Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

ABSTRACT

Introduction: Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a complication that is typically associated with conditioning for hematopoietic stem cell transplantation (HSCT). In patients with concomitant multi-organ dysfunction, mortality may be >80%. Recently, the European Society for Blood and Marrow Transplantation established separate criteria for diagnosis and severity of VOD/SOS for adults and children, to better reflect current understanding of the disease.

Areas covered: This review provides an overview of post-HSCT hepatic VOD/SOS and defibrotide, including its pharmacological, clinical, and regulatory profile. In children and adults following HSCT, defibrotide is approved for the treatment of hepatic VOD/SOS with concomitant renal or pulmonary dysfunction in the United States and for the treatment of severe hepatic VOD/SOS in the European Union. Day +100 survival rates with defibrotide are superior to those of historical controls receiving best supportive care only, and safety profiles are similar.

Expert commentary: Defibrotide appears to act through multiple mechanisms to restore thrombo-fibrinolytic balance and protect endothelial cells, and there are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT. An ongoing randomized controlled trial in children and adults will better assess the clinical value of defibrotide as a preventive medication.

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/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT) that causes significant morbidity and, outside of relapse, it is one of the principal causes of transplant-related mortality [1]. For optimal diagnosis and treatment, it is of pivotal importance for physicians to be aware of the substantial and newly recognized differences in VOD/SOS between adult and pediatric patients. Adults with VOD/SOS typically present with fluid retention, ascites, jaundice, weight gain, and painful hepatomegaly, with no other identifiable cause for the hepatic disease [2]. One of the most important features in pediatric patients with VOD/SOS is that up to one-third present without hyperbilirubinemia; this is also the case in severe VOD/SOS [3].

Patients with severe VOD/SOS experience cerebral, renal, or respiratory comorbidities indicative of life-threatening MOD [4]. A 2010 meta-analysis of 19 studies noted an overall mortality rate of >80% for patients with severe VOD/SOS [5]. More recent data show that compared with patients without VOD/SOS, patients with severe VOD/SOS after HSCT have a 5.9-fold higher risk of inpatient mortality and significantly higher healthcare utilization and costs [6]. Studies found a fourfold increased Day +100 mortality in children with the diagnosis VOD/SOS post-HSCT, independent of retroactively assessed severity [7,8].

A meta-analysis of 135 studies that included nearly 25,000 recipients of HSCT between 1979 and 2007 found a 14% mean incidence of VOD/SOS (range, 0–62%) [5]. The incidence of VOD/SOS ranged from 10 to 60% following allogeneic HSCT with myeloablative conditioning regimens and from 5 to 30% following autologous HSCT [3]. More recently, the use of reduced intensity conditioning (RIC) regimens has decreased the incidence of VOD/SOS [3,9], although VOD/SOS still occurs and has been reported in 9% of patients in an RIC setting [10].

In contrast, the incidence of VOD/SOS in children averages to approximately 20% across various studies, with reported incidences as high as 60% in high-risk populations (e.g. infantile osteopetrosis) [8,11,12], making VOD/SOS an important transplant complication of childhood. VOD/SOS has also been reported in children with Wilms tumor, rhabdomyosarcoma, and brain tumors treated with conventional chemotherapy, particularly combination therapies including actinomycin D [3,8,13–16].

In addition to differences between populations, another reason that reported prevalence of VOD/SOS varies in the literature is the use of different diagnostic criteria: the Baltimore criteria (bilirubin ≥2 mg/dL plus 2 or more of ascites, ≥5% weight gain, and hepatomegaly) and the modified Seattle criteria (2 or more of bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2% of baseline), both of which require diagnosis within the first 3 weeks post-HSCT [3–5,17,18]. These criteria are more than 2 decades old, and thus predate important changes in the understanding of the disease (e.g. onset after Day +21, which may occur in 15–20% of cases, and presentation without hyperbilirubinemia in pediatric patients) and in practice (e.g. the widespread use of RIC and the availability of effective therapy) [2,3,19]. Therefore, the European Society for Blood and Marrow Transplantation (EBMT) has proposed updated diagnostic and severity grading criteria for adults [2] and for pediatric patients [3]. Of note, in response to the missing focus of the established criteria on pediatric characteristics, the EBMT has proposed criteria for diagnosis and severity grading specifically for children, which have been separated from the new criteria specifically for adults [2,3].

The new EBMT criteria for diagnosis of VOD/SOS in adults recognize two forms of the disease based on timing of onset (Table 1) [2]. Classical (early onset) VOD/SOS occurs during the first 21 days post-HSCT, as with the Baltimore criteria, and late-onset VOD/SOS occurs >21 days post-HSCT. The EBMT new classification criteria for grading of suspected VOD/SOS in adults are based on onset of first clinical symptoms, bilirubin levels and kinetics (doubling within 48 h is a stand-alone criterion for severe disease), transaminases, weight increase, and renal function (Table 2) [2]. The VOD/SOS EBMT grading system, which needs to be validated in prospective clinical studies, parallels the 5 categories used in the Common Terminology Criteria for Adverse Events (CTCAE): mild (grade 1), moderate (grade 2), severe (grade 3), very severe (grade 4), and death (grade 5). Important contributions of the new adult diagnostic criteria, including recognition of late-onset VOD/SOS beyond Day +21 and the standardized grading of VOD/SOS, will facilitate prospective assessment of these patients and the monitoring of their responses to treatment.

Table 1. New EBMT criteria for VOD/SOS diagnosis in children and adults.

Children [3]	Adults [2]
● No limitation for time of onset of VOD/SOS Presence of ≥2 of the following^a: ● Unexplained consumptive and transfusion-refractory thrombocytopenia^b ● Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain >5% above baseline value ● Hepatomegaly (best if confirmed by imaging)^c above baseline value ● Ascites (best if confirmed by imaging)^c above baseline value ● Rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 h	Classical VOD/SOS (≤21 days post HSCT) Bilirubin ≥2 mg/dL and 2 of the following: ● Painful hepatomegaly ● Weight gain >5% ● Ascites
	Late-onset VOD/SOS (>21 days post HSCT) Classical VOD/SOS beyond day 21 Or Histologically proven VOD/SOS Or Presence of ≥2 of the following: ● Bilirubin ≥2 mg/dL (or 34 µmol/L) ● Painful hepatomegaly ● Weight gain >5% ● Ascites And hemodynamic and/or ultrasound evidence of VOD/SOS

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

^aWith the exclusion of other potential differential diagnoses.

