Post Transplant Cyclophosphamide (PTCY) as Sole Graft Versus Host Disease (GVHD) Prophylaxis for Matched Allotransplant: CYRIC

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Study Testing Prophylaxis Feasibility of Graft Versus Host Disease With Only High Dose Cyclophosphamide Post-transplantation for Patients Eligible to a Reduced-intensity Conditioning Regiment Prior to Allogenic Transplantation With a Compatible Familial or Non-familial Donor.

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: Fludarabine
* Drug: Clofarabine
* Radiation: Full body irradiation
* Drug: Cyclophosphamide
* Drug: Cyclophosphamide
* Other: stem cell transplantation
* Other: nuclear cells
* Drug: Thymoglobulin Injectable Product


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LYMPHOID HEMOPATHY without ATG<br>patients with lymphoid hemopathy | Drug: Fludarabine<br>* 30 mg/m² Intravenous 5 days from Day-6 to Day-2<br>Radiation: Full body irradiation<br>* 2 grays at Day-1<br>Drug: Cyclophosphamide<br>* 14 mg/kg intravenous 2 days at Day - 6 and day -5<br>Drug: Cyclophosphamide<br>* 50 mg/kg intravenous 2 days at day +3 and day +4<br>* Other names: hight dose;Other: stem cell transplantation<br>* at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)<br>* Other names: graft;Other: nuclear cells<br>* CD3+ cells if needed after transplantation<br>* Other names: Donor Lymphocytes Injection (DLI);|
| Experimental: MYELOID HEMOPATHY without ATG<br>patients with myeloid hemopathy | Drug: Clofarabine<br>* 30 mg/m² Intravenous 5 days from Day-6 to Day-2<br>Radiation: Full body irradiation<br>* 2 grays at Day-1<br>Drug: Cyclophosphamide<br>* 14 mg/kg intravenous 2 days at Day - 6 and day -5<br>Drug: Cyclophosphamide<br>* 50 mg/kg intravenous 2 days at day +3 and day +4<br>* Other names: hight dose;Other: stem cell transplantation<br>* at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)<br>* Other names: graft;Other: nuclear cells<br>* CD3+ cells if needed after transplantation<br>* Other names: Donor Lymphocytes Injection (DLI);|
| Experimental: LYMPHOID HEMOPATHY witH ATG<br>patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence | Drug: Fludarabine<br>* 30 mg/m² Intravenous 5 days from Day-6 to Day-2<br>Radiation: Full body irradiation<br>* 2 grays at Day-1<br>Drug: Cyclophosphamide<br>* 14 mg/kg intravenous 2 days at Day - 6 and day -5<br>Drug: Cyclophosphamide<br>* 50 mg/kg intravenous 2 days at day +3 and day +4<br>* Other names: hight dose;Other: stem cell transplantation<br>* at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)<br>* Other names: graft;Other: nuclear cells<br>* CD3+ cells if needed after transplantation<br>* Other names: Donor Lymphocytes Injection (DLI);Drug: Thymoglobulin Injectable Product<br>* At day -2 2.5 mg/kg for patients inclued after 14 dec 2020<br>* Other names: ATG;|
| Experimental: MYELOID HEMOPATHY with ATG<br>patients inclued after 14 dec 2020, received a conditionnement regimen with ATG on Day -2 to reduce GVHD GRADE 1-2 incidence | Drug: Clofarabine<br>* 30 mg/m² Intravenous 5 days from Day-6 to Day-2<br>Radiation: Full body irradiation<br>* 2 grays at Day-1<br>Drug: Cyclophosphamide<br>* 14 mg/kg intravenous 2 days at Day - 6 and day -5<br>Drug: Cyclophosphamide<br>* 50 mg/kg intravenous 2 days at day +3 and day +4<br>* Other names: hight dose;Other: stem cell transplantation<br>* at D0 intraveinous Depending on donor : the stem cells will be extracted from blood (CD34+) or from bone marrow (CD34+ and nuclear cells)<br>* Other names: graft;Other: nuclear cells<br>* CD3+ cells if needed after transplantation<br>* Other names: Donor Lymphocytes Injection (DLI);Drug: Thymoglobulin Injectable Product<br>* At day -2 2.5 mg/kg for patients inclued after 14 dec 2020<br>* Other names: ATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral haemopoietic stem cell transplant, High dose cyclophosphamide, acute GVHD, allogenic transplantation, RIC (reduced-intensity conditioning)