Recent developments with defibrotide for the treatment of hepatic veno-occlusive disease/sinusoidal obstruction syndrome

ABSTRACT

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening condition associated with endothelial cell damage due to hematopoietic cell transplantation (HCT) conditioning or chemotherapy not associated with HCT. Defibrotide is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States and Canada, and severe hepatic VOD/SOS in patients aged >1 month in the European Union.

Areas covered: VOD/SOS results from prolonged endothelial cell activation from exposure to chemotherapy or radiotherapy. PubMed was searched for articles on defibrotide without publication date restrictions. In vitro evidence suggests defibrotide has a protective effect on endothelial cells. The efficacy of defibrotide for the treatment of VOD/SOS with multi-organ dysfunction has been shown in clinical trials. Defibrotide has a favorable safety profile comparable to best supportive care in patients with severe forms of VOD/SOS.

Expert opinion: As defibrotide treatment for VOD/SOS is most effective when initiated early, medical teams should familiarize themselves with the risk factors for VOD/SOS development and be able to recognize early signs and symptoms. Preclinical data indicate that defibrotide has a protective effect on endothelial cells that may contribute to its efficacy in VOD/SOS and that may render the drug applicable for other indications.

KEYWORDS:

• Veno-occlusive disease
• sinusoidal obstruction syndrome
• multi-organ dysfunction/multi-organ failure
• VOD/SOS risk factors
• VOD/SOS prophylaxis
• defibrotide

1. Introduction

Hepatic veno-occlusive disease (VOD) also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of conditioning for hematopoietic cell transplantation (HCT) or nontransplant-associated chemotherapy. Development of hepatic VOD/SOS with associated multi-organ dysfunction (MOD; typically renal or pulmonary) is associated with over 80% mortality post-HCT [1]. Defibrotide is the only FDA- and EMEA-approved treatment for any form of hepatic VOD/SOS [2,3]. Defibrotide has demonstrated improved efficacy outcomes compared to standard interventions in trials and studies, including a phase 3 trial [4], an expanded-access protocol [5], and as part of a compassionate-use program (CUP) [6]. The following review discusses the pathophysiology of VOD/SOS, defibrotide’s proposed mechanism of action in this context, and emerging data regarding its therapeutic potential. Articles evaluated in this review were identified through a search of PubMed for articles on defibrotide, without any restriction on publication date.

2. Overview of VOD/SOS

2.1. Incidence

A meta-analysis of 135 studies with adult and pediatric patients undergoing HCT reported an overall mean VOD/SOS incidence of 13.7% (95% confidence interval [CI], 13.3–14.1%) after transplant; among all cases of VOD/SOS, the incidence of severe VOD/SOS with associated MOD ranged from 0% to 77% with a mortality rate of 84.3% [1]. The reported incidence of VOD/SOS following allogeneic HCT with myeloablative conditioning regimens ranges from 0% to 40%, and from 0% to 12% following autologous HCT [1]. The incidence of VOD/SOS in pediatric populations is approximately 20% but has been reported to be as high as 60% in infantile osteopetrosis [1,7]. The overall reported incidence in adults is approximately 10% [7]. The development of VOD/SOS is not restricted to patients undergoing HCT. In one study, 12% of patients receiving gemtuzumab without transplant developed VOD/SOS [8]. In a separate study, 13% of patients receiving inotuzumab ozogamicin with or without HCT [9] developed VOD/SOS. In the absence of other risk factors or exposures, VOD/SOS is generally rare in patients treated with conventional chemotherapy without HCT [10].

2.2. Risk factors

Identification of at-risk patients plays an important role in the prompt diagnosis and early treatment of VOD/SOS [11]. Some of the pretransplant, patient-related factors associated with increased risk of VOD/SOS include very young or old age [12,13], genetic factors [14], Eastern Cooperative Oncology Group (ECOG) performance status 2 to 4 (vs 0–1; adult measure) [15], Karnofsky (>age 15) performance score <90% [14], high serum ferritin [14,16], cytomegalovirus seropositivity [17], hypoalbuminemia [18], and pre-existing liver conditions such as elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) enzymes pre-HCT, or hepatitis C [14,15] (Table 1). Risk factors may also include factors associated with the underlying disease itself and its treatment, including use of gemtuzumab ozogamicin [14,19] or inotuzumab ozogamicin [9], and iron overload [14,16]. The timing of gemtuzumab ozogamicin prior to HCT has also been shown in multiple retrospective studies to be a risk factor for VOD/SOS [20,21]. In particular, a retrospective multicenter study of acute leukemia patients found a short interval between gemtuzumab ozogamicin and allograft (≤3.5 months) was associated with a higher incidence of VOD/SOS (10.5% vs 4% for other intervals) [22]. Pediatric diseases associated with a higher risk of VOD/SOS include infantile osteopetrosis, congenital macrophage activation syndromes, thalassemia with hepatomegaly, and neuroblastoma [7]. Due to the variety of risk factors associated with VOD/SOS, a risk score calculator was developed to help identify high-risk patients. This pretransplant risk score incorporated patient- and transplant-related factors and stratified allogeneic HCT patients into four distinct risk groups [23].

Table 1. Key risk factors for VOD/SOS [9,12–19,24–31].

Patient-related factors	Transplant-related factors
Very young or old age Pre-existing hepatic condition Previous liver disease Elevated ALT/AST levels Hepatitis-C positive Hypoalbuminemia CMV seropositivity Prior treatment Gemtuzumab ozogamicin Inotuzumab ozogamicin Prior abdominal radiation Genetic predisposition ECOG PS 2–4 (adults) Karnofsky index <90% High serum ferritin Iron overload	Allogeneic transplant Unrelated/HLA mismatch Previous HCT Conditioning regimen Busulfan-based regimen Myeloablative regimen Prior abdominal radiation Total body/hepatic irradiation GvHD prophylaxis Sirolimus in patients who receive post-HCT methotrexate Antiviral prophylaxis

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; ECOG PS, Eastern Cooperative Oncology Group performance status; GvHD, graft-versus-host disease; HCT, hematopoietic cell transplant; HLA, human leukocyte antigens; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome.

In the transplant population, risk of developing VOD/SOS is higher in those undergoing allogeneic versus autologous HCT [24]. Chemotherapeutic or immunotherapeutic exposures associated with VOD risk include busulfan-based conditioning regimens [25], myeloablative conditioning regimens [26], and prior abdominal radiation [27]. Use of unrelated [28] and mismatched donor stem cell sources [18] increases VOD risk, as does the receipt of more than one HCT [29]. Sirolimus is associated with VOD/SOS when used in patients who also receive post-transplant methotrexate [30] (Table 1). The risk of VOD development appears to be reduced in patients who receive T-cell-depleted grafts [31].

Additionally, radiation therapy can lead to sinusoidal occlusion. High-dose radiation is associated with progressive fibrous obliteration of small branches of the hepatic veins [32]. Chronic oxidative stress may drive the progression of radiation-induced tissue injury [33]. Radiation therapy also impairs endothelium-dependent vasodilation of conduit arteries, thus decreasing the bioavailability of nitric oxide [34], leading to further vasoconstriction.

2.3. Pathophysiology

It is hypothesized that the initiating event associated with VOD development is damage to the vascular endothelium [35,36]. This, in turn, leads to endothelial cell activation and the classic findings of VOD/SOS including hypercoagulability, overactive immune-response and inflammation, increased vascular permeability, and diffuse vasoconstriction [37]. With prolonged activation, sinusoidal endothelial cells lose their fenestration, and gaps appear in the sinusoidal wall as the endothelial cells round up, allowing red blood cells into the space of Disse and detaching the endothelial lining. The sloughed cells embolize downstream, where they ultimately obstruct sinusoidal flow [37,38].

Endothelial-cell injury promotes a prothrombotic-hypofibrinolytic state, as reflected in elevated levels of von Willebrand factor and plasminogen activator inhibitor, as well as in reduced levels of thrombomodulin and tissue plasminogen activator [37]. Thickening of the subintimal zone, sclerosis, and narrowing of the venular lumen contribute to further vasculature compromise [37,39]. If left untreated, VOD/SOS can progress to portal hypertension, hepatorenal syndrome, obliteration of terminal hepatic venules, MOD, and multi-organ failure (MOF) [26,40].

2.4. Diagnosis

The classic physical exam and laboratory findings of VOD/SOS are hepatomegaly, weight gain, and hyperbilirubinemia. Traditionally, VOD/SOS has been diagnosed using the Baltimore [41] or modified Seattle criteria [26]. More recently, the European Society for Blood and Marrow Transplantation (EBMT) developed newer diagnostic criteria for both children [7] and adults [42]. The EBMT criteria incorporate newer data regarding pathophysiology [24] and rely on recent advances in diagnostic techniques (Table 2). For adults, the EBMT includes criteria for diagnosing late-onset VOD/SOS, which had not been used in prior definitions. These criteria also recognize that late-onset VOD/SOS can occur without hyperbilirubinemia. The EBMT pediatric criteria do not have a limit for timing of VOD/SOS onset and do not include bilirubin levels as part of diagnostic criteria, as it is not uncommon to develop VOD/SOS in the absence of hyperbilirubinemia (Table 2). The EBMT criteria for determining VOD/SOS severity for pediatric and adult patients are presented in Table 3.

Table 2. EBMT diagnostic criteria for VOD/SOS.