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

^cSuggested: imaging (ultrasound, computed tomography, or magnetic resonance imaging) immediately before HSCT to determine baseline value for both hepatomegaly and ascites.

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. EBMT grading criteria for VOD/SOS in children and adults.

		Pediatric Patients^a [3]				Adult Patients^b [2]
Parameter		Mild	Moderate	Severe	Very Severe MOD	Mild^c	Moderate^c	Severe	Very Severe MOD^d
Persistent RT^e		<3 days	3–7 days	>7 days		–	–	–	–
Time since first clinical symptoms of VOD/SOS^f		– Not included –				>7 days	5–7 days	≤4 days	Any time
Bilirubin	Mg/dL	<2^e,g		≥2^e,g		≥2 to <3	≥3 to <5	≥5 to <8	≥8
	µmol/L	<34^e,g		≥34^e,g		≥34 to <51	≥51 to <85	≥85 to <136	≥136
Ascites^e		Minimal	Moderate	Paracentesis necessary		–	–	–	–
Bilirubin kinetics		–	–	–	Doubling within 48 h	–	–	Doubling within 48 h	–
Transaminases (+GLDH in pediatric patients)		≤2× normal	>2 and ≤5× normal	>5× normal		≤2× normal	>2 to ≤5 × normal	>5 to ≤8× normal	>8× normal
Weight increase		– Not included –				<5%	≥5 to <10%	≥5 to <10%	≥10%
Coagulation		Normal		Impaired	Impaired; need replacement of coagulation factors	– Not included –
Renal function		GFR 89–60 mL/min	GFR 59–30 mL/min	GFR 29–15 mL/min	GFR <15 mL/min (renal failure)	<1.2 × baseline creatinine	≥1.2 to <1.5× baseline creatinine	≥1.5 to <2× baseline creatinine	≥2 × baseline creatinine or other signs of MOD
Pulmonary function (oxygen requirement)		<2 L/min	>2 L/min	Invasive pulmonary ventilation (including CPAP)		– Not included –
Central nervous system		Normal			New onset cognitive impairment	– Not included –

CPAP: continuous positive airway pressure; EBMT: European Society for Blood and Marrow Transplantation; GFR: glomerular filtration rate; GLDH: glutamate dehydrogenase; MOD: multiorgan dysfunction; RT: refractory thrombocytopenia.

^aPatients who fulfill criteria in different categories must be classified in the most severe category. The kinetics of the evolution of cumulative symptoms within 48 h predicts severe disease.

^bPatients who fulfill ≥2 criteria in 2 different categories must be classified in the most severe category.

^cPatients with ≥2 risk factors for VOD/SOS, should be in upper grade.

^dPatients with MOD must be classified as very severe.

^ePresence of ≥2 of these criteria qualifies for an upgrade to very severe VOD/SOS.

^fTime 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.

^gExcluding 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. 2017 [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

The EBMT criteria for diagnosis of VOD/SOS in pediatric patients have no limit for timing of VOD/SOS onset and require the presence of ≥2 of the criteria listed in Table 1 [3]. The EBMT criteria properly reflect, for the first time, the distinct clinical presentation of VOD/SOS in pediatric patients. Persistent refractory thrombocytopenia, an observation already made by McDonald et al. in their seminal paper [18] and by many others [17,20,21] is now recognized as a sensitive marker for early diagnosis in children. Persistence of platelet transfusion dependency is a marker for active disease and severe VOD/SOS. Of note, a fixed level of hyperbilirubinemia is not required, because up to a third of children do not present with this symptom even in severe disease. Also, weight gain is no longer fixed arbitrarily at 2 or 5% (modified Seattle and Baltimore criteria, respectively). The dynamics of the disease are reflected in a steady rise of bilirubin and/or a weight gain despite proper fluid intake and use of diuretics, both over 3 consecutive days. The specificity of the criteria is raised by introducing reproducibility via imaging (ultrasound suggested) of hepatomegaly and/or ascites.

Similar to the adult criteria, the pediatric VOD/SOS EBMT grading system parallels the 5 categories used in the CTCAE (Table 2). Indicators for severe disease include liver function tests (aspartate transaminase, alanine transaminase, glutamate dehydrogenase), bilirubin levels and kinetics (doubling within 48 h of bilirubin kinetics is an indicator of very severe VOD/SOS), severe and productive ascites necessitating paracentesis for relief of imminent respiratory insufficiency, and coagulopathy needing replacement. Renal deficit, pulmonary insufficiency, and new onset cognitive impairment reflect VOD/SOS-associated MOD [3]. Thus, the newly established pediatric criteria for diagnosis best reflect the particularities in children and raise the sensitivity for early diagnosis and prompt therapeutic intervention.

In both adults and children, the pathophysiology of VOD/SOS is linked to endothelial cell (EC) damage and hepatocellular injury, believed to be caused by the toxic metabolites generated by the conditioning regimen used to prepare patients for HSCT [4]. In addition to HSCT, VOD/SOS can also be a complication of conventional radiation therapy and high-dose chemotherapy, especially in children [3], and has been described in the setting of exposure to pyrrolizidine alkaloids, or after solid-organ transplantation [19,22]. The VOD/SOS pathophysiologic cascade promotes a prothrombotic-hypofibrinolytic state, which involves increases in von Willebrand factor and plasminogen activator inhibitor, as well as decreases in thrombomodulin and tissue plasminogen activator [23]. Injured ECs round up, creating gaps in the sinusoidal barrier, and allowing red blood cells, leukocytes, and cellular debris into the space of Disse, promoting sloughing of sinusoidal cells, which embolize downstream, causing obstruction of sinusoidal flow [19]. Thickening of the subintimal zone, sclerosis, and narrowing of the venular lumen contribute to further deterioration of the vasculature [23]. The pathophysiologic cascade may progress to portal hypertension, hepatorenal syndrome, obliteration of terminal hepatic venules, and multiorgan dysfunction (MOD; sometimes called multiorgan failure) [18,21].

The main risk factors for VOD/SOS can be grouped into four categories: transplant related, patient/disease related, hepatic related, and pediatric specific [19]. Careful assessment and screening for risk factors such as obesity, alcoholism, preexisting liver function testing abnormalities, previous imaging abnormalities, and history of viral hepatitis are warranted prior to HSCT [24].

