1. Hepatic Sinusoidal Obstruction Syndrome After Stem Cell Transplantation: Current Management
Nelson Chao, MD, MBA Donald D. and Elizabeth G. Cooke Professor Medicine and Immunology Duke University
Chief, Division of Hematologic Malignancies and Cellular Therapy BMT Director Duke Cancer Institute Durham, North Carolina
I am Nelson Chao, MD, Professor of Medicine and Immunology at Duke University in Durham, North Carolina. In this activity, I discuss current management of hepatic sinusoidal obstruction syndrome (SOS) formerly known as veno-occlusive disease, following stem cell transplantation.  
SOS was initially reported in Jamaican children drinking herbal teas that are known to contain pyrrolizidine alkaloids or alkylating agents.
This potentially life-threatening complication can also result from hematopoietic stem cell transplantation (HSCT) related to conditioning regimens that may result in the production of toxic metabolites by the hepatocytes in the liver.[1] In addition, alloreactivity is postulated to play a role in this damage and activation, which could explain the higher rate of these complications after allogeneic SCT and suggests that endothelial injury may be one of the driving forces of graft-vs-host disease (GVHD).
Reference:
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12:
Supported by an educational grant from Jazz Pharmaceuticals

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3. Faculty Disclosure
Nelson Chao, MD, MBA, has no real or apparent conflicts of interest to report.

4. Liver Anatomy 101
The portal vein drains the gut into the liver, where the hepatic artery provides nutrition and oxygenation. The hepatic veins drain into the inferior vena cava and back to the heart. The right lower picture shows a central vein that the portal veins drain into, and the portal triad, which comprises the bile canaliculi, the hepatic capillary, the arterial capillary, and the portal vein. As the blood drains from the portal triad into the central vein, it goes through 3 different zones.
Reference:
Illustration Copyright © by The Johns Hopkins Health System Corporation and The Johns Hopkins University.  Illustration created by Mike Linkinhoker.  With permission from the Johns Hopkins Division of Gastroenterology and Hepatology. (
Images provided by The Johns Hopkins University. Used by permission.

5. Cell Toxicity Resulting From Chemo Damages Lining of Liver Sinusoids
HSCT, hematopoietic stem cell transplantation.
This drawing shows a blood vessel with red cells flowing through it in a pristine, undamaged setting. SOS is initiated when the HSCT conditioning regimen spurs toxic metabolites that damage and activate endothelial cells.[1]
Reference:
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12:
Red blood cells
Toxic metabolites
Sinusoidal endothelial cells
Platelets
Toxic metabolites resulting from the HSCT conditioning regimen damage and activate the sinusoidal endothelial cells
Richardson PG, et al. Expert Opin Drug Saf. 2013;12:

6. SOS Characterized by Increased Clot Formation and Reduced Clot Breakdown
PAI-1,plasminogen activator inhibitor-1; TF, tissue factor; SOS, sinusoidal obstruction syndrome.
In the event of damage, there is the potential for SOS.[1] Damage to the endothelial cells allows for the deposition of fibrin. Expression of adhesion molecules, tissue factor, and plasminogen activator inhibitor-1 is increased. These lead to platelet aggregation, fibrin formation, and increased clot formation in the sinusoids.
SOS pathogenesis is related to zone 3, which is around the central vein and is poorly oxygenated. Zone 3 has a high concentration of glutathione, which is important to metabolize chemotherapy agents. If glutathione is depleted, toxins build up and can result in hepatic necrosis.
Red blood cells
Cytokines
Fibrin
Heparanase
Adhesion molecules
Tissue factor
PAI-1
Platelets
The narrowing of the sinusoids, embolized endothelial cells, and increased clot formation lead to obstruction of the sinusoids, ie, SOS
Richardson PG, et al. Expert Opin Drug Saf. 2013;12:

7. SOS: Clinical Presentation
SOS characterised by
Rapid weight gain
Ascites
Painful hepatomegaly
Jaundice
Right upper quadrant pain
Symptoms usually present within the first 3-4 wks following HSCT but can occur later
SOS can be a progressive disease
Severe SOS is associated with multiorgan failure and a high mortality rate (> 80%)
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
SOS is characterized by the clinical presentation, including rapid weight gain, ascites, painful hepatomegaly, jaundice, and right upper quadrant pain.[2,3] These usually occur within the first 3-4 weeks following transplantation but have been observed to occur later as well. SOS can be progressive in the sense that it is associated with multiorgan failure. If this occurs, there is very high mortality of > 80%.
Coppell JA, et al. Biol Blood Marrow Transplant. 2010;16: Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;

