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Security criteria (MTD)
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| LYMPHOID HEMOPATHY without ATG | Experimental | patients with lymphoid hemopathy |
|
| MYELOID HEMOPATHY without ATG | Experimental | patients with myeloid hemopathy |
|
| LYMPHOID HEMOPATHY witH ATG | Experimental | patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence |
|
| MYELOID HEMOPATHY with ATG | Experimental | patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Fludarabine | Drug | 30 mg/m² Intravenous 5 days from Day-6 to Day-2 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of grade 3 and 4 acute GVHD cortico-resistant | acute GVHD will be evaluated from International Mount Sinai criteria | 100 days after transplantation |
| Measure | Description | Time Frame |
|---|---|---|
| Engraftment | number of days in aplasia (neutrophils< 0.5 Giga/L and platelets<20 G/l, number of transfusions (red blood and platelets) | one year |
| Engraftment | chimerism |
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Inclusion Criteria:
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:
Contra-indications to cyclophosphamide:
Cardiac condition preventing high dose cyclophosphamide utilization :
Minor
Patient under guardianship or curatorship
Patient under judicial protection
Known or suspected hypersensitivity to cyclophosphamide
Known or suspected hypersensitivity to rabbit proteins
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nantes Uh | Nantes | France |
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| Clofarabine | Drug | 30 mg/m² Intravenous 5 days from Day-6 to Day-2 |
|
| Full body irradiation | Radiation | 2 grays at Day-1 |
|
| Cyclophosphamide | Drug | 14 mg/kg intravenous 2 days at Day - 6 and day -5 |
|
| Cyclophosphamide | Drug | 50 mg/kg intravenous 2 days at day +3 and day +4 |
|
|
| stem cell transplantation | Other | at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells) |
|
|
| nuclear cells | Other | CD3+ cells if needed after transplantation |
|
|
| Thymoglobulin Injectable Product | Drug | At day -2 2.5 mg/kg for patients inclued after 14 dec 2020 |
|
|
| one year |
| disease free survival (DFS) | blood and bone marrow analysis | one year, the last follow-up visit |
| Overall survival (OS) | clinical follow-up | one year, the last follow-up visit |
| graft and relapse free survival | time between Day O and relapse | one year |
| chronic GVHD | chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD | one year |
| non relapse mortality (NRM) | number of death unrelated to relapse or disease progression | last follow-up visit |
| Chimerism | proportion of full and mixed donor chimerism | 1, 2, 3, 6 and 12 months after transplantation |
| Immune reconstitution | lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates | 3, 6 and 12 months after transplantation |
| Identification of ghost factors associated with GVHD | Statistical Models to Identify Subjects with Ghost Prognosis Factors Nguyen JM. 2015 | one year |
| Adverse events of grade 3 and 4 after transplantation | time of occurring and frequency of grade 3 and grade 4 adverse events (CTCAE criteria) | one year |
| Infections frequency | 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 | one year |
| compare OS between patients with ATG and patients without ATG | OS | one year, last follow-up visit |
| compare grade 2-4 and 3-4 acute GVHD between patients with ATG and patients without ATG | acute GVHD will be evaluated from International Mount Sinai criteria | one year |
| compare chronic GVHD between patients with ATG and patients without ATG | chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD | one year |
| compare DFS between patients with ATG and patients without ATG | DFS | one year, last follow-up visit |
| compare Relapse between patients with ATG and patients without ATG | Relapse | one year, last follow-up visit |
| compare NRM between patients with ATG and patients without ATG | NRM | one year, last follow-up visit |
| compare Infections frequency between patients with ATG and patients without ATG | 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 | one year |
| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| C024352 | fludarabine |
| D000077866 | Clofarabine |
| D003520 | Cyclophosphamide |
| D033581 | Stem Cell Transplantation |
| D014180 | Transplantation |
| ID | Term |
|---|---|
| D000227 | Adenine Nucleotides |
| D011685 | Purine Nucleotides |
| D011687 | Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D001087 | Arabinonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D009711 | Nucleotides |
| D012265 | Ribonucleotides |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D017690 | Cell Transplantation |
| D064987 | Cell- and Tissue-Based Therapy |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D013514 | Surgical Procedures, Operative |
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