1.1. Overview of treatments for VOD/SOS

1.1.1. Prevention

The two main approaches to prevent VOD/SOS due to patient-related and transplant-related risk factors are to address/reverse risk factors and to use pharmacologic prevention/prophylaxis [1,2,22]. Patient-related risk factors include age extreme, Karnofsky status score below 90%, metabolic syndrome, advanced disease, thalassemia, genetic factors, and hepatic dysfunction [2]. Measures to address patient-related reversible risk factors include reducing iron overload in patients with thalassemia [22] and delaying HSCT until resolution of reversible conditions such as hepatitis and other active disease [2]. Also, for patient-related risk factors involving age and comorbidities, measures to reduce the incidence of VOD/SOS include use of RIC regimens, especially in older adults and adults with comorbidities or who are heavily pretreated [22].

Transplant-related risk factors include unrelated and/or mismatched donor, and use of pretransplant therapy or conditioning known to be toxic to the endothelium (e.g. busulfan) [2]. Measures to address transplant-related risk factors include avoidance of cyclophosphamide with high-dose busulfan (and other high-risk drugs); monitoring of busulfan pharmacokinetics to target a specific therapeutic window; use of intravenous (IV) instead of oral busulfan dosing; and reduced dosing for children [2,9,22]. However, although these measures may reduce the incidence of VOD/SOS, it may still occur after RIC or IV busulfan [10,16,25] or in children with certain high-risk diseases [26].

Pharmacologic prevention entails avoidance of hepatotoxic and nephrotoxic drugs, if possible [2,27], and aggressive fluid management [1]. Currently, there are no drugs with regulatory-approved indications for VOD/SOS prophylaxis, and evidence for most therapies is limited [28]. Use of heparin prophylaxis is controversial: a 2006 meta-analysis of 12 studies found no statistically significant reduction in VOD/SOS risk [29]. However, 2 of 3 randomized controlled trials (RCTs) included in the meta-analysis reported a significant decrease in the incidence of VOD/SOS [19,30–32]. Data on prophylaxis with ursodeoxycholic acid are inconclusive; some studies found a significant benefit, and others have not found a benefit in reducing the incidence of VOD/SOS [19,25,33,34]. Of note, ursodeoxycholic acid reduces bilirubin levels via stimulation of bile acid secretion, but this change in bilirubin may not be therapeutic [35]. As discussed later in this manuscript, a pediatric phase III RCT of prophylaxis in high-risk pediatric patients found reduced incidence of VOD/SOS in patients undergoing HSCT receiving prophylactic defibrotide [26].

1.1.2. Treatment

Defibrotide is the only medication with an approved indication for the treatment of post-HSCT severe hepatic VOD/SOS in the European Union and hepatic VOD/SOS with pulmonary or renal dysfunction in the USA [19]. In particular, in children, it was demonstrated that early use of defibrotide was associated with a better outcome and overall survival [36,37]. The recommended dose is 6.25 mg/kg given every 6 h (25 mg/kg/day) as a 2-h IV infusion administered for ≥21 days and, if symptoms of VOD/SOS have not resolved, continue treatment until resolution of signs/symptoms of VOD/SOS [38] (up to 60 days) [39]. This evidence is reflected in the new pediatric criteria so that the use of this effective medication is moved to ‘almost first suspicion’ of post-HSCT VOD/SOS [3].

In addition, patients are started on supportive care to minimize extracellular fluid accumulation without exacerbating renal damage, with the goal of maintaining baseline weight [4]. Fluids and sodium balance is managed with cautious use of diuretics (e.g. spironolactone, furosemide); hepatotoxic medications (e.g. paracetamol for pain control) should be avoided, if possible [19]. Symptomatic measures to reduce discomfort caused by sizable ascites or pleural effusions include oxygen therapy in conjunction with analgesia [1,19]. Particularly in children, paracentesis and rarely thoracentesis, as appropriate, are the most effective measures to avoid ventilator support due to mechanical obstruction. Patients with fluid accumulation and uncontrolled renal failure require hemodialysis/hemofiltration; MOD requires transfer to an intensive care unit [1,19]. In rare cases, supportive care with a transjugular intrahepatic portosystemic shunt may be considered for patients with less advanced VOD/SOS and there are a few case reports of hepatic transplantation in the most severe diseases [19].

2. Introduction to defibrotide

2.1. Chemistry

Chemically, defibrotide is a sodium salt of polydeoxyribonucleotide. Produced by the controlled depolymerization of porcine intestinal mucosal DNA, defibrotide is composed of 90% single-stranded phosphodiester oligonucleotides (average length 50mer; range 9–80mer) and 10% double-stranded phosphodiester oligonucleotides [40,41]. Defibrotide contains two distinct aptamer sequences that confer its thrombin-antagonizing properties [42].

2.2. Pharmacodynamics

Although not yet completely elucidated, results of preclinical studies indicate that defibrotide has multiple mechanisms of action, primarily involving EC protection, reduced activation, and enhancement of plasmin enzymatic activity [41,43–46].

In preclinical studies, defibrotide prevents the activation of macrovascular and microvascular endothelia caused by soluble factors released to blood by autologous HSCT [43]. Other studies have found that defibrotide binds to ECs, protecting the endothelium from chemotherapy, tumor necrosis factor-alpha, serum starvation, perfusion damage, oxidative stress, and inflammation [41,43,47–50]. Palomo et al. clearly showed that although defibrotide is actively taken up by ECs via macropinocytosis; inhibition of this mechanism did not affect its activity on the manipulation of the expression of various endothelial markers of activation. Therefore, it is thought that defibrotide exerts these protective effects primarily through interaction with EC membranes, but the internalization raises the possibility of other mechanisms of action that require further investigation [47]. Defibrotide also increases tissue plasminogen activator and thrombomodulin expression, and decreases von Willebrand factor and plasminogen activator inhibitor-1 expression, supporting endothelial structure, tone, and function [40,45,46,50–52]. Other researchers have found that defibrotide enhances enzymatic activity of plasmin, leading to the hydrolysis of fibrin clots [45,46,53].

2.3. Pharmacokinetics and metabolism

In healthy volunteers, a single 6.25 mg/kg dose of defibrotide given as a 2-h infusion has a T_max at 2 h, a half-life of approximately 43 min, and does not induce or inhibit cytochrome P450 metabolism [38]. An average of 93% of defibrotide is bound to human plasma protein; the drug’s volume of distribution ranges from 8.1 to 9.1 L [39]. Primarily during the first 4 h following administration of defibrotide 6.25–15 mg/kg doses as 2-h infusions, approximately 5–15% of the total dose is excreted in urine unmetabolized [39]. There is no apparent accumulation of defibrotide after multiple doses in animals, healthy volunteers, and patients with renal impairment [54,55]. Defibrotide is not cleared by intermittent hemodialysis [55].

