Significant international attention has been directed to the most pressing problem of the financial crisis of 2008/2009 -- global liquidity shortages. The use of adequate foreign exchange reserves during the crisis helped alleviate pressures. However, this was only partially effective in a number of important cases. Some countries also needed to rely on external official financing. The aim of this article is to compare and analyse the main sources of official global liquidity -- foreign exchange reserves, bilateral swap lines of central banks, regional financial arrangements arid IMF resources. To reach effective outcomes in relation to the accumulation of FX reserves and a strengthening of the global financial safety nets, effective international coordination will be necessary. Adapted from the source document.
Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of conditioning for hematopoietic stem cell transplantation (HSCT) and is associated with patient and transplant-related risk factors, such as prior therapies, underlying diagnoses, and conditioning regimen. Unpredictable in its occurrence and severity, VOD/SOS is clinically characterized by painful hepatomegaly, hyperbilirubinemia, ascites, and weight gain. Overall estimated prevalence is 14% post-HSCT, while rates in some high-risk populations (eg, osteopetrosis or prior gemtuzumab ozogamicin) are >60% (Wadleigh M et al. Blood . 2003;102:1578-82; Corbacioglu S et al. Bone Marrow Transplant . 2006;38:547-53). Evidence suggests that defibrotide stabilizes endothelial cells, with direct and endothelial-cell mediated restoration of the thrombo-fibrinolytic balance. Defibrotide is approved in the European Union for the treatment of severe hepatic VOD/SOS in patients receiving HSCT, and is available in the United States through an expanded-access study. In a previously reported randomized clinical trial, defibrotide prophylaxis for VOD/SOS in high-risk pediatric patients undergoing HSCT reduced the overall incidence of VOD/SOS by day +30 post-HSCT. Here we report novel subgroup analyses of VOD/SOS incidence from this trial in patients with specific VOD/SOS risk factors at baseline. Methods This was a phase 3, multicenter, open-label, randomized, controlled trial in patients aged 5% weight gain. Patients were randomized to standard care with or without defibrotide prophylaxis dosed at 25 mg/kg/day in 4 divided infusions of 6.25 mg/kg. Osteopetrosis was a stratification variable. Defibrotide began the same day as HSCT conditioning and continued for 30 days post-HSCT, or ≥14 days for patients discharged from hospital before day +30 post-HSCT. Control patients who developed VOD/SOS received defibrotide treatment. The primary endpoint was incidence of VOD/SOS at day +30 post-HSCT. Results The intent-to-treat population included 356 patients: 180 randomized to defibrotide prophylaxis and 176 in the control group. Mean (SD) age was 6.6 (5.3) years, and 40.7% of patients were female. Demographic and clinical characteristics, including VOD/SOS risk factors (Table), were well-matched in the defibrotide and control groups. The most common risk factors among all patients were conditioning with busulfan and melphalan (58%), preexisting liver disease (27%), and second myeloablative transplantation (13%). VOD/SOS occurred by day +30 post-HSCT in 22 (12%) patients in the defibrotide prophylaxis group vs 35 (20%) patients in the control group. For the stratification variable, osteopetrosis, rates of VOD/SOS were 14% in the defibrotide prophylaxis arm and 67% in the control arm (Table). Differences in rates of VOD/SOS were lowest for adrenoleukodystrophy (no cases) and prior abdominal irradiation (11% vs 13%, respectively) (Table). Conclusions Across risk-factor subgroups, the rate of VOD/SOS was lower in patients receiving defibrotide compared with controls (except adrenoleukodystrophy: no VOD/SOS in either group). In particular, rates of VOD/SOS by day +30 were reduced by ≥50% in the defibrotide arm vs the control arm among patients with osteopetrosis, hemophagocytic lymphohistiocytosis, second myeloablative transplantation, and prior gemtuzumab treatment. Although the total numbers of patients with these risk factors were small, these between-group differences are of clinical interest and should be further explored. | Risk Factor | Defibrotide (n=180) | Control (n=176) | | --- | --- | --- | --- | | Total n | VOD/SOS incidence (n=22; 12.2%) n (%*) | Total n | VOD/SOS incidence (n=35; 20.0%) n (%*) | | Adrenoleukodystrophy | 1 | 0 (0) | 1 | 0 (0) | | Osteopetrosis | 7 | 1 (14) | 6 | 4 (67) | | Prior abdominal irradiation | 9 | 1 (11) | 8 | 1 (13) | | Hemophagocytic lymphohistiocytosis | 10 | 0 (0) | 15 | 6 (40) | | Prior gemtuzumab | 11 | 2 (18) | 5 | 2 (40) | | Allogeneic HSCT for leukemia | 17 | 2 (12) | 11 | 2 (18) | | Second myeloablative transplantation | 25 | 2 (8) | 23 | 4 (17) | | Pre-existing liver disease | 41 | 6 (15) | 54 | 12 (22) | | Busulfan/melphalan conditioning | 106 | 15 (14) | 99 | 17 (17) | * *Percent of patients with VOD/SOS. Table. Support: Jazz Pharmaceuticals Disclosures Corbacioglu: Gentium S.p.A.: Consultancy, Honoraria. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. Bader: Amgen: Consultancy; Medac: Other: Institutional grants; Neovii: Other: Institutional grants; Riemser: Other: Institutional grants; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy.
