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

ABSTRACT

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable condition associated with endothelial-cell damage due to conditioning for hematopoietic stem-cell transplantation (HSCT) or chemotherapy without HSCT. Mortality in patients with VOD/SOS and multi-organ dysfunction (MOD) may be >80%.

Areas covered: Defibrotide is the only approved drug for the treatment of severe hepatic VOD/SOS after HSCT in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction in the United States. Its efficacy in patients with VOD/SOS with MOD post-HSCT was demonstrated in a clinical-trial program that included a historically controlled treatment study, a phase 2 trial, and a large T-IND expanded-access program that also included patients without MOD and who received chemotherapy without HSCT.

Expert commentary: Defibrotide appears to protect endothelial cells and restore the thrombolytic–fibrinolytic balance. It addresses a significant clinical need and has demonstrated favorable Day +100 survival and overall adverse-event rates that seem similar to control groups receiving supportive care alone. Currently, defibrotide is under investigation for the prevention of VOD/SOS in high-risk pediatric and adult patients.

KEYWORDS:

• Defibrotide
• endothelial cell activation
• fibrinolysis
• hematopoietic stem cell transplantation
• hepatic veno-occlusive disease
• multi-organ dysfunction
• multi-organ failure
• sinusoidal obstruction syndrome
• thrombosis

1. Introduction

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplantation (HSCT) [1–3]. It is characterized by painful hepatomegaly, hyperbilirubinemia, rapid weight gain, and accumulation of ascitic fluid within the abdomen [1]. VOD/SOS typically develops during the first 21 days following transplantation [4], although delayed onset may occur [3,5,6]. The mean incidence is estimated to be 13.7% (range 0–62%) following myeloablative conditioning for HSCT [7,8], and approximately 9% in a study of patients receiving HSCT with reduced-intensity conditioning [9]. The mortality risk for patients who develop hepatic VOD/SOS with multi-organ dysfunction (MOD), also known as multi-organ failure, typically characterized by pulmonary and/or renal dysfunction, has been estimated to be >80% [7].

VOD/SOS is not a disease restricted to the transplantation setting. It may also develop in patients receiving chemotherapy or calicheamicin–antibody drug conjugates not associated with HSCT [1,3,10]. In a recent interim report from a large prospective treatment study of patients with VOD/SOS, approximately 11% of enrolled patients had not received HSCT [11]. The incidence of VOD/SOS in acute lymphoblastic leukemia patients treated with inotuzumab ozogamicin is higher than in patients receiving standard chemotherapy (13% vs. <1%, respectively) [10]. An increased risk for development of VOD/SOS, with or without HSCT, also has been well recognized in acute myeloid leukemia patients treated with another monoclonal antibody, gemtuzumab ozogamicin [12].

In the transplantation setting, exposure to inotuzumab or gemtuzumab prior to HSCT increases the risk of developing VOD/SOS, which appears to be associated with a shorter time between drug treatment and the start of HSCT conditioning, as well as the type of conditioning [10,12]. Among 212 patients who received inotuzumab in 3 studies, VOD/SOS developed in 2 patients with prior HSCT, 14 with HSCT following inotuzumab, and 5 with HSCT both before and after inotuzumab treatment (of note, VOD/SOS also developed in 5 patients without HSCT) [10]. In the retrospective study of gemtuzumab, 9 (64%) of 14 patients who received gemtuzumab prior to HSCT developed VOD/SOS, in contrast with 4 (8%) of 48 without gemtuzumab exposure prior to HSCT [12].

The British Committee for Standards in Haematology (BCSH) and the British Society for Blood and Marrow Transplantation (BSBMT) guidelines on treatment of VOD/SOS recommend that all patients should be assessed for risk factors before HSCT [4]. Among the known risk factors are pre-transplant patient characteristics (e.g. age, disease type, preexisting liver condition, prior treatment with certain chemotherapeutic agents, prior abdominal radiation) and transplant-related risk factors (e.g. graft type, conditioning regimen, graft-versus-host disease [GVHD] prophylaxis regimen) [3,13]. The BCSH/BSBMT further recommend that reversible patient risk factors (e.g. iron overload in patients with thalassemia) be appropriately addressed prior to HSCT [4].

The multifactorial and complex pathophysiology of VOD/SOS is believed to involve a cascade of injury leading to sinusoidal endothelial cell (EC) and hepatocyte damage [1–3]. It is believed that under conditions where metabolism is impaired (e.g. glutathione store depletion, drug–drug interaction leading to P450 inhibition), toxic chemotherapy and/or its metabolites accumulate in zone 3 of the hepatic acinus. Accumulation of these toxins leads to direct injury and ballooning of sinusoidal ECs, thus compromising the fenestrated endothelium and allowing extravasation of red blood cells into the space of Disse. The resulting extraluminal compression of the sinusoidal tract, combined with sinusoidal thrombosis triggered by platelet activation and proinflammatory/procoagulant activation from direct EC injury, ultimately leads to central venous and/or sinusoidal obstruction [1,2,14,15].

