Cladribine Dose Escalation in Conditioning Regimen Prior to Allo-HSCT for Refractory Acute Leukemia and Myelodysplastic Syndromes

• Fludarabine-Cladribine-Busulfan conditioning regimen (Drug): Conditioning regimen will be performed from day -6 to day -2 and contains: * Fludarabine 10 mg/m²/d during 5 days (day-6 to day-2). * Cladribine during 5 days (day-6 to day-2) at one the following define dose level: * Dose 1: 10 mg/m²/d * Dose 2: 15 mg/m²/d * Dose 3: 20 mg/m²/d * Dose 4: 25 mg/m²/d * IV busulfan will be given on day-6 using fixed dose as following: * If age ≤ 60 years: starting dose of 130 mg/m² * If age > 60 years: starting dose of 100 mg/m² No busulfan will be administered at day-5, allowing the pharmacokinetic (PK) analyses . Subsequent infusion of IV busulfan will be performed from day-4 to day-2 at the dose recommended by PK analyses

Primary outcomes

• estimation of the maximal tolerable dose,if any,and recommended phase II dose of cladribine administered as in combination with fludarabine and PK-guided IV busulfan prior Allo-HSCT for refractory acute leukemia and myelodysplastic syndrome (MDS) [30 days after Allo-HSCT]: Occurrence ratio of dose-limiting toxicity defined as any grade ≥ 3 toxicity according to CTCAE (version 4.03 ) attributable to conditioning regimen (extra-medullary toxicity), considered to be related or probably related to the Cla-Fu-Bu RTC by the investigator.

Secondary outcomes

• Cumulative incidence of acute Graft versus host disease [100 days]: Cumulative incidence of acute Graft versus host disease according to Gluckberg's classification
• Cumulative incidence of chronic Graft versus host disease [1 year]: Cumulative incidence of chronic Graft versus host disease according to NIH classification
• Cumulative incidence of relapse [1 year]: Cumulative incidence of relapse at 1 year
• Cumulative incidence of Non Relapse Mortality [100 days, 1 year]: Cumulative incidence of Non Relapse Mortality at day +100 and 1 year after Allo-HSCT

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Age 18-70
* ECOG 0 or 1
* Acute leukemia (AML or ALL) without criteria for CR or high risk MDS without criteria for CR
* Availability of a donor among following oHLA identical sibling oHaploidentical donor o10/10 or 9/10 allele-level HLA matched unrelated donor
* Signed informed consent
* Patient affiliated to the national "Social Security" regimen or beneficiary of this regimen

Exclusion Criteria:

* Contraindication for Allo-HSCT
* Cord blood Allo-HSCT
* Current active disease or positive serology for HIV, and/or HCV with detectable viremia and/ or HBV with positive Hbs Antigen.
* Renal failure with creatinine clearance < 30 ml/ min
* Decompensated haemolytic anaemia
* Hypersensitivity to an active substance or to any of the excipients
* Acute urinary infection
* Pre-existing haemorrhagic cystitis
* Woman of childbearing potential not using an effective contraception .
* Pregnant or lactating women
* Any serious concurrent uncontrolled medical disorder
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

• Raynier Devillier, MD,PhD, Principal investigator, Institut Paoli-Calmettes