A randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral selinexor (KPT-330) to standard induction chemotherapy in AML and high risk myelodysplasia (MDS) (IPSS-R > 4.5) in patients aged >66 years .

• Patients eligible for standard chemotherapy.

• Patients 66 years and older

• Patients with:

o 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

o acute leukemia’s of ambiguous lineage according to WHO 2008 or

o a diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R > 4.5

• Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:

o Serum creatinine ≤1.0 mg/dL (≤88.7 μmol/L); if serum creatinine >1.0 mg/dL (>88.7 μmol/L), then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where the Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if patient is female) x (1.212 if patient is black) NOTE: if serum creatinine is measured in μmol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 μmol/L and use the above mentioned formula.

o Serum bilirubin ≤ 2.5 x upper limit of normal (ULN)

o Aspartate transaminase (AST) ≤ 2.5 x ULN

o Alanine transaminase (ALT) ≤ 2.5 x ULN

o Alkaline phosphatase ≤ 2.5 x ULN

• WHO performance status 0, 1 or 2

• Written informed consent.

• Male and female patients must use an effective contraceptive method if relevant during the study and for a minimum of 6 months after study treatment.

• Acute promyelocytic leukemia

• Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is allowed

• Concurrent history of active malignancy in the two past years prior to diagnosis except for:

o Basal and squamous cell carcinoma of the skin

o in situ carcinoma of the cervix

• Blast crisis of chronic myeloid leukemia

• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera)

• Cardiac dysfunction as defined by:

o Myocardial infarction within the last 6 months of study entry, or

o Reduced left ventricular function with an ejection fraction < 50% ad measured by MUG scan or echocardiogram or

o Unstable angina or

o New York Heart Association (NYHA) grade II or greater congestive heart failure (see Appendix I) or

o Unstable cardiac arrthythmias

• Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance

• Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study.

• Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.

• Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.

• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule