Prophylactic Defibrotide in High-Risk Pediatric HSCT: Solution or New Set of Challenges?

Background: Sinusoidal obstructive syndrome (SOS) is a serious and often fatal complication of hematopoietic stem cell transplantation (HSCT), particularly affecting high and very high-risk patients. Despite some known risk factors, a thorough review of high-risk pediatric patients in the United States who undergo HSCT is needed to understand the main risk factors for SOS, the impact on healthcare, and patient outcomes with prophylactic defibrotide. The effectiveness of prophylactic defibrotide in preventing SOS remains unclear, with previous trials, including one that ended early due to lack of efficacy, not providing definitive answers. However, prophylactic defibrotide continues to be used by physicians. This study aims to evaluate its efficacy in preventing SOS in high-risk groups and assess its impact on clinical outcomes.

Methods: This retrospective cohort study included 10,633 encounters from 8,441 unique patients, stratified into high-risk (n=9,584) and very high-risk (n=666) groups based on the Harmony trial criteria. High-risk patients were identified by factors such as prior HSCT, active viral infection, hepatotoxic drug use, or advanced disease status. Very high-risk patients had multiple risk factors or severe baseline liver dysfunction. Encounters were categorized into three groups: no defibrotide (n=9,606), prophylactic defibrotide (n=344), and treatment defibrotide (n=683). Data were collected and analyzed using the Pediatric Health Information Systems database, focusing on the incidence of SOS, length of hospital stay, ICU admission rates, overall mortality, and total costs. Statistical analyses included Mixed-effects regression model with significance set at p<0.05.

Results: In the high-risk group, SOS incidence was 1.4% in the no defibrotide group compared to 26.5% in the prophylactic defibrotide group. In the very high-risk group, the incidence was 2.4% in the no defibrotide group compared to 31.0% in the prophylactic defibrotide group. The median hospital stay for the high-risk group was 32 (IQR 24-43) days for no defibrotide and 40 days (IQR 31-60) for prophylactic defibrotide (p<0.001). In the very high-risk group, the median stay was 46 (IQR 36-79) days for no defibrotide and 56 (IQR 41-96) days for prophylactic defibrotide (P=.332). ICU admission rates for the high-risk group were 30.4% for no defibrotide and 50.7% for prophylactic defibrotide (p<0.001). In the very high-risk group, ICU admission rates were 44.7% for no defibrotide and 69.0% for prophylactic defibrotide (p=0.069). Mortality rates in the high-risk group were 2.6% for no defibrotide and 7.9% for prophylactic defibrotide (p<0.001). In the very high-risk group, mortality rates were 9.2% for no defibrotide and 23.8% for prophylactic defibrotide (p=0.004). Total costs for the high-risk group were $267,945 for the no defibrotide group and $569,934 for the prophylactic defibrotide group. For the very high-risk group, total costs were $312,842 for the no defibrotide group and $624,561 for the prophylactic defibrotide group. Acute GVHD incidence was higher in the prophylactic defibrotide group (11.9% in high risk and 7.1% in very high risk) compared to the no defibrotide group (7.1% in high risk and 12.4% in very high risk). Chronic GVHD showed minimal differences, with a slight increase in the prophylactic group (0.7% in high risk and 0% in very high risk) compared to the no defibrotide group (0.3% in high risk and 0.6% in very high risk). Infections, including central line infections and sepsis, were more common in the prophylactic defibrotide group. Central line infections were 10.6% in high risk and 14.3% in very high risk compared to 6.9% in high risk and 11.2% in very high risk for no defibrotide. Sepsis incidence was 15.9% in high risk and 26.2% in very high risk for prophylactic defibrotide compared to 10.4% in high risk and 22.6% in very high risk for no defibrotide.

Conclusion: Prophylactic defibrotide does not seem to reduce the incidence of SOS in high and very high-risk patients. Additionally, it is linked with significantly higher ICU admissions, longer hospital stays, increased mortality, and higher total costs. There is also an increased incidence of acute GVHD and infections in the prophylactic defibrotide group. These results highlight the need for alternative prophylactic strategies and the importance of prospective trials to refine SOS prevention protocols.