A randomized phase II multicenter study to assess the tolerability and efficacy of the addition of ibrutinib to 10-day decitabine in UNFIT (i.e. HCT-CI >= 3) AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) patients aged >= 66 years.A study in the frame of the masterprotocol of parallel randomized phase II studies in UNFIT-older AML/high-risk MDS patients.

INTERVENTION: Patients in this study are treated with 10‐day decitabine treatment with or without ibrutinib. The starting dose of ibrutinib will be 560 mg once daily. During the part A run‐in phase the dose level of ibrutinib will be established. CONDITION: Acute Myeloid Leukemia (AML), Myelodysplasia ; ; PRIMARY OUTCOME: Cumulative CR/CRi rate after 3 cycles SECONDARY OUTCOME: ? Safety and tolerability (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia). ; ; ? Efficacy profile (response rate (CR, CRi, PR), event free survival (EFS) and overall survival (OS)). ; ; ? Days of staying in hospital and transfusion needs. ; ; ? Prognostic value of MRD (by flowcytometry or PCR). ; ; ? Gene mutations predictive of response, EFS and OS by exploratory analysis. ; ; ? Prognostic value of baseline physical and functional conditions using comprehensive geriatric assessment tools (short physical performance battery (SPPB) and activities of daily living (ADL) on treatment outcome. ; ; ; ; Translational outcomes: ; ; ‐ To determine the impact of 3 days ibrutinib monotherapy (pre‐treatment) on WBC count, circulating blast count, and kinome (using mass cytometry kinome). ; ; ‐ To identify potential biomarkers (using mass cytometry kinome; methylome) in bone marrow and peripheral blood which are of prognostic importance in both arms, and whether they are of predictive importance for response. ; ; ‐ To identify methylome profiles in CD34+ bone marrow blasts and stroma cells which are of prognostic importance in both arms, and whether they are of predictive importance for response. ; INCLUSION CRITERIA: Patients with: ‐ a diagnosis of AML and related precursor neoplasms according to WHO 2008 classification (excluding acute promyelocytic leukemia) including secondary AML (after an antecedent hematological disease (e.g. MDS) and therapy‐related AML, or ‐ acute leukemia's of ambiguous lineage according to WHO 2008 or ‐ a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS‐R > 4.5 ? Patients 66 years and older. ? Patients NOT eligible for standard chemotherapy, defined as HCT‐CI >= 3. or Patient NOT eligible for standard chemotherapy for other reasons (wish of patient). ? WBC =< 30 x10^9/L (prior hydroxyurea allowed for a maximum of 5 days, stop 2 days before start decitabine treatment) ? Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values: ‐ Serum creatinine =< 2.5 mg/dL (=< 221.7 ìmol/L), unless considered