CLINICAL DATA

Efficacy of Defitelio was evaluated in 689 patients1,2

Studies included a broad range of adult and pediatric patients with VOD with renal or pulmonary dysfunction following HSCT1-3

Study 11,4
Study 21
Study 32,3
Study design
Phase 3 
prospective
Phase 2 
prospective
Expanded access 
study
Number of 
patients
102
75
512
VOD associated 
with:

Multi-organ 
dysfunction 
(pulmonary, renal, 
or both)a

Multi-organ 
dysfunctionb

Renal or pulmonary dysfunctionc

Median number of days on treatment,
days (range)
21.5 (1, 58)
19.5 (3, 83)
21d (1, 91)
Treatment dose 
of Defitelio
6.25 mg/kg infusion every 6 hours
Median age, years (range)
21 (<1, 72)
32 (<1, 61)
14 (<1, 69)
Type of 
transplant, n (%)
Allogeneic
Autologous
90 (88)
12 (12)
67 (89)
8 (11)
450 (88)
61 (12)
Ventilator or 
dialysis 
dependent at 
study entry, n (%)
34 (33)
8 (11)
225 (42)

aA diagnosis of VOD was made using Baltimore criteria (bilirubin ≥2 mg/dL and at least 2 of the following: hepatomegaly, ascites, and weight gain >5%) by Day +21 post HSCT.4-6

bA diagnosis of VOD was made using Baltimore criteria (bilirubin ≥2 mg/dL and at least 2 of the following: ascites, weight gain >5% from baseline, hepatomegaly, or right upper quadrant pain) by Day +35 post HSCT.5-7

cA diagnosis of VOD was made using Baltimore criteria (bilirubin ≥2 mg/dL and at least 2 of the following: hepatomegaly, ascites, and weight gain ≥5%) by Day +35 post HSCT or modified Seattle criteria (presentation by Day 20 post HSCT of at least 2 of the following: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, and weight gain >2% of baseline).2,4-6,8

dDuration of treatment from first dose to last dose is presented because days without treatment were not captured for the expanded access study.1

Up to double the rate of survival with Defitelio plus supportive care vs supportive care alone for patients with VOD1,2

Survival at Day +100 post HSCT with Defitelio across studies in adult and pediatric patients with MOD1,2

survival day 1 chart survival day 2 chart

EXPECTED DAY +100 SURVIVAL WITH SUPPORTIVE CARE ONLY

21% TO 31%

Based on published reports and analyses of patient-level data for individuals with hepatic VOD with renal or pulmonary dysfunction who received supportive care or interventions other than Defitelio.1

Study design1,2

The efficacy of Defitelio was investigated in 3 studies: 2 prospective clinical trials (Study 1 and Study 2) and an expanded access study (Study 3), which included 689 adult and pediatric patients with hepatic VOD with renal or pulmonary dysfunction following HSCT. Patients received Defitelio at a dose of 6.25 mg/kg every 6 hours.

Delays in Defitelio initiation were associated with increased mortality at Day +1002

In an exploratory post hoc analysis from Study 32

  • Analysis of Study 3 indicated that increased mortality at Day +100 was associated with longer delays in Defitelio administration following a diagnosis of VOD with renal or pulmonary dysfunction (confirmed by the Cochran-Armitage trend test; P<0.001)
    • Analysis based on adult and pediatric patients (n=512) with a diagnosis of VOD with renal or pulmonary dysfunction
    • The reason for initiation delay following diagnosis was not assessed in this expanded access study

In an exploratory post hoc analysis
Patients with VOD with bilirubin levels <2 mg/dL treated with Defitelio had better outcomes9

This was an exploratory post hoc analysis from Study 3 of patients with VOD with renal or pulmonary dysfunction9

Survival at Day +100 post HSCT in patients with MOD who were treated with Defitelio9

