Prophylactic Defibrotide in Allogeneic Stem Cell Transplantation: Low Morbidity and Zero Mortality from Veno-Occlusive Disease.
Authors: Dignan Fiona L. , Gujral Dorothy , Ethell Mark E. , Treleaven Jennifer , Morgan Gareth , Potter Michael 
Published: October 2019

Abstract
Veno-occlusive disease (VOD) is a common complication following the intensive conditioning regimens used in stem cell transplantation (SCT). The reported incidence is between 10–60% and the clinical spectrum varies from mild, reversible disease to a severe disorder with a mortality rate approaching 100% by day 100 post SCT (McDonald et al. Ann Intern Med1993, 118, 255–267). Defibrotide has recently been shown to be effective in the treatment of severe VOD in several series (Chopra et al. Br J Haematol2000, 111, 1122–1129; Richardson et al. Blood2002, 100, 4337–4343).
Only one report to date details the use of prophylactic defibrotide in the allogeneic SCT population. This study showed a significant reduction in VOD in patients treated with prophylactic defibrotide and heparin (Chalandon et al. Biol Blood Marrow Transplant2004, 10, 347–354). We report a retrospective review of the incidence of VOD in 58 adult patients who received defibrotide prophylaxis during allogeneic SCT from May 2004 to December 2005. Heparin was not used routinely.
Patients received 5mg/kg of defibroide twice daily IV from day + 1 to day + 21. All patients were assessed daily by clinical examination including weight and abdominal girth and laboratory tests including liver function tests. The Baltimore criteria were used to diagnose VOD. If VOD was suspected then US of the liver with a doppler test was performed.
No patients met the Baltimore criteria for VOD and no patients died of suspected VOD within 100 days of SCT. The transplant related mortality was 5/58 (8.6%) of patients. Three patients died of bronchopnemonia, one of E.Coli septicaemia and one of multi-organ failure secondary to infection. VOD was not felt to have contributed to the deaths of any of these patients.
The dose of defibrotide was increased to 10mg/kg four times daily IV in 3 patients in whom VOD formed part of the differential diagnosis for deranged liver function tests but who did not meet the Baltimore criteria. None of these patients had a positive US scan. One of these patients had a liver biopsy suggestive of mild VOD but also showed features consistent with GVHD and viral infection. The liver function of the other two patients improved after hepatotoxic drugs were stopped. All of these patients were alive at 100 days post transplant with no features of VOD.
Patients tolerated defibrotide well and the drug did not have to be discontinued in any patient. There were no cases of haemorrhagic complications attibutable to defibrotide.
It seems unlikely that differences in clinical characteristics accounted for the low incidence of VOD as many of our patients had several high risk factors. Sixty-seven % (39/58) had received a transplant from an unrelated donor, 18/58 (31%) had received a previous transplant and 28/58 (48%) had received either cyclophosphomide or busulphan as part of their conditioning regimen. This review suggests that the use of prophylactic defibrotide may reduce the incidence of VOD following allogeneic SCT.
Defibrotide may be effective without concurrent heparin but a randomised controlled trial would be useful to further investigate this issue.