New EBMT criteria for adult patients		New EBMT criteria for pediatric patients
Classical VOD/SOS ≤21 days post-HCT	Late-onset VOD/SOS >21 days post-HCT	No limitation for time of onset of VOD/SOS Presence of two or more of the following^a: Unexplained consumptive and transfusion-refractory thrombocytopenia^b ^cOtherwise unexplained weight gain on three consecutive days despite the use of diuretics or a weight gain 45% above baseline value ^cHepatomegaly (best if confirmed by imaging) above baseline value ^cAscites (best if confirmed by imaging) above baseline value Rising bilirubin from a baseline value on three consecutive days or bilirubin ≥2 mg/dL within 72 h
Bilirubin ≥2 mg/dL and two of the following criteria must be present: Painful hepatomegaly Weight gain >5% Ascites	Classical VOD/SOS beyond day 21 OR Histologically proven VOD/SOS OR Two of the following criteria must be present: Bilirubin ≥2 mg/dL (or 34 μmol/L) Painful hepatomegaly Weight gain >5% Ascites^c AND hemodynamic and/or ultrasound evidence of VOD/SOS

Abbreviations: CT, computed tomography; EBMT, European Society for Blood and Marrow Transplantation; HCT, hematopoietic cell transplantation; MRI, magnetic resonance imaging; US, ultrasonography; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome. ^aWith the exclusion of other potential differential diagnoses. ^b≥1 weight-adjusted platelet substitution/day to maintain institutional transfusion guidelines. ^cSuggested: imaging (US, CT, or MRI) immediately before HCT to determine baseline value for both hepatomegaly and ascites. These symptoms/signs should not be attributable to other causes.

Adapted from Corbacioglu S et al. [7] and Mohty M et al. [42].

Table 3. EBMT criteria for assessing disease severity.

	Mild^a	Moderate^a	Severe	Very severe (all patients with MOD^b)
Severity grading of a suspected VOD/SOS in adults^c
Time since first clinical symptoms of VOD/SOS^d	>7 days	5–7 days	≤4 days	Any time
Bilirubin (mg/dL)	≥2 and <3	≥3 and <5	≥5 and <8	≥8
Bilirubin (μmol/L)	≥34 and <51	≥51 and <85	≥85 and <136	≥136
Bilirubin kinetics			Doubling within 48 h
Transaminases	≤2 x normal	>2 and ≤5 x normal	>5 and ≤8 x normal	>8 x normal
Weight increase	<5%	≥5% and <10%	≥5% and <10%	≥10%
Renal function	<1.2 x baseline at transplant	≥1.2 and <1.5 x baseline at transplant	≥1.5 and <2 x baseline at transplant	≥2 x baseline at transplant or other signs of MOD/MOF
	Mild	Moderate	Severe	Very severe (all patients with MOD^b)
Severity grading of a suspected VOD/SOS in children^e
LFT^f (ALT, AST, GLDH)	≤2 x normal	>2 and ≤5x normal	>5
Persistent RT^f	<3 days	3–7 days	>7 days
Bilirubin (mg/dL)^f,g	<2		≥2
Bilirubin (μmol/L)	<34		≥34
Ascites^f	Minimal	Moderate	Necessity for paracentesis (external drainage)
Bilirubin kinetics				Doubling within 48 h
Coagulation	Normal	Normal	Impaired coagulation	Impaired coagulation with need for replacement coagulation factors
Renal function GFR (mL/min)	89–60	59–30	29–15	<15 (renal failure)
Pulmonary function (oxygen requirement)	<2 L/min	>2 L/min	Invasive pulmonary ventilation (including CPAP)
CNS	Normal	Normal	Normal	New onset cognitive impairment

Adapted from Corbacioglu S et al. [7] and Mohty M et al. [42].

Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CPAP, continuous positive airway pressure; CTCAE, Common Terminology Criteria for Adverse Events; EBMT, European Society for Blood and Marrow Transplantation; GFR, glomerular filtration rate; GLDH, glutamate dehydrogenase; LFT, liver function test; MOD, multi-organ dysfunction; MOF, multi-organ failure; RT, refractory (e.g., not responsive to treatment) thrombocytopenia; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease. ^aIn the case of presence of two or more risk factors for SOS/VOD, patients should be in the upper grade. ^bPatients with MOD must be classified as very severe. ^cPatients belong to the category that fulfills two or more criteria. If patients fulfill two or more criteria in two different categories, they must be classified in the most severe category. Patient weight increase ≥5% and <10% is considered by default as a criterion for severe SOS/VOD; however, if patients do not fulfill other criteria for severe SOS/VOD, weight increase ≥5% and <10% is therefore considered as a criterion for moderate SOS/VOD. ^dTime from the date when the first signs/symptoms of SOS/VOD began to appear (retrospectively determined) and the date when the symptoms fulfilled SOS/VOD diagnostic criteria. ^eIf patient fulfills criteria in different categories they must be classified in the most severe category. In addition, the kinetics of the evolution of cumulative symptoms within 48 h predicts severe disease. ^fPresence of ≥2 of these criteria qualifies for an upgrade to CTCAE level 4 (very severe SOS/VOD). ^gExcluding pre-existent hyperbilirubinemia due to primary disease.