Survival at day 100 chart

Use of VOD diagnostic criteria (ie, EBMT and Cairo/Cooke) that does not require bilirubin levels ≥2 mg/dL may allow for earlier VOD identification and diagnosis and potentially improve outcomes.9

Anicteric VOD was more common in pediatric patients (29%), although it also occurred in adult patients (15%).9,e

Limitations of subanalysis: This open-label, single-arm, expanded access study was not powered for post hoc analyses or for statistical analysis within subgroups. No formal statistical comparisons were made.9

Corbacioglu S, Kernan NA, Pagliuca A, et al. Incidence of anicteric veno-occlusive disease/sinusoidal obstruction syndrome and outcomes with defibrotide following hematopoietic cell transplantation in adult and pediatric patients. Biol Blood Marrow Transplant. 2020;26(7):1342-1349. Used with permission. ©2020 Elsevier.

Use of VOD diagnostic criteria (ie, EBMT and Cairo/Cooke) that does not require bilirubin levels ≥2 mg/dL may allow for earlier VOD identification and diagnosis and potentially improve outcomes.9

Anicteric VOD was more common in pediatric patients (29%), although it also occurred in adult patients (15%).9,e

Day 100 survival was lower in patients with VOD with bilirubin ≥2 mg/dL (hyperbilirubinemia) regardless of time between HSCT and VOD diagnosis9

Delaying VOD diagnosis until bilirubin levels are ≥2 mg/dL may worsen patient outcomes9

Study Design9

The initial protocol required diagnosis by Day 35 post HSCT per Baltimore criteria or biopsy and to have MOD by Day 45. Criteria were amended to include patients diagnosed by modified Seattle criteria,f patients without MOD, and patients with disease onset after Day 35.

This post hoc analysis of patients with VOD post HSCT in the T-IND study examined the incidence in patients with a bilirubin level <2 mg/dL before and after Day 21 post HSCT and evaluated survival in adult and pediatric patients with or without hyperbilirubinemia and with or without MOD who were treated with Defitelio.

Of the 803 patients post HSCT in the study, MOD was reported in 226 of the 449 patients (50%) diagnosed by Baltimore criteria, in 112 of the 331 (34%) diagnosed by modified Seattle criteria, and in 14 of the 23 (61%) diagnosed by biopsy, respectively.

The primary efficacy endpoint was survival at Day +100 post HSCT.

The safety profile of Defitelio in the T-IND study was similar to previous Defitelio studies.

eAmong the patients with bilirubin <2 mg/dL at diagnosis, 34 of 132 pediatric patients (26%) and 20 of 49 adult patients (41%) had MOD.9

fThe modified Seattle criteria used in this study required at least 2 of the following clinical findings: bilirubin ≥2 mg/dL, ascites (radiographic or physical examination), weight gain ≥5% above baseline, or hepatomegaly increased over baseline.9

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.

HSCT=hematopoietic stem-cell transplantation; MOD=multi-organ dysfunction; T-IND=treatment-investigational new drug; VOD=veno-occlusive disease.

References: 1. Defitelio [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals 2. Kernan NA, Grupp S, Smith AR, et al. Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. Br J Haematol. 2018;181(6):816-827. 3. Data on file. DEF-2018-022. Palo Alto, CA: Jazz Pharmaceuticals. 4. 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. 5. 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. 6. Jones RJ, Lee KS, Beschorner WE, et al. Venoocclusive disease of the liver following bone marrow transplantation. Transplantation. 1987;44(6):778-783. 7. Richardson PG, Soiffer RJ, Antin JH, et al. Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial. Biol Blood Marrow Transplant. 2010;16(7):1005-1017. 8. 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. 9. Corbacioglu S, Kernan NA, Pagliuca A, et al. Incidence of anicteric veno-occlusive disease/sinusoidal obstruction syndrome and outcomes with defibrotide following hematopoietic cell transplantation in adult and pediatric patients. Biol Blood Marrow Transplant. 2020:26(7):1342-1349.