Defibrotide Low-Dose Continuous Infusion After Allogeneic Stem Cell Transplantation as Prophylaxis for Veno-Occlusive Disease of the Liver.

Abstract

3483 Defibrotide (DF) has been shown to be effective in the treatment and prophylaxis of the veno-occlusive disease (VOD) of the liver, a relatively common complication after allogeneic stem cell transplant (SCT). We report our experience in 46 consecutive adult patients (pts). The pts (mean age 41 yrs, range 16–66) were affected by leukemia (22), lymphoma (15), multiple myeloma (4), myelodisplasia (2), solid tumor (2), Fanconi anemia (1). Risk factors for VOD were: resistant disease 9, previous transplant 8, B virus hepatitis 6, liver metastases 1, lymphoma of the liver 1, increased transaminases before conditioning 7. All were transplanted from their HLA-identical siblings; the conditioning regimen was reduced in 17, while it was conventional in 29. All the pts received a combination of drugs as conditioning regimen, 23 of them received Busulfan and 8 of them oral Busulfan. 15 received bone marrow and 31 peripheral blood as source of stem cells. None was T-cell depleted; the GVHD prophylaxis regimen was: CsA alone or combined with MTX 45, FK506+MTX 1. For VOD prophylaxis no heparin was administered, while DF was given at the dose of 10 mg/Kg in continuous iv infusion starting on day +1 until day +21 after the SCT. DF was very well tolerated and no hemorrhagic complications were seen. Blood coagulation significant alterations were: prolonged PT (4/46), prolonged aPTT (3/46), elevated fibrinogen (24/46), (never over 800 mg/dl), low level (less than 50%) of ATIII and/or protein C and or protein S (2/46). By using the VOD Baltimore criteria, only 1 case of VOD was observed on day +29 in a patient who died at day +36 with VOD, aspergillosis and CMV pneumonia. The bilirubin was more than 2 times the normal value in 26/46; US-scan of the liver and Doppler, performed in 16 pts with a possible sign of VOD, was positive only in the patient who died for VOD. We documented 32 infectious complications (16 FUO, 9 gram positive bacteremias, 3 pneumonia and 4 invasive aspergillosis). We documented acute GVHD in 14 pts (12 grade I-II and 2 grade III). Five pts died between +36 and +100 but none for VOD (3 for progression of their disease and 2 for aspergillosis). Our laboratory data demonstrated modest alterations of the coagulative parameters, low consumption of coagulative factors and reduced fibrinolysis. Since in this at risk transplanted population only 1 VOD has been observed, DF low-dose continuous infusion, without heparin, seems able to play a relevant role in the VOD prophylaxis. On considering the favourable results by us and others, the absence of toxicity and the low cost of the drug, we intend to continue this experience with DF as VOD prophylaxis, even if we foretell a large randomized study to find better indications. Disclosures: No relevant conflicts of interest to declare.

Defibrotide for the prevention of hepatic veno‐occlusive disease after hematopoietic stem cell transplantation: a systematic review

“…Another eight studies (23-30) were case series. Eight studies (18,21,(24)(25)(26)(28)(29)(30) were published as abstracts from conference proceedings. Table 1 shows the characteristics of the studies that met the inclusion criteria for evaluating the use of DF for preventing VOD.…”

“…A total of 1230 patients (median 60, range 5-356) were involved. These patients underwent HSCT for hematological diseases (18,19,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) and malignant infantile osteopetrosis (20). In seven studies (18,20,21,23,26,29,30), patients included were all at high risk for VOD or with at least one high-risk criteria for VOD.…”

“…In seven studies (18,20,21,23,26,29,30), patients included were all at high risk for VOD or with at least one high-risk criteria for VOD. The ages varied with six studies (18-20, 23, 24, 29) included only pediatric patients: three studies (21,25,27) included only adults and three studies (22,28,30) included both adults and children. The ages of patients in one study were not clearly stated (26).…”

“…The ages of patients in one study were not clearly stated (26). The type of transplant included patients undergoing all allogeneic transplants in five trials (20,23,25,27,28), a mixture of both allogeneic and autologous transplants in seven trails (18,19,21,22,24,26,30). The type of transplant was not reported in one study (29).…”

“…The conditioning regimen varied and included myeloablative and reduced intensity regimen, busulfan and Cy-TBI conditioning regimen, and others. The dosage of DF was different in the 13 trials and varied from 10 to 40 mg/kg/d in children (18-20, 22-24, 28-30) and 800-1600 mg/d in adults (21,22,25,27,28,30). The type of DF administration included infusion in most studies (18,(20)(21)(22)(25)(26)(27)(28)(29) and oral in two studies (23,30).…”