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)

Study objectives

Primary objectives:

• Part A Run-in:

To select in a randomized approach the feasible dose level of lenalidomide when given orally at three variable dose levels (at 20 mg/day 1-21; 15 mg/day 1-21 or 10 mg/day 1-21) in combination with standard induction cycles I and II in patients with AML/ MDS with IPSS-R> 4.5.

• Part A:

To evaluate the effect of lenalidomide on EFS (Event Free Survival) at the selected feasible dose level when combined with remission induction chemotherapy cycles I and II in a randomized comparison to remission induction cycles I and II without addition of lenalidomide.

• Part B:

To evaluate the effect on the Cumulative incidence of relapse (CIR) of 6 cycles of maintenance therapy with lenalidomide treatment (10 mg/day for 21 days followed by 14 days rest) after post remission chemotherapy cycle III or autoHSCT versus observation only.

Secondary objectives:

• Part A

o To investigate the efficacy of lenalidomide in combination with remission induction chemotherapy cycles I and II (in comparison with the same treatment without lenalidomide) in all patients with regard to complete remission rate (CR/ CRi), DFS, CIR and OS
o To investigate the efficacy of lenalidomide in combination with remission induction chemotherapy cycles I and II in molecularly and cytogenetically distinguishable subsets with regard to complete remission rate (CR/CRi), DFS, CIR and OS
o To evaluate the treatment effects according to MRD measurements following therapy by standardized sampling of bone marrow/blood following remission induction treatment
o To determine the prognostic value of molecular markers and gene expression profiles of the leukemia cells assessed at diagnosis for both remission induction treatments
o To investigate the toxicities of lenalidomide in combination with remission induction chemotherapy cycles I and II
o To compare CIR after autoHSCT and cycle III according to molecular markers and MRD measurements
o To evaluate the effect of lenalidomide on the feasibility of collecting adequate autologous stem cell grafts and the probability of proceeding to autoHSCT

• Part B

o To investigate the efficacy of lenalidomide with regard to DFS and OS measured from 2nd randomization
o To investigate post remission and post-transplant toxicities and need for transfusions when lenalidomide is applied after post remission chemotherapy/autoHSCT
o To evaluate the efficacy of lenalidomide as post-remission therapy to prevent relapse in all randomized patients, but also in relationship with the distinctive risk categories of AML (as based on cytogenetics and molecular genetics) and MRD estimates

Participation conditions

Inclusion criteria for registration/randomization 1

• Age 18-65 years, inclusive
• 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 diagnosis of refractory anemia with excess of blasts (MDS) and IPSS-R score > 4.5

• WHO performance status 0, 1 or 2
• Sampled bone marrow and/ blood cells at diagnosis for centralized molecular analysis and MRD evaluation, 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.
• 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 (>88.7μmol/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.
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

• Written informed consent
• Ability and willingness to adhere to the lenalidomide Pregnancy Prevention Program

Exclusion criteria for registration/randomization 1

• Previous therapy with lenalidomide
• Acute promyelocytic leukemia
• Myeloproliferative neoplasia
• Previous treatment for AML or high risk MDS (IPSS-R > 4.5), except hydroxyurea
• Concurrent history of active malignancy in two past years prior to diagnosis except for:

o basal and squamous cell carcinoma of the skin
o in situ carcinoma of the cervix

• 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% as measured by MUG scan or echocardiogram or
o Unstable angina, or
o Unstable cardiac arrhythmias

• Hypersensitivity to the active substance or to any of the excipients of the drug product
• Pregnant or lactating females
• Unwilling or not capable to use effective means of birth control
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Inclusion criteria for randomization 2a (Part B)

• CR or CRi
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 75 x 109/L
• Serum creatinine clearance ≥ 30 ml/min
• Total bilirubin ≤ 2.5 x ULN
• AST ≤ 2.5 x ULN
• ALT ≤ 2.5 x ULN

Exclusion criteria for randomization 2a (Part B)

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

Centre Hospitalier de Luxembourg - CHL