Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative therapy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Most of the patients requiring an allo-HSCT are above 50 years of age and are transplanted with a reduced intensity conditioning (RIC) regimen. The optimal RIC and Graft Versus Host Disease (GVHD) prophylaxis regimen allowing a good control of the disease while preventing GVHD remains to be determined for elderly patients. A phase III trial comparing the conventional RIC fludarabine-busulfan 2 days to fludarabine-treosulfan demonstrated an advantage for the flu-treosulfan arm in terms of event free survival (EFS), that should therefore be considered as the new standard of RIC regimen for AML and MDS. GVHD prevention has a crucial role in post-transplant outcomes by potentially interfering with the graft-versus-leukemia (GVL) effect and immune reconstitution. Anti-thymocyte globulins (ATG) are recommended to reduce the risk of acute and chronic GVHD in transplants performed with matched unrelated donors. However, the optimal type of ATG between the 2 approved brands (ATG-thymoglobulin and ATLG-grafalon) displaying distinct characteristics and the optimal dose of ATG are still unknown. In a retrospective study of patients transplanted mainly with RIC with matched related and unrelated donors for haematological malignancies, Anti-T lymphocyte globulin (ATLG) was associated with a reduction of grade II-IV acute GVHD in comparison to ATG without increasing the incidence of relapse.

This phase III randomised study propose to compare GVHD prevention with ATG versus ATLG in AML and MDS patients above 50 years of age transplanted with a matched unrelated donor following a fludarabine-treosulfan RIC, with the hypothesis that ATLG would better control GVHD in this population of patients thus limiting the risk of morbidity and mortality of the procedure.

Inclusion Criteria:

1. Age ≥ 50 and ≤ 70 years

2. Patient between 50 and 55 years should be unfit for a myeloblative conditioning (SORROR score ≥2)

3. AML requiring allogeneic stem cell transplantation (intermediate or high-risk AML) in complete cytologic response (CR1 or above) or MDS requiring allogeneic stem cell transplantation (IPSS≥ 1.5 or IPSS-R > 4.5 or IPSS-R > 3-4.5 with risk features [rapide blast increase, life-threatening neutropenia (<0.3 G/L) or thrombopenia (<30G/L) or high transfusion needs (>2/month for 6 months)]

4. Without an HLA matched related donor

5. Having an identified matched HLA 10/10 unrelated donor

6. With usual criteria for HSCT:

   1. ECOG performans status ≤ 2
   2. No severe and uncontrolled infection
   3. Cardiac left ventricular ejection fraction ≥50%
   4. Lung DLCO > 40%
   5. Adequate organ function: ASAT and ALAT ≤ 3N, total bilirubin ≤ 2N, creatinine clearance ≥ 50 mL/min (except if those abnormalities are linked to the hematological disease)

7. With health insurance coverage

8. Having signed a written informed consent

9. Contraception methods must be prescribed during all the duration of the research

NB: The authorized contraceptive methods are:

• For women of childbearing age and in absence of permanent sterilization: oral, intravaginal or transdermal combined hormonal contraception, oral, injectable or transdermal progestogen-only hormonal contraception, intrauterine hormonal releasing system (IUS), sexual abstinence (only if this the preferred and usual lifestyle of the participants).
• For man in absence of permanent sterilization: sexual abstinence, condoms

Exclusion Criteria:

1. Cancer in the last 5 years (except basal cell carcinoma of the skin or "in situ" carcinoma of the cervix)
2. Uncontrolled infection
3. Seropositivity for HIV or HTLV-1 or active hepatitis B or C
4. Yellow fever vaccine and all others live virus vaccines within 2 months before transplantation
5. Heart failure according to NYHA (II or more) or Left ventricular ejection fraction < 50%.
6. Lung DLCO ≤ 40%
7. Preexisting acute hemorrhagic cystitis
8. Renal failure with creatinine clearance < 50ml / min
9. Pregnancy (β-HCG positive) or breast-feeding
10. Patients with any debilitating medical or psychiatric illness, which would preclude the realization of the SCT or the understanding of the protocol
11. Patient under state medical aid
12. Patient under legal protection (protection of the court, or in curatorship or guardianship).
13. For Grafalon: Hypersensitivity to the active substance or to any of the excipients
14. For Thymoglobulin: Hypersensitivity to rabbit proteins or to any of the excipients
15. Participation in other interventional clinical trials
16. Any contraindication mentioned in the SmPC of all auxiliary medicinal products planned to be used in the trial: cyclosporine, mycophenolate mofetil, fludarabine, treosulfan