3. Clinical efficacy of defibrotide in VOD/SOS

3.1. Treatment

3.1.1. Early-phase clinical studies for the treatment of VOD/SOS

Table 3 summarizes the results from the early-phase clinical studies of defibrotide for the treatment of patients with post-HSCT hepatic VOD/SOS. A retrospective analysis of data from 19 patients enrolled in a US multicenter compassionate-use program (CUP) reported initial clinical safety, tolerability, and efficacy data of defibrotide in patients with hepatic VOD/SOS and MOD following HSCT [56]. Eligible patients received defibrotide starting at a dose of 10 mg/kg/day given in four divided doses each as a 2-h IV infusion, for a planned 14-day minimum. Forty-two percent of patients had an observed complete response (CR), defined as evidence of improvement in VOD/SOS-related symptoms with a decrease in bilirubin to <2 mg/dL; 32% of patients survived past Day +100.

Table 3. Early clinical studies of DF for the treatment of severe hepatic VOD/SOS after HSCT.

Study	Pt Characteristics	DF Dosing	Safety	Efficacy^a
US CUP March (pts treated 1995-August 1997) [56]	N = 19 Median age 40 y (range, 4–58) Dx: Hematologic malignancy (n = 13); solid tumor (n = 5); thalassemia (n = 1) HSCT: Allo (n = 8); auto (n = 11)	Dose escalation starting at 10 mg/kg/d (maximum dose 60 mg/kg/day) Median bilirubin at start of DF: 22.3 mg/dL (range, 11.7–54.4)	No DF discontinuation due to toxicity No severe hemorrhage related to DF administration	CR: 42% Day +100 survival: 32% Alive 217–1046 days post-HSCT: 26%
European CUP [57]	N = 40 Median age 30 y (range, 1–64) Dx: Hematologic malignancy (n = 35); breast cancer (n = 2); neuroblastoma (n = 2); Fanconi’s anemia (n = 1) HSCT: Allo (n = 26); auto (n = 14) MOD: 26 (65%) pts	10–40 mg/kg/d Median bilirubin at start of DF: 140.2 µmol/L (range, 8.5–1094.4) Median duration of treatment: 18 d (range, 2–71)	Generally no significant AEs In 1 pt, DF discontinued due to rectal bleeding with hemolysis and thrombocytopenia, unclear if TRAE	CR: 55% Survival at Day +100: 43%
US CUP^b (pts treated March 1995-May 2001) [58]	N = 88 Median age 35 y (range, 0.7–62) Dx: Hematologic malignancy (n = 63); solid tumors (n = 17); nonmalignant disease (n = 8) HSCT: Allo (n = 60); auto (n = 28) MOD: 85 (96%) pts	Dose escalation starting at 10 mg/kg/d Median bilirubin at start of DF: 12.6 mg/dL (range, 2.0–54.4) Median duration of treatment: 15 d (range, 1–139)	No worsening of clinical bleeding No grade 3–4 TRAE Grade 1–2 AEs included nausea, transient mild systolic hypotension, fever, abdominal cramping vasomotor symptoms	CR: 36% Survival at Day +100: 35% Most responses seen at DF doses 20–40 mg/kg/day
European retrospective study of pediatric and adolescent pts treated October 1998-October 2002 [36]	N = 45 Median age 8.2 y (range, 0.2–20) Dx: Hematologic malignancy (n = 28); solid tumors (n = 6); nonmalignant disease (n = 11) HSCT: Allo (82%); auto (18%) MOD: 22 (49%) pts	Median dose: 40 mg/kg/d (range, 10–110) Median bilirubin: 83.8 µmol/L (range, 15.4–744) Median duration of treatment: 17 d (range 1–83)	Coagulation abnormalities present pre-DF in 16 pts did not lead to DF discontinuation DF discontinued in 3 (7%) pts, including 1 pt with diarrhea No other grade 3–4 TRAEs	CR: 76% Survival Day +100: 64% CR in 11 (69%) of 16 pts with coagulation disorders
Randomized phase II dose-finding trial (pts treated April 2000-April 2006) [59]	N = 149 Arm A (n = 75): Median age 32 y (range, 0–61); pediatric (34%), adult (69%); hematologic malignancy (80%), neuroblastoma (3%); other (17%); allo-HSCT (89%) auto-HSCT (11%); >1 compromised organ systems (99%) Arm B (n = 74): Median age 34 y (range, 0–63); pediatric (34%), adult (66%); hematologic malignancy (76%), neuroblastoma (4%); other (20%); allo-HSCT (84%), auto-HSCT (16%); >1 compromised organ systems (97%)	For both arms, starting dose: 10 mg/kg/d Arm A: 25 mg/kg/d Arm B: 40 mg/kg/d Duration of treatment: Arm A (median, 19 d; range, 2–82); arm B (median, 20 d; range 2–65)	Grade 3–4 AEs: All (89%), arm A (85%), arm B (92%) Grade 5 AEs: All (17%), arm A (16%), arm B (19%) Any grade TRAEs: All (8%), arm A (7%), arm B (10%) Grade 3–4 TRAEs: All (3%), arm A (3%), arm B (4%) No TRAEs leading to death 25 mg/kg/day dose selected for phase III DF trials based on more favorable AE profile	CR Overall: All (46%), arm A (49%), arm B (43%) Pediatric pts: All (57%), arm A (70%), arm B (46%) Adult pts: All (40%), arm A (39%), arm B (42%) Day +100 survival Overall: All (42%); arm A (44%); arm B (39%) Pediatric pts: All (52%), arm A (70%), arm B (36%) Adult pts: All (37%), arm A (33%), arm B (41%)

AE: adverse event; allo: allogeneic; auto: autologous; CR: complete response; CUP: compassionate-use program; DF: defibrotide; dx: diagnosis; GVHD: graft versus host disease; MOD: multiorgan dysfunction; NR: not reported; pt(s): patient(s); TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aCR generally defined as bilirubin <34.2 µmol/L (2 mg/dL) and complete resolution of all other MOD- and VOD/SOS-related symptoms.

^bIncludes 19 pts previously reported in [56].

A retrospective analysis of data from 40 patients enrolled in a European defibrotide CUP, including 65% with MOD, reported a 55% CR rate and a 43% survival rate at Day +100 [57]. Updating and expanding on the initial US CUP defibrotide experience, an analysis of data from 88 patients reported a 36% CR rate and a 35% Day +100 survival rate, with no worsening of clinical bleeding and no grade 3–4 treatment-related adverse events (TRAEs) [58]. Similarly, a retrospective exploratory analysis of 2008–2011 data from the Center for International Blood and Marrow Transplantation Research (CIBMTR) reported 39% survival at Day +100 for 41 first-time HSCT recipients with VOD/SOS treated with defibrotide compared with a 31% survival rate in patients with VOD/SOS not receiving defibrotide [60]. CIBMTR further reported a higher rate of VOD/SOS resolution in defibrotide treated patients (51.2%) compared with patients not receiving defibrotide (22.1%).

A retrospective analysis of data from 45 children and adolescents treated with defibrotide for hepatic VOD/SOS after HSCT reported a 76% CR rate and a 64% Day +100 survival rate [36]. Moreover, because the average time from diagnosis to defibrotide was 1 day in patients achieving CR but 5.5 in patients who did not achieve CR, this report showed for the first time that earlier initiation of defibrotide after VOD/SOS onset is associated with improved outcomes.

An open-label, prospective, multicenter, randomized dose-finding trial (25 vs. 40 mg/kg/day) identified defibrotide 25 mg/kg/day as the optimal dose in patients with post-HSCT VOD/SOS with MOD [59]. Based on similar efficacy results between arms (CR rates of 49% and 43% and Day +100 survival rates of 44% and 39% in the 25 and 40 mg/kg day arm, respectively) and somewhat better tolerability in the 25 mg/kg/day arm, 25 mg/kg/day was chosen as the dose to test in future studies. In this study, the recommended minimum duration of treatment was 14 days; however, the median dosing was 19.5 days [59]. Subsequent studies therefore adopted a minimum recommended treatment duration of 21 days [59,61].

3.1.2. Phase III and other large clinical studies for the treatment of VOD/SOS

Table 4 summarizes the design and efficacy results of a phase III trial and two other large clinical studies of defibrotide for hepatic VOD/SOS. A historically controlled open-label phase III trial prospectively evaluated the efficacy and safety of defibrotide 25 mg/kg/day for ≥21 days in patients with post-HSCT VOD/SOS with MOD [61]. Investigators used a historical control group because of logistical and ethical considerations of withholding a promising treatment from a control group of seriously ill patients for a disease with a typically dismal outcome and without proven treatment options. The trial found a statistically significant 23% estimated improvement in Day +100 survival among patients treated with defibrotide (median duration of treatment, 21.5 days) versus the historical control group treated with best supportive care only (P = .0109, propensity adjusted), a statistically significant 19% between group difference in CR rate (P = .0160, propensity adjusted), with tolerability that was generally similar between arms (Figure 1)

Table 4. Phase III and other large clinical studies of DF for treatment or prophylaxis^a of hepatic VOD/SOS after HSCT.

Study	Pt Characteristics	DF Dosing	Efficacy^b
Phase III open-label RCT of defibrotide prophylaxis vs. no prophylaxis in VOD/SOS high-risk children treated with myeloablative conditioning before HSCT (pts treated January 2006–January 2009) [8]	N = 356 DF group (n = 180): Median age 5.1 y (range <1–18); hematologic malignancy (46%), solid tumor (24%), other (30%); allo-HSCT (71%) Control group (n = 176): Median age 4.6 (range <1–18); hematologic malignancy (46%), solid tumor (24%), other (30%); allo-HSCT (69%) Groups had similar baseline characteristics	DF group treated with 25 mg/kg/d starting on same day as pre-HSCT conditioning regimen and continuing for 30 days post-HSCT or for ≥14 days if discharged from hospital before 30 days Median duration of DF prophylaxis: 35 days (range 4–71)	Primary end point VOD/SOS by 30 days post-HSCT: DF 12% vs. control 20% (−7.7% risk difference; P = 0.0507) No difference in median time from HSCT to VOD/SOS t
Nonrandomized historically controlled, open-label, phase III study (DF-treated pts enrolled from July 2006–June 2008) [61]	N = 134 DF group (n = 102): Median age 21 y (range, 0–72); age ≤16 y (43%); ventilator/dialysis dependent at study entry (33%); median bilirubin 4.9 (range 1–41.4); allo-HSCT (88%) Historical control group (n = 32): Median age 18 y (range, 1–57); age ≤16 y (44%); ventilator/dialysis-dependent at study entry (22%); median bilirubin (4.9 (range 2.1–57); allo-HSCT (84%) No statistical differences between groups	DF group treated at 25 mg/kg/d for ≥21 days; continued beyond 21 days until resolution of VOD/SOS or discharge from hospital Median duration of DF treatment: 21.5 days (range 1–58)	Primary end point Day +100 survival: DF 38% vs. control 25%; between-group difference 23% (95% CI, 5.2–40.8; P = .0109) CR by Day +100: DF 26% vs. control 13%; between-group difference 19% (95% CI, 3.5–34.6; P = .0160)
International CUP in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 1998–March 2009) [62]	N = 710 (303 pediatric, 407 adults) Median age 25.0 y (range, 0.2–70.0) Dx in ≥2% of pts: Hematologic malignancy (69%); neuroblastoma (5%); SCID (2%); thalassemia (3%) Type of treatment that led to VOS/SOS: HSCT (89%); non-HSCT chemotherapy/radiotherapy (11%) Type of HSCT: Allo (71%); auto (16%); other (2%) MOD: 292 (41%) pts	Median dose: 25 mg/kg/d (range 10–80) Median duration of treatment: 15 days (range 1–119)	Kaplan–Meier estimate Day +100 survival (n = 701): 54% Day +100 survival: Overall (44%), pediatric (50%), adult (40%)
Expanded-access T-IND protocol in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 2007–December 2013) [63]	N = 681 (n = 573 in the HSCT evaluable population used in this interim analysis) Age groups: ≤16 y (n = 319; 56%); >16 y (n = 254; 44%) Dx: Hematologic malignancy (69%); neuroblastoma (8%); immunodeficiency (3%); other (20%) Type of HSCT: Allo (88%); auto (12%) MOD: 351 (61%) pts	Treated at 25 mg/kg/d for ≥21 days	Kaplan–Meier estimate Day +100 survival (n = 573): Overall (54%), pediatric (54%), adult (45%) Day +100 survival: Overall (50%)

AE: adverse event; allo: allogeneic; auto: autologous; CI: confidence interval; CR: complete response; DF: defibrotide; MOD: multiorgan dysfunction; NR: not reported; pt(s): patient(s); RCT: randomized controlled trial; SCID: severe combined immunodeficiency; HSCT: hematopoietic stem cell transplantation; TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aVOD/SOS prophylaxis is not an approved licensed indication for defibrotide; it is an investigational use.