The sloughing of necrotic ECs from the endothelial lining further obstructs the sinusoidal flow [2]. The result is obstruction of central venous blood flow and ischemia in zone 3. Later effects can include collagen deposition and fibrotic obstruction of the central and small hepatic veins [15]. Sinusoidal obstruction may then lead to portal hypertension, reversal of hepatic venous flow, hepatorenal pathophysiology, and MOD [1,16,17].

1.1. Diagnosis

Traditionally, VOD/SOS is diagnosed within 21 days of HSCT by the Baltimore criteria, which require hyperbilirubinemia, or within 20 days by the modified Seattle criteria, for which elevated bilirubin is not mandated [17,18] (Table 1). However, a wide range of presentations has been characterized in the past 20–30 years that is not covered by these criteria [3], and important differences between adults and pediatric patients have been observed [3,19] (Table 2). Use of abdominal ultrasound with Dopplers to assess for portal venous blood flow reversal also may aid in diagnosis in cases where standard clinical criteria are not met. Finally, a liver biopsy, preferably a transjugular approach with measurement of transhepatic venous pressure gradients, can be extremely helpful to establish the diagnosis of VOD/SOS, and rule out other causes of liver injury such as hepatic GVHD [3,5].

Table 1. Criteria established for diagnosis of VOD/SOS patients [5,6,18,19].

		New EBMT criteria for adult patients		New EBMT criteria for pediatric patients
Modified Seattle criteria	Baltimore criteria	Classical VOD/SOS^a	Late-onset VOD/SOS^b	No limitation for time of onset
Presence before day 20 post-HSCT of at least two of the following:	Presence of bilirubin ≥2 mg/dL before day 21 post-HSCT and at least two of the following:	Presence of bilirubin ≥2 mg/dL and at least two of the following:	Classical VOD/SOS beyond Day 21 OR Histologically proven VOD/SOS OR Presence of at least two of the following:	Presence of at least two of the following^c:
Bilirubin ≥2 mg/dL			Bilirubin ≥2 mg/dL (or 34 µmole/L)	Rising bilirubin on three consecutive days^d OR Presence of bilirubin ≥2 mg/dL within 72 h
Hepatomegaly, right upper quadrant pain	Hepatomegaly	Painful hepatomegaly	Painful hepatomegaly	Hepatomegaly^d,e
Ascites with or without unexplained weight gain >2%^d	Weight gain >5%^d	Weight gain >5%^d	Weight gain >5%^d	Unexplained weight gain on three consecutive days (despite the use of diuretics) OR Weight gain >5%^d
	Ascites	Ascites	Ascites	Ascites^d,e
			AND Hemodynamical and/or ultrasound evidence of VOD/SIS	Unexplained consumptive and transfusion-refractory thrombocytopenia^f

EBMT: European Society for Blood and Marrow Transplantation; HSCT: hematopoietic stem cell transplant; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aDay ≤21 post-HSCT.

^bDay >21 post-HSCT.

^cWith the exclusion of other potential differential diagnoses.

^dIncrease from baseline.

^eImaging suggested immediately before HSCT to determine baseline values.

^f≥ 1 weight-adjusted platelet transfusion/day to maintain institutional guidelines.

Adapted from Mohty M et al. Bone Marrow Transplant. 2016;51(7):906–912 and Corbacioglu S et al. Bone Marrow Transplant. [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

Table 2. Major differences in the EBMT’s recently proposed diagnostic criteria for VOD/SOS [6].

Criteria	Adult	Pediatric
Incidence	Approximately 10%	Approximately 20%
		In high-risk patients, up to 60%
Risk factors	Established risk factors	Additional risk factors:
		Infants
		Selected pediatric/genetic diseases with incidences above average
Clinical presentation	Late-onset VOD/SOS is rare	Late-onset VOD/SOS in 20%
	Anicteric VOD/SOS is rare	Anicteric VOD/SOS in 30%
		Hyperbilirubinemia, if present: Is frequently pre-existent Occurs late during VOD/SOS Is typical of severe VOD/SOS
Need for proper assessment of ascites and hepatomegaly		High incidence of disease-related hepatomegaly and ascites pre-HSCT Imaging recommended for confirmation
Treatment		Defibrotide for severe VOD/SOS with MOD associated with better results compared with adults
Prevention		Defibrotide demonstrated efficacy for prevention of VOD/SOS (randomized prospective trial)

MOD: multi-organ dysfunction; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

Adapted from Corbacioglu S et al. Bone Marrow Transplant. [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

The European Society for Blood and Marrow Transplantation (EBMT) has recently proposed updated criteria for VOD/SOS [5,6] (Table 1), as well as detailed prospective severity grades that may facilitate earlier recognition of severe VOD/SOS in pediatric and adult patients [5,6], and guide appropriate treatment [20] (Table 3).

Table 3. New EBMT criteria for severity grading of suspected VOD/SOS [5,6].

