The Pathology, Diagnosis, and Treatment of Hepatic VOD/SOS Post SCT: Current Status and Novel Strategies

2008 ASBMT Online Seminar
Paul G. Richardson, MD
Dana-Farber Cancer Institute
Harvard School of Medicine

Objectives: Veno-occlusive disease/sinusoidal syndrome (VOD/SOS) associated with stem cell transplantation (SCT) remains one of the most serious complications after myeloablative hematopoietic SCT, and as part of a spectrum of toxicities characterized by microangiopathy is one of the most common regimen-related toxicities characterized by endothelial injury accompanying SCT. Clinical diagnosis of hepatic VOD/SOS is based on the clinical triad of painful hepatomegaly, hyperbilirubinemia (=2 mg/dl) and unexplained fluid retention (weight gain =5%), with no apparent other causes for these symptoms. Whilst the spectrum of disease is broad, severe VOD/SOS is typically associated with multiorgan failure (MOF) and carries a mortality in excess of 80%. Systemic and anticoagulant thrombolytic strategies have been tested extensively in this disease, but are largely ineffective and are associated with significant bleeding complications. With approximately 20,000 stem cell transplants per year in the US and an incidence of up to 5000 cases of VOD/SOS, of which 800-1600 of these patients have severe disease, and an increasing incidence of VOD/SOS in children, there is a need for new treatment strategies. Successful novel therapeutic approaches will likely modulate endothelial cell injury without causing systemic bleeding or other toxicity, protect the host without compromising anti-tumor effect of cytotoxic therapy, and have activity in a spectrum of vascular injury syndromes during SCT. Recently, defibrotide (DF), a polydisperse mixture of single-stranded oligonucleotide derived from porcine intestinal muscosa with antithrombotic and fibrinolytic effects on microvascular endothelium (VEC), has emerged as an active and well-tolerated therapy for patients with severe VOD. Defibrotide has multi-functional pharmacology and selective activity on lipopolysaccharide-injured micro-VEC. Multiple studies have demonstrated 30–60% complete remission rates and promising D+100 survival with DF treatment in patients with established severe VOD and MOF. Currently, as DF has shown efficacy in severe VOD/MOF, novel trial designs to support the evaluation of DF in this setting are underway. Prevention of VOD is also a priority for patients undergoing SCT and a uniformly successful approach remains to be developed, although preliminary studies of DF as prophylaxis suggesting potential benefit with decreased incidence and improved survival. As other novel therapies are introduced into the treatment paradigm, DF in addition to these treatment strategies will hopefully further improve outcome and management of patients undergoing SCT at risk of this complication.