^bCR generally defined as bilirubin <34.2 µmol/L (2 mg/dL) and complete resolution of all other MOD- and VOD/SOS-related symptoms.

Republished with permission from Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan

Failure, Richardson PG, et al, [published online 11 August 2017]; permission conveyed through Copyright Clearance Center, Inc.

Figure 1. Kaplan-Meier estimates of overall survival (panel A) and time to CR (panel B) for defibrotide-treated patients and historical control group in the phase 3 treatment trial [61].

CI: confidence interval; CR: complete response. 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.

A final analysis from a large international CUP program reported on data from 710 patients with hepatic VOD/SOS following HSCT (89%) or nontransplant-related chemotherapy/radiotherapy treatments (11%) [62]. When the CUP started, the recommended defibrotide starting dose was 10 mg/kg/day (IV 4 divided doses each over 2 h) to be titrated up to a maximum of 60 mg/kg/day; in 2004 the recommended defibrotide dose was changed to 25 mg/kg/day based on a presentation of data from a phase II study later published in 2010 [59]. The Day +100 survival rate was 54% for 701 patients with available data and 58% in the 25 mg/kg/day group (n = 272); in subgroup analyses of Day +100 survival, pediatric patients (65%) fared better than adults (46%; Figure 2), and patients without MOD (52%) fared better than patients with MOD (33%). In the subgroup of patients with chemo/radiotherapy, Day +100 survival was 67.5% in those with MOD and 74.2% for those without MOD.

Figure 2. Survival at Day +100 in pediatric patients (n = 303) and adults (n = 407) from a large compassionate use program [62].

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/.

As part of an expanded access treatment (T-IND) protocol, patients with VOD/SOS (with or without MOD) received IV defibrotide 6.25 mg/kg every 6 h (25 mg/kg/day) with a recommended treatment duration of ≥21 days [63]. In an interim analysis of 681 patients enrolled in the study, 642 met VOD/SOS criteria and received defibrotide; 573 (89.3%) had undergone HSCT, and the other 69 (10.7%) had developed VOD/SOS following chemotherapy alone. The large HSCT population, with a mean age of 20.6 years, included 319 children (age ≤16 years) and 254 adults (age >16 years). Overall, 61.3% of patients had VOD/SOS with MOD and 38.7% did not have MOD. Kaplan–Meier estimated survival at Day +100 was 53.8% for the overall HSCT population, 54.5% for the pediatric subgroup, and 44.9% for the adult subgroup. A subgroup of 76 patients with late-onset VOD/SOS (VOD/SOS diagnosed >30 days post-HSCT (median age, 42 years) had a 34.2% Day +100 survival rate [63]. A post hoc analysis of the smaller post-chemotherapy group (82 patients treated by day 30 after start of chemotherapy) showed a Day +70 survival rate of 74.1% [64]. To explore the impact of time from VOD/SOS diagnosis to start of defibrotide treatment, a post hoc analysis of the HSCT population looked at Day +100 survival for all patients treated before/after days as well as the trend across days for patients treated on each particular day [65]. Approximately one-third of patients were treated on the day of diagnosis and >90% by the end of day 7. The analysis of patients before/after specific days showed that shorter delay was associated with improved survival, which was confirmed by a statistically significant trend across specific days (P < .001). No specific day post-diagnosis proved to be a viable cutoff for this benefit [65].

3.2. Prevention

There are no medications with regulatory approval for the prevention/prophylaxis of VOD/SOS. Several studies suggest that defibrotide has potential in this area. Corbacioglu et al. reported on 20 patients with infantile osteopetrosis, consecutively transplanted between 1996 and 2005 [11]. Eleven patients were transplanted between 1996 and 2001 and experienced an overall incidence of VOD/SOS of 63.6% (7/11). VOD/SOS with MOD occurred in three patients and one patient died due to VOD/SOS-related MOD. Among 9 patients consecutively transplanted between 2001 and 2005 with defibrotide prophylaxis, only 1 patient (11.1%) was diagnosed retrospectively with moderate VOD/SOS.

Another study compared 52 consecutively transplanted adult patients treated with defibrotide prophylaxis versus 52 historical controls [66]. Although none of the defibrotide-treated patients developed VOD/SOS (by Baltimore criteria), 19% of patients in the control group developed VOD/SOS and 3 died due to VOD/SOS. In an updated report of an expanded cohort of 258 treated patients and 258 controls, none of the patients receiving defibrotide developed VOD/SOS compared with 4.8% of controls (P < .001) [67]. Another finding of interest in this HSCT population was that the rate of acute graft versus host disease (GVHD) was significantly lower in the defibrotide group at 1 year (31% vs. 42%; P = .026), although the Day +100 rates were similar (27% and 29%, respectively) [67].

An uncontrolled retrospective analysis of data from 58 patients who received defibrotide prophylaxis during allogeneic HSCT found that none of the patients had VOD/SOS (Baltimore criteria) and none died of suspected VOD/SOS within 100 days of transplantation [68]. Another retrospective analysis of 47 consecutive patients given defibrotide prophylaxis during HSCT found 4 cases of clinical VOD/SOS (modified Seattle criteria) that resolved within 14 days after the dose of defibrotide was increased [69].

A 2012 open-label, phase III RCT compared defibrotide prophylaxis versus no prophylaxis in pediatric patients (age <18 years) with ≥1 risk factors for developing VOD/SOS post-HSCT (Table 4) [26]. Considered risk factors included preexisting liver disease, second myeloablative HSCT, allogeneic HSCT for leukemia beyond second relapse, conditioning with busulfan and melphalan, previous treatment with gemtuzumab ozogamicin, and diagnosis of inherited hemophagocytic lymphohistiocytosis, adrenoleukodystrophy, or osteopetrosis. The study demonstrated a reduction in VOD/SOS onset by Day +30 post-HSCT for the defibrotide prophylaxis versus control (12% vs. 20%; P = .0488 Z test; P = .0507 log-rank test). Adverse events (AEs) were similar between groups (Table 5). The rate of acute GVHD was reduced in the defibrotide arm at 30 days (P = .0057) and 100 days (P = .0034).