Adult
	Mild^a	Moderate^a	Severe	Very severe with MOD^b
CTCAE	1	2	3	4
Time since first clinical symptoms of VOD/SOS^c	>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 ≤48 h
Transaminases (× normal)	≤2	>2 and ≤5	>5 and ≤8	>8
Weight increase^d	<5%	≥5% and <10%	≥5% and <10%	≥10%
Renal function (× baseline creatinine at transplant)	<1.2	≥1.2 and <1.5	≥1.5 and <2	≥2 OR other signs of MOD
Pediatric
	Mild^a	Moderate^a	Severe	Very severe with MOD^b
LFT^e (ALT, AST, GLDH)	≤2 × normal	>2 and ≤5 × normal	>5
Persistent RT^e	<3 days	3–7 days	>7 days
Bilirubin (mg/dL)^e, f Bilirubin (μmol/L)	<2 <34		≥2 ≥34
Ascites^e	Minimal	Moderate	Necessity for paracentesis (external drainage)
Bilirubin kinetics				Doubling ≤48 h
Coagulation	Normal	Normal	Impaired	Impaired
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

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; RT: refractory thrombocytopenia; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aPatients belong to the category that fulfills two or more criteria. In the case of presence of two or more risk factors for VOD/SOS, patients should be placed in the more severe grade.^bPatients with MOD must be classified as very severe.

^cTime from the date when the first signs/symptoms began to appear and the date when the symptoms fulfilled VOD/SOS diagnostic criteria.

^dIncrease from baseline.

^ePresence of ≥2 of these criteria qualifies for an upgrade to CTCAE level 4 (very severe SOS/VOD).

^fExcluding preexistent hyperbilirubinemia due to primary disease.

Adapted from Mohty M et al. Bone Marrow Transplant. 2016;51(7):906–912 and Corbacioglu S et al. Bone Marrow Transplant. [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

2. Body of review

2.1. Overview of treatments

Previous standard-of-care treatment strategies for VOD/SOS after HSCT have focused on supportive care measures, including adequate fluid and sodium balance, and avoidance of hepato- and nephrotoxic drugs [3,4,20,21], whereas an effective therapeutic treatment had remained an unmet medical need. However, clinical trials have now demonstrated the efficacy of defibrotide for the treatment of VOD/SOS in patients with MOD following HSCT, and it is today the only approved treatment available for these patients in the United States and the European Union (see Section 2.5) [22,23].

The clinical evidence for the efficacy and safety of alternative treatments to defibrotide is limited [4]. Data are limited for methylprednisolone [4,24–26] and include a retrospective study of 9 pediatric patients (4 also treated with defibrotide), 8 with MOD, 7 of whom survived [25], and the BCSH/BSBMT guideline notes that it may be considered for use in the treatment of VOD/SOS although caution is recommended due to the risk of infections [4]. On the other hand, N-acetylcysteine did not improve liver toxicity after HSCT [27] and is not routinely recommended for use in the treatment of VOD/SOS due to lack of efficacy [4,27,28]. Fibrinolytic treatment strategies using tissue plasminogen activator (tPA), with or without heparin, have been assessed in a number of small studies [4]. One of the larger studies of tPA (n = 42) retrospectively found 25% Day +100 survival but a 24% rate of severe hemorrhage [29]. Another retrospective study (n = 56) did not report Day +100 survival but suggested that dose-limited tPA may reduce the risk of hemorrhage [30]. Fibrinolytic treatments are generally not recommended by BCSH/BSBMT due to the associated risk of hemorrhage [4]. The BCSH/BSBMT guideline does not recommend prostaglandin E₁, pentoxifylline, heparin (unfractionated and low molecular weight), or antithrombin as prophylaxis due to lack of efficacy and/or increased toxicity [4,31]. Treatment with ursodeoxycholic acid can reduce hydrophobic bile acids that can be toxic to hepatic parenchymal cells, which may reduce the incidence of severe acute GVHD in HSCT patients, and it has been suggested as prophylaxis for VOD/SOS [3,4,32,33]; however, clinical results have been mixed, with a systematic review showing a relative risk of VOD/SOS of 34–36% in adults compared with no treatment [32] while other studies do not, including a prospective, controlled study in 242 HSCT patients that found no difference in incidence of VOD/SOS [33]. In certain cases of refractory ascites and severe portal hypertension, a transjugular intrahepatic portosystemic shunt, or even hepatic transplantation, may be considered after consultation with hepatology and critical care specialists [4,34–37].

2.2. Introduction to defibrotide sodium

2.2.1. Chemistry

Defibrotide (sodium salt) is a complex polydisperse mixture of primarily single-stranded oligodeoxyribonucleotides derived from mammalian tissue (porcine mucosa) by controlled depolymerization [38–42]. It has aptameric activity on the vascular endothelium and antithrombotic, thrombolytic, anti-inflammatory, and anti-ischemic properties [43–45].

2.2.2. Pharmacodynamics

In vitro, defibrotide has been shown to bind to various sites predominantly located on the plasma membranes of the vascular endothelium [44,46]. It acts as an adenosine receptor agonist and is thought to have affinity for receptors A₁ and A₂ [39], although a recent in vitro study was unable to find support for this interaction [46].

Additional in vitro data show that defibrotide is internalized into the ECs, where it promotes protection of activated ECs through profibrinolytic and antithrombotic effects, as well as exhibiting anti-inflammatory and anti-adhesion activity [22,23,44,46,47]. Defibrotide may also provide mild anticoagulant protection of ECs from damage caused by chemotherapy, tumor necrosis factor α, serum starvation, and perfusion, and it may decrease influx and activity of inflammatory mediators, including leukocyte adhesion molecules, without affecting the clinical efficacy of chemotherapy [47–50]. Additionally, defibrotide has been shown to attenuate the generation of reactive oxygen species and restore endothelial nitric oxide synthase levels in the face of oxidative stress [46].