In patients for whom the diagnosis of VOD/SOS is unclear, liver biopsy may be required to exclude other diagnoses. However, due to the risk of complications, liver biopsy is generally performed only when absolutely necessary for diagnosis [43]. Recent studies have identified potential biomarkers of endothelial injury as a means of predicting VOD/SOS. A study of biomarkers before and after transplant found that thrombomodulin, von Willebrand factor, and soluble intercellular adhesion molecule 1 (sICAM-1) were significantly elevated in VOD/SOS patients relative to patients without VOD/SOS pretransplant and up to 14 days post-transplant [44].

2.5. VOD/SOS prophylaxis

Some studies support prophylaxis in high-risk patients to reduce risk of VOD/SOS in patients receiving HCT and improve patient outcomes. Heparin and antithrombin have been shown to be effective in reducing VOD/SOS incidence in some trials [45,46]. However, due to significant risk of hemorrhage and inconsistent efficacy results neither drug is recommended as a prophylactic strategy for VOD/SOS [43]. Ursodeoxycholic acid has also been used for VOD/SOS prophylaxis and is recommended in the British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) guidelines [43]. Defibrotide is being investigated for VOD/SOS prophylaxis and has also been recommended by the BCSH/BSBMT guidelines for both adult and pediatric patients [43].

2.6. Supportive care

Early recognition of the signs and symptoms of VOD/SOS is critical, and therapy should be initiated as soon as possible after diagnosis. In mild cases of VOD/SOS, when caught very early, supportive care with aggressive fluid management can be life-saving. The first steps are often aimed at preventing worsening of renal function by maintaining adequate fluid and sodium balance [14] and by avoiding nephrotoxic medications [11]. Diuretics are often used to reduce fluid overload; however, care must be taken to maintain renal perfusion [11]. Renal compromise is common in severe VOD/SOS, which can be the result of diuresis resulting in prerenal azotemia or of hepatorenal syndrome. In some cases, hemodialysis is indicated [11]. Another common occurrence in severe or worsening VOD/SOS is development of ascites. Removal of ascites by paracentesis is sometimes required [11].

Other proposed treatments for VOD/SOS include tissue plasminogen activator and N-acetylcysteine, although both have inherent limitations. Tissue plasminogen activator is not recommended due to the risk of life-threatening bleeding [43,47], and N-acetylcysteine is not recommended due to a lack of efficacy [43]. Methylprednisolone may be considered for use in VOD/SOS; however, efficacy is limited and use of steroids should be balanced with the risk of infection in immunocompromised patients [43].

3. Defibrotide

While supportive care is a critical part of managing the symptoms and clinical sequalae of VOD/SOS, defibrotide is the only approved medication clinically shown to halt the underlying pathophysiologic process of VOD/SOS itself. In 2013, the BCSH and BSBMT recommended defibrotide for the treatment of VOD/SOS in adults and children [43]. Similarly, the EBMT has stated that defibrotide is the only proven treatment for VOD/SOS [24].

Defibrotide is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States and Canada, and to treat severe hepatic VOD/SOS in patients aged >1 month in the European Union [2,3]. The approved dose for adult and pediatric patients is 6.25 mg/kg given every 6 h (25 mg/kg/day) as a 2-h intravenous infusion, which is recommended for at least 21 days [2,3]. The use of defibrotide is contraindicated in patients with concomitant administration of systemic anticoagulant or fibrinolytic therapy and with known hypersensitivity to defibrotide or any of its excipients [2,3]. It is recommended that defibrotide be discontinued at least 2 h prior to an invasive procedure [2,3]. Treatment should be initiated as early as possible after diagnosis; earlier initiation has been associated with higher survival [5].

3.1. Chemistry

Chemically, defibrotide is a sodium salt composed of 90% single-stranded and 10% double-stranded phosphodiester oligonucleotides [48,49]. It is produced through the controlled depolymerization of porcine intestinal mucosal DNA [48,49]. Defibrotide contains two distinct aptamer sequences that confer its thrombin-antagonizing properties [50].

