PATHOPHYSIOLOGY OF VOD/SOS

VOD/SOS can progress to multi-organ failure within a few days1

Take a closer look at the cascade of events that precedes the clinical manifestations of VOD/SOS.

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Progressive cascade of VOD/SOS

Based on experimental models, buildup of toxic metabolites from HSCT conditioning regimens may trigger activation of and damage to sinusoidal endothelial cells in the liver. This can lead to a cascade of events that is potentially life-threatening.2-5

Hepatocytes

Hepatocytes

endothelial cell

Endothelial cells

red blood cell

Red blood cells

white blood cell

White blood cells

platelet activated

Platelets

extracellular matrix

Extracellular matrix

1 healthy sinusoid

Healthy sinusoid

  • Sinusoidal endothelial cells provide a barrier between the blood and hepatocytes and regulate hemostasis, permeability, vascular tone, and immune and inflammatory responses6
2 endothelial damage

Endothelial damage

  • Activation of endothelial cells triggers expression of cytokines and adhesion molecules, activating inflammatory pathways that cause additional endothelial damage4,5
  • Release of the enzyme heparanase contributes to degradation of the extracellular matrix, loss of cytoskeletal structure, and gap formation between sinusoidal endothelial cells3,5
  • Degradation of the extracellular matrix leads to detachment of endothelial cells from the sinusoidal lining6,7
3 sinusoid narrowing

Sinusoidal narrowing

  • This ongoing degradation of the endothelium allows red blood cells, leukocytes, and cellular debris to move into the space of Disse3-5
  • This can lead to sinusoidal narrowing, which may lead to endothelial cells embolizing downstream and contribute to sinusoidal blockage3-5
4 sinusoid blockage

Sinusoidal blockage

  • Sinusoidal endothelial cell damage also triggers the expression of multiple factors that regulate coagulation and fibrinolysis (table A)2,4,5
  • All of these events can lead to a procoagulant and hypofibrinolytic state, where fibrin deposition, clot formation, and sinusoidal narrowing can cause further blockage2,4,5
  • Hepatocyte cell death is a consequence of sinusoidal disruption, and further sinusoidal obstruction may lead to a reduction in hepatic venous outflow and to postsinusoidal hypertension3-6

The cascade of events appears to start before clear clinical and LABORATORY manifestations are evident.4,5,8

TABLE A: FACTORS THAT REGULATE COAGULATION AND FIBRINOLYSIS5,9,10

Factor
Function
von Willebrand factor
Stimulates platelet aggregation
Tissue factor
Promotes activation of factor X
Plasminogen activator inhibitor-1
Reduces fibrinolysis

Clinical manifestations and progression of VOD/SOS

Sinusoidal obstruction may lead to a reduction in hepatic venous outflow and to postsinusoidal hypertension, resulting in clinical signs and symptoms.3-5

Most common signs and symptoms of VOD/SOS3,8,11

  • Excessive platelet transfusions consistent with refractory thrombocytopenia
  • Weight gain due to fluid retention
  • Hepatomegaly
  • Right upper quadrant pain
  • Elevated bilirubin
  • Elevated serum transaminase and alkaline phosphatase
  • Ascites

Vigilant monitoring for the first 21 days after hsct is critical to detect VOD/SOS.11

Although VOD/SOS generally emerges within the first 21 days, it can occur later.11,12

Recognize the factors shown to greatly increase the risk of VOD/SOS in patients post HSCT8,12-15

Level of Riska

Patient and Disease-
Related Risk Factors

HEPATIC-RELATED
RISK FACTORS

TRANSPLANT-RELATED
RISK FACTORS

10-20 times
greater risk

  • Prior norethindrone treatment
  • Previous inotuzumab treatment
  • Previous gemtuzumab treatment
  • Bilirubin >1.5 mg/dL

3-10 times
greater risk

  • GSTM1 null genotype
  • Sepsis post HSCT
  • Age (age <2 years, older age)
  • Previous liver disease
  • Ferritin ≥950 ng/mL
  • Elevated AST/ALTb
  • High intensity/MAC regimens
  • GvHD prophylaxis
  • Horse ATG treatment
    (aplastic anemia)

