Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure

Abstract

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of hematopoietic stem cell transplantation (HSCT). Characterized by a prothrombotic-hypofibrinolytic state, VOD/SOS typically presents with hyperbilirubinemia, ascites, weight gain and painful hepatomegaly; VOD/SOS with multiorgan failure may be associated with >80% mortality. Treatment has been mainly supportive. However, defibrotide is now approved in the USA for treatment of hepatic VOD/SOS with renal or pulmonary dysfunction following HSCT and in the EU for treatment of severe hepatic VOD/SOS post-HSCT. In vitro evidence suggests defibrotide may restore thrombotic-fibrinolytic balance at the endothelial level and protect endothelial cells. Defibrotide has demonstrated significant reduction in VOD/SOS-related mortality and resolved VOD/SOS-related symptoms, with a manageable safety profile. KEYWORDS• defibrotide • diagnostic criteria • efficacy • mechanism of action • multiorgan dysfunction • pathophysiology • safety • sinusoidal obstruction syndrome • treatment • veno-occlusive disease Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening and unpredictable complication of toxic injury mainly from conditioning regimens for hematopoietic stem cell transplantation (HSCT) [1,2]. Although less common, VOD/SOS also may develop as a result of primary chemotherapy, immunotoxin conjugated therapies or radiation, particularly in children [1][2][3][4]. Mean prevalence of VOD/SOS among post-HSCT patients was estimated to be 13.7% (95% confidence interval [CI] = 13.3-14.1%), based on a review of 135 studies, each conducted in more than 50 patients between 1979 and 2007 [5]. VOD/SOS with multiorgan failure (MOF; also sometimes referred to as multiorgan dysfunction) occurs in an estimated 30-40% of patients with VOD/SOS after HSCT [6], and carries a mortality rate that exceeds 80% [5]. Children differ substantially from adults, with an incidence of VOD/ SOS approximately two-to three-fold higher overall [4,[7][8][9], and rates as high as 30-60% in highrisk subpopulations like infants and those with inherited diseases like familial hemophagocytic lymphohistiocytosis, thalassemia [10] and osteopetrosis [7,11,12]. Clinical presentation also differs in children, who often lack hyperbilirubinemia [4,7,13,14], the hallmark of VOD/SOS. Development of VOD/SOS after HSCT involves a complex pathophysiologic cascade initiated by the toxic injury from the conditioning regimen, with subsequent endothelial-cell damage and activation, and a prothrombotichypofibrinolytic state leading to central venous occlusion and/or sinusoidal obstruction [1,15,16]. The initial toxic injury occurs to sinusoidal endothelial cells and hepatocytes in zone 3 of the liver acinus. Because endothelial cells help regulate the equilibrium between pro-and antithrombotic factors, their injury may lead to progressive deterioration of thrombofibrino...

Defibrotide sodium for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome

“…In the 25 mg/kg/day dosegroup, AEs were reported by 47% of patients. Overall safety and efficacy were consistent with prior studies on defibrotide in VOD/ SOS ( Figure 1 and Table 4) [62,63].…”

“…The results from the historically controlled treatment trial are further supported by those of a study using retrospective Table 5. Comparative studies of defibrotide for VOD/SOS treatment [62]. data from the Center for International Blood and Marrow Transplantation Research (CIBMTR); 8341 patients who underwent allogeneic HSCT between 2008 and 2011 were retrieved; 3.2% met criteria for VOD/SOS, and 1.2% met criteria for VOD/ SOS with MOD [66].…”

Systematic review of defibrotide studies in the treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS)

“…In most cases, however, patient-level data were not available to control for heterogeneity between studies, including differences in baseline characteristics, such as severity of MOD (eg, reduced pulmonary/renal function vs ventilator/dialysis dependence), which represents a limitation in that it was not possible to retrospectively apply the new severity criteria proposed by EBMT or to pool safety data. Another consideration in interpretation of these results is that the largest reports were from single-arm studies designed to provide access to defibrotide [30,38]; however, the estimated Day + 100 survival results are comparable to those of the phase 3 historically controlled trial (in patients with MOD only, with a propensity-adjusted numberneeded-to-treat of five to prevent one death) [3,42,43], and the safety profile in the phase 3 study helps illustrate the range of AEs associated with VOD/SOS and MOD irrespective of treatment with defibrotide.…”

Biological Activities of Rhamnan Sulfate Extract from the Green Algae Monostroma nitidum (Hitoegusa)

“…This, in turn, accelerates blood coagulation and platelet aggregation, leading to the formation of microthrombi in the capillary of various organs and the induction of disseminated intravascular coagulation (DIC) [41], which may result in multiple-organ failure (MOF) [42] or severe bleeding. Moreover, hemolytic uremic syndrome (HUS) caused by Escherichia coli O-157 infection [43], sinusoidal obstructive syndrome (SOS)/veno-occlusive disease (VOD) [44,45], and transplantation-associated thrombotic microangiopathy (TA-TMA) [46] are all disorders or conditions that result from endothelial damage and are therefore symptoms of endothelial damage. To prevent the onset of these diseases, it is quite important to prevent the inflammation of the endothelium.…”