8. SOS: Risk Factors Pt related[1-3] Transplant related[1-3] Age
Malignant disease
Disease relapse
Status of the liver (eg cirrhosis, fibrosis)
High AST/ALT ratio
Previous liver radiation
Viral hepatitis[4]
Iron overload[4]
Transplant related[1-3]
Allogeneic transplant
Donor type
Bone marrow–derived stem cell origin (vs peripheral derived)
Fever in conditioning
Second transplant
Abdominal irradiation
Prior treatment with gemtuzumab
Conditioning regimen
Hepatotoxic drugs
SOS, sinusoidal obstruction syndrome.
Risk factors for SOS can be thought of as 2 different groups.[1-4] One is patient related and includes age, type of disease, relapse, liver status, high aspartate aminotransferase:alanine aminotransferase ratio, previous radiation, viral hepatitis, and iron overload. However, SOS can also be exacerbated or induced by the stem cell transplantation. Of note, allogeneic transplantations confer a higher risk of SOS. Other transplantation-related factors that affect the risk of SOS include the type of donated blood (bone marrow or peripheral), whether a patient is febrile at the time of conditioning, if it is a second transplantation, previous radiation, radiation as part of the preparatory regimen prior to treatment with gemtuzumab, the type of conditioning regimen, and the quantity of hepatotoxic drugs the patient is receiving.
References:
1. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;
2. Carreras E, et al. Bone Marrow Transplant. 2011;46:
3. Carreras E, et al. Blood. 1998;92:
4. EBMT personal communication
1. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012; Carreras E, et al. Biol Blood Marrow Transplant. 2011;17: Carreras E, et al. Blood. 1998;92: EBMT, personal communication.

9. SOS: Incidence Group Studies, n Pts, N Pts With SOS, n
Mean incidence, %
All pts
135
24,980
3425
13.7
Baltimore 33
5261
503
9.6
Seattle 78
14,798
2565
17.3
Auto-HSCT 19
3967
344
8.7*
Allo-HSCT 67
11,285
1453
12.9*
Pre-1994 50
10,943
1260
11.5†
Post-1994 74
12,234
1805
14.6†
Outcome %
Mild SOS
8.0
Moderate SOS
64.4
Severe SOS
27.6
Death due to SOS
18.4‡
Not resolved§
9.2
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
The incidence of SOS is typically 10% to 15% of patients receiving stem cell transplantation.[1,2] The mean incidence has been approximately 14% for decades. The bottom table of patient outcomes shows that mortality for patients who develop severe SOS is nearly 20%.
References:
1. Coppell JA, et al. Biol Blood Marrow Transplant. 2010;16:
2. Carreras E, et al. Blood. 1998;92:
*P < †P < ‡1% of the whole series; 66.7% of severe SOS. §When the pt died of other causes.
Coppell JA, et al. Biol Blood Marrow Transplant. 2010;16: Carreras E, et al. Blood. 1998;92:

10. SOS: Clinical Diagnosis
Original Seattle Criteria[1]
Baltimore Criteria[2]
Presentation before Day 30 post-HSCT of 2 or more of the following:
Jaundice
Hepatomegaly and right upper quadrant pain
Ascites ± unexplained weight gain
Bilirubin ≥ 2 mg/dL (~ 34 µmol/L) before Day 21 post-HSCT and at least 2 of the following:
Hepatomegaly
Ascites
Weight gain ≥ 5% from baseline
Modified Seattle Criteria[2]
Presentation before Day 20 post-HSCT of 2 of the following:
Bilirubin > 2 mg/dL (~ 34 µmol/L)
Hepatomegaly or right upper quadrant pain of liver origin
Unexplained weight gain of > 2% baseline due to fluid accumulation
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
As mentioned, SOS is a clinical diagnosis. The original descriptions were from Seattle[1] and Baltimore.[2] The Seattle criteria include jaundice, hepatomegaly, right upper quadrant pain, and ascites. The Baltimore criteria include hepatomegaly, ascites, and weight gain of more than 5% from baseline. The modified criteria commonly used now comprise hyperbilirubinemia with bilirubin > 2, hepatomegaly, right upper quadrant pain, and an unexplained weight gain > 2% from baseline due to fluid accumulation.
The key problem is that because SOS is a clinical diagnosis and there is no biomarker that defines the disease, weight gain could be due to heart failure or vascular leak or could be primarily from a renal etiology. Hepatomegaly or ascites could result from heart failure or from an infection, posttransplantation liver proliferative disease, or portal vein thrombosis. Jaundice is quite common and can be associated with GVHD, calcineurin inhibitors given to prevent GVHD, biliary infections, total parenteral nutrition, or a plethora of other drugs the patient may be receiving. In addition, jaundice could be due to hemolysis.
There are several ways to distinguish among these competing diagnoses. An important imaging study is Doppler ultrasound of the liver, which helps determine whether ascites is present and how much, if there is reversal in the portal vein, whether the hepatic artery resistance index is > 0.75, and whether there is an abnormal portal vein waveform. If necessary, a liver biopsy can be done, preferably intrajugularly, since most patients will be thrombocytopenic. If they have significant SOS, they will have coagulopathy as well.
References:
1. McDonald GB, et al. Hepatology. 1984;4:
2. DeLeve LD, et al. Hepatology. 2009;49:
1. McDonald GB, et al. Hepatology. 1984;4: DeLeve LD, et al. Hepatology. 2009;49:

