Graft Versus Host Disease
Conditions
Keywords
Peripheral haemopoietic stem cell transplant, High dose cyclophosphamide, acute GVHD, allogenic transplantation, RIC (reduced-intensity conditioning)
Brief summary
Acute or chronic graft versus host disease is still the major complication of stem cells transplantation regarding morbidity and mortality. Recently, high dose cyclophosphamide utilization early after post-transplantation (day+ 3 and +4) not only for patients with HLA- haploidentical donor but also for patients with Human Leukocyte Antigen (HLA)-compatible donor, showed a great control of graft versus host disease after transplantation, allowing to consider stopping immunosuppressive treatment after the transplantation (Neoral=cyclosporine, cell-cept=mycophenolate mofetil). Indeed, this step has already been completed in myeloablative transplantation in adult patients. This approach could enable to avoid in the end several complications related to long term immunosuppressive drugs administration, while promoting quicker immunity recovery.
Detailed description
The BALTIMORE conditioning regiment will be used in this study with peripheral stem cell transplantation and fludarabine will be replaced by clofarabine for myeloid diseases (Acute Myeloide Leukemia, Myelodysplasia , myelofibrosis, Chronic Myeoloid Leukemia..) because of better antitumoral activity in this setting.
Interventions
DRUGFludarabine
30 mg/m² Intravenous 5 days from Day-6 to Day-2
DRUGClofarabine
30 mg/m² Intravenous 5 days from Day-6 to Day-2
RADIATIONFull body irradiation
2 grays at Day-1
DRUGCyclophosphamide
14 mg/kg intravenous 2 days at Day - 6 and day -5
OTHERstem cell transplantation
at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)
OTHERnuclear cells
CD3+ cells if needed after transplantation
At day -2 2.5 mg/kg for patients inclued after 14 dec 2020
Sponsors
Nantes University Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* adults ≤ 70 years old * indication to stem cells transplantation with reduced-intensity conditioning regimen * with a HLA-compatible familial 10/10 or non-familial donor * Written signed informed consent form * woman with childbearing potential under efficient control birth method during the trial and up to 12 months after cyclophosphamide stop * men under efficient control birth method during the trial and up to 6 months after cyclophosphamide stop * Negative serology to B and C hepatitis and to HIV * Affiliated to social security
Exclusion criteria
* \- Eligible to myeloablative contioning regimen * Other progressive malignancy disease or history of prior other malignancy in the last two years, with the exception of: curatively treated basal cell carcinoma or carcinoma in situ of the cervix * Progressive mental illness disease * Pregnant or Breastfeeding woman * woman with childbearing potential without any efficient control birth * Serious concomitant infection and not controlled * Contra-indications to allogenic transplantation, especially: * Cardiac: left ventricular ejection fraction \<45% assessed by transthoracic echography or isotopic method (isotopic gamma-angiography) * Respiratory: DLCO limiting fludarabine and busulfan use (DLCO\< 40% of theorical value) * Renal: creatinine clearance \< 60ml/min (MDRD method) * Hepatic: transaminases \>5 Uper Per Normal (UPN) or bilirubin\> 2 UPN * Contra-indications to cyclophosphamide: * Urinary tract infections * Acute urothelial toxicity due to cytotoxic chemotherapy or to radiotherapy * Obstruction of urines flow * Pre-existing hemorrhagic cystitis * Yellow fever vaccination * Cardiac condition preventing high dose cyclophosphamide utilization : * New York Heart Association (NYHA) functional class II, III or IV * Rhythmic, valvular or ischemic cardiomyopathy * Minor * Patient under guardianship or curatorship * Patient under judicial protection * Known or suspected hypersensitivity to cyclophosphamide * Known or suspected hypersensitivity to rabbit proteins
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of grade 3 and 4 acute GVHD cortico-resistant | 100 days after transplantation | acute GVHD will be evaluated from International Mount Sinai criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| disease free survival (DFS) | one year, the last follow-up visit | blood and bone marrow analysis |
| Overall survival (OS) | one year, the last follow-up visit | clinical follow-up |
| graft and relapse free survival | one year | time between Day O and relapse |
| chronic GVHD | one year | chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD |
| non relapse mortality (NRM) | last follow-up visit | number of death unrelated to relapse or disease progression |
| Chimerism | 1, 2, 3, 6 and 12 months after transplantation | proportion of full and mixed donor chimerism |
| Immune reconstitution | 3, 6 and 12 months after transplantation | lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates |
| Identification of ghost factors associated with GVHD | one year | Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015 |
| Engraftment | one year | number of days in aplasia (neutrophils\< 0.5 Giga/L and platelets\<20 G/l, number of transfusions (red blood and platelets) |
| Infections frequency | one year | time of occurring and frequency of viral (CytoMegalo Virus, Epstein Barr virus , BKV, adenovirus), bacterial, parasite and yeast infections, evaluated by Polymerase Chain Reaction (PCR), blood and urines cultures, biopsy if applicable |
| compare OS between patients with ATG and patients without ATG | one year, last follow-up visit | OS |
| compare grade 2-4 and 3-4 acute GVHD between patients with ATG and patients without ATG | one year | acute GVHD will be evaluated from International Mount Sinai criteria |
| compare chronic GVHD between patients with ATG and patients without ATG | one year | chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD |
| compare DFS between patients with ATG and patients without ATG | one year, last follow-up visit | DFS |
| compare Relapse between patients with ATG and patients without ATG | one year, last follow-up visit | Relapse |
| compare NRM between patients with ATG and patients without ATG | one year, last follow-up visit | NRM |
| compare Infections frequency between patients with ATG and patients without ATG | one year | time of occurring and frequency of viral (CytoMegalo Virus, Epstein Barr virus , BKV, adenovirus), bacterial, parasite and yeast infections, evaluated by Polymerase Chain Reaction (PCR), blood and urines cultures, biopsy if applicable |
| Adverse events of grade 3 and 4 after transplantation | one year | time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria) |
Countries
France
Outcome results
None listed