3.2. Pharmacodynamics

Defibrotide has a complex mechanism of action that is thought to include profibrinolytic, antithrombotic, anti-inflammatory, anti-ischemic, and antiadhesive activities. The drug also has demonstrated endothelial-protective properties in vitro [49,51–54]. Defibrotide has been shown to protect endothelial cells from toxic, inflammatory, and reperfusion damage by reducing cell activation. It has also been shown to restore thrombo-fibrinolytic function [49,53,55–58] (Figure 1). In a preclinical study, defibrotide showed a protective effect on endothelial cells by preventing the proinflammatory and prothrombotic phenotypes that develop after autologous HCT [53]. Defibrotide binds to the surface of endothelial cells, protecting the endothelium from chemotherapeutic damage (while allowing preservation of antitumor activity [35]), tumor necrosis factor-alpha, serum starvation, perfusion damage, oxidative stress, and inflammation [35,49,53,58–60]. Anti-inflammatory and antioxidant properties of defibrotide were observed in a preclinical study using an endothelial cell line of hepatic origin [58]. It is hypothesized that this protective effect may be related to defibrotide’s interaction with the membranes of endothelial cells. After attachment to the membrane, defibrotide is internalized into the cell, raising the possibility of additional intra-cellular activity [58]. Defibrotide may increase tissue plasminogen activator and thrombomodulin expression and decrease von Willebrand factor and plasminogen activator inhibitor-1 expression, which help restore thrombo-fibrinolytic balance, thus supporting endothelial structures and function [35,48,55,57,61,62]. Defibrotide also may enhance the enzymatic activity of plasmin, leading to the hydrolysis of fibrin clots [55,57,63].

Figure 1. Proposed pharmacologic actions of defibrotide. Defibrotide has been shown to protect endothelial cells by reducing proinflammatory and prothrombotic phenotypes following HCT. Defibrotide has been hypothesized to protect the endothelium through a direct interaction with the endothelial membrane and restoration of the thrombo-fibrinolytic balance. Factors involved in coagulation appear in yellow text. 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; upregulation or downregulation of these factors is indicated with (+) and (−), respectively. Yellow circles with red centers indicate inhibition. Green arrows represent activation and red arrows represent production. Abbreviations: cAMP, cyclic adenosine monophosphate; CysLT, cysteinyl leukotriene; FPA, fibrinogen peptide A; HCT, hematopoietic cell transplantation; ICAM1, intracellular adhesion molecule; LFA1, leukocyte function-associated antigen 1; NO, nitric oxide; 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. [49] with permission from Elsevier.

3.3. Pharmacokinetics and metabolism

A single 6.25 mg/kg dose of defibrotide given as a 2-h infusion in healthy subjects has a time to maximum plasma concentration (T_max) of 2 h [64], a half-life of 43 min [65], and does not affect cytochrome P450 metabolism [65]. An average of 93% of defibrotide is bound to human plasma protein, and the volume of distribution ranges from 8.1 to 9.1 [3]. Approximately 5% to 15% of the total dose is excreted in the urine unmetabolized [3]. No accumulation of defibrotide was seen after multiple doses in animals, healthy volunteers, or in patients with renal impairment [52,64]. Defibrotide is not cleared by intermittent hemodialysis [64].

4. Defibrotide efficacy and safety

4.1. Phase 2 study

In a dose-finding phase 2 study [66], patients received either 25 mg/kg/day or 40 mg/kg/day intravenous defibrotide administered in divided doses every 6 h for ≥14 days or until complete response (total serum bilirubin <2 mg/dL with resolution of VOD-related MOF), VOD/SOS progression, or any unacceptable toxicity occurred. The day +100 post-HCT survival rates were 44% and 39%, respectively, with no significant difference between treatment arms (P = 0.619). There was also no significant difference in the rate of adverse events between treatment arms (7% vs 10%, P = 0.563). Due to the lack of differences between the dosages, 25 mg/kg/day was selected for use in phase 3 trials [66].

4.2. Phase 3 study

A phase 3 study was conducted in 102 patients with hepatic VOD/SOS and advanced MOD (i.e., renal and/or pulmonary dysfunction) [4]. The defibrotide group was compared with 32 historical controls from the same institutions who did not receive defibrotide and who were treated before defibrotide was available at their institution. The primary endpoint was post-transplant survival at day +100; complete response to defibrotide was defined as resolution of parameters used to document VOD/SOS and MOD before day +100. Unadjusted survival probabilities at day +100 in the patients who received defibrotide versus the control group were 38.2% versus 25%, respectively. After adjustment for ventilator and/or dialysis dependency at study entry, age (≤16 years vs >16 years), allogeneic versus autologous transplant, and prior HCT (0 vs ≥1) to account for possible imbalance in this nonrandomized setting, there remained a 23% difference between the groups (P = 0.0109). Observed day +100 complete response rates were 25.5% for defibrotide and 12.5% for controls, with an adjusted difference of 19% (P = 0.0160, propensity adjusted; Figure 2). Defibrotide was generally well tolerated with rates of common hemorrhagic adverse events similar to rates observed in historical controls (defibrotide, 64% vs controls, 75%) [4].