Table 5. Defibrotide safety/tolerability in phase III and other large clinical studies.

Study	No. of Pts	Safety
Phase III open-label RCT of defibrotide prophylaxis vs. no prophylaxis in VOD/SOS high-risk children treated with myeloablative conditioning before HSCT [8]	DF group: n = 177 (pts received DF for prophylaxis and for treatment of VOD/SOS) Control group: n = 176 (36 pts received DF for treatment of VOD/SOS)	All AEs: DF 87%, control 88% Serious AEs: DF 61%, control 59% AEs leading to discontinuation: 10, 12% Severe AEs: 37, 37% AEs leading to death: 18, 16% TRAEs (DF arm, control arm): All (6, 4%); serious (1, 3%); leading to discontinuation (1, 2%); severe (2, 3%); leading to death (1%, 0) Overall hemorrhage: DF 22%, control 21% Possible, likely, or certain TRAEs (DF arm, control arm): Coagulopathy (0, 1%); GI hemorrhage (1, 2%); abdominal pain (1%, 0); hemorrhagic diarrhea (1%, 0); hematemesis (1%, 0); mouth hemorrhage (1%, 0); nausea (1%, 0); upper GI hemorrhage (0, 1%); vomiting (1%, 0); prolonged activated partial thromboplastin time (0, 1%); prolonged prothrombin time (1%, 1%); epistaxis (1%, 1%); hemothorax (1%, 1%); pulmonary hemorrhage (0, 1%); hemorrhage (1%, 1%); microangiopathy (0, 1%)
Nonrandomized historically controlled, open-label, phase III study [61]	DF group: n = 102 Historical control group: n = 32	Most common any grade AEs in >13% of DF pts (DF, control): Hypotension (39, 50%); diarrhea (24, 38%), MOD (15, 9%); pyrexia (14, 28%); vomiting (20, 25%) Selected other AEs (DF, control): Common hemorrhagic AEs (64, 75%); coagulopathy (2, 16%); disseminated intravascular coagulation (1, 3%) Median time to hemorrhage onset: DF 7 days, control 4 days Early DF discontinuation possibly due to possible TRAE: 10.7% Fatal AEs (DF, control): All (64, 69%); ≥1 hemorrhagic AE leading to death (15, 6%); most common fatal AE pulmonary alveolar hemorrhage (7, 6%)
International CUP December 1998–March 2009 [62]	N = 710	TRAE data not available Most common AEs: New/worsening MOD (20%), hepatic VOD/SOS progression (11%), sepsis (7%), GVHD (4%), GI hemorrhage (3%) Most common AEs leading to death: New/worsening MOD (20%), VOD/SOS progression (11%), sepsis (7%), GVHD (4%), recurrent cancer (2%), recurrent AML (2%), pneumonia (2%) Withdrawal due to AEs: 9%, primarily due to hemorrhage (7%) and GI disorders (3%)
Expanded-access T-IND protocol in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 2007–December 2013) [63]	N = 573 in the HSCT evaluable population used in this interim analysis	All AEs: 69.6% (similar between MOD and no MOD groups); most commonly hypotension (13.8%) and new or worsening MOD (12.7%) TRAEs: 21.6% (similar between MOD and no MOD groups); most commonly pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.3%), and epistaxis (3.1%) Serious AE: 51.7%; most commonly MOD (12.6%) and progression of VOD/SOS (9.8%) Fatal TRAEs: 3.1%; most commonly pulmonary hemorrhage (0.9%)

AE: adverse event; AML: acute myelogenous leukemia; DF: defibrotide; HSCT: hematopoietic stem cell transplantation; NS: not significant; pt(s): patient(s); RCT: randomized controlled trial; TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

Republished with permission from Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure, Richardson PG et al. [published online 11 August 2017]; permission conveyed through Copyright Clearance Center, Inc.

The results of these and other studies were analyzed in a meta-analysis of 1230 patients, which found an overall mean incidence of VOD/SOS of 4.7% among patients receiving prophylactic defibrotide compared with an incidence of 13.7% in 135 studies not using VOD/SOS prophylaxis (P < .005) [70]. Further, the incidence of severe VOD/SOS was 0.8% in defibrotide patients with a relative risk of 0.31 compared with no prophylaxis [70].

The ongoing, manufacturer-supported, NCT02851407 phase III clinical trial is comparing the efficacy and safety of defibrotide with best supportive care versus best supportive care alone in the prevention of hepatic VOD/SOS in pediatric (age ≥1 month and ≤16 years) and adult patients undergoing HSCT. With a planned enrollment of 400 patients, this study is currently enrolling.

4. Safety profile and tolerability

Table 5 summarizes safety data from the larger, more recent clinical studies. In the studies that compared defibrotide treatment with a control group (best supportive care), the incidence of AEs was comparable between groups [26,61], suggesting that observed AEs might have been associated with preexisting disease, comorbidities, and/or complications of the HSCT.

For example, the phase III historically controlled trial in patients with VOD/SOS and MOD reported that all but 1 of the 102 defibrotide-treated patients and all 32 historical control patients experienced ≥1 AE [61]. 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 in the defibrotide arm included hemorrhagic events and hypotension. In the interim report of the expanded-access T-IND study, which included patients with and without MOD as well as patients who had received chemotherapy without HSCT, AEs that occurred in >10% of patients were hypotension (13.8%) and new or worsening MOD (12.7%), and AEs that were attributed by investigators to treatment occurred in 21.6% of patients [63]. In the pediatric prevention trial, the incidence of AEs was much the same between groups: 154/177 (87%) in the defibrotide prophylaxis group and 155/176 (88%) in the controls [26]. For hemorrhage, the most common treatment-related AE, cumulative incidence was also similar, with 39/177 (22%) in the defibrotide prophylaxis group and 37/176 (21%) in the controls [26].