11. SOS: Grading Factor Grade of SOS Mild Moderate Severe Bilirubin, mg/dL
< 5
5.1-8
> 8
Liver function
> 3 x normal
3-8 x normal
> 8 x normal
Weight above baseline
< 2%
2% to 5%
> 5%
Renal function
Normal
< 2 x normal
> 2 x normal
Rate of change
Slow
Rapid
SOS, sinusoidal obstruction syndrome.
In my practice, I grade SOS as mild, moderate, or severe, based on the patient’s bilirubin level, liver function test abnormalities, weight, renal function, and, probably of most importance for therapy, the rate of change.[1] Remember, SOS is a clinical diagnosis, and a bilirubin elevation, liver function test abnormality, or weight gain is commonly multifactorial in these patients.
Reference:
1. Chao N. Blood. 2014;123:
Chao N. Blood. 2014;123:

12. SOS: Classification
SOS presents with a wide spectrum of severity and is typically categorized as mild, moderate, or severe[1,2]
Severity of SOS
Symptoms
Mild
Self-limiting
No treatment required
Moderate
Evidence of liver injury
Requires treatment (pain medication, diuretics and other supportive care)
Pts usually recover
Severe
Unresolved symptoms or death before 100 days post-HSCT
Multiorgan failure, severe hyperbilirubinemia with rapid weight gain
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
Mild SOS is self‑limiting and does not require much treatment.[1,2] In moderate SOS, there is clear evidence of liver injury. Treatment is needed, but mostly supportive care. Again, most patients will recover. In patients with severe SOS, however, the symptoms not only persist but progress, leading to multiorgan failure, very high bilirubin levels, and rapid weight gain.
References:
DeLeve LD, et al. Hepatology. 2009;49:
McDonald GB, et al. Ann Intern Med. 1993;118:
1. DeLeve LD, et al. Hepatology. 2009;49: McDonald GB, et al. Ann Intern Med. 1993;118:

13. SOS: Symptoms by Severity
Mild
Moderate
Severe
Weight gain before Day 20, % increase
7.0 (± 3.5)
10.1 (± 5.3)
15.5 (± 9.2)
Maximum total serum bilirubin before Day 20, mg/dL
4.7 (± 2.9)
7.9 (± 6.6)
26.0 (± 15.2)
Pts with edema, % 23 70 85
Pts with ascites, % 5 16 48
Mortality rate before Day 100, % 9 98
SOS, sinusoidal obstruction syndrome.
There is progressively more weight gain with increased severity of symptoms. In one study, 7.0% of patients with mild SOS symptoms had weight gain before Day 20 vs 15.5% of those with severe symptoms.[1] Likewise, bilirubin levels and rates of edema, ascites, and mortality before Day 100 are all higher with more severe symptoms.
Reference:
1. McDonald GB, et al. Ann Intern Med. 1993;118:
McDonald GB, et al. Ann Intern Med. 1993;18:

14. SOS Confers ≥ 4-Fold Higher Risk of Death in Children
Study
Day +100 Mortality in Pts With SOS, % (n/N)
Day +100 Mortality in Pts Without SOS, % (n/N)
Risk of Death (95% CI)
P Value
Barker, et al 2003[1]
38.5
(10/26)
9.5
(11/116)
4.97*
( )
.001
Corbacioglu et al. 2012[2]
25.0
(14/57)
6.0
(17/285)
18.6†
( )
< .0001
SOS, sinusoidal obstruction syndrome.
SOS confers at least a 4-fold higher risk of death in children according to multiple studies. The mortality in pediatric patients with SOS is approximately 5-fold to 19-fold higher than in those without SOS.[1,2] This significantly increased risk of death highlights the importance of early diagnosis and intervention in SOS.
References:
1. Barker CC, et al. Bone Marrow Transplant. 2003;32:79-87.
2. Corbacioglu S, et al. Lancet. 2012;379:
*Relative risk between groups. †Difference in risk between groups.
Early diagnosis and treatment is essential!
1. Barker CC, et al. Bone Marrow Transplant. 2003;32: Corbacioglu S, et al. Lancet. 2012;379:

