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

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.

For this reason, the investigators now wish to test the administration of a combination of a high dose of early post-transplant CY (PTCY) and methotrexate (MTX) on days (D) D+1, D+4, D+6, D+11 (doses already performed in MAC transplant prophylaxis), with anti-lymphocyte serum (ALS) with RIC conditioning, without ciclosporin or MMF.

The investigators hypothesize that administration of this PTCY+MTX combination will enable immunosuppressive drugs to be discontinued as early as D+11 post-transplant, compared with the usual average of 3 to 4 months.

Eligibility Criteria:
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