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

Abstract

Introduction

Sinusoidal obstructive syndrome (SOS) is a life-threatening complication that can arise after hematopoietic stem cell transplantation (HSCT), especially in high-risk pediatric patients. Despite some understanding of key risk factors, a detailed review of these high-risk groups in the U.S. is essential to better assess the contributing factors, healthcare implications, and patient outcomes associated with prophylactic defibrotide use. Previous studies, including one that was terminated early due to lack of efficacy, have not provided conclusive results on its effectiveness. However, its use persists, making it important to evaluate its real-world efficacy in preventing SOS and its effect on patient outcomes.

Study Design

A retrospective study was conducted on 10,250 patient encounters involving 8,200 unique pediatric patients. The study population was divided into high-risk (n=9,584) and very high-risk (n=666) groups based on the Harmony trial criteria. High-risk patients were defined by factors such as prior transplants, active infections, use of hepatotoxic medications, or advanced disease. Very high-risk patients had multiple risk factors or significant liver dysfunction. The patients were divided into three categories: those who received no defibrotide (n=9,606), prophylactic defibrotide (n=344), and treatment defibrotide (n=683). Data were analyzed for outcomes such as the development of SOS, duration of hospital stays, ICU admissions, mortality rates, and costs. The analysis used a mixed-effects regression model, with statistical significance set at p<0.05.

Findings

In the high-risk group, SOS occurred in 1.4% of patients who did not receive defibrotide compared to 26.5% in those who did. For the very high-risk group, SOS occurred in 2.4% of patients without defibrotide and 31.0% in those with prophylactic use. Median hospital stays for high-risk patients were 32 days in the no defibrotide group vs. 40 days in the prophylactic group (p<0.001). ICU admissions were significantly higher in the prophylactic group (50.7% vs. 30.4%, p<0.001). Mortality was also higher for the prophylactic group (7.9% vs. 2.6%, p<0.001), with increased costs for prophylactic defibrotide patients. Similarly, acute GVHD, infections, and sepsis rates were elevated in the prophylactic group.

Conclusion

Prophylactic defibrotide does not seem to lower the occurrence of SOS in high and very high-risk pediatric HSCT patients. Instead, it is linked to higher rates of ICU admissions, longer hospitalizations, increased mortality, and elevated costs. The findings suggest a need for alternative preventative approaches and additional studies to improve SOS prevention in this patient population.