Figure 2. Kaplan–Meier estimate of day +100 survival rate and day +100 CR rate. (a) overall survival distribution and (b) time to CR in the defibrotide and historical-control groups to day 100 (supportive). Abbreviations: CI, confidence interval; CR, complete response; HCT, hematopoietic cell transplantation. Republished with permission of the American Society of Hematology, from Richardson et al. [4]; permission conveyed through Copyright Clearance Center, Inc.

4.3. Compassionate-use program

From December 1998 to March 2009, defibrotide was made available to patients through an international CUP [6]. Defibrotide was provided for 1,129 patients, and outcome forms were returned for 710 patients who received at least one documented dose. The recommended dose was initially 10 mg/kg/day with titration to a recommended maximum of 60 mg/kg/day, with some patients receiving 80 mg/kg/day, based on tolerability and clinical efficacy. Subsequently, the dosing recommendation was amended to 25 mg/kg/day after results of the dose-finding study were published in 2004 [6,66]. Across all doses, the pooled Kaplan-Meier estimate of survival at day +100 was 54% (95% CI, 50–58%). The estimated survival at day +100 in 272 patients receiving 25 mg/kg/day was 58% (95% CI, 51–64%). Survival at day +100 was 65% (95% CI, 59–71%) in pediatric patients, and 46% (95% CI, 41–51%) in adult patients. Adult patients without MOD had estimated survival near 65%, versus 46% in those with MOD. Safety results were consistent with previous studies of defibrotide in patients with VOD/SOS. Adverse events were reported in 53% of patients, with the most common being progression of VOD/SOS, MOD, graft-versus-host disease (GvHD), and sepsis [6].

4.4. Expanded-access protocol

In the United States, defibrotide was available through an expanded-access treatment protocol for investigational new drugs (T-IND) to treat VOD/SOS in patients with and without MOD after HCT or nontransplant-related chemotherapy [5]. Patients received intravenous defibrotide 25 mg/kg/day with a recommended treatment duration of at least 21 days. Of these 1,154 patients, n = 1000 (86.7%) underwent HCT before receiving defibrotide (570 children [0 months to 16 years] and 430 adults). Of these patients, 51.2% had VOD/SOS with MOD. The pooled Kaplan-Meier estimated survival at day +100 was 58.9% (Figure 3(a)); survival was 67.9% in the pediatric subgroup and 47.1% for the adult subgroup. The most common treatment-related adverse events were pulmonary hemorrhage (4.6%), gastrointestinal hemorrhage (3.0%), epistaxis (2.3%), and hypotension (2.0%). A post-hoc analysis of patients presenting with symptoms of VOD/SOS revealed that earlier administration of defibrotide was associated with improved survival (nominal P <0.001) [5]. Reasons for any treatment delay were not assessed. While early initiation of defibrotide therapy was associated with better outcomes, late intervention with defibrotide provided clinical benefit as well.

Figure 3. Results of defibrotide T-IND–day +100 survival rates in HCT (A) and non-HCT (B) patients. Abbreviations: HCT, hematopoietic cell transplant; MOD, multi-organ dysfunction; VOD/SOS, veno-occlusive disease/sinusoidal obstruction syndrome. Reused from Kernan et al. [5] (a) and Kernan et al. [10] (b); permissions conveyed through Copyright Clearance Center, Inc.

In a separate T-IND analysis, the effects of defibrotide were reported in patients who developed VOD/SOS following chemotherapy in the absence of HCT [10]. Out of 137 patients, n = 82 initiated defibrotide within 30 days of the first chemotherapy dose. In this group of 82 patients, n = 66 (80.5%) were aged ≤16 years. The overall Kaplan–Meier estimated day +70 survival was 74.1% (95% CI, 63.0–82.3); survival probabilities were 65.8% in patients with MOD (n = 38) and 81.3% in patients without MOD (n = 44), respectively (Figure 3(b)). Estimated survival was 80.1% in pediatric patients (n = 66) and 50.0% in adult patients (n = 16). Treatment-related adverse events occurred in 26.8% of patients and included hemorrhagic events (mouth, 3.7%; pulmonary, 3.7%; epistaxis, 2.4%; hematochezia, 2.4%), as well as encephalopathy, hypotension, and nausea (2.4% each) [10].

A post-hoc analysis of the T-IND study investigated the impact of the timing of initiation of defibrotide following VOD/SOS diagnosis on patient outcomes. This analysis found that earlier initiation of defibrotide was associated with significantly higher day +100 survival in the overall post-HCT population (P ≤0.001); improved survival with early initiation was observed in pediatric patients (P <0.001) and suggested in adults (P = 0.055) [5]. A pooled analysis of the phases 2 and 3 studies and the T-IND study showed that among patients who achieved a complete response more than half of the patients required >3 weeks of persistent treatment with defibrotide (phase 2/3, 53.3%; T-IND, 60.3%) [67]. These analyses suggest that early initiation of defibrotide treatment and continued defibrotide therapy play an important role in outcomes.