Through increased tPA and thrombomodulin expression, decreased von Willebrand factor, decreased heparanase expression, and decreased plasminogen activator inhibitor-1 activity, defibrotide decreases the procoagulant activity and increases the enzymatic, fibrinolytic activity of plasmin, which support extracellular matrix integrity, tissue homeostasis, and EC structure, as shown in vitro [22,23,39,40,47,48,51–53].

Defibrotide (originally called ‘Fraction P’) was initially approved for the treatment of thrombophlebitis and as prophylaxis of deep vein thrombosis in Italy [44,54]. The rationale for the first use in VOD/SOS began with a search for an agent with demonstrated antithrombotic properties that did not seem to be associated with a substantial increase in bleeding risk [55]. A number of studies suggested the potential efficacy of defibrotide in vascular disorders, including peripheral vascular disease, microvascular thrombotic states, and chemotherapy-related hemolytic uremic syndrome [54,56–58]. Defibrotide has been demonstrated to have no significant or clinically relevant effect on cardiac electrophysiology with no prolongation of the QTc interval at doses 2.4–4 times higher than therapeutically indicated [22,23]. Tolerability of defibrotide appeared to be acceptable with a relative lack of systemic anticoagulant activity, which suggested a possible therapeutic advantage over other available treatments, especially when coupled with a potential for ameliorating diverse manifestations of vascular injury [55]. Based on these properties, however, concomitant use of thrombolytic therapy (e.g. tPA) is contraindicated [22,23].

2.2.3. Pharmacokinetics and metabolism

Defibrotide is administered in 4 doses per day (every 6 h) of 6.25 mg/kg (i.e. 25 mg/kg/day) given as 2-h infusions [22,23]. In healthy subjects, defibrotide has a half-life of ~43 min, T_max at 2 h (end of infusion), and does not induce or inhibit cytochrome P450 metabolism [22,23]. An open-label phase 1 study on the effect of hemodialysis and on severe or end-stage renal disease on defibrotide pharmacokinetics found that dose adjustments in patients with renal impairment are not required due to limited urinary excretion and lack of accumulation [59].

2.3. Clinical efficacy

2.3.1. Early phase/phase 1 studies

The clinical safety, tolerability, and efficacy of defibrotide in VOD/SOS with MOD were first evaluated in a multicenter emergency use program in 1998 [55]. Other early trials provided consistent, promising results, including the early European compassionate-use study [60], and an expansion of the initial study [61]. A retrospective multicenter study in pediatric patients with and without MOD found that Day +100 survival was 64% after treatment with defibrotide, with a corresponding overall rate of complete response to treatment (i.e. resolution of symptoms of VOD/SOS and MOD) of 76% [45] (Table 4). In general, phase 1 studies reported complete response rates of 36–76% and Day +100 survival rates of 32–64% [45,51,55,60,61].

Table 4. Key early phase clinical studies of defibrotide for treatment of VOD/SOS [62].

Study (N)	Condition/Population	Design	Key endpoints	Other results	Conclusions
N = 19 [55]	VOD/SOS with MOD post-HSCT	DF 5–60 mg/kg/d (dose escalation until response/toxicity)	CR: 42% Minimal toxicity at tested doses	Day +100 survival: 32%	CR rate, Day +100 survival and absence of significant DF-associated toxicity was encouraging and warranted further evaluation
N = 40 [60]	VOD/SOS post-HSCT	DF 10–40 mg/kg/d (dose by physician discretion)	CR: 55%	Day +100 survival: 43% No serious TRAEs	European data for CR rate, Day +100 survival; absence of significant DF-associated toxicity
N = 88 [61]	VOD/SOS with MOD post-HSCT	DF 5–60 mg/kg/d (dose escalation until response/toxicity)	CR: 36% Active dose range 25–40 mg/kg/d	Day +100 survival: 35% No serious AEs or TRAEs	CR rate, Day +100 survival; absence of significant TRAEs
N = 45 [45]	VOD/SOS post-HSCT	Retrospective, pediatric patient study; Dose escalation based on tolerability	CR: 76%	Day +100 survival: 64%	In multivariate analysis, early intervention was significantly associated with CR
N = 149 [51]	VOD/SOS with MOD post-HSCT	Randomized, dose-finding, ≥14 days:	Day +100 CR:	Day +100 survival:	DF appears effective
			Arm A, 49%	Arm A, 44%	in treating VOD/SOS with MOD post-HSCT with low rates of TRAEs
		Arm A, DF 25 mg/kg/d	Arm B, 43%	Arm B, 39%
				Overall TRAE incidence: 8% (greater at 40 vs. 25 mg/kg/d)
		Arm B, DF 40 mg/kg/d			25 mg/kg/d selected as phase 3 dose
N = 710 [63]	VOD/SOS post-HSCT or after chemotherapy not associated with HSCT	Global, multicenter compassionate-use program	Day +100 survival:	Day +100 survival:	Safety and efficacy were consistent with previous clinical studies of DF for the management of VOD/SOS with or without MOD; No protocol was in place and reports were voluntary without on-site monitoring
			DF, 54%	DF 25 mg/kg/day, 58%
				Pediatric, 65.4%
		DF 10–80 mg/kg/d:		Adult, 46.1%
		Median dose, 25 mg/kg/d Median duration, 15 days		Without MOD: 64.7%
				With MOD: 39.7%
				Non-HSCT without MOD: 74.2%
				Non-HSCT with MOD: 67.5%
				(Kaplan–Meier estimated survival)
				AEs:
				Overall incidence, 53%
				DF 25 mg/kg/day, 47%

AE: adverse event; CR: complete response; DF: defibrotide; HSCT: hematopoietic stem cell transplant; MOD: multi-organ dysfunction; TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

Republished with permission of Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure, Richardson PG, et al, 6(3), and 2017; permission conveyed through Copyright Clearance Center, Inc.

2.3.2. Phase 2 studies

An open-label, prospective, multicenter, randomized dose-finding phase 2 trial compared 2 doses of defibrotide (25 mg/kg/day [n = 75] and 40 mg/kg/day [n = 74]) and found no significant difference in efficacy between doses [51]. In the study, the minimum recommended duration of treatment was 14 days; however, defibrotide was administered for medians of 19 and 20 days, respectively, in the 25- and 40-mg/kg/day arms. Rates of complete response, the primary endpoint, and Day +100 survival post-HSCT were 46% and 42%, respectively. The overall incidence of treatment-related adverse events (AEs) was similar for the low and high doses (7% and 10%, respectively). Pediatric patients demonstrated similar incidences of bleeding events for the low and high doses (68% vs. 52%; P = 0.377), although hypotension was apparently more common among those receiving the higher dose (52% vs. 26%; P = 0.083). Those receiving the higher dose had a numerically higher incidence of AEs assessed as being likely or definitely related to defibrotide (68% vs. 39%; P = 0.081) [51]. Based on these efficacy and safety findings, defibrotide 25 mg/kg/day was selected as the dosage for investigation in the historically controlled treatment trial discussed in Section 2.3.3, with a recommended minimum duration of 21 days.

In a large international multicenter compassionate use program (n = 710), conducted between December 1998 and March 2009 [63], defibrotide at 10, 25, 40, 60, or 80 mg/kg/day was administered for a median of 15 days to patients with VOD/SOS, with or without MOD (89% of patients had received HSCT). While the overall Kaplan–Meier estimated Day +100 survival was 54%, it was 58% for the 25 mg/kg/day dose group (the approved dose; 65.4% in the pediatric and 46.1% in the adult 25 mg/kg/day dose subgroups). Patients without MOD had an estimated survival of 64.7% compared with 39.7% among those with MOD. The highest estimated survival, 74.2%, was in the subgroup of non-HSCT patients without MOD (n = 41). AEs were reported by 53% of patients, most commonly MOD (20%), progression of VOD/SOS (11%), sepsis (7%), and GVHD (4%). In the 25 mg/kg/day dose-group, 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].

Figure 1. Outcome from international compassionate-use program [63]. Survival to Day +100 by dose (N = 701). ^a

Vertical lines signify censored data. ^aExcludes nine patients with missing HSCT or nontransplantation-associated chemo-radiotherapy dates. ^bApproved dose in the European Union and in the United States. CI, confidence interval; HSCT, hematopoietic stem cell transplantation. Reprinted from Biology of Blood and Marrow Transplantation, 22/10, Corbacioglu S, et al, Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program, 1874–1882, Copyright (2016), with permission from American Society for Blood and Marrow Transplantation. doi:10.1016/j.bbmt.2016.07.001. URL for Creative Commons user license: https://creativecommons.org/licenses/by-nc-nd/4.0/.

2.3.3. Comparative studies of defibrotide for VOD/SOS treatment

In a historically controlled treatment trial, the efficacy and safety of defibrotide at 25 mg/kg/day in VOD/SOS with MOD were compared with those of patients from a historical control group who met the study’s inclusion criteria but were treated at the study’s centers prior to the availability of defibrotide at that institution (Figure 2) [64]. Initiation of a randomized study had been rejected on ethical grounds due to the life-threatening nature of VOD/SOS with MOD, the lack of effective alternative agents, and compelling evidence of efficacy from several prior defibrotide studies. To identify an appropriate control group, nearly 7000 medical charts of HSCT patients hospitalized at each participating center were sequentially reviewed in reverse chronological order starting 6 months prior to the first approved use of defibrotide at that site. This methodology was designed to control for institutional standards of care. Treatment was recommended for at least 21 days, and the median duration of treatment was 21 days, which was similar to the 21-day timeframe between median day of diagnosis and onset of complete response. The trial confirmed significantly higher Day +100 survival rates for patients receiving defibrotide vs. best supportive care (38.2% vs. 25.0%, respectively, with a propensity-adjusted between-group estimated difference of 23%; P = 0.0109) and higher Day +100 complete response rates (25.5% vs. 12.5%, respectively, propensity-adjusted between-group estimated difference of 19%; P = 0.160), with tolerability that was generally similar between arms. AEs occurred at a frequency of 98% and 100% for the defibrotide and historical control groups, respectively. The most common AEs were hypotension (39.2% and 50.0%, respectively) and diarrhea (23.5% and 37.5%, respectively). No difference was observed in the overall incidence of common hemorrhagic AEs (64% and 75%, respectively) [64].