5. Regulatory affairs

Defibrotide was first approved in Italy in 1986 for deep vein thrombosis prophylaxis and thrombophlebitis treatment, and then in 1993 for the treatment of peripheral obstructive (mild-to-moderate) arteriopathy [54]. The manufacturer withdrew the marketing authorization in 2009 primarily to support the evaluation of defibrotide in clinical trials in the USA and Europe. In October 2013, the European Commission granted orphan marketing authorization with an ‘orphan designation’ for severe hepatic VOD/SOS in HSCT in adults and children older than 1 month [38,71]. In March 2016, the US FDA approved defibrotide for the treatment of adult and pediatric patients with hepatic VOD/SOS, with renal or pulmonary dysfunction following HSCT [39].

6. Conclusions

Clinical studies of defibrotide support its use in the regulatory-approved indication of treatment for hepatic VOD/SOS in children and adults following HSCT, with concomitant renal or pulmonary dysfunction in the USA and in patients with severe VOD/SOS in the European Union [38,39,59,61–63]. Response rates appear favorable in comparison with historical controls, and the safety profile is similar to that of best supportive care [61]. There are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT [26], and an ongoing RCT in children and adults will provide data to better assess the clinical value of defibrotide as a preventive medication.

7. Expert commentary

Defibrotide is the drug with the largest body of evidence for therapeutic efficacy in the treatment of patients with VOD/SOS, with and without MOD. There is mounting evidence that early intervention and even preemptive/prophylactic use of defibrotide in certain high-risk patients may be associated with a superior outcome [11,26,65,66,68,69]. Evidence from a subgroup analysis of Day +100 survival from large studies suggests that defibrotide may be particularly effective in children [62,63] and suggested potential in a phase III pediatric prophylaxis study [26].

Established diagnostic criteria, modified Seattle and Baltimore, may have substantial drawbacks for sensitivity and, considering the lack of hyperbilirubinemia in children, also specificity. Therefore, the new EBMT diagnostic criteria for VOD/SOS in children may well raise the awareness for early symptoms and consecutive preemptive intervention with defibrotide. This might be reflected in a reduced incidence of morbidity and mortality, properly assessable with the new criteria for severity.

In adults, the recognition of late-onset VOD/SOS has the potential to improve recognition and treatment of VOD/SOD after hospital discharge. As with children, new diagnostic and severity criteria also account for recent developments in treatment (e.g. RIC, alternative donors), and future refinements (e.g. imaging modalities as well as identification of signs including refractory thrombocytopenia and biomarkers), are expected to provide increased sensitivity and specificity. When available, anticipated data on prophylactic use of defibrotide in high-risk adult and pediatric patients will provide important new information regarding optimal management of VOD/SOS.

The duration of treatment may be placed in direct correlation to the start of treatment based on diagnostic criteria used (Figure 3). On one end, the rigid Baltimore criteria with the obligatory hyperbilirubinemia might not trigger the diagnosis of VOD/SOS in a third of pediatric patients at all, or may be a late indicator, potentially delaying treatment initiation. On the other end are the pediatric EBMT criteria with the sensitive triggers of refractory thrombocytopenia and the dynamic of weight gain and hyperbilirubinemia. These differences between the Baltimore and new pediatric EBMT criteria might lead to prolonged treatment with futile outcome (Baltimore) versus early onset and a shorter treatment duration (EBMT).

Figure 3. Earlier recognition and treatment of VOD/SOS may reduce time to recovery.

The duration of treatment must be individualized to reflect the dynamics of the diseases. While the labeling for defibrotide recommends treatment for at least 21 days, factors that can affect treatment duration can be divided into 2 categories: dynamic and static. Dynamic criteria are persistent refractoriness to platelet transfusions under treatment; reduced third-spacing reflected in an effective diuresis; ceasing productive/active ascites reflected in a reduced drainage; and the resolution of coagulopathy, reflecting amelioration of hepatocytic damage. Static criteria are persistent flow reversal (if ever present), hyperbilirubinemia, and hepatomegaly. The decision to stop treatment should be based on the following consideration: dynamic criteria must be fulfilled because they represent disease activity on the endothelial level, and static criteria can be fulfilled, since hyperbilirubinemia and hepatomegaly in particular will take longer to resolve, are the consequences of post-endothelial damage, and do not reflect active disease as directly as the dynamic criteria.

There is also a subset of patients (especially pediatric patients) with a very high risk for VOD/SOS who will benefit from the prophylactic use of defibrotide. These include patients with osteopetrosis, hemophagocytic lymphohistiocytosis, and other macrophage activation syndromes, infants, and patients with high-risk neuroblastoma.

8. Five-year view

Areas of potential interest for future studies of defibrotide include the use of higher doses of defibrotide in infants, prophylaxis in specific subgroups (see above), and combination therapies with defibrotide and other endothelial-targeting drugs. Building on data in the treatment of patients receiving chemotherapy without HSCT [62,63], further areas of investigation might include efficacy of defibrotide to treat VOD/SOS due to alkaloid ingestion or solid-organ transplant. The diagnosis of VOD/SOS based on updated pediatric and adult criteria and severity scales is expected to improve timely identification of patients who would benefit from treatment. Future validated biomarkers will help identify patients at risk of VOD/SOS. Another area where defibrotide might find a role is in the prevention of GVHD (as suggested in the phase III pediatric prophylaxis study), transplant-associated microangiopathy, and other systemic endothelial complications.

Key issues

• Clinical studies of defibrotide support its use in the regulatory-approved indication of treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) following hematopoietic stem cell transplantation (HSCT) in children and adults, in severe VOD/SOS (European Union) or with concomitant renal or pulmonary dysfunction (United States).

• Day +100 survival and complete response rates significantly higher in comparison with historical controls.

• The safety profile is manageable.

• There are promising data on the use of defibrotide for VOD/SOS prophylaxis in high-risk children undergoing HSCT.

• An ongoing RCT in children and adults will better assess the clinical value of defibrotide as a preventive medication.

Declaration of interest

Selim Corbacioglu served as a consultant for and received honoraria from Gentium/Jazz Pharmaceuticals. Paul G. Richardson has served on advisory committees and as a consultant, and received research funding from Jazz Pharmaceuticals.

The authors thank Monica Nicosia, PhD, and John Norwood of The Curry Rockefeller Group, LLC, Tarrytown, NY, USA, 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 and edited the manuscript for scientific accuracy. 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 Review of Gastroenterology & Hepatology was made independently by the authors.

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.

Additional information

Funding

Jazz Pharmaceuticals, Inc, provided funding to The Curry Rockefeller Group, LLC, for support in writing and editing this manuscript.