15. High Costs Associated With Managing Complications of HSCT
Incremental Cost* in US$ 2004
Recovery of neutrophils
48,789
SOS
53,009
IP/DAH
40,741
Infection
17,553
Renal/bladder toxicity
26,775
Neurological toxicity
43,639
Cardiac toxicity
33,256
Grade II-IV acute GVHD
46,414
Relapse
17,890
In-hospital death
50,476
DAH, diffuse alveolar hemorrhage; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; IP, idiopathic pneumonia; SOS, sinusoidal obstruction syndrome.
Saito and colleagues[1] conducted a study that showed the tremendous cost of managing complications associated with HSCT. Results showed that SOS is one of the most expensive complications of HSCT, costing approximately $53,000 in 2004 dollars.
Reference:
1. Saito AM, et al. Biol Blood Marrow Transplant. 2008;14:
*Incremental cost is the estimated cost difference in dollars between pts who have a specific baseline characteristic, experience a specific complication, or relapse and those who do not.
Saito AM, et al. Biol Blood Marrow Transplant. 2008;14:

16. SOS: Prophylaxis
The following drugs have been used with varying success to prevent SOS from the beginning of conditioning until Day post-HSCT
Drug
Evidence for Efficacy
Sodium heparin 100 U/kg/day continuous infusion
2 studies have shown benefit, but others show a strong risk of adverse events with use
Prostaglandin E1
Benefit when combined with heparin; no benefit when administered alone
Ursodeoxycholic acid 600–900 mg/day
4 trials and 2 studies have shown a reduction in SOS incidence
N-acetylcysteine
Limited evidence
Low-molecular-weight heparin
Enoxaparin or fraxiparin are safe and may show benefit
Preemptive antithrombin III replacement therapy
Ineffective
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
Because of toxicity and mortality concerns of SOS, prophylaxis has been a goal for decades.[1] Sodium heparin (low-dose, continuous infusion) has shown a statistically significant decrease in incidence of SOS in 2 studies, but several other trials have shown no benefit, and there is potential for increased bleeding. Prostaglandin E1 is potentially useful to prevent SOS when combined with heparin, but of no benefit when administered alone. Ursodeoxycholic acid is probably one of the most commonly used prophylactic mechanisms, as 4 trials and 2 studies have shown a clear, significant decrease in SOS incidence. Low-molecular-weight heparin has been shown to be potentially beneficial as well as safe. N-acetylcysteine has been used in some cases, but there are few data to support its use. Preemptive use of antithrombin III replacement does not appear to be effective.
Reference:
1. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;
Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012:

17. Phase III EBMT Pediatric Trial: Defibrotide as SOS Prophylaxis After HSCT
Conditioning
Day 30 post-HSCT
Minimum 14 days of treatment
Defibrotide 25 mg/kg/day
Day 1 of conditioning → Day 30 post-HSCT (n = 180)
No SOS
Pts younger than 18 yrs of age at risk of SOS after HSCT (allo or auto)
(N = 356)
Treat until resolution
SOS
allo, allogeneic; auto, autologous; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
Another agent being studied for prophylaxis of SOS is defibrotide, a mixture of oligonucleotides derived from porcine intestinal mucosa prepared by controlled depolymerization of DNA.[1] Corbacioglu and colleagues[2] conducted a phase III open-label trial of defibrotide as SOS prophylaxis after transplantation in a pediatric population. Patients (N = 356) were younger than 18 years of age and at risk for SOS after either allogeneic or autologous SCT. All patients received a conditioning regimen and then transplantation, with 176 randomized to no prophylaxis and 180 to defibrotide from Day 1 of conditioning through Day 30 posttransplantation.
The objective was to assess whether the prophylactic use of defibrotide could reduce the incidence and severity of SOS in high-risk pediatric patients undergoing SCT. The primary endpoint was development of SOS by Day 30 after transplantation, and secondary endpoints were SOS severity and the incidence and severity of acute GVHD.
References:
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12:
2. Corbacioglu S, et al. Lancet. 2012;379:
No Prophylaxis
(n = 176)
SOS
No SOS
Corbacioglu S, et al. Lancet. 2012;379:

