Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC Hepatic Sinusoidal Obstruction Syndrome After Stem Cell Transplantation:

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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

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

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;12:123-136. Images used by permission.

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;12:123-136. Images used by permission.

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;16:157-168. 4. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;176-195.

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;176-195. 5. Carreras E, et al. Biol Blood Marrow Transplant. 2011;17:1713-172. 6. Carreras E, et al. Blood. 1998;92:3599-3604. 7. EBMT, personal communication.

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 < .001 †P < .05 ‡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;16:157-168. 6. Carreras E, et al. Blood. 1998;92:3599-3604.

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;4:116-122.9. DeLeve LD, et al. Hepatology. 2009;49:1729-1764.

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;123:4023-4026.

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;118:255-267. 9. DeLeve LD, et al. Hepatology. 2009;49:1729-1764.

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;18:255-267.

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* (2.11-11.71) .001 Corbacioglu et al 2012[12] 25.0 (14/57) 6.0 (17/285) 18.6† (7.1-30.1) < .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;32:79-87. 13. Corbacioglu S, et al. Lancet. 2012;379:1301-1309.

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;14:197-207.

SOS: Prophylaxis The following drugs have been used with varying success to prevent SOS from the beginning of conditioning until Day +21-30 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. 2012:176-195.

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;379:1301-1309.

Defibrotide as SOS Prophylaxis After HSCT (Phase III): Incidence of SOS 25 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;379:1301-1309.

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;379:1301-1309.

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;12:123-136. 15. Defibrotide [package insert]. 4. Carreras E. In: Apperley J, et al, eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. 2012;176-195. 16. Dignan FL, et al. Br J Haematol. 2013;163:444-457.

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;16:1005-1017.

Phase II Trial of Defibrotide in Severe SOS: OS at Day +100 Post HSCT 50 40 % Survival at Day +100 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;16:1005-1017.

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;16:1005-1017.

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 2009. Abstract 654.

Phase III 2005-01 Trial of Defibrotide in Severe SOS: CR at Day +100 30 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 2009. Abstract 654.

Phase III 2005-01 Trial of Defibrotide in Severe SOS: OS at Day +100 90 80 P = .0341 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 2009. Abstract 654.

Phase III Defibrotide Subset Analysis: Pts With SOS From T-IND Study 201/425 enrolled in T-IND-2006-05 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 14.1-41.1* P < .0001 3.6-31.0† 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 2013. Abstract 700. 21. Mohty M, et al. Bone Marrow Transplant. 2015;50:781-789.

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 2013. Abstract 700. 21. Mohty M, et al. Bone Marrow Transplant. 2015;50:781-789.

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.

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.