The present project is a multicenter, phase II trial which aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation.

This is a prospective, multicenter, non-randomized phase II study. The aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation.

Because the investigators focus our interest on relapsed MDS and low marrow blast count relapsed AML, the investigators postulate that one cycle at higher doses of azacytidine given at 100 mg/m² during 5 days is enough to induce temporary disease control, as suggested by the predictive value of the immediate response rate after the first cycle described in the study of Czibere et al. Starting with cycle 2, the investigators propose to administer DLI along with azacytidine to optimise the immunomodulatory effect. Because these immunomodulatory effects have been described at low dose, the investigators postulate that 35 mg/m² given during 5 days is enough to harness a graft-versus-leukemia effect and induce durable remissions without exacerbating GvHD. DLI will be given every other cycle following an escalated-dose regimen.

The investigators have estimated a sample size of 50 patients to be recruited during 4 years with a 2-year follow-up and a 3-year long-term follow-up. The whole study will be completed within 9 years.

Inclusion Criteria:

1. Patients:

   • Age ≥ 18 years
   • Be able to understand and sign informed consent
   • Fertile patients must use a reliable contraception method

2. Disease status at transplantation:

   • AML in first or subsequent complete remission (< 5% marrow blasts)
   • MDS with less than 10% marrow blasts at the time of transplantation

3. Transplantation:

   • Allogeneic transplantation using a sibling or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of one allele or one antigen or 1 antigen + 1 allele or 1 antigen + 1 DQB1 antigen or 2 alleles mismatches.
   • Myeloablative or reduced-intensity conditioning
   • Second transplantation is allowed
   • Donor is willing to donate lymphocytes

4. Clinical situation:

   • Cytological relapse after allo-SCT defined as the recurrence of more than 5% blasts on bone marrow aspiration (AML) or evidence of MDS
   • Immunophenotypic relapse defined as the recurrence of an abnormal phenotype on flow cytometry in bone marrow aspirate (only in case of a specific phenotype).
   • Cytogenetic or molecular relapse defined as the persistence or recurrence of a cytogenetic abnormality or molecular marker in bone marrow aspiration or peripheral blood. WT1 expression is not considered as reliable marker for relapse in this protocol but FLT3-ITD, NPM1, CEBPA, or translocation-specific markers (such as MLL-PTD, AML-ETO, CBFB-MYH11) are.

5. Immunosuppressive therapy should have been stopped before inclusion.

Exclusion Criteria:

• More than 30% marrow blasts at the time of inclusion
• Extramedullary relapse including CNS involvement
• ECOG Performance status > 2
• Active acute grade II-IV GvHD at the time of inclusion
• Active chronic GvHD requiring systemic therapy at the time of inclusion
• Uncontrolled infection
• HIV positive
• Acute or chronic heart failure (NYHA class III or IV) or symptomatic ischemic heart disease or ejection fraction < 35% or uncontrolled arrhythmia
• Severe liver failure (total bilirubin > 3 mg/dL, SGPT > 4 X upper normal limit)
• Severe pulmonary failure (corrected DLCo < 35%)
• Terminal renal failure requiring dialysis
• Severe neurological or psychiatric disorders
• Concurrent investigational drug.
• Other treatment for relapse, except for hydroxyurea but it should be stopped before inclusion in the study.
• Female who is pregnant or breastfeeding