Randomized study with a run-in dose-selection phase to assess the added value of lenalidomide in combination with standard remission-induction chemotherapy and post-remission treatment in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or high risk myelodysplasia (MDS) (IPSS-R risk score > 4.5)

First randomization:
1. Age 18-65 years, inclusive
2. Patients with
a. 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
b. Acute leukemia’s of ambiguous lineage according to WHO 2008 or
c. A diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R score > 4.5
3. WHO performance status 0, 1 or 2
4. Sampled bone marrow and/ blood cells at diagnosis for centralized molecular analysis, MRD evaluation and biobanking, unless in case of a dry marrow tap with no possibility to collect marrow cells. In cases of marrow tap failure only blood cells will be sampled.
5. Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
a. 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 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 umol/L, recalculate it in mg/dL according to the equation: 1 mg/dL = 88.7 umol/L) and use above mentioned formula.
b. Serum bilirubin ≤2.5 x upper limit of normal (ULN)
c. Aspartate transaminase (AST) ≤ 2.5 x ULN
d. Alanine transaminase (ALT) ≤ 2.5 x ULN
e. Alkaline phosphatase ≤ 2.5 x ULN
6. Written informed consent
7. Ability and willingess to adhere to the lenalidomide Pregnancy Prevention Program

Second randomization:
1. CR or CRi
2. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
3. Platelet count ≥ 75 x 10^9/L
4. Serum creatinine clearance ≥ 30 ml/min or estimated glomerular filtration rate (GFR) >60mL/min/1.73 m2
5. Total bilirubin ≤ 2.5 x ULN
6. AST ≤ 2.5 x ULN
7. ALT ≤ 2.5 x ULN

First randomization:
1. Previous therapy with lenalidomide
2. Acute promyelocytic leukemia
3. Myeloproliferative neoplasia
4. Previous treatment for AML or high risk MDS (IPSS-R > 4.5), except hydroxyurea
5. Concurrent history of active malignancy in two past years prior to diagnosis except for:
a. Basal and squamous cell carcinoma of the skin
b. In situ carcinoma of the cervix
6. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera)
7. Cardiac dysfunction as defined by:
a. Myocardial infarction within the last 6 months of study entry, or
b. Reduced left ventricular function with an ejection fraction < 50% as measured by MUG scan or echocardiogram or
c. Unstable angina, or
d. Unstable cardiac arrhythmias
8. Pregnant or lactating females
9. Unwilling or not capable to use effective means of birth control
10. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Second randomization:
1. Severe cardiac dysfunction (NYHA classification II-IV, see appendix G)
2. Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix F)
3. Severe neurological or psychiatric disease
4. Serious active infections
5. Previous serious toxicities related to the use of lenalidomide
6. CMV reactivation, which is not responsive to first line valganciclovir