18. Defibrotide as SOS Prophylaxis After HSCT (Phase III): Incidence of SOS25 20 15
n = 35 20%
Incidence of SOS (%) 10
n = 22 12% 5
Control (n = 176)
Defibrotide (n = 180)
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
The prophylaxis results showed a significant benefit to defibrotide. A total of 35 patients (20%) in the control group developed SOS compared with 22 (12%) in the prophylaxis group. There was no significant difference in SOS-associated mortality at Day 100: 2% with defibrotide and 6% with no prophylaxis. However, mortality at Day 100 was 4 times higher in patients who developed SOS compared with those who did not (25% vs 6%, respectively).[1]
Reference:
1. Corbacioglu S, et al. Lancet. 2012;379:
No significant difference in SOS-associated mortality at 100 days after HSCT: 2% with defibrotide vs 6% in control group (P = .10)
However, mortality at 100 days was 4 times higher in pts with vs without SOS (25% vs 6%; P < .0001)
Corbacioglu S, et al. Lancet. 2012;379:

19. Defibrotide as SOS Prophylaxis After HSCT (Phase III): Graft-vs-Host Disease
GVHD Parameter, n (%)
Defibrotide (n = 122)
Control (n = 117)
P Value
aGVHD by Day +30
42 (34)
61 (52)
.0057
aGVHD severity by Day +30
Grade 1
Grade 2
Grade 3
Grade 4
21 (17)
13 (11)
4 (3)
26 (22)
5 (4)
.0062
aGVHD by Day +100
57 (47)
76 (65)
.0046
aGVHD severity by Day +100
30 (25)
18 (15)
33 (28)
30 (26)
9 (8)
.0034
aGVHD, acute graft-vs-host disease; GVHD, graft-vs-host disease; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
The rates of GVHD were notable. In the defibrotide arm (n = 122), the rate by Day +30 was 34% with defibrotide vs 52% with no prophylaxis. This was a significant difference (P = .0057).[1] Most cases were grade 1/2, which is an interesting observation that will need to be verified in additional studies.
Reference:
1. Corbacioglu S, et al. Lancet. 2012;379:
Corbacioglu S, et al. Lancet. 2012;379:

20. Defibrotide as Treatment for SOS
Defibrotide is a mixture of oligonucleotides derived from porcine intestinal mucosa[1]
Prepared by controlled depolymerisation of DNA[1]
Defibrotide is approved in the EU for the treatment of severe hepatic SOS in pts undergoing HSCT[2]
Indicated in adults and in adolescents, children, and infants older than 1 mo of age[2]
Defibrotide is recommended by the EBMT and BCSH/BSBMT for the treatment of SOS in adults and children[3,4]
The BCSH/BSBMT also recommended defibrotide for the prophylaxis of SOS[4]
BCSH, British Committee for Standards in Haematology; BSBMT, British Society for Blood and Marrow Transplantation; EBMT, European Group for Blood and Marrow Transplantation; EU, European Union; HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome.
Prevention of SOS is preferable to having to treat the condition for many reasons—one of those reasons being the limited availability of treatment options for SOS. One of the most promising drugs for SOS treatment is defibrotide. It is approved in the European Union, but not yet in the United States, for the treatment of severe hepatic SOS in patients undergoing stem cell transplantation. Defibrotide is indicated for the treatment of SOS in patients older than 1 month of age and is recommended by the European Group for Blood and Marrow Transplantation, the British Committee for Standards in Haematology, and the British Society for Blood and Marrow Transplantation.[2-4] The British groups also recommend defibrotide as prophylaxis for SOS. Defibrotide has received a Fast Track designation for treatment of patients with severe SOS by the US Food and Drug Administration.
References:
Richardson PG, et al. Expert Opin Drug Saf. 2013;12:
Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;
3. Defibrotide [package insert]
4. Dignan FL, et al. Br J Haematol. 2013;163:
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12: Defibrotide [package insert]. 3. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation ; Dignan FL, et al. Br J Haematol. 2013;163:

