Defibrotide for children and adults with hepatic veno-occlusive disease post hematopoietic cell transplantation

Figures & data

Table 1. New EBMT criteria for VOD/SOS diagnosis in children and adults.

Children [3]	Adults [2]
● No limitation for time of onset of VOD/SOS Presence of ≥2 of the following^a: ● Unexplained consumptive and transfusion-refractory thrombocytopenia^b ● Otherwise unexplained weight gain on 3 consecutive days despite the use of diuretics or a weight gain >5% above baseline value ● Hepatomegaly (best if confirmed by imaging)^c above baseline value ● Ascites (best if confirmed by imaging)^c above baseline value ● Rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 h	Classical VOD/SOS (≤21 days post HSCT) Bilirubin ≥2 mg/dL and 2 of the following: ● Painful hepatomegaly ● Weight gain >5% ● Ascites
	Late-onset VOD/SOS (>21 days post HSCT) Classical VOD/SOS beyond day 21 Or Histologically proven VOD/SOS Or Presence of ≥2 of the following: ● Bilirubin ≥2 mg/dL (or 34 µmol/L) ● Painful hepatomegaly ● Weight gain >5% ● Ascites And hemodynamic and/or ultrasound evidence of VOD/SOS

EBMT: European Society for Blood and Marrow Transplantation; HSCT: hematopoietic stem cell transplantation; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aWith the exclusion of other potential differential diagnoses.

^b≥1 weight-adjusted platelet transfusion/day to maintain institutional guidelines.

^cSuggested: imaging (ultrasound, computed tomography, or magnetic resonance imaging) immediately before HSCT to determine baseline value for both hepatomegaly and ascites.

Adapted from Mohty M et al. Bone Marrow Transplant. 2016;51(7):906–912 and Corbacioglu S et al. Bone Marrow Transplant. [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

Table 2. EBMT grading criteria for VOD/SOS in children and adults.

		Pediatric Patients^a [3]				Adult Patients^b [2]
Parameter		Mild	Moderate	Severe	Very Severe MOD	Mild^c	Moderate^c	Severe	Very Severe MOD^d
Persistent RT^e		<3 days	3–7 days	>7 days		–	–	–	–
Time since first clinical symptoms of VOD/SOS^f		– Not included –				>7 days	5–7 days	≤4 days	Any time
Bilirubin	Mg/dL	<2^e,g		≥2^e,g		≥2 to <3	≥3 to <5	≥5 to <8	≥8
	µmol/L	<34^e,g		≥34^e,g		≥34 to <51	≥51 to <85	≥85 to <136	≥136
Ascites^e		Minimal	Moderate	Paracentesis necessary		–	–	–	–
Bilirubin kinetics		–	–	–	Doubling within 48 h	–	–	Doubling within 48 h	–
Transaminases (+GLDH in pediatric patients)		≤2× normal	>2 and ≤5× normal	>5× normal		≤2× normal	>2 to ≤5 × normal	>5 to ≤8× normal	>8× normal
Weight increase		– Not included –				<5%	≥5 to <10%	≥5 to <10%	≥10%
Coagulation		Normal		Impaired	Impaired; need replacement of coagulation factors	– Not included –
Renal function		GFR 89–60 mL/min	GFR 59–30 mL/min	GFR 29–15 mL/min	GFR <15 mL/min (renal failure)	<1.2 × baseline creatinine	≥1.2 to <1.5× baseline creatinine	≥1.5 to <2× baseline creatinine	≥2 × baseline creatinine or other signs of MOD
Pulmonary function (oxygen requirement)		<2 L/min	>2 L/min	Invasive pulmonary ventilation (including CPAP)		– Not included –
Central nervous system		Normal			New onset cognitive impairment	– Not included –

CPAP: continuous positive airway pressure; EBMT: European Society for Blood and Marrow Transplantation; GFR: glomerular filtration rate; GLDH: glutamate dehydrogenase; MOD: multiorgan dysfunction; RT: refractory thrombocytopenia.

^aPatients who fulfill criteria in different categories must be classified in the most severe category. The kinetics of the evolution of cumulative symptoms within 48 h predicts severe disease.

^bPatients who fulfill ≥2 criteria in 2 different categories must be classified in the most severe category.

^cPatients with ≥2 risk factors for VOD/SOS, should be in upper grade.

