criteria predicting progression of VOD and fatality or had evidence of multiorgan failure (MOF), and were defined as 'poor-risk'. DF was commenced intravenously at a median of 14 d (range, -2 d to 53 d) post SCT at doses ranging from 10 to 40 mg/kg. The median duration of therapy was 18 d (range, 2--71 d). Twenty-two patients showed a complete response (CR) (bilirubin < 34.2 micromol/l and resolution of signs/symptoms of VOD and end-organ dysfunction) [CR = 55%, confidence interval (CI) 40--70%] and 17 patients (43%) are alive beyond d +100. Ten poor-risk patients showed a complete response (CR = 36%, CI 21--51%). These results demonstrate that DF is an active treatment for VOD following SCT and a randomized trial is now underway in order to further evaluate its role.

Topics: Acute Disease; Adolescent; Adult; Bilirubin; Breast Neoplasms; Child; Child, Preschool; Female; Fibrinolytic Agents; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Hodgkin Disease; Humans; Infant; Leukemia, Myeloid; Male; Middle Aged; Multiple Myeloma; Polydeoxyribonucleotides; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome

We investigated the effects of Defibrotide (D), a natural polydeoxyribonucleotide, on acute myocardial ischemia (AMI) in anesthetized cats. A permanent ligature was placed around the left anterior descending coronary artery (LAD) 12-14 mm from its origin. Ventricular fibrillation and death were exceptional and when they occurred the cats were not included in the evaluation. Pretreatment of cats with D, 32 mg Kg-1 h-1, i.v. infusion, maintained throughout the 5 h occlusion period, reduced AMI-ST segment increases and increased the diminished pressure-rate index (PRI). AMI-induced changes in lactate, ATP and CPK in ischemic tissue were prevented by D. PGI2 gave the same results as D. Atenolol prevented the loss of myocardial CPK, but had no favourable effects on lactate and ATP in ischemic tissue. The beneficial effects of D in AMI reported here could be partly attributed to its ability to enhance PGI2 release from vascular walls; D might also relieve ischemia by improvement of local tissue oxygenation, energy supplies and platelet function by its ability to deaggregate platelet clumps.

Topics: Acute Disease; Adenosine Triphosphate; Animals; Atenolol; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Epoprostenol; Fibrinolytic Agents; Hemodynamics; Lactates; Male; Myocardium; Polydeoxyribonucleotides