21. Phase II Trial: Defibrotide in Pts With Severe SOS
Low-Dose Defibrotide
10 mg/kg Day 1, 25 mg/kg/day Days 2-14 (n = 75)
Treat for ≥ 14 days or until CR, SOS progression, unacceptable toxicity, or comorbidities
(n = 141)
Adults and children with severe SOS
(N = 149)
High-Dose Defibrotide
10 mg/kg Day 1, 40 mg/kg/day Days 2-14 (n = 74)
Eligibility: Baltimore criteria or liver biopsy
Randomized, open-label trial
Severe SOS: MOF or 30% risk of severe SOS per Bearman model
Dosing: defibrotide IV in 4 divided doses every 6 hrs
Supportive care given throughout treatment
CR, complete response; IV, intravenous; MOF, multiorgan failure; SOS, sinusoidal obstruction syndrome.
Richardson and colleagues[1] conducted a randomized, open-label phase II trial of defibrotide in patients with severe SOS. Patients (N = 149) were randomized to a low dose (10/25 mg/kg/day) vs a high dose (10/40 mg/kg/day) and were treated for 14 days until CR or progression. Eligibility was determined using either the Baltimore criteria or a liver biopsy. Severe SOS was defined as multiorgan failure or a 30% risk of SOS according to the Seattle criteria (ie, Bearman model[2]). Defibrotide was given intravenously in 4 divided doses every 6 hours, with standard supportive care.
The primary objective was CR, which was defined as a total serum bilirubin level < 2 mg/dL after the initiation of defibrotide, with resolution of all SOS-related multiorgan failure. The secondary objective was to assess safety and determine the dose for phase III trials and other studies. Other goals included resolution of renal, pulmonary, and central nervous system dysfunction, including a creatinine decrease to < 2 times baseline and/or the resolution of dialysis dependence, no oxygen requirement, and no encephalopathy.
References:
1. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:
2. Bearman SI, et al. J Clin Oncol. 1988;6:
Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

22. Phase II Trial of Defibrotide in Severe SOS: OS at Day +100 Post HSCT50 40
% Survival at Day Post-HSCT 30
44% 33/75
39% 29/74 20
HSCT, hematopoietic stem cell transplantation; OS, overall survival; SOS, sinusoidal obstruction syndrome.
Results did not show a statistically significant difference in survival between the high-dose and low-dose arms: Day +100 OS was 39% and 44%, respectively. Because of this, the lower dose was chosen for further testing.[1]
Reference:
1. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16: 10
Arm A 25 mg/kg/day (n = 75)
Arm B 40 mg/kg/day (n = 74)
Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

23. Phase II Trial of Defibrotide in Severe SOS: Grade 3-5 AEs
AE, n (%)
Arm A 25 mg/kg/day
Arm B 40 mg/kg/day
P Value
Any AE
71 (95)
73 (99)
.367
Grade 3/4
64 (85)
68 (92)
.303
Grade 5
12 (16)
14 (19)
.671
Treatment-related AEs
5 (7)
7 (10)
.563
2 (3)
3 (4)
.681 -
Most common grade 3-5 AEs
Renal failure
19 (25)
27 (37)
.159
Hypotension
20 (27)
23 (31)
.591
Hypoxia
13 (17)
25 (34)
.025
Pulmonary, other
16 (21)
17 (23)
.846
AE, adverse event; SOS, sinusoidal obstruction syndrome.
Rates of adverse events were not significantly different between doses, including grade 3/4 events, which were seen in 85% of patients with the lower dose and 92% of patients with the higher dose. However, fewer than 5% of these events were thought to be treatment related. There was slightly less hypoxia with the lower dose.[1]
In summary, there was no significant difference in the CR rate or survival with either dose of defibrotide. Both 25 mg/kg and 40 mg/kg were effective, and the dose of 25 mg/kg/day was selected for further trials due to a slightly more favorable safety profile.
Reference:
1. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:
Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

24. Phase III 2005-01 Trial of Defibrotide in Severe SOS
IV 25 mg/kg/day in 4 divided doses (n = 102)
Pts with severe SOS and MOF after HSCT
(N = 134)
Historical Controls
(n = 32)
Eligibility: Baltimore criteria by Day +21 and renal failure with or without pulmonary failure by Day +28
Defibrotide treatment duration
Minimum: 21 days
Median: 22 days (range: 1-60)
Historical control subjects selected by independent medical review committee (blinded to outcome)
HSCT, hematopoietic stem cell transplantation; IV, intravenous; MOF, multiorgan failure; SOS, sinusoidal obstruction syndrome.
Again, Richardson and colleagues[1] conducted the phase III trial of defibrotide in patients with severe SOS and multiorgan failure after HSCT. The patients (N = 134) received a dose of 25 mg/kg/day for 21 days and were compared with a historical control group that was picked by the eligibility criteria (Baltimore criteria by Day 21, renal failure with or without pulmonary failure by Day 28). The median duration of treatment was 22 days.
The primary objective was the CR rate by Day +100 after HSCT; CR was defined as total bilirubin of < 2 mg/dL and resolution of multiorgan failure. Secondary objectives were OS by Day +100 and Day +180 after the transplantation, safety of the dose, and the schedule of defibrotide. The historical control group was selected by an independent medical review committee, which was blinded to outcomes. Because SOS with multiorgan failure has such high mortality, a trial randomizing patients to placebo or best supportive care was considered but rejected based on ethical concerns.
Reference:
1. Richardson PG, et al. ASH Abstract 654.
Richardson PG, et al. ASH Abstract 654.