^dPatients with MOD must be classified as very severe.

^ePresence of ≥2 of these criteria qualifies for an upgrade to very severe VOD/SOS.

^fTime from the date when the first signs/symptoms of SOS/VOD began to appear (retrospectively determined) and the date when the symptoms fulfilled SOS/VOD diagnostic criteria.

^gExcluding preexistent hyperbilirubinemia due to primary disease.

Adapted from Mohty M et al. Bone Marrow Transplant. 2016;51(7):906–912 and Corbacioglu S et al. Bone Marrow Transplant. 2017 [published online 31 July 2017] as licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

Table 3. Early clinical studies of DF for the treatment of severe hepatic VOD/SOS after HSCT.

Study	Pt Characteristics	DF Dosing	Safety	Efficacy^a
US CUP March (pts treated 1995-August 1997) [56]	N = 19 Median age 40 y (range, 4–58) Dx: Hematologic malignancy (n = 13); solid tumor (n = 5); thalassemia (n = 1) HSCT: Allo (n = 8); auto (n = 11)	Dose escalation starting at 10 mg/kg/d (maximum dose 60 mg/kg/day) Median bilirubin at start of DF: 22.3 mg/dL (range, 11.7–54.4)	No DF discontinuation due to toxicity No severe hemorrhage related to DF administration	CR: 42% Day +100 survival: 32% Alive 217–1046 days post-HSCT: 26%
European CUP [57]	N = 40 Median age 30 y (range, 1–64) Dx: Hematologic malignancy (n = 35); breast cancer (n = 2); neuroblastoma (n = 2); Fanconi’s anemia (n = 1) HSCT: Allo (n = 26); auto (n = 14) MOD: 26 (65%) pts	10–40 mg/kg/d Median bilirubin at start of DF: 140.2 µmol/L (range, 8.5–1094.4) Median duration of treatment: 18 d (range, 2–71)	Generally no significant AEs In 1 pt, DF discontinued due to rectal bleeding with hemolysis and thrombocytopenia, unclear if TRAE	CR: 55% Survival at Day +100: 43%
US CUP^b (pts treated March 1995-May 2001) [58]	N = 88 Median age 35 y (range, 0.7–62) Dx: Hematologic malignancy (n = 63); solid tumors (n = 17); nonmalignant disease (n = 8) HSCT: Allo (n = 60); auto (n = 28) MOD: 85 (96%) pts	Dose escalation starting at 10 mg/kg/d Median bilirubin at start of DF: 12.6 mg/dL (range, 2.0–54.4) Median duration of treatment: 15 d (range, 1–139)	No worsening of clinical bleeding No grade 3–4 TRAE Grade 1–2 AEs included nausea, transient mild systolic hypotension, fever, abdominal cramping vasomotor symptoms	CR: 36% Survival at Day +100: 35% Most responses seen at DF doses 20–40 mg/kg/day
European retrospective study of pediatric and adolescent pts treated October 1998-October 2002 [36]	N = 45 Median age 8.2 y (range, 0.2–20) Dx: Hematologic malignancy (n = 28); solid tumors (n = 6); nonmalignant disease (n = 11) HSCT: Allo (82%); auto (18%) MOD: 22 (49%) pts	Median dose: 40 mg/kg/d (range, 10–110) Median bilirubin: 83.8 µmol/L (range, 15.4–744) Median duration of treatment: 17 d (range 1–83)	Coagulation abnormalities present pre-DF in 16 pts did not lead to DF discontinuation DF discontinued in 3 (7%) pts, including 1 pt with diarrhea No other grade 3–4 TRAEs	CR: 76% Survival Day +100: 64% CR in 11 (69%) of 16 pts with coagulation disorders
Randomized phase II dose-finding trial (pts treated April 2000-April 2006) [59]	N = 149 Arm A (n = 75): Median age 32 y (range, 0–61); pediatric (34%), adult (69%); hematologic malignancy (80%), neuroblastoma (3%); other (17%); allo-HSCT (89%) auto-HSCT (11%); >1 compromised organ systems (99%) Arm B (n = 74): Median age 34 y (range, 0–63); pediatric (34%), adult (66%); hematologic malignancy (76%), neuroblastoma (4%); other (20%); allo-HSCT (84%), auto-HSCT (16%); >1 compromised organ systems (97%)	For both arms, starting dose: 10 mg/kg/d Arm A: 25 mg/kg/d Arm B: 40 mg/kg/d Duration of treatment: Arm A (median, 19 d; range, 2–82); arm B (median, 20 d; range 2–65)	Grade 3–4 AEs: All (89%), arm A (85%), arm B (92%) Grade 5 AEs: All (17%), arm A (16%), arm B (19%) Any grade TRAEs: All (8%), arm A (7%), arm B (10%) Grade 3–4 TRAEs: All (3%), arm A (3%), arm B (4%) No TRAEs leading to death 25 mg/kg/day dose selected for phase III DF trials based on more favorable AE profile	CR Overall: All (46%), arm A (49%), arm B (43%) Pediatric pts: All (57%), arm A (70%), arm B (46%) Adult pts: All (40%), arm A (39%), arm B (42%) Day +100 survival Overall: All (42%); arm A (44%); arm B (39%) Pediatric pts: All (52%), arm A (70%), arm B (36%) Adult pts: All (37%), arm A (33%), arm B (41%)

