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

Phase 2TerminatedNCT03263767

Nantes University Hospital47 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Graft Versus Host Disease

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Incidence of grade 3 and 4 acute GVHD cortico-resistant

acute GVHD will be evaluated from International Mount Sinai criteria

Time frame: 100 days after transplantation

Secondary Outcomes

Engraftment

number of days in aplasia (neutrophils\< 0.5 Giga/L and platelets\<20 G/l, number of transfusions (red blood and platelets)

Time frame: one year

Engraftment

chimerism

Time frame: one year

disease free survival (DFS)

blood and bone marrow analysis

Time frame: one year, the last follow-up visit

Overall survival (OS)

clinical follow-up

Time frame: one year, the last follow-up visit

graft and relapse free survival

time between Day O and relapse

Time frame: one year

chronic GVHD

chronic GVHD will be assessed with NCI criteria for evaluation of chronic GVHD

Time frame: one year

non relapse mortality (NRM)

number of death unrelated to relapse or disease progression

Time frame: last follow-up visit

Chimerism

proportion of full and mixed donor chimerism

Time frame: 1, 2, 3, 6 and 12 months after transplantation

Immune reconstitution

lymphocytes, monocytes, T4, T8, Natural Killer (NK), B cells rates

Time frame: 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

Time frame: 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)

Time frame: 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

Time frame: one year

compare OS between patients with ATG and patients without ATG

Time frame: 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

Time frame: 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

Time frame: one year

compare DFS between patients with ATG and patients without ATG

DFS

Time frame: one year, last follow-up visit

compare Relapse between patients with ATG and patients without ATG

Relapse

Time frame: one year, last follow-up visit

compare NRM between patients with ATG and patients without ATG

NRM

Time frame: one year, last follow-up visit

compare Infections frequency between patients with ATG and patients without ATG

Time frame: one year

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes