Graft Versus Host Disease
Conditions
Keywords
indication for HSCT, matched related donor, MRD, Matched Unrelated Donor, MUD
Brief summary
• The primary aim of the present trial is to assess in a randomized fashion the benefit on standard graft-versus-host disease (GVHD) prophylaxis of the addition of ATG-Fresenius S ® in transplants from matched related donors (MRD) and of anti-CD20 rituximab in transplants from matched unrelated donors (MUD). Both safety and efficacy of the treatment will be assessed, in particular in respect to the clinical status of the patient, i.e. prevention of graft failure and chronic GvHD and of Ebstein Barr virus (EBV) viremia for MUD patients. The conditioning proposed combines myeloablative drugs with a favorable safety profile such as treosulfan, thiotepa (Tepadina®) and fludarabine with the intent to reduce the traditional immediate and late toxicity of busulfan and cyclophosphamide.
Detailed description
For patients transplanted from a MRD The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to: * primary and secondary graft failure, * aGVHD II-IV, * cGVHD, * death, whichever occurs first. For patients transplanted from a MUD The primary end-point is the cumulative incidence of a combined end-point defined as the time from randomization to: * aGVHD II-IV, * EBV viremia, whichever occurs first.
Interventions
BIOLOGICALpolyclonal antibody
iv at a dose of 5 mg/kg within 8 hours on day -4,-3,-2 (total dose 15 mg/kg)
DRUGRituximab
single infusion of200 mg/m2 on day -1
DRUGTreosulfan
iv at a dose of 14 g/m² within 120 minutes on day -7, - 6, -5 (total dose of 42 g/m²)
DRUGFludarabine
iv at a dose of 30 mg/ m² within 30 minutes on day -7, -6, -5,-4,-3 after treosulfan
DRUGThiotepa
iv at a dose of 8 mg/kg on day - 3 divided into 2 infusions at 12 hrs intervals
DRUGCyclosporine A
iv at a dose of 3 mg/kg/day starting from day -1 and a dose adjustment will be done to obtain plasma levels of 150-250 ng/mL
DRUGMethotrexate
iv at a dose of 15 mg/m2 on day +1, at a dose of 10 mg/m2 on day + 3 and + 6
Sponsors
University of Milano Bicocca
medac GmbH
Fresenius AG
Franco Locatelli
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
28 Days to 64 Years
Healthy volunteers
No
Inclusion criteria
* non malignant haematological and inherited metabolic disorders benefiting from an allogeneic HSCT conditioned with a myeloablative regimen * Availability of a matched related donor (MRD) or Matched Unrelated Donor (MUD) * Lansky or Karnofsky Index ≥ 60 * Inherited metabolic disorders: DQ ≥ 70 (+ MRI Loes score ≤ 9 for adrenoleukodystrophy) * Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by: * Serum creatinine ≤ 1.5 × upper limit of normal (ULN) * Heart shortening fraction (left-ventricle) \> 28 % or LVEF \> 55% * Serum bilirubin ≤ 1.5 × ULN (except for Wolman disease), * AST and ALT ≤ 2.5 × ULN (except for thalassemic syndromes and Wolman disease) * Pulmonary function: if cooperative: FEV1 and FVC on pulmonary function testing \> 60 %; if non cooperative: pulse oximetry \> 95 % in room air * Availability of autologous back up marrow (\> 2 x 108 TNC+ cells/kg or \> 2 x 106 CD34+ cells/kg) for MUD * Adequate contraception in female patients of child-bearing potential * Signed informed consent
Exclusion criteria
* Any malignancy * Liver cirrhosis evidenced on liver histology (performed in suspicious cases or in case of Wolman disease) * HIV- positivity * Clinically significant pleural effusion or ascites * Pregnancy or lactation * Known hypersensitivity to trial drugs * Participation in another experimental drug trial in the 2 months preceding enrollment * Non-cooperative behaviour or non-compliance * Previous HSCT
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute graft-versus-host disease (aGVHD) II-IV and chronic GvHD | From date of randomization assessed up to 100 months | For patients transplanted from a MRD The cumulative incidence of a combined end-point defined as the time from randomization to: * primary and secondary graft failure, * aGVHD II-IV, * cGVHD, * death, whichever occurs first. For patients transplanted from a MUD The cumulative incidence of a combined end-point defined as the time from randomization to: * aGVHD II-IV, * EBV viremia, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Chronic graft-versus-host disease (cGVHD) | From date of randomization assessed up to 100 months | The cumulative incidence and severity of cGVHD |
| Treatment related mortality (TRM) | From date of randomization assessed up to 100 months | The incidence of TRM |
| Overall survival (OS) | From date of randomization assessed up to 100 months | The overall survival probability |
Countries
Italy
Outcome results
None listed