25. Phase III 2005-01 Trial of Defibrotide in Severe SOS: CR at Day +10030
Defibrotide treatment group (n = 102)
Historical control group (n = 32) 25 20
CR or Survival by Day +100 (%) 15
24% 10 5 9%
CR, complete response; SOS, sinusoidal obstruction syndrome.
The data showed a clear difference in response and survival at 100 days posttransplantation. The OS and CR rates were significantly better in the defibrotide group. Hemorrhagic events were similar between groups, at 65% to 69%. A total of 18% of treated patients experienced drug-related toxicity that led to discontinuation.[1]
Reference:
1. Richardson PG, et al. ASH Abstract 654.
CR Day +100
Adverse events: hemorrhagic events similar between treatment and control arms (65% vs 69%)
18% of treated pts experienced a drug-related toxicity that led to discontinuation
Richardson PG, et al. ASH Abstract 654.

26. Phase III 2005-01 Trial of Defibrotide in Severe SOS: OS at Day +10090 80
P = Log-rank test 70 60
OS (%) 50 40
38% 30
HSCT, hematopoietic stem cell transplantation; OS, overall survival; SOS, sinusoidal obstruction syndrome.
The Kaplan-Meier curves for OS at Day +100 showed significantly greater survival in the defibrotide group vs historical controls (P = .0341).[1]
In summary, defibrotide improved CR and OS by Day +100 in patients with severe SOS. It was well tolerated, and the toxicities observed in this trial were similar to those seen in previous studies.
Reference:
1. Richardson PG, et al. ASH Abstract 654.
25% 20
Defibrotide treatment group 10
Historical control group 10 20 30 40 50 60 70 80 90
100
Days Post-HSCT
Richardson PG, et al. ASH Abstract 654.

27. Phase III Defibrotide Subset Analysis: Pts With SOS From T-IND Study
201/425 enrolled in T-IND study met eligibility criteria for phase III trial
Consistent efficacy shown in the comparison to the historical control group between T-IND subset and phase III trial (preliminary data):
T-IND Subset
Phase III Trial
Defibrotide
(n = 201)
Control
(n = 32)
(n = 102)
CR (Day +100), % (n/N) 33
(66/201) 9
(3/32) 24
(24/102)
95% CI *
P < .0001 †
P = .0131
Survival (Day +100), % 51 25 38
P = .0005
P = .0341
CR, complete response; SOS, sinusoidal obstruction syndrome.
A related subset analysis of 201 patients enrolled in a different defibrotide trial (T-IND ) who met the same eligibility criteria as for the phase III trial were compared with the historical control group used in the trial.[1,2]
Results showed consistent efficacy between the subset of patients from the T-IND study and defibrotide-treated patients in the trial. CR rates at Day +100 were very similar (33% in T-IND subset and 24% in the phase III trial). OS at Day +100 was also similar (51% and 38%), both favoring the defibrotide-treated groups.
References:
1. Richardson PG, et al. ASH Abstract 700.
2. Mohty M, et al. Bone Marrow Transplant. 2015;50:
*Adjusted difference in CR between treatment arms using Normal Approximation and Z-test.
†Propensity-score adjusted difference in CR between treatment arms.
Richardson PG, et al. ASH Abstract Mohty M, et al. Bone Marrow Transplant. 2015;50:

28. Phase III Defibrotide Subset Analysis: Delay in Defibrotide Initiation
Delay in the initiation of defibrotide > 2 days from SOS/sSOS diagnosis results in significantly lower CR rate and higher mortality at Day +100 post-SCT
Time From SOS Diagnosis to Defibrotide Administration (N = 406)
 2 days
(n = 272)
> 2 days
(n = 134)
P Value
CR (Day +100), % (n/N)
39 (105/272) 25
(33/134)
.0052
Survival (Day +100), % 61 38
< .0001
CR, complete response; SCT, stem cell transplantation; SOS, sinusoidal obstruction syndrome; sSOS, severe sinusoidal obstruction syndrome.
It is notable that there was a difference in survival if there was a delay in starting defibrotide. A delay of more than 2 days from the point of time when severe SOS was diagnosed resulted in a significantly lower CR rate and, of more importance, higher mortality. In this study, the CR rate at Day +100 was 39% with prompt treatment vs 25% for patients who had to wait 2 days or more. Likewise, the OS rate at Day +100 was 61% compared with 38%, respectively.[1,2]
References:
1. Richardson PG, et al. ASH Abstract 700.
2. Mohty M, et al. Bone Marrow Transplant. 2015;50:
Richardson PG, et al. ASH Abstract Mohty M, et al. Bone Marrow Transplant. 2015;50:

