1. Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Hepatic Sinusoidal Obstruction Syndrome After Stem Cell Transplantation: Current Management
Supported by an educational grant from Jazz Pharmaceuticals
Image: Don W. Fawcett/Copyright©2015 Science Source. All Rights Reserved

2. Liver Anatomy 101
2. Images provided by The Johns Hopkins University. Used by permission.

3. Cell Toxicity Resulting From Chemo Damages Lining of Liver Sinusoids
Red blood cells
Toxic metabolites
Sinusoidal endothelial cells
Platelets
Toxic metabolites resulting from the HSCT conditioning regimen damage and activate the sinusoidal endothelial cells
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12: Images used by permission.

4. SOS Characterized by Increased Clot Formation and Reduced Clot Breakdown
PAI-1,plasminogen activator inhibitor-1; TF, tissue factor; SOS, sinusoidal obstruction syndrome.
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
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12: Images used by permission.

5. 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.
3. 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;

6. SOS: Risk Factors Pt related[3-5] Transplant related[3-5] 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[3-5]
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
ALT, alanine aminotransferase; AST, aspartate aminotransferase; SOS, sinusoidal obstruction syndrome.
4. 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.

7. 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.
*P < †P < ‡1% of the whole series; 66.7% of severe SOS. §When the pt died of other causes.
3. Coppell JA, et al. Biol Blood Marrow Transplant. 2010;16: Carreras E, et al. Blood. 1998;92:

8. SOS: Clinical Diagnosis
Original Seattle Criteria[7]
Baltimore Criteria[8]
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[8]
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.
8. McDonald GB, et al. Hepatology. 1984;4: DeLeve LD, et al. Hepatology. 2009;49:

9. 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.
10. Chao N. Blood. 2014;123:

10. SOS: Classification
SOS presents with a wide spectrum of severity and is typically categorized as mild, moderate, or severe[7,8]
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.
8. McDonald GB, et al. Ann Intern Med. 1993;118: DeLeve LD, et al. Hepatology. 2009;49:

11. 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.
11. McDonald GD, et al. Ann Intern Med. 1993;18:

12. 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[11]
38.5
(10/26)
9.5
(11/116)
4.97*
( )
.001
Corbacioglu et al 2012[12]
25.0
(14/57)
6.0
(17/285)
18.6†
( )
< .0001
SOS, sinusoidal obstruction syndrome.
*Relative risk between groups. †Difference in risk between groups.
Early diagnosis and treatment is essential!
12. Barker CC, et al. Bone Marrow Transplant. 2003;32: Corbacioglu S, et al. Lancet. 2012;379:

13. 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.
*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.
14. Saito AM, et al. Biol Blood Marrow Transplant. 2008;14:

14. 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.
4. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012:

15. 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.
No Prophylaxis
(n = 176)
SOS
No SOS
13. Corbacioglu S, et al. Lancet. 2012;379:

16. 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.
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)
13. Corbacioglu S, et al. Lancet. 2012;379:

17. 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.
13. Corbacioglu S, et al. Lancet. 2012;379:

18. 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[14]
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[3,15]
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.
1. Richardson PG, et al. Expert Opin Drug Saf. 2013;12: Defibrotide [package insert] 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:

19. 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.
17. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

20. 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. 10
Arm A 25 mg/kg/day (n = 75)
Arm B 40 mg/kg/day (n = 74)
17. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

21. 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.
17. Richardson PG, et al. Biol Blood Marrow Transplant. 2010;16:

22. 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.
19. Richardson PG, et al. ASH Abstract 654.

23. 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.
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
19. Richardson PG, et al. ASH Abstract 654.

24. 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.
25% 20
Defibrotide treatment group 10
Historical control group 10 20 30 40 50 60 70 80 90
100
Days Post-HSCT
19. Richardson PG, et al. ASH Abstract 654.

25. 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.
*Adjusted difference in CR between treatment arms using Normal Approximation and Z-test.
†Propensity-score adjusted difference in CR between treatment arms.
20. Richardson PG, et al. ASH Abstract Mohty M, et al. Bone Marrow Transplant. 2015;50:

26. 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.
20. Richardson PG, et al. ASH Abstract Mohty M, et al. Bone Marrow Transplant. 2015;50:

27. 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.

28. 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.