A Multicenter Prospective Phase II Study of Antithrombin-III Based Treatment for Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation

Introduction: Endothelial injury of sinusoids and hepatic veins is the initial event in veno-occlusive disease (VOD). This results in the activation of the coagulation cascade and inflammatory processes, which leads to hypercoagulable state and consumption of the natural anticoagulants including antithrombin-III (AT-III). The coagulopathy due to VOD can lead to multiorgan failure and death. Supplementation with AT-III concentrate was shown to reduce VOD-related mortality in several published studies. We conducted a multicenter prospective phase II trial to evaluate the efficacy and safety of AT-III based treatment for VOD after hematopoietic stem cell transplantation (HSCT).

Methods: Between August 2013 and May 2015, patients with VOD were enrolled from 5 institutes in South Korea to received AT-III based treatment. VOD was diagnosed without limitation of onset time, when patients had 2 or more of the following features: serum total bilirubin of greater than 2 mg/dL, hepatomegaly or right upper quadrant pain of liver origin, or unexplained weight gain of greater than 2% over baseline. Prophylaxis and other treatments of VOD were allowed as per standard operating procedure of the institutes. AT-III was loaded at 50 IU/kg every 8 hours for 3 times and maintenance doses were given at 50 IU/kg every 24 hours. The target AT-III level was 120% or above. AT-III level was measured before the 2^nd maintenance dose (pre-M2) and the same dose was continued if the target level was reached. The maintenance dose was adjusted to [50×weight (kg)+{(120-pre-M2 level)×weight (kg) /1.4}] IU every 24 hours if the target level was not reached. AT-III treatment was continued until complete response (CR) (all the parameter of VOD disappear), or up to 2 weeks if VOD continue to progress.

Results: Twenty patients were enrolled and 19 patients (11 male, 8 female) were eligible for analysis. Patients underwent HSCT at a median age of 20.8 years old for hematologic malignancies, solid tumors, and non-malignant diseases. Sixteen patients received busulfan and/or total body irradiation containing conditioning. Patients were diagnosed with VOD at median day 18 (range, day 6-30) and 2 patients had concomitant organ failures. AT-III treatment was started at median 0 day (range, 0-6 days) from VOD diagnosis. The median AT-III level was 67% (range, 46-99%) before the start of treatment. Twelve patients (63.2%) reached the target pre-M2 level with treatment. Ten out of these 12 patients had more than 6 maintenance doses administered and all of them maintained the target level before the 6^th maintenance dose. Of the 7 patients who did not reach the target pre-M2 level, 5 patients received adjusted doses and 2 of these patients (40.0%) reached the target level before the 4^th escalated dose. Thirteen patients (68.4%) achieved CR at median 18 days (range, 6-54 days) from treatment. A greater percentage of patients who reached the target pre-M2 level, compared to those patient who did not, achieved CR (n=11/12, 91.7% versus n=2/7, 28.6%). Two patients experienced adverse events (grade 4 hemoptysis and grade 5 pulmonary hemorrhage) related to the AT-III treatment. At a median follow-up of 65 days (range, 4-395 days) from treatment, the probability of death from VOD or VOD related organ failure or complication related to AT-III treatment was 29.4%. Three patients died of VOD or VOD related organ failure at median 22 days from treatment. One patient died of AT-III related pulmonary hemorrhage at 26 days from treatment. The probability of death from VOD/VOD related organ failure or treatment complication was lower in patients who reached the target pre-M2 level compared to those who did not (20.0% versus 42.9%, P=0.29).

Conclusions: A large percentage of the patients who reached the target pre-M2 AT-III level achieved CR. However, additional treatment strategies may be needed for the patients who do not reach the target pre-M2 AT-III level with current dosage of AT-III treatment.