SIGNS OF RENAL OR PULMONARY DYSFUNCTION

Be alert for the possible signs of renal or pulmonary dysfunction

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Renal dysfunction may include1-3

  • Decreased urinary output
  • Elevated creatinine levels (≥1.5 x baseline)
  • Decreased creatinine clearance
  • Decreased glomerular filtration rate
  • Need for dialysis
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Pulmonary dysfunction may include2-5

  • Pulmonary infiltrates
  • Pleural effusion
  • Reduced oxygen saturation
  • Need for supplemental oxygen (nasal cannula)
  • Ventilator dependence

VOD/SOS can progress to multi-organ failure within a few days6

VOD/SOS is a post-HSCT complication affecting endothelial cells in the sinusoids of the liver6,7

Across age groups, incidence of VOD/SOS post HSCT is around 15%8,9,a

In children and infants, studies found incidence as high as 39%10

RAPIDLY PROGRESSIVE

In a study that assessed VOD/SOS after HSCT

UP TO ~50%

of cases developed MOD11,b

Overall mortality associated with posttransplant complications across multiple studies

  • Infection: Prospective cohort study; 415 patients with infection; allogeneic HSCT
  • aGvHD: Retrospective chart review of 475 patients with aGvHD; allogeneic HSCT
  • VOD/SOS with MOD: A subanalysis of 19 studies, drawn from a larger meta-analysis of 135 studies published between 1979 and October 2007, reported the mortality rate of patients with severe VOD/SOS who received supportive care only
 

MISSED DIAGNOSIS

In a retrospective study7,c

202 patients with HSCT died of multi-organ failure

Patients identified from the EBMT registry

70/202 patients fit a VOD/SOS diagnosis

Diagnosis was determined from applying the most common VOD/SOS scoring systems (modified Seattle, classic EBMT/Baltimore, late EBMT) using data collected from the last month before multi-organ failure–induced death. No postmortem pathology was available to confirm the diagnosis

48/70 of those patients were undiagnosed at time of death

The majority of missed cases developed well beyond 21 days post transplant

VOD/SOS-RELATED MULTI-ORGAN FAILURE IS A MISSED CAUSE OF DEATH7

aAn average based on multiple studies and meta-analyses including more than 65,000 adult and pediatric patients.8

bBased on an estimate using the Baltimore criteria and taken from a study conducted by Carreras et al that used 2 sets of diagnostic criteria to estimate the incidence of VOD/SOS after HSCT.11

cBased on retrospectively applying modified Seattle, classic EBMT/Baltimore, or late EBMT criteria using data collected from adult patients (aged >18 years) the last month before multi-organ failure–induced death. Data from 253 adult patients who underwent allo-HSCT procedures between 2010 and 2018, provided by the EBMT Acute Leukemia Working Party.7

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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.

EBMT=European Society for Blood and Marrow Transplantation; HSCT=hematopoietic stem-cell transplantation; MOA=mechanism of action; MOD=multi-organ dysfunction; SOS=sinusoidal obstruction syndrome; VOD=veno-occlusive disease.

References: 1. Ng CK, Chan MH, Tai MH, et al. Hepatorenal syndrome. Clin Biochem Rev. 2007;28(1):11-17. 2. Richardson PG, Riches ML, Kernan NA, et al. Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure. Blood. 2016;127(13):1656-1665. 3. Richardson PG, Murakami C, Jin Z, et al. Multi-institutional use of defibrotide in 88 patients after stem cell transplantation with severe veno-occlusive disease and multisystem organ failure: response without significant toxicity in a high-risk population and factors predictive of outcome. Blood. 2002;100(13):4337-4343. 4. 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. 5. McDonald GB, Hinds MS, Fisher LD, et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients. Ann Intern Med. 1993;118(4):255-267. 6. 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. 7. Bazarbachi AH, Al Hamed R, Labopin M, et al. Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party. Bone Marrow Transplant. 2021;56(4):917-927. 8. Corbacioglu S, Grupp SA, Richardson PG, et al. Prevention of veno-occlusive disease/sinusoidal obstruction syndrome: a never-ending story and no easy answer. Bone Marrow Transplant. 2023;58(8):839-841. 9. 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. 10. Cheuk DKL, Wang P, Lee TL, et al. Risk factors and mortality predictors of hepatic veno-occlusive disease after pediatric hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;40(10):935-944. 11. Carreras E, Díaz-Beyá M, Rosiñol L, et al. The incidence of veno-occlusive disease following allogeneic hematopoietic stem cell transplantation has diminished and the outcome improved over the last decade. Biol Blood Marrow Transplant. 2011;17(11):1713-1720. 12. Schuster MG, Cleveland AA, Dubberke ER, et al. Infections in hematopoietic cell transplant recipients: results from the organ transplant infection project, a multicenter, prospective, cohort study. Open Forum Infect Dis. 2017;4(2):1-7. 13. Holtan SG, Yu J, Choe HK, et al. Disease progression, treatments, hospitalization, and clinical outcomes in acute GVHD: a multicenter chart review. Bone Marrow Transplant. 2022;57(10):1581-1585.