1-3 times
greater risk

  • Inborn errors of metabolism
  • Leukemia diagnosis
  • Previous abdominal radiation
  • Impaired pulmonary function
  • KPS score <90%
  • ECOG PS 2-4
  • Advanced disease status
  • Elevated AST/ALT
  • Hepatitis C
  • Previous HSCT
  • Allogeneic vs autologous HSCT
  • Unrelated/HLA mismatch
  • Total body irradiation
  • Early neutrophil engraftment

aBased on odds ratio. Odds ratio represents the odds that a complication will occur if the risk factor is present, compared with the odds of the complication occurring if the risk factor is absent.15

bThe odds ratio for elevated AST/ALT ranges from 2.4 to 4.6.14

Previous use of inotuzumab and gemtuzomab carries increased risk for VOD/SOS

Incidence of VOD/SOS post HSCT following prior inotuzumab ozogamicin treatment16,17

INO-VATE ALL Phase 3 Clinical Study
 

Incidence of VOD/SOS post HSCT following prior gemtuzumab ozogamicin treatment18

Restrospective Clinical Trial Analysis

cIn a study of 58 patients (including 1 adolescent) with R/R B-ALL to evaluate treatment with inotuzumab ozogamicin prior to allo-HSCT between 2016 and 2022. Seventeen of 56 patients had VOD/SOS, and 9 of those patients (53%) died due to VOD/SOS with multi-organ failure.16

dIn a Phase 3 multicenter, open‐label, randomized study that included 326 patients (inotuzumab ozogamicin [n=164] or investigator's choice of chemotherapy [n=162]) with R/R ALL, 79 of whom received inotuzumab ozogamicin and subsequent allogeneic HSCT. Five of the 18 VOD/SOS events that occurred post HSCT were fatal. Of the 32 patients in the standard care group (n=143) who underwent follow-up HSCT, 1 case of VOD/SOS was reported and was fatal.17,19

More recent treatment options carry their own risks of VOD/SOS

CAR T20

Retrospective, multicenter study of 39 adult patients who underwent an allo-HSCT after anti-CD19 CAR T therapy between January 2017 and April 2021 for LBCL. It demonstrated that this CAR T therapy may pose a high risk for hepatic toxicity and VOD

Risk factors in patients with hepatic VOD:

Conditioning intensitye:

  • Low: n=4
  • Intermediate: n=2

Interim anticancer therapy:

  • Received 1 therapy: n=2
  • Received 2 therapies: n=1

Gene therapy21

Phase 3 trial of 52 patients with transfusion-dependent β-thalassemia who received gene therapy after preparing with busulfan conditioning, which poses a known risk of VOD

Hepatic VOD was the most common serious AE, occurring in 5 of 52 patients, and was attributed to busulfan conditioning

eLow-intensity conditioning was thiotepa-based and intermediate-intensity conditioning included fludarabine and treosulfan.20

Myeloablative conditioning Regimens ALSO heighten the risk of VOD22

An open-label, randomized, placebo-controlled study of patients undergoing myeloablative HSCT found VOD incidence of 12% (n=22/180)

Discover diagnostic criteria

IMPORTANT SAFETY INFORMATION AND INDICATION

Contraindications

Defitelio is contraindicated in the following conditions:

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Warnings and Precautions

Hemorrhage

Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.

Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Please see full Prescribing Information.

Indication

Defitelio® (defibrotide sodium) is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT).

IMPORTANT SAFETY INFORMATION

Contraindications

Defitelio is contraindicated in the following conditions:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy
  • Known hypersensitivity to Defitelio or to any of its excipients

Warnings and Precautions

Hemorrhage

Defitelio may increase the risk of bleeding in patients with VOD after HSCT. Do not initiate Defitelio in patients with active bleeding. Monitor patients on Defitelio for signs of bleeding. If bleeding occurs, withhold or discontinue Defitelio.

Concomitant systemic anticoagulant or fibrinolytic therapy may increase the risk of bleeding and should be discontinued prior to Defitelio treatment. Consider delaying Defitelio administration until the effects of the anticoagulant have abated.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, urticaria, and angioedema have occurred in less than 2% of patients treated with Defitelio. One case of an anaphylactic reaction was reported in a patient who had previously received Defitelio. Monitor patients for hypersensitivity reactions, especially if there is a history of previous exposure. If a severe hypersensitivity reaction occurs, discontinue Defitelio, treat according to the standard of care, and monitor until symptoms resolve.

Most Common Adverse Reactions

The most common adverse reactions (incidence ≥10% and independent of causality) with Defitelio treatment were hypotension, diarrhea, vomiting, nausea, and epistaxis.

Please see full Prescribing Information.

