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

Conditions: Graft Versus Host Disease; Hematologic Malignancy

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.

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

Keywords: hematopoietic stem cell allograft (allo-csh) methotrexate (mtx) post-transplant cyclophosphamide (ptcy)