4.5. Pooled analysis of clinical trials

In a systematic review of defibrotide studies, a random-effects model was used for pooling data [68]. A total of 10 studies with 1,691 patients who received defibrotide at or close to the approved dosage of 25 mg/kg/day were included. Day +100 survival following HCT in this group was 56% (95% CI, 49–63%). For patients with MOD and without MOD, day +100 survival was 44% (95% CI, 35–52%) and 71% (95% CI, 67–75%), respectively. Safety results were not pooled for this review due to differences in how adverse events were reported, but the range of adverse clinical events was consistent with the known safety profile of defibrotide [68]. Similarly, an observational study from the Center for International Blood and Marrow Transplant Research (CIBMTR) reported that patients with severe VOD/SOS who received defibrotide (n = 41) had an improved rate of resolution of VOD/SOS at day +100 (51%) relative to patients not treated with defibrotide (29%; n = 55) [69].

4.6. Safety evaluation

The safety profile of defibrotide has been consistent across studies, with the most common reported adverse events being hemorrhage and hypotension [4,5,66]. In large clinical trials, the incidence of adverse events in patients treated with defibrotide was comparable to the incidence in control groups receiving best supportive care only [4,6].

The methods used to report adverse events are not uniform across individual studies [4,6,10,66]. Despite this, the reported events from these studies are generally consistent with the safety profile reported in the phase 3 historically controlled trial [4]. In this trial, 101 of the 102 defibrotide-treated patients, and 100% of the 32 historical controls, experienced ≥1 adverse event. Hypotension was the most common single adverse event by preferred term in both groups (defibrotide, 39%; historical controls, 50%), and diarrhea was common in both groups (24% vs 38%). Common hemorrhagic events occurred in 64% of defibrotide-treated patients and 75% of controls in the study. The most frequent hemorrhagic sequelae between those receiving defibrotide versus controls were, respectively, pulmonary alveolar (12% vs 16%), gastrointestinal (8% vs 9%), and cerebral (3% vs 3%). The median time to onset of hemorrhage was longer in the defibrotide group than in the historical-control group (7 vs 3.5 days). Based on the above findings, hemorrhage and hypotension were assessed by investigators as the most common events that were possibly related to defibrotide treatment [4]. In the T-IND study, which included patients with and without MOD, adverse events occurred in 71% of patients post-HCT; 21% of patients had ≥1 adverse event that was deemed by investigators to be at least possibly related to defibrotide treatment [5].

5. Conclusion

In children and adults who develop VOD/SOS after HCT, survival, particularly in those who also have MOD, remains a significant clinical challenge. Over the past three decades, supportive care measures in the early post-transplant period have continued to improve. Despite advances in early detection and improvements in supportive care, the only proven therapy for VOD/SOS with MOD is defibrotide [24]. Updated, prospective diagnostic and severity guidelines are now available for children [7] and for adults [42], and trial results clearly indicate that early initiation of defibrotide when VOD/SOS is diagnosed leads to improved survival outcomes [5]. Though defibrotide’s exact mechanism of action in the setting of VOD/SOS remains to be fully elucidated, in vitro evidence suggests that the drug protects endothelial cells and restores thrombo-fibrinolytic balance, which is a critical step for VOD/SOS reversal [70]. Results from a large phase 3 study [4], as well as findings from both the CUP [6] and T-IND [5] studies, confirm that defibrotide improves outcomes in both pediatric and adults patients with VOD/SOS, with or without MOD.

6. Expert opinion

Early initiation of defibrotide treatment is linked to improved outcomes [5]. Whether prophylactic use of defibrotide might provide additional clinical benefit in patients identified as high risk for VOD/SOS development is currently under investigation. Other therapies proposed for VOD/SOS prophylaxis have included ursodeoxycholate and heparin. Ursodeoxycholate is well tolerated, with minimal evidence for efficacy [71]. Heparin is associated with unacceptable bleeding risk in the post-HCT setting [43].

