Pediatric Trial Investigating the Incidence & Outcome of Veno-Occlusive Disease With the Prophylactic Use of Defibrotide (VOD-DF)

• The primary objective is to evaluate if prophylactic DF has an impact on the:
• The aim of this trial is to evaluate prophylactic Defibrotide (DF) in a pediatric patient population at high risk for Veno-occlusive Disease (VOD).
• - incidence of VOD,
• - the severity of VOD and
• - the mortality due to VOD

• The secondary objectives are to:
• - evaluate if prophylactic DF compared to the therapeutic use of DF alone is associated with a better long-term survival
• - evaluate if prophylactic DF has an impact on the incidence of graft-versus-host disease (GvHD
• - collect data on eventual side effects of DF in the pediatric transplant population
• - collect data on the potential benefit of DF on the incidence and severity of TTP

The aim of this trial is to evaluate whether the prophylactic use of Defibrotide (DF) in pediatric patients (age less than 18 years) undergoing stem cell transplantation and who are at high risk of developing hepatic Veno-occlusive Disease (VOD) will have an impact on the incidence and severity of the disease. Patients will be randomly assigned to one of two treatment arms: Those allocated to the Prophylactic Arm will receive the study drug (Defibrotide) from the day of conditioning onwards. Patients allocated to the Control Arm will receive the study drug (Defibrotide) from the day that VOD is diagnosed.

Comparison/control intervention and duration of the intervention:

Patients will be assigned randomly to either the Defibrotide (DF) prophylaxis arm or the control arm. Those allocated to the DF prophylaxis arm (DF 25 mg/kg/d iv in 4 doses) will begin treatment at day of conditioning and stop at day +30 after Stem Cell Transplantation (SCT) or upon discharge from inpatient care. There is no dose adjustment for a patient of the study arm who developed VOD, they continue with the 25mg/kg/d iv.

Patients allocated to the control arm receive no prophylactic measures and will start DF (25 mg/kg/d iv in 4 doses) beginning at day of diagnosis of Veno-occlusive Disease (VOD) according to modified Seattle criteria. Treatment will be stopped at complete resolution of symptoms. In both arms patients who developed VOD will continue DF until:

• complete resolution of the ascites and
• reversion of the hepatopedal flow (if present) and
• normalization of the total and direct bilirubin

• Drug: Defibrotide
  Defibrotide 25 mg/kg/d
• Drug: Defibrotide
  Defibrotide 25 mg/kg/d iv in 4 doses beginning at day of conditioning until day +30 or until discharge from inpatient care (with a minimum treatment of 14 days) if VOD does not occur.
• Drug: Defibrotide
  Defibrotide 25 mg/kg/d iv therapeutically when patients fulfil modified Seattle criteria

• Experimental: Prophylaxis Arm
  Interventions:

  • Drug: Defibrotide
  • Drug: Defibrotide
• Active Comparator: Control Arm
  Interventions:

  • Drug: Defibrotide
  • Drug: Defibrotide

Inclusion Criteria:

• Age <18 years

• myeloablative conditioning and autologous or allogeneic stem cell transplantation with at least one of the following risk factors for VOD:

  1. Pre-existing liver disease
  2. Second myeloablative HSCT
  3. History of treatment with gemtuzumab ozogamicin (MYLOTARGÒ, GO, CMA-676, Wyeth)
  4. Allogeneic HSCT for leukemia beyond the second relapse
  5. Osteopetrosis (OP)
  6. Conditioning with busulfan and melphalan
  7. Macrophage activating syndromes (MAS, like hemophagocytic lymphohistiocytosis, Griscelli, Chediak-Higashi
  8. Adrenoleukodystrophy (ALD)

Exclusion Criteria:

• Pregnant patients
• Patients who are transplanted but do not fulfill any of the above mentioned criteria

• Gentium SpA
• Deutsche Krebshilfe e.V., Bonn (Germany)