AE: adverse event; allo: allogeneic; auto: autologous; CR: complete response; CUP: compassionate-use program; DF: defibrotide; dx: diagnosis; GVHD: graft versus host disease; MOD: multiorgan dysfunction; NR: not reported; pt(s): patient(s); TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aCR generally defined as bilirubin <34.2 µmol/L (2 mg/dL) and complete resolution of all other MOD- and VOD/SOS-related symptoms.

^bIncludes 19 pts previously reported in [56].

Table 4. Phase III and other large clinical studies of DF for treatment or prophylaxis^a of hepatic VOD/SOS after HSCT.

Study	Pt Characteristics	DF Dosing	Efficacy^b
Phase III open-label RCT of defibrotide prophylaxis vs. no prophylaxis in VOD/SOS high-risk children treated with myeloablative conditioning before HSCT (pts treated January 2006–January 2009) [8]	N = 356 DF group (n = 180): Median age 5.1 y (range <1–18); hematologic malignancy (46%), solid tumor (24%), other (30%); allo-HSCT (71%) Control group (n = 176): Median age 4.6 (range <1–18); hematologic malignancy (46%), solid tumor (24%), other (30%); allo-HSCT (69%) Groups had similar baseline characteristics	DF group treated with 25 mg/kg/d starting on same day as pre-HSCT conditioning regimen and continuing for 30 days post-HSCT or for ≥14 days if discharged from hospital before 30 days Median duration of DF prophylaxis: 35 days (range 4–71)	Primary end point VOD/SOS by 30 days post-HSCT: DF 12% vs. control 20% (−7.7% risk difference; P = 0.0507) No difference in median time from HSCT to VOD/SOS t
Nonrandomized historically controlled, open-label, phase III study (DF-treated pts enrolled from July 2006–June 2008) [61]	N = 134 DF group (n = 102): Median age 21 y (range, 0–72); age ≤16 y (43%); ventilator/dialysis dependent at study entry (33%); median bilirubin 4.9 (range 1–41.4); allo-HSCT (88%) Historical control group (n = 32): Median age 18 y (range, 1–57); age ≤16 y (44%); ventilator/dialysis-dependent at study entry (22%); median bilirubin (4.9 (range 2.1–57); allo-HSCT (84%) No statistical differences between groups	DF group treated at 25 mg/kg/d for ≥21 days; continued beyond 21 days until resolution of VOD/SOS or discharge from hospital Median duration of DF treatment: 21.5 days (range 1–58)	Primary end point Day +100 survival: DF 38% vs. control 25%; between-group difference 23% (95% CI, 5.2–40.8; P = .0109) CR by Day +100: DF 26% vs. control 13%; between-group difference 19% (95% CI, 3.5–34.6; P = .0160)
International CUP in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 1998–March 2009) [62]	N = 710 (303 pediatric, 407 adults) Median age 25.0 y (range, 0.2–70.0) Dx in ≥2% of pts: Hematologic malignancy (69%); neuroblastoma (5%); SCID (2%); thalassemia (3%) Type of treatment that led to VOS/SOS: HSCT (89%); non-HSCT chemotherapy/radiotherapy (11%) Type of HSCT: Allo (71%); auto (16%); other (2%) MOD: 292 (41%) pts	Median dose: 25 mg/kg/d (range 10–80) Median duration of treatment: 15 days (range 1–119)	Kaplan–Meier estimate Day +100 survival (n = 701): 54% Day +100 survival: Overall (44%), pediatric (50%), adult (40%)
Expanded-access T-IND protocol in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 2007–December 2013) [63]	N = 681 (n = 573 in the HSCT evaluable population used in this interim analysis) Age groups: ≤16 y (n = 319; 56%); >16 y (n = 254; 44%) Dx: Hematologic malignancy (69%); neuroblastoma (8%); immunodeficiency (3%); other (20%) Type of HSCT: Allo (88%); auto (12%) MOD: 351 (61%) pts	Treated at 25 mg/kg/d for ≥21 days	Kaplan–Meier estimate Day +100 survival (n = 573): Overall (54%), pediatric (54%), adult (45%) Day +100 survival: Overall (50%)