Figure 2. Kaplan–Meier estimated survival to Day +100 in the historically controlled treatment trial [64].

Republished with permission of American Society of Hematology, from Phase 3 Trial of Defibrotide for the Treatment of Severe Veno-Occlusive Disease and Multi-Organ Failure, Richardson PG, et al, 127, 13 and 2016; permission conveyed through Copyright Clearance Center, Inc.

An expanded-access treatment (T-IND) protocol for the treatment of VOD/SOS in patients with and without MOD, had the clinical objective to make defibrotide 25 mg/kg/day available for patients and generate prospective data on outcomes [11]. This open-label, single-arm study was designed to provide access to defibrotide and did not include onsite monitoring. Interim results from the T-IND study, which encompassed a broadly inclusive VOD/SOS patient population and was the largest prospective evaluation of defibrotide for treatment of VOD/SOS to date (N = 642), showed an overall Day +100 survival of 50.3% and 45.3% for the subgroup with MOD. The Day +100 survival was 54.5% and 44.9% in the pediatric and adult subgroups, respectively. AEs were reported in 69.6% of patients, most commonly hypotension (13.8%) and new or worsening MOD (12.7%). Overall, AEs assessed as treatment-related were reported in 21.6% of patients, and were generally similar between patients with and without MOD. The most common treatment-related AEs were pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.3%), and epistaxis (3.1%), which were consistent with prior studies of defibrotide [54]. The recommended duration of treatment was ≥21 days (median, 21 days) [11], which was similar to the previously observed length between median time to diagnosis (13 days) and median time to onset of complete response (34.5 days) in the historically controlled treatment study [64], as well as the median length of treatment in a phase 2 trial [51].

A post-hoc exploratory analysis of 573 HSCT patients from the T-IND study, including 351 (61.3%) with MOD, demonstrated a significant trend for improved Day +100 survival with earlier treatment initiation post-diagnosis, which was confirmed by the Cochran-Armitage trend test (P < 0.001) in both the overall post-HSCT population and the MOD subgroup [65]. Overall, 31.9% of patients received defibrotide on the day of diagnosis, and 93.0% had initiated treatment by day 7 post-diagnosis; reason for treatment delay was not assessed. Moreover, there was no day post-diagnosis that provided a clinically apparent cutoff for better outcomes, and earlier treatment was consistently associated with a survival benefit. These results are consistent with a previous pediatric study, which reported that patients with complete response had an average treatment delay of 1 day from diagnosis to initiation of treatment, compared with an average 5.5 days in those who did not achieve complete response [45].

The results from the historically controlled treatment trial are further supported by those of a study using retrospective 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]. Among these patients with VOD/SOS, 1.2% (n = 101) had concomitant MOD and 3.3% (n = 275) did not have MOD. For analysis, patients with VOD/SOS and MOD were further divided into two groups: treated (n = 41) and not treated (n = 55) with defibrotide. The overall Day +100 survival was 39% in patients receiving defibrotide compared with 30.9% in those not receiving defibrotide. The Day +100 survival was 40.0% and 37.5% for pediatric and adult patients receiving defibrotide, respectively. Resolution of VOD/SOS at Day +100 was 51% in the defibrotide group (56% for pediatric and 43.8% for adult patients), and 29% in the non-defibrotide group. In addition, defibrotide was associated with reduced incidence (23.1% vs. 37.7%) and severity of acute GVHD compared with patients not receiving defibrotide (Table 5) [66].

Table 5. Comparative studies of defibrotide for VOD/SOS treatment [62].

Study N	Condition/Population	Design	Key endpoints	Other results	Conclusions
Historically controlled	VOD/SOS with advanced MOD post-HSCT	Nonrandomized comparison of DF 6.25 mg/kg IV every 6 h/ 25 mg/kg/d for ≥21 days vs. controls	Day +100 CR: DF, 24%	Day +100 survival:	DF improves survival and CR by Day +100 in patients with VOD/SOS and MOD post-HSCT; DF is generally well tolerated
				DF, 38%
N = 134			Control, 9% (P = 0.0131)	Control, 25% (P = 0.0341)
DF: 102
				Hemorrhagic AEs:
Controls: 32 [64]				DF, 65%
				Control, 69%
T-IND	VOD/SOS with and without MOD	Open-label T-IND DF 6.25 mg/kg IV every 6 h/ 25 mg/kg/d for ≥21 days	Day +100 survival: 50.3% (Kaplan–Meier estimate, 53.8%)	Day +100 survival:	DF improves survival in diverse population;
N = 642				With MOD, 45.3%
Post-hoc: 573 [11,65]				Without MOD, 58.1%	earlier initiation of treatment appears to be beneficial
				Pediatric, 54.5%
				Adults, 44.9%
				AEs were reported by 69.6% of patients
				Delayed initiation of treatment shows a significant increased Day +100 mortality (P < 0.001)
Observational	VOD/SOS with MOD	Observational data submitted to CIBMTR	Day +100 survival:	Day +100 survival:	DF improves survival and CR by Day +100 in patients with severe VOD/SOS; DF may reduce the cumulative incidence of GVHD
N = 8431 [66]			DF, 39% Non-DF, 30.9%	DF, pediatric, 40.0%
				DF, adults, 37.5%
				Resolution of VOD/SOS:
				DF, 51%
				Non-DF, 29%
				DF, pediatric, 56%
				DF, adults, 43.8%
				Incidence of GVHD:
				DF, 23.1%
				Non-DF, 37.7%

