Defibrotide in Prevention of Liver Toxicity in Patients at High Risk of VOD after HSC Transplantation.

Defibrotide has been proposed as preventive treatment of Veno Occlusive Disease (VOD), data on its use are, however, limited and its effectiveness not yet demonstrated. We have administered Defibrotide as prevention of VOD in pts treated with HSC transplantation because of haematological malignancies, all patients were at high VOD risk because of hyper-ferritinemia (>800 ng/ml) or because not in CR of their underlying disease at time of transplant or being overweight (Actual BW>20% of Ideal BW) or because Hepatitis virus B or C sero-positive. 120 pts were treated with Defibrotide, 77 pts received allogeneic HSC tx and 43 autologous HSC tx, 105 received a myeloablative conditioning (55 pts it was based on busulfan) and 15 pts received a RIC. 48% of patients were affected with Acute leukemia, 23% with Lymphomas, 17% with Multiple Myeloma, 12% by other malignancies. Defibrotide was administered i.v. at dosage of 600 mg/d. from the day of conditioning was started to day +25 together with heparin at low dose (100 IU/Kg c.i.).

RESULTS: after prophylaxis with Defibrotide a bilirubin value above 2.5 mg/dl during the first 30 days was observed in 16/120 pts (13%), 7/120 pts (5%) reached Seattle’s VOD criteria but had spontaneous resolution of liver toxicity, only 1 patient (0.8%) had a severe VOD and MOF. Overall survival at 3 years was 60% and it was 54% in allo-transplanted patients. We compared results with those obtained in a group of 78 pts treated by allogeneic or autologous transplants and who received low dose heparin only and not Defibrotide because they were considered at low risk of VOD. Percentage of pts who developed a bilirubin level > 2.5 mg/dl (p=0.12) and percentage of patients that reached criteria for VOD were not different (p= 0.08) in these two groups, numbers of red blood cell transfusions were comparable (p=0.07). When all the 198 studied patients were analyzed using logistic regression for factors important in the development of a bilirubinemia above 2.5 mg/dl we found to be important: use of MTX as prophylaxis of GVHD (P=0.004; Odds ratio 5,153), allogeneic transplant (P=0.007; Odds ratio 7,127) and baseline value of bilirubin (P=0.02; Odds Ratio 4,690).

Conclusions: Use of Defibrotide in prophylaxis of VOD after HSC transplantation is safe and when employed in patients at high risk of VOD, it leads to an incidence of severe VOD below 1% with a frequency of liver toxicity equivalent to that found in patients having low risk features. To conclude on efficacy of Defibrotide in comparison to low dose heparin alone, a large randomised comparison is warranted.