AE: adverse event; allo: allogeneic; auto: autologous; CI: confidence interval; CR: complete response; DF: defibrotide; MOD: multiorgan dysfunction; NR: not reported; pt(s): patient(s); RCT: randomized controlled trial; SCID: severe combined immunodeficiency; HSCT: hematopoietic stem cell transplantation; TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

^aVOD/SOS prophylaxis is not an approved licensed indication for defibrotide; it is an investigational use.

^bCR generally defined as bilirubin <34.2 µmol/L (2 mg/dL) and complete resolution of all other MOD- and VOD/SOS-related symptoms.

Republished with permission from Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan

Failure, Richardson PG, et al, [published online 11 August 2017]; permission conveyed through Copyright Clearance Center, Inc.

Figure 1. Kaplan-Meier estimates of overall survival (panel A) and time to CR (panel B) for defibrotide-treated patients and historical control group in the phase 3 treatment trial [61].

CI: confidence interval; CR: complete response. Republished with permission of American Society of Hematology, from Phase 3 Trial of Defibrotide for the Treatment of Severe Veno-Occlusive Disease and Multi-Organ Failure, Richardson PG, et al, 127, 13 and 2016; permission conveyed through Copyright Clearance Center, Inc.

Figure 2. Survival at Day +100 in pediatric patients (n = 303) and adults (n = 407) from a large compassionate use program [62].

Reprinted from Biology of Blood and Marrow Transplantation, 22/10, Corbacioglu S, et al, Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease: Final Results From the International Compassionate-Use Program, 1874–1882, Copyright (2016), with permission from American Society for Blood and Marrow Transplantation. doi:10.1016/j.bbmt.2016.07.001. URL for Creative Commons user license: https://creativecommons.org/licenses/by-nc-nd/4.0/.

Table 5. Defibrotide safety/tolerability in phase III and other large clinical studies.