For defibrotide, one phase 3 controlled open-label study in 356 pediatric patients undergoing HCT reported significantly lower rates of VOD/SOS in children receiving prophylactic defibrotide [72]. The primary endpoint was incidence of VOD/SOS by 30 days after HCT. Of 180 patients in the defibrotide group, 22 (12%) had VOD/SOS 30 days after HCT compared with 35 (20%) of 176 controls (Z test for competing risk analysis P = 0.0488; log-rank test P = 0.0507). Two (1%) of 180 patients in the defibrotide group had VOD/SOS-associated renal failure compared with 10 (6%) of 176 controls (P =0.0169) [72]. A phase 3 trial is currently underway in adults and children at high or very high risk of VOD/SOS comparing defibrotide administered 1 day before the beginning of conditioning for a recommended minimum of 21 days, with best supportive care alone (ClinicalTrials.gov identifier: NCT02851407). Several studies have also examined prophylaxis with defibrotide in adult HCT patients [73–75]. In a retrospective study of 49 patients who received defibrotide as VOD/SOS prophylaxis during the course of HCT, VOD/SOS was occurred in 1 patient and no day +100 treatment-related mortality was reported [73].

The pediatric prophylaxis study also found evidence of reduced incidence of GvHD after allogeneic HCT at 30 days (34% vs 52%) and 100 days (47% vs 65%; P = 0.0046) [72]. A phase 2 trial has been initiated to investigate the potential role of defibrotide in prevention of acute GvHD in adults and children (ClinicalTrials.gov identifier: NCT03339297). The CIBMTR observational study also reported evidence of reduced incidence of GvHD following defibrotide prophylaxis. The day +100 incidence of grade 2 to 4 acute GvHD was 23.1% in patients receiving defibrotide versus 37.7% in patients who did not receive defibrotide. The incidence of grade 3 to 4 acute GvHD was 10.9% versus 28.6%, respectively [69].

Recent analyses investigated the effect of early initiation and continued therapy with defibrotide on patient outcomes. In an analysis of timing of defibrotide initiation in post-HCT VOD/SOS patients, earlier initiation significantly improved survival in pediatric patients (P <0.001) and there was a trend toward improved survival in adult patients (P = 0.055) as well [5]. In a pooled analysis of a phase 2 and a phase 3 study of defibrotide, the time to complete response was >3 weeks in 53.3% of patients [67]. These data suggest that defibrotide treatment should be initiated soon after VOD/SOS diagnosis and maintained until the resolution of symptoms.

The current BCSH/BSBMT guidelines for the treatment and management of post-HCT VOD/SOS recommend defibrotide prophylaxis for pediatric patients with specific VOD/SOS risk factors (e.g., pre-existing hepatic disease, conditioning with busulfan-based regimens) and suggest it for adult patients with similar risk factors [43]. The guidelines also suggest ursodeoxycholic acid for the prevention of VOD/SOS. Additionally, the guidelines recommend defibrotide in the treatment of VOD/SOS in adult and pediatric patients [43].

Finally, future directions for defibrotide include plans to investigate its use in transplant-associated thrombotic microangiopathy and in other settings of endothelial cell injury associated with cellular therapy, such as chimeric antigen receptor T-cell therapy–associated neurotoxicity and other immune-based treatment associated strategies [76].

Article highlights

• Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening condition associated with endothelial cell damage due to hematopoietic cell transplantation (HCT).

• Identifying high-risk patients plays an important role in the prompt diagnosis and early treatment of VOD/SOS.

• VOD/SOS prophylaxis may be an effective strategy for improving patient outcomes.

• Defibrotide has been shown to be an effective treatment for patients with VOD/SOS with multi-organ dysfunction (MOD) and has a favorable safety profile.

• Defibrotide is recommended for VOD/SOS prophylaxis in high-risk patients and is being further investigated for VOD/SOS prevention.

Box 1. Drug summary

Table

Drug name	Defibrotide
Phase	Postmarketing
Indication	Approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States and Canada, and to treat severe hepatic VOD/SOS in patients aged >1 month in the European Union
Date and location of ODD	29 July 2004, in the European Union
Pharmacology description/mechanism of action	Defibrotide binds to the surface of endothelial cells, protecting the endothelium from chemotherapeutic damage
Route of administration	Intravenous infusion
Pivotal trial	Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127(13):1656-1665

Declaration of interest

SA Grupp has served on a steering committee and as a consultant to Jazz Pharmaceuticals. PG Richardson has served on advisory committees and as a consultant and received research funding from Jazz Pharmaceuticals. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank J Trott and L Herold, medical writers at The Curry Rockefeller Group, LLC, Tarrytown, NY, for providing medical writing support, and The Curry Rockefeller Group for editorial support in formatting, proofreading, copy editing, and fact checking, which was funded by Jazz Pharmaceuticals in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

Jazz Pharmaceuticals also reviewed the manuscript to assist with data accuracy as it pertained to sponsored studies and company-supported clinical trials; they then had the opportunity to provide additional information to the authors for their consideration in this context. Although Jazz Pharmaceuticals was involved in the topic concept and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Expert Opinion of Orphan Drugs was made independently by the authors.

Additional information

Funding

Editorial support was funded by Jazz Pharmaceuticals.