. 2019 Oct 1;55(3):485–495. doi: 10.1038/s41409-019-0705-z

Table 4.

Main studies on defibrotide in SOS/VOD

Reference; Phase; Number of patients	Condition	Design	CR rate	Others results
Richardson et al. [58] Retrospective CUP N = 19	Adult and pediatric Severe SOS post HCT	Compassionate use; DF: 5–60 mg/kg/day (individual patient dose escalation, until response/toxicity)	CR: 42% Minimal toxicity at doses tested	Day +100 survival: 32%
Richardson et al. [59] Phase I/II N = 88	Adult and pediatric Severe SOS post HCT	Emergency use; DF: 5–60 mg/kg/day (intrapatient dose escalation, until response/toxicity)	CR: 36% Active dose range 25–40 mg/kg/day	Day +100 survival: 35% No serious AEs attributed to DF
Richardson et al. [30] Phase II N = 149	Adult and pediatric Severe SOS post HCT	Randomized, dose-finding; Arm A: DF 25 mg/kg/day Arm B: DF 40 mg/kg/day For 14 days or more	Day +100 CR: 46% Effective dose 25 mg/kg/day	Day +100 survival: 42% Overall SAE incidence: 8% (greater at 40 vs. 25 mg/kg/day)
Richardson et al. [27] Phase III N = 102	Adult and pediatric Severe SOS post HCT	Nonrandomized, comparison to historical control; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) for 21 days or more	Day +100 CR DF 24% HC 9% (p = 0.0131)	Day +100 mortality: DF 62%; HC 75% (p = 0.0341) Hemorrhagic AEs: DF 65%; HC 69%
Corbacioglu et al. [28] Compassionate use program N = 710	Adult and pediatric <18 years (N = 303) ≥18 years (N = 407) SOS non-HCT (N = 68) SOS post HCT (N = 628) Severe SOS (N = 292)	Investigational new drug protocol; DF: 10–80 mg/kg /day (median 25 mg/kg/day) for a median of 15 days (range, 1–119)	Day +100 CR Non-HCT 40% SOS/VOD post HCT 47% Severe SOS/VOD post HCT 29%	Day +100 survival: Pediatric: 69% Adults: 49% Severe SOS: 41% Nonsevere SOS: 68% Overall hemorrhagic AEs: 12%
Kernan et al. [29] Prospective T-IND N = 1000 (non-SCT excluded)	Adult and pediatric ≤16 years (N = 570) >16 years (N = 430) Severe SOS (N = 512)	Investigational new drug protocol; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) for 21 days or more		Day +100 survival: 58.9% Pediatric: 67.9% Adults: 47.1% Severe SOS: 49.5% Nonsevere SOS: 68.9% Overall hemorrhagic AEs: 29%
Corbacioglu et al. [51] Phase III N = 356	Pediatric SOS/VOD prophylaxis post HCT	Randomized comparison; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) from start conditioning to 30 days post HCT (at least 14 days if discharge before) Control: cross over to the DF arm in case of SOS/VOD onset	SOS/VOD incidence: DF 12% Control 20% p = 0.0488	Day +100 SOS/VOD related mortality: DF 2%, control 6%, p = 0.10 No difference in AEs and hemorrhagic AEs

Reference; Phase; Number of patients

Condition

Design

CR rate

Others results

Richardson et al. [58]

Retrospective CUP N = 19

Adult and pediatric

Severe SOS post HCT

Compassionate use; DF: 5–60 mg/kg/day (individual patient dose escalation, until response/toxicity)

CR: 42%

Minimal toxicity at doses tested

Day +100 survival: 32%

Richardson et al. [59]

Phase I/II N = 88

Adult and pediatric

Severe SOS post HCT

Emergency use; DF: 5–60 mg/kg/day (intrapatient dose escalation, until response/toxicity)

CR: 36%

Active dose range 25–40 mg/kg/day

Day +100 survival: 35%

No serious AEs attributed to DF

Richardson et al. [30]

Phase II N = 149

Adult and pediatric

Severe SOS post HCT

Randomized, dose-finding; Arm A: DF 25 mg/kg/day Arm B: DF 40 mg/kg/day For 14 days or more

Day +100 CR: 46%

Effective dose 25 mg/kg/day

Day +100 survival: 42%

Overall SAE incidence: 8%

(greater at 40 vs. 25 mg/kg/day)

Richardson et al. [27]

Phase III N = 102

Adult and pediatric

Severe SOS post HCT

Nonrandomized, comparison to historical control; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) for 21 days or more

Day +100 CR

DF 24%

HC 9%

(p = 0.0131)

Day +100 mortality: DF 62%; HC 75% (p = 0.0341)

Hemorrhagic AEs: DF 65%; HC 69%

Corbacioglu et al. [28]

Compassionate use program N = 710

Adult and pediatric

<18 years (N = 303)

≥18 years (N = 407)

SOS non-HCT (N = 68)

SOS post HCT (N = 628)

Severe SOS (N = 292)

Investigational new drug protocol; DF: 10–80 mg/kg /day (median 25 mg/kg/day) for a median of 15 days (range, 1–119)

Day +100 CR

Non-HCT 40%

SOS/VOD post HCT 47%

Severe SOS/VOD post HCT 29%

Day +100 survival: Pediatric: 69%

Adults: 49%

Severe SOS: 41%

Nonsevere SOS: 68%

Overall hemorrhagic AEs: 12%

Kernan et al. [29]

Prospective T-IND N = 1000 (non-SCT excluded)

Adult and pediatric

≤16 years (N = 570)

>16 years (N = 430)

Severe SOS (N = 512)

Investigational new drug protocol; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) for 21 days or more

Day +100 survival: 58.9%

Pediatric: 67.9%

Adults: 47.1%

Severe SOS: 49.5%

Nonsevere SOS: 68.9%

Overall hemorrhagic AEs: 29%

Corbacioglu et al. [51]

Phase III N = 356

Pediatric

SOS/VOD prophylaxis post HCT

Randomized comparison; DF: 6.25 mg/kg IV q6h (25 mg/kg/day) from start conditioning to 30 days post HCT (at least 14 days if discharge before)

Control: cross over to the DF arm in case of SOS/VOD onset

SOS/VOD incidence: DF 12%

Control 20% p = 0.0488

Day +100 SOS/VOD related mortality: DF 2%, control 6%, p = 0.10

No difference in AEs and hemorrhagic AEs

SOS sinusoidal obstruction syndrome, CUP compassionate use program, HSCT hematopoietic stem cell transplantation, DF defibrotide, CR complete remission, AE adverse event