AE=adverse event; ALL=acute lymphoblastic leukemia; ALT=alanine aminotransferase; AML=acute myeloid leukemia; AST=aspartate aminotransferase; ATG=antithymocyte globulin; CAR T=chimeric antigen receptor T-cell; CD19=cluster of differentiation 19; ECOG PS=Eastern Cooperative Oncology Group performance score; FDA=Food and Drug Administration; GSTMI=glutathione S-transferase mu 1; GvHD=graft-vs-host disease; HLA=human leukocyte antigen; HSCT=hematopoietic stem-cell transplantation; KPS=Karnofsky Performance Scale; LBCL=large B-cell lymphoma; MAC=myeloblative conditioning; R/R=relapsed/refractory; SOS=sinusoidal obstruction syndrome; VOD=veno-occlusive disease.

References: 1. Yoon JH, Min GJ, Park SS, et al. Incidence and risk factors of hepatic veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation in adults with prophylactic ursodiol and intravenous heparin or prostaglandin E1. Bone Marrow Transplant. 2021;56(7):1603-1613. 2. Coppell JA, Richardson PG, Soiffer R, et al. Hepatic veno-occlusive disease following stem cell transplantation: incidence, clinical course, and outcome. Biol Blood Marrow Transplant. 2010;16(2):157-168. 3. Carreras E. Early complications after HSCT. In: Apperley J, Carreras E, Gluckman E, Masszi T, eds. The EBMT Handbook. 6th ed. Paris, France: European School of Haematology; 2012:176‐195. 4. Richardson PG, Ho VT, Cutler C, et al. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. Biol Blood Marrow Transplant. 2013;19(suppl 1):S88-S90. 5. Richardson PG, Corbacioglu S, Ho VT, et al. Drug safety evaluation of defibrotide. Expert Opin Drug Saf. 2013;12(1):123-136. 6. Vion AC, Rautou PE, Durand F, et al. Interplay of inflammation and endothelial dysfunction in bone marrow transplantation: focus on hepatic veno-occlusive disease. Semin Thromb Hemost. 2015;41(6):629-643. 7. DeLeve LD, Shulman HM, McDonald GB. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease). Semin Liver Dis. 2002;22(1):27-41. 8. Cairo MS, Cooke KR, Lazarus HM, Chao N. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation. Br J Haematol. 2020;190(6):822-836. 9. Coppell JA, Brown SA, Perry DJ. Veno-occlusive disease: cytokines, genetics, and haemostasis. Blood Rev. 2003;17(2):63-70. 10. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood. 1995;85(11):3005-3020. 11. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2015;168(4):481-491. 12. Mohty M, Malard F, Abecassis M, et al. Revised diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a new classification from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2016;51(7):906-912. 13. Corbacioglu S, Jabbour EJ, Mohty M. Risk factors for development of and progression of hepatic venoocclusive disease/sinusoidal obstruction syndrome. Biol Blood Marrow Transplant. 2019;25(7):1271-1280. 14. Dalle JH, Giralt SA. Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: risk factors and stratification, prophylaxis, and treatment. Biol Blood Marrow Transplant. 2016;22(3):400-409. 15. Szumilas, M. Explaining odds ratios. J Can Acad Child Adolesc Psychiatry. 2010;19(3):227-229. 16. Kayser S, Sartor C, Giglio F, et al. Impact of inotuzumab ozogamicin on outcome in relapsed or refractory acute B-cell lymphoblastic leukemia patients prior to allogeneic hematopoietic stem cell transplantation and risk of sinusoidal obstruction syndrome/venous occlusive disease. Haematologica. 2024;109(5):1385-1392. 17. Besponsa [prescribing information]. New York, NY: Pfizer. 18. Magwood-Golston JS, Kessler S, Bennett CL. Evaluation of gemtuzumab ozogamycin associated sinusoidal obstructive syndrome: findings from an academic pharmacovigilance program review and a pharmaceutical sponsored registry. Leuk Res. 2016;44:61-64. 19. Kantarjian HM, DeAngelo DJ, Advani AS, et al. Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study. Lancet Haematol. 2017;4(8):e387-e398. 20. Fried S, Shouval R, Walji M, et al. Allogeneic hematopoietic cell transplantation after chimeric antigen receptor T cell therapy in large B cell lymphoma. Transplant Cell Ther. 2023;29(2):99-107. 21. Locatelli F, Lang P, Wall D, et al; CLIMB THAL-111 Study Group. Exagamglogene autotemcel for transfusion-dependent
β-thalassemia. N Engl J Med. 2024;390(18):1663-1676. 22. Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial. Lancet. 2012;379(9823):1301-1309.