The use of defibrotide in blood and marrow transplantation

Abstract

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

Figure 1.

Proposed pharmacologic actions of defibrotide. Factors involved in coagulation are depicted in yellow, factors released from endothelial cells are in the green area, factors involved in endothelial cell activation are in the orange area, and factors involved in platelet activation are in the purple area. Yellow circle with red center, inhibition, increase (+) or decrease (–); green arrow, activation; red arrow, production. cAMP, cyclic adenosine monophosphate; CysLT, cysteinyl leukotriene; FPA, fibrinogen peptide A; ICAM, intracellular adhesion molecule; IL-6, interleukin 6; LFA1, leukocyte function-associated antigen 1; LTB4, antileukotriene B4; MHC, major histocompatibility complex; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NO, nitric oxide; NOS, nitric oxide synthase; PAI-1, plasminogen activator inhibitor-1; PAF, platelet-activating factor; PGE₂, prostaglandin E2; PGI₂, prostaglandin I2; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TNFα, tumor necrosis factor-α; TXA₂, thromboxane A2; VEGF, vascular endothelial growth factor. Reprinted from Pescador et al with permission.

Figure 2.

Anatomy of the hepatic sinusoid. The hepatic sinusoids are lined by a population of microvascular LSECs that separate hepatocytes and stellate cells from leukocytes circulating through the liver in the blood. Fenestrations in the LSEC lining allow the passive exchange of molecules between the space of Dissé and the blood, as well as direct contact of lymphocyte filopodia with hepatocyte microvilli. The liver interstitium is highly enriched in cells of the innate immune system (such as antigen-presenting dendritic, Kupffer, natural killer, and NKT cells [not shown]) and in T cells, which participate in adaptive immune responses. Mediators produced by both parenchymal and nonparenchymal cells, including IL-10, TGFβ, arginase, and PGE₂, regulate immune function within the liver. LSEC, liver sinusoidal endothelial cells; TGFβ, transforming growth factor-β. Reprinted from Thomson et al with permission.

Figure 3.

Primary end points of phase 3 study in defibrotide-treated patients vs historical controls receiving supportive treatment. (A) Kaplan-Meier estimates of overall survival distribution and (B) complete response (defined as total bilirubin <2 mg/dL and resolution of MOD/MOF) at day +100 following HSCT. Reprinted from Richardson et al with permission.