29. SOS Management: Future Directions
Earlier intervention
Prior to the development of advanced multiorgan failure
Combination studies
Defibrotide with N-acetylcysteine, antithrombin III, methylprednisolone, other endothelial-targeting agents
Prophylaxis
Allogeneic HSCT, high-risk autologous HSCT
HSCT, hematopoietic stem cell transplantation; SOS, sinusoidal obstruction syndrome. 
Looking forward, current data show that earlier intervention is important for successful treatment of SOS. Treatment and prophylaxis of SOS can help patients avoid advanced multiorgan failure. Studies of defibrotide combinations have shown promising results (eg, with N-acetylcysteine, antithrombin III, methylprednisolone, or other endothelial-targeting agents). Prophylaxis clearly benefits patients receiving either allogeneic or autologous SCT. The European pediatric study showed a significant benefit to defibrotide as prophylaxis, and it would be interesting to study this in adult patients as well.
Future research may also look at high-risk subgroups, such as those who receive sirolimus and busulfan, gemtuzumab, or a mismatched unrelated allogeneic SCT. Other indications that are underpinned by an endothelial injury and activation and the effects of inflammation include GVHD and prevention of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome or other variants of transplantation-related thrombotic microangiopathy.

30. SOS Management: Summary
Traditional SOS prophylactic regimens are either ineffective or have limited evidence supporting their efficacy
SOS management strategies are generally supportive, with nurses playing a key role
The > 80% mortality rate of severe SOS highlights the need for more effective treatment
Defibrotide is indicated for the treatment of severe SOS in adults, children, and infants older than 1 mo of age
Defibrotide recommended for SOS prophylaxis by the BCSH/ BSBMT
Defibrotide is generally well tolerated
BCSH, British Committee for Standards in Haematology; BSBMT, British Society for Blood and Marrow Transplantation; SOS, sinusoidal obstruction syndrome.
In summary, the traditional SOS prophylactic regimens have either been ineffective or have limited evidence supporting their efficacy. SOS management strategy is generally supportive; nurses play a key role. The 80% or higher mortality with severe SOS highlights the need for more effective treatment.
Defibrotide is indicated in Europe for the treatment of severe SOS in patients older than 1 month of age. Defibrotide is recommended for SOS prophylaxis by 2 British medical organizations. Finally, defibrotide is generally well tolerated. Of note, defibrotide is not yet approved in the United States, but a new drug application has been submitted to the US Food and Drug Administration, which has accorded it fast track status.

31. SOS Management: Summary
Many traditional SOS prophylactic regimens are either ineffective or have limited evidence supporting their efficacy
SOS management strategies are generally supportive, with nurses playing a key role
The > 80% mortality rate of severe SOS with multiorgan failure highlights the need for more effective treatment
Defibrotide is indicated in Europe for the treatment of severe SOS in adults, children, and infants older than 1 mo of age
Defibrotide recommended for SOS prophylaxis by the BCSH/ BSBMT
Defibrotide is generally well tolerated
BCSH, British Committee for Standards in Haematology; BSBMT, British Society for Blood and Marrow Transplantation; SOS, sinusoidal obstruction syndrome.
In summary, many of the traditional SOS prophylactic regimens have either been ineffective or have limited evidence supporting their efficacy. SOS management strategy is generally supportive; nurses play a key role. The 80% or higher mortality of severe SOS with multiorgan failure highlights the need for more effective treatment.
Defibrotide is indicated in Europe for the treatment of severe SOS in patients older than 1 month of age. Defibrotide is recommended for SOS prophylaxis by 2 British medical organizations. Finally, defibrotide is generally well tolerated. Of note, defibrotide is not yet approved in the United States, but a new drug application has been submitted to the US Food and Drug Administration, which has accorded it fast track status.

32. Go Online for More CCO Coverage of SCT Complications and Hepatic Disease!
CCO programs and conference coverage on management of hepatic disease InPractice modules on stem cell transplantation and management of post-transplantation complications
clinicaloptions.com/oncology