In Vitro Monitoring of Defibrotide Prophylaxis for Endothelial Complications Following Allogeneic Stem Cell Transplantation.

Defibrotide (DF) is a polydisperse mixture of 90 % single-stranded polydeoxyribonucleotides with anti-thrombotic, pro-fibrinolytic and anti-apoptotic functions. DF is already successfully used in the treatment of hepatic veno-occlusive disease in allogeneic stem cell transplantation (SCT). Our observation that DF can also protect endothelial cells (EC) from conditioning (fludarabine (F-Ara))-mediated apoptosis(1) prompted us to apply it prophylactically to patients (pts) at risk for endothelial complications. Pending on the magnitude of risk, pts received 200–800mg every 6h in 2h-infusions, usually from day (d) −7 until d+21 post SCT.

Circulating EC (CEC) as a marker of conditioning-mediated endothelial toxicity(2) were detected by magnetic bead separation of CD146+ cells from EDTA blood of 50 SCT pts (33 DF, 17 NO DF) and co-staining with Ulex Europaeus antigen lectin 1. CEC maxima until d+100 post SCT were compared between the two groups. DF pts showed significantly lower maxima of CEC than untreated pts (1085 [±1012] in the DF treatment group vs. 2595 [±1910] CEC/mL in non-DF pts, respectively, p=0.0007). Similarly, when CEC maxima were compared in the time period of DF prophylaxis, again, DF pts had less cell counts (562 [±794] vs. 1548 [±1575] CEC/mL in control pts, respectively, p=0.005). Interestingly, this observation also held true for the heavily pre-treated diagnostic subgroup of acute myeloid leukemia (AML) pts (683 [±807] DF vs. 3467 [±2664] non-DF, p=0.007). These preliminary analyses suggest the protective efficacy of DF prophylaxis in the course of SCT. The final proof of principle is to be validated in long-term clinical follow-ups.