Allogeneic cord blood stem cell transplantation is a potentially curative therapy for patients with haematological malignancies. We have extensive experience with the use of Cord Blood Transplantation (CBT) in patients with advanced myeloid malignancies. In adults however, the 40% Non-Relapse Mortality (NRM) rate observed after CBT conditioned with a myeloablative conditioning has encouraged the development of CBT with Reduced Intensity Conditioning (RIC). Our previous national CBT protocol (the Minicord French protocol - NCT00797758) showed that RIC CBT can reduce NRM, but relapse remains the main post-transplant event (>30% at one year). Thus, the development of reduced toxicity rather than RIC conditioning for CBT is warranted in order to improve the outcome of such transplants by limiting NRM and reducing relapse rate. The Fludarabine, ATG and intensified doses of IV Busulfan (9.6 mg/Kg total dose) regimen is a well-established preparative regimen for reduced-intensity/toxicity conditioning prior to allogeneic stem cell transplantation using peripheral blood stem cells mobilized with G-CSF (ClinicalTrials.gov Identifier: NCT00841724). However, such regimen is likely not sufficient to allow for CB cell engraftment. Thiotepa is an alkylating and radio-mimetic agent with a large anti-tumor activity including leukemic cells, the ability to cross the blood-brain barrier and to improve engraftment of hematopoietic stem cells. This drug has been combined to usual conditioning regimen without increasing the toxicity but improving the engraftment rate and potentially reducing the relapse rate. Thus, in the context of adult CBT for high risk myeloid malignancies, we propose to prospectively evaluate a reduced toxicity conditioning based on the association of Thiotepa, Fludarabine, IV Busulfan and ATG with the objective to achieve acceptable NRM rates, and to allow for improved anti-leukemic control based on the cytotoxic component of the conditioning regimen itself, while waiting for the long term immune-mediated disease control (GVL effect).

Inclusion Criteria:

• Age ≥18 years and ≤ 65 years
• Patients diagnosed with one of the following diseases (validation of the indication of allogeneic

HSCT with an alternative source of hematopoietic stem cells by centers' local RCP):

• Acute myelogenous leukemia (AML) with intermediate or high risk features ((≥ intermediate risk 1) in CR1 or above according to centers' decision
• Myelodysplastic syndromes with International Prognostic Scoring System (IPSS) score ³ 2 (cf. appendix 3) or with symptomatic pancytopenia according to centers' decision
• Chronic myelomonocytic leukemia (CMML)
• Both MDS and CMML should have ≤ 10% blasts at transplantation
• Absence of a matched sibling or unrelated donor (10/10 or 9/10 if mismatch on HLA Cw, based on each center's donor selection criteria)
• Cord blood units must be matched with patient at 4, 5, or 6/6 HLA loci, (class I antigenic & class II allelic level)with a minimum of 3.5 x 10^7 TNC/kg recipient body weight in the pre-thawed fraction and with ≥2.5x10^7 TNC/kg for the richest cord blood unit and ≥ 1.5x10^7 TNC/kg for the poorest blood unit in case of 2 cord blood units
• Performance status : OMS score ≤ 1 (cf. appendix 5)
• Cardiac function - left ventricular ejection fraction ≥ 45%.
• Pulmonary function - diffusion capacity of at least 50% predicted.
• Serum creatinine clearance 0 ml/min.
• SGPT 4x normal , serum bilirubin < 2 x normal.
• Written informed consent.
• Progestative treatment for women with persisting menstrual periods

Exclusion Criteria:

• Presence of a matched sibling or unrelated available donor (10/10 or 9/10 if mismatch on HLA Cw in centers performing 9/10 HLA mismatched transplants)
• Active infection at time of conditioning. In case of uncertainty regarding whether a previous infection is resolved or not, this will be discussed with the PI on a case by case basis.
• Pregnancy in women with child bearing potential (pregnancy test performed within 2-4 weeks of study entry).
• HIV positive
• Active CNS leukemia
• Chronic or active Hepatitis B or Hepatitis C. If questions about liver health discuss with PI and strongly consider liver biopsy.
• Poor performance status : OMS score > 1
• Life expectancy is severely limited by concomitant illness and expected to be <12 weeks.
• Left ventricular ejection fraction <45%. Uncontrolled arrhythmias or symptomatic cardiac disease.
• Symptomatic pulmonary disease. FEV1, FVC and DLCO <50% of expected corrected for hemoglobin.
• Serum creatinine clearance (Crockoft) below 50 mL/m per 1.73 m² or requiring dialysis
• Vaccination with alive vaccine (virus or bacteria) < 3 months
• Fludarabine contra-indication
• Thymoglobuline contra-indication
• Patient under guardianship or curatorship