Study Testing Two Conditioning Regimen With a Single Prophylaxis of GVHD by Cyclophosphamide and Methotrexate Post-transplant in Patients Eligible for Matched-donor Allograft Transplantation
Methotrexate: 15 mg/m² on Day+1 after graft (=Day0) 10 mg/m² 3 days on Day+4/Day+6/Day+11 after graft (=Day0)
Post-Transplant Cyclophosphamide: 50 mg/kg intravenous 2 days on Day+3/Day+5 after graft (=Day0)
Fludarabine: Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)
Cycophosphamide: Conditioning regimen: 14.5 mg/kg intravenous 2 days on Day-6/Day-5 before graft (=Day0)
Anti-Thymoglobulin: Conditioning regimen: 2.5 mg/kg intravenous on Day-2 before graft (=Day0)
total body irradiation: 2 grays on Day-1 before graft (=Day0)
hematopoietic stem cells: High dose of hematopoietic stem cells derived from peripheral blood on transplantation day (=Day0 graft)
Graft nuclear cells: Graft nuclear cells CD3+ cells if needed after transplantation
Donor Lymphocytes Injection: DLI with CD3+ if relapse after transplantation or in prevention of relapse
Clofarabine: Conditioning regimen: 30 mg/m² Intravenous 5 days from Day-6 to Day-2 (Day-6/Day-5-/Day-4/Day-3/Day-2 before graft (=Day0)
Thiotepa: Conditioning regimen: 5 mg/kg Intravenous at Day-6 before graft (=Day0)
Busulfan: Conditioning regimen: 3.2 mg/kg Intravenous 2 days at Day-2 and Day-1 before graft (=Day0)
Fludarabine: Conditioning regimen: 40 mg/m² intravenous 4 days on Day-5/Day-4/Day-3/Day-2 before graft (=Day0)
Study summary
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-CSH).
Recently, in the context of semi-identical (=haploidentical) HLA donors, but also of compatible HLA donors, the use of cyclophosphamide (CY) administered in high doses at early post-transplant (PT) (=PTCY) (Days +3 and +4 or +5) has shown excellent control of acute and chronic GVH, even enabling the discontinuation of other immunosuppressive drugs administered after allo-CSH (ciclosporin, mycophenolate mofetyl (MMF) or Cellcept).
This step has already been taken in the context of allo-CSH with myeloablative conditioning (MAC), which is a minoritary conditioning in adults.
However, in the context of allo-CSH with reduced-intensity conditioning (RIC), which predominates in adults, this strategy seems insufficient to prevent the risk of GVHD.
The idea of reducing the use of immunosuppressants in the context of RIC/HLA-compatible transplants seems, however, still relevant, in order to reduce their adverse effects, improve patients' quality of life and enhance the reconstitution of the post-transplant immune system.
Eligibility
Sex
ALL
Min age
18 Years
Max age
70 Years
Healthy volunteers
No
Inclusion Criteria:
* Age: ≥ 18 and ≤ 70 years old
* Patient with hematologic malignancy
* Indication for HSC allograft with attenuated conditioning
* Pluripotent stem cell (PSC) engraftment
* Availability of a 10/10 familial or non-familial HLA compatible donor
* Consent to the protocol
* ECOG \<=2
* Woman of childbearing age with negative pregnancy test and on highly effective contraception during treatment and for a period of 12 months after stopping MTX and CY
* Man of childbearing age with highly effective contraception during treatment and for a period of 6 months after stopping MTX and CY and a period of 12 months after stopping MTX and CY if TBF conditioning regimen arm
* Negative Hepatitis B, C, HIV serologies
* Social security affiliation
Exclusion Criteria:
* History of allograft
* Patient eligible for myeloablative conditioning (MAC)
* Bone marrow transplant
* Other progressive cancerous disease, or antecedent of cancer in the last five years, with the exception of a carcinoma of the skin or a carcinoma in situ of the uterine cole treated and in remission.
* Progressive psychiatric condition
* Pregnant or breastfeeding woman,
* Woman or man of childbearing age with lack of effective contraception
* Serious and uncontrolled concomitant infection
* Cardiac: systolic ejection fraction \< 50% by transthoracic ultrasound or by isotopic method (isotope gamma angiography), NYHA II, III or IV heart failure, active rhythmic, valvular or ischemic heart disease or anteriority
* Respiratory with EFR: DLCOc \<40% of theoretical
* Renal: creatinine clearance \< 50 ml/min (assessment with MDRD method)
* Urological: active urinary tract infection, history of acute urothelial toxicity due to cytotoxic chemotherapy or radiotherapy, known obstruction of urinary flow, pre-existing hemorrhagic cystitis
* Hepatic: transaminases greater than 5 times normal or bilirubin greater than 2 times normal
* Person protected by law (major under guardianship, curatorship or legal protection)
* Vaccination against yellow fever in the last year
* Known or suspected hypersensitivity to rabbit proteins as well as to the active substance and excipients of all investigational and ancillary drugs administered during the study,
* Contraindication to any of the investigational or adjuvant drugs administered during the study
* Patient not speaking French
Primary outcome measure(s)
Incidence of grade 3-4 acute GVHD following allo-CSH for all patients and for each conditioning group (Baltimore and TBF). — Post-transplant through study completion, an average of 1 year Estimation of the incidence of grade 3 and 4 acute GVHD following allo-CSH (excluding post-DLI\* acute GVHD) according to Mount Sinai criteria.
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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