AE: adverse event; CIBMTR: Center for International Blood and Marrow Transplantation Research; CR: complete response; DF: defibrotide; GVHD: graft versus host disease; HSCT: hematopoietic stem cell transplant; IV: intravenous; MOD: multi-organ dysfunction; T-IND: treatment investigational new drug expanded access protocol; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

Republished with permission of Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure, Richardson PG, et al, 6(3), and 2017; permission conveyed through Copyright Clearance Center, Inc.

2.3.4. Phase 3 studies for the prevention of VOD/SOS

With the goal of assessing the prophylactic effects of defibrotide on the development of VOD/SOS, an open-label, randomized, controlled phase 3 trial of 356 pediatric patients at high risk of developing VOD/SOS post-HSCT was conducted [41]. Patients were randomly allocated to receive defibrotide at 25 mg/kg/day for VOD/SOS prevention vs best supportive care. Patients in either arm were allowed to receive defibrotide as treatment if VOD/SOS developed. The study reported a substantial reduction in VOD/SOS onset by Day +30 post-HSCT for the defibrotide prophylaxis group vs control group (incidence 12% vs 20%; P = 0.0488, Z test; P = 0.0507, log-rank test). The AE rates were similar between groups. Moreover, as in the CIBMTR observational study, the rate of acute GVHD was reduced in the defibrotide arm at 30 (P = 0.0057) and 100 days (P = 0.0034) [41].

Defibrotide is being investigated in an ongoing international trial as prophylaxis in adult and pediatric patients receiving HSCT who are at high and very-high-risk of developing VOD/SOS (ClinicalTrials.gov identifier, NCT02851407) [67].

2.3.5. Safety profile and tolerability

The incidence of AEs in patients receiving defibrotide is comparable to that in control groups, which suggests that the observed AEs may be associated with preexisting illnesses, comorbidities, or complications of the HSCT, rather than the treatment [41,54,64]. Among the AEs assessed as treatment-related, hemorrhage and hypotension were found to be the most common [41,51,54,64]. AE reporting methodology differed for individual studies; however, they were generally consistent with the safety profile found in the historically controlled trial [64], which reported an overall AE incidence of 99% in the treated patients and 100% in the untreated controls. Hypotension was the most frequent AE (39% for defibrotide, 50% for controls), and common hemorrhagic AEs, which included pulmonary alveolar and gastrointestinal hemorrhage, occurred in 64% of defibrotide-treated patients and 75% of controls. Related AEs included hemorrhage and hypotension [64]. In addition to VOD/SOS, defibrotide has demonstrated acceptable tolerability in the treatment of severe malaria, as well as a number of cardiovascular conditions, such as deep vein thrombosis, chronic venous insufficiency, peripheral vascular disorders, thrombophlebitis, microangiopathy, and acute myocardial infarction [54].

2.4. Regulatory affairs

Originally approved in Italy for the treatment of thrombophlebitis and prevention of deep vein thrombosis, and later for the treatment of mild-to-moderate peripheral obstructive arteriopathy, defibrotide has been investigated for the treatment of peripheral obliterative arterial disease, arterial sufficiency, and symptoms of phlebitis [68]. The drug was ultimately withdrawn in 2009 at the request of the marketing authorization holder [69], primarily to support investigation of other indications.

In October 2013, defibrotide was granted marketing authorization by the European Commission (European Medicines Agency) as the first approved treatment of severe hepatic VOD/SOS after HSCT therapy, indicated in adults and pediatric patients ≥1 month of age [69]. In March 2016, defibrotide became the first drug approved by the United States Food and Drug Administration for the treatment of adult and pediatric patients with hepatic VOD/SOS and renal or pulmonary dysfunction following HSCT [22,70].

3. Conclusions

Hepatic VOD/SOS is a potentially fatal condition that is thought to result from a pathophysiologic cascade following EC damage, frequently due to the conditioning regimen for HSCT [3]. VOD/SOS with MOD has been associated with a mortality rate of >80% by Day +100 post-HSCT [7]. Defibrotide has demonstrated efficacy in the treatment of these critically ill patients when compared with supportive care alone and has an overall AE rate that is similar to that of the best supportive care [5,54].

Defibrotide appears to protect the ECs at a key early juncture in the pathophysiologic cascade of VOD/SOS, through its profibrinolytic and antithrombotic effects, as well as its anti-inflammatory and anti-adhesion properties [46,54].

Defibrotide is the only approved drug in the United States and the European Union with VOD/SOS indications: 25 mg/kg/day for at least 21 days for the treatment of VOD/SOS post-HSCT [3,5,6,22,23], in patients with severe VOD/SOS in the European Union and in patients with pulmonary or renal dysfunction in the United States (treatment up to 60 days). Moreover, earlier initiation of treatment after diagnosis has been associated with significantly improved Day +100 survival in a post-hoc analysis [65]. Although defibrotide is still under active investigation for prevention of VOD/SOS in high-risk adult and pediatric patients scheduled to undergo HSCT, a previous phase 3 pediatric prevention trial showed promising results.

4. Expert commentary

Although developments in transplantation technique and evolution of supportive care have improved the survival for patients with VOD/SOS, defibrotide meets a significant current clinical need. Defibrotide, which is thought to restore the thrombolytic–fibrinolytic balance and provides EC protection, has consistently demonstrated favorable Day +100 survival rates while offering an AE rate that is similar to best supportive care. The rarity and dismal outcomes associated with VOD/SOS with MOD impose ethical limitations on study design; however, when all the data are taken together, these studies show a consistent effect across a large proportion of patients with this disease. In contrast, alternative and unapproved treatment options typically have limited support for efficacy and/or problematic safety profiles. Defibrotide is the only therapy approved in the United States for treatment of VOD/SOS with renal or pulmonary dysfunction post-HSCT and the European Union for the treatment of severe VOD/SOS post-HSCT.

Improved management and care of patients pre-HSCT, systematic risk assessment and management, rapid and accurate diagnosis, and prompt initiation of defibrotide treatment post-diagnosis are important tools to improve the Day +100 survival. Looking ahead, further research on defibrotide as prophylaxis for VOD/SOS is warranted, and an ongoing phase 3 trial is investigating the efficacy and safety of this drug plus best supportive care compared with best supportive care alone in the prevention of hepatic VOD/SOS in high- or very-high-risk adult and pediatric patients undergoing HSCT (ClinicalTrials.gov identifier NCT02851407).

5. Five-year view

Adoption of the new EBMT diagnosis and severity guidelines will help refine identification and treatment protocols for patients with VOD/SOS. More accurate delineation of risk factors for VOD/SOS could encompass identification of potential biomarkers and dynamic clinical markers that could alert clinicians to earlier diagnosis and subsequently, earlier initiation of treatment with defibrotide. In addition, results of the ongoing prophylaxis trial (NCT02851407) will inform decisions about the use of defibrotide to prevent occurrence of VOD/SOS. Finally, other areas of interest for further investigation could build on the current understanding of the therapeutic profile of defibrotide, and identify specific subgroups that may benefit from treatment, such as sirolimus-exposed patients, prior gemtuzumab or inotuzumab use, and patients with mismatched, unrelated allogeneic HSCT. These could include prophylaxis in specific patient cohorts (e.g. patients undergoing high-risk allogeneic HSCT; Clinicaltrials.gov identifier NCT02851407), combination therapies using defibrotide and other endothelial targeting agents, endothelial injury/activation and thrombofibrinolytic effects in conditions with similar underlying pathophysiology, the role in other syndromes characterized by microangiopathy [54,56], and effect on prevention of acute GVHD [41,71,72].

Key issues

• Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is associated with conditioning for hematopoietic stem-cell transplantation (HSCT), calicheamicin-antibody drug conjugates, or chemotherapy alone, which may damage the sinusoidal endothelium and lead to platelet activation and thrombosis. In patients with VOD/SOS and multi-organ dysfunction (MOD), the mortality rate may be >80%.

• Defibrotide, which is thought to restore thrombofibrinolytic balance, is the only drug approved for the treatment of severe VOD/SOS with MOD in adult and pediatric patients after HSCT.

• Efficacy of defibrotide was demonstrated in a historically controlled treatment study in patients with VOD/SOS and MOD and a phase 2 trial; these results were supported by those of a large phase 3 T-IND expanded-access study, which included subgroups (pediatric and adult patients, post-chemotherapy, VOD/SOS without MOD).

• Safety of defibrotide seems to be similar to that of best supportive care alone. Rates of adverse events were similar between treatment and control populations (eg, a historically controlled treatment study and a phase 3 pediatric prevention study).

• Defibrotide is not approved for use as prophylaxis; however, a phase 3 trial found reduced incidence of VOD/SOS in a high-risk pediatric population treated with prophylactic defibrotide, and the drug is being further investigated in an ongoing phase 3 trial in adults and children (ClinicalTrials.gov identifier, NCT02851407).

Declaration of interest

P Richardson has served on an advisory board and received research funding from Jazz Pharmaceuticals. V Ho has received honoraria from Jazz Pharmaceuticals. N Chao reports research funding from Jazz Pharmaceuticals. F Dignan has received honoraria and research funding from Jazz Pharmaceuticals. M Mohty has received honoraria and 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Medical writing assistance supported by Jazz Pharmaceuticals was provided by Daniel Famer, PhD, The Curry Rockefeller Group and John Norwood, The Curry Rockefeller Group.

Additional information

Funding

Editorial support for this manuscript was funded by Jazz Pharmaceuticals.