Study	No. of Pts	Safety
Phase III open-label RCT of defibrotide prophylaxis vs. no prophylaxis in VOD/SOS high-risk children treated with myeloablative conditioning before HSCT [8]	DF group: n = 177 (pts received DF for prophylaxis and for treatment of VOD/SOS) Control group: n = 176 (36 pts received DF for treatment of VOD/SOS)	All AEs: DF 87%, control 88% Serious AEs: DF 61%, control 59% AEs leading to discontinuation: 10, 12% Severe AEs: 37, 37% AEs leading to death: 18, 16% TRAEs (DF arm, control arm): All (6, 4%); serious (1, 3%); leading to discontinuation (1, 2%); severe (2, 3%); leading to death (1%, 0) Overall hemorrhage: DF 22%, control 21% Possible, likely, or certain TRAEs (DF arm, control arm): Coagulopathy (0, 1%); GI hemorrhage (1, 2%); abdominal pain (1%, 0); hemorrhagic diarrhea (1%, 0); hematemesis (1%, 0); mouth hemorrhage (1%, 0); nausea (1%, 0); upper GI hemorrhage (0, 1%); vomiting (1%, 0); prolonged activated partial thromboplastin time (0, 1%); prolonged prothrombin time (1%, 1%); epistaxis (1%, 1%); hemothorax (1%, 1%); pulmonary hemorrhage (0, 1%); hemorrhage (1%, 1%); microangiopathy (0, 1%)
Nonrandomized historically controlled, open-label, phase III study [61]	DF group: n = 102 Historical control group: n = 32	Most common any grade AEs in >13% of DF pts (DF, control): Hypotension (39, 50%); diarrhea (24, 38%), MOD (15, 9%); pyrexia (14, 28%); vomiting (20, 25%) Selected other AEs (DF, control): Common hemorrhagic AEs (64, 75%); coagulopathy (2, 16%); disseminated intravascular coagulation (1, 3%) Median time to hemorrhage onset: DF 7 days, control 4 days Early DF discontinuation possibly due to possible TRAE: 10.7% Fatal AEs (DF, control): All (64, 69%); ≥1 hemorrhagic AE leading to death (15, 6%); most common fatal AE pulmonary alveolar hemorrhage (7, 6%)
International CUP December 1998–March 2009 [62]	N = 710	TRAE data not available Most common AEs: New/worsening MOD (20%), hepatic VOD/SOS progression (11%), sepsis (7%), GVHD (4%), GI hemorrhage (3%) Most common AEs leading to death: New/worsening MOD (20%), VOD/SOS progression (11%), sepsis (7%), GVHD (4%), recurrent cancer (2%), recurrent AML (2%), pneumonia (2%) Withdrawal due to AEs: 9%, primarily due to hemorrhage (7%) and GI disorders (3%)
Expanded-access T-IND protocol in pts with hepatic VOD/SOS following HSCT or non-HSCT-related chemotherapy/radiotherapy (pts treated December 2007–December 2013) [63]	N = 573 in the HSCT evaluable population used in this interim analysis	All AEs: 69.6% (similar between MOD and no MOD groups); most commonly hypotension (13.8%) and new or worsening MOD (12.7%) TRAEs: 21.6% (similar between MOD and no MOD groups); most commonly pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.3%), and epistaxis (3.1%) Serious AE: 51.7%; most commonly MOD (12.6%) and progression of VOD/SOS (9.8%) Fatal TRAEs: 3.1%; most commonly pulmonary hemorrhage (0.9%)

AE: adverse event; AML: acute myelogenous leukemia; DF: defibrotide; HSCT: hematopoietic stem cell transplantation; NS: not significant; pt(s): patient(s); RCT: randomized controlled trial; TRAE: treatment-related adverse event; VOD/SOS: veno-occlusive disease/sinusoidal obstruction syndrome.

Republished with permission from Future Medicine, from Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with Multiorgan Failure, Richardson PG et al. [published online 11 August 2017]; permission conveyed through Copyright Clearance Center, Inc.

Figure 3. Earlier recognition and treatment of VOD/SOS may reduce time to recovery.

Corbacioglu S, Carreras E, Ansari M, et al. Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in pediatric patients: a new classification from the European Society For Blood and Marrow Transplantation. Bone Marrow Transplant. published online July 31 2017. doi: 10.1038/bmt.2017.161.

 Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Richardson PG, Elias AD, Krishnan A, et al. Treatment of severe veno-occlusive disease with defibrotide: compassionate use results in response without significant toxicity in a high-risk population. Blood. 1998;92(3):737–744.

 PubMed Web of Science ®Google Scholar

Chopra R, Eaton JD, Grassi A, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: results of the European compassionate-use study. Br J Haematol. 2000;111(4):1122–1129.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Corbacioglu S, Greil J, Peters C, et al. Defibrotide in the treatment of children with veno-occlusive disease (VOD): a retrospective multicentre study demonstrates therapeutic efficacy upon early intervention. Bone Marrow Transplant. 2004;33(2):189–195.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Corbacioglu S, Kernan N, Lehmann L, et al. Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Expert Rev Hematol. 2012;5(3):291–302.

 PubMed Web of Science ®Google Scholar

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.

 PubMed Web of Science ®Google Scholar

Corbacioglu S, Carreras E, Mohty M, et al. Defibrotide for the treatment of hepatic veno-occlusive disease: final results from the international compassionate-use program. Biol Blood Marrow Transplant. 2016;22(10):1874–1882.

 PubMed Web of Science ®Google Scholar

Richardson PG, Smith AR, Triplett BM, et al. Defibrotide for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome: interim results from a treatment IND study. Biol Blood Marrow Transplant. 2017;23(6):997–1004.

 PubMed Web of Science ®Google Scholar