Acute Myeloid Leukemia Myelodysplasia
Conditions
Interventions
First, we will establish in a randomized run-in study the dose level of 
lenalidomide in addition to the standard induction treatment of 
idarubicin/cytarabine (cycle I) and daunorubicine/cytarabine (cycle II) (part 
A-run-in). 
Following the dose-selection phase the study will continue as a randomized 
study for induction therapy (part A). 
Subsequently, we will also investigate the effect of lenalidomide maintenance 
treatment (10 mg/day) by randomization to be administered in first CR.
Sponsors
HOVON
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: Part A: 1. Age 18-65 years, inclusive 2. 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 score > 4.5 3. WHO performance status 0, 1 or 2 4. Sampled bone marrow and/ blood cells 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 5. Adequate renal and hepatic functions as indicated by the following laboratory values: - 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 m^2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m^2) = 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. - Serum bilirubin <=2.5 x upper limit of normal (ULN) - Aspartate transaminase (AST) <= 2.5 x ULN - Alanine transaminase (ALT) <= 2.5 x ULN - Alkaline phosphatase <= 2.5 x ULN 6. Written informed consent 7. Ability and willingness to adhere to the lenalidomide Pregnancy Prevention Program, Part B: 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/1.73^2 5. Total bilirubin <= 2.5 x ULN 6. AST <= 2.5 x ULN 7. ALT <= 2.5 x ULN
Exclusion criteria
Exclusion criteria: Part A: 1. Previous therapy with lenalidomide 2. Acute promyelocytic leukemia 3. Previous treatment for AML or high risk MDS (IPSS-R > 4.5), except hydroxyurea 4. Concurrent history of active malignancy in two past years prior to diagnosis except for: - basal and squamous cell carcinoma of the skin - in situ carcinoma of the cervix 5. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease etcetera) 6. Cardiac dysfunction as defined by: - Myocardial infarction within the last 6 months of study entry, or - Reduced left ventricular function with an ejection fraction < 50% as measured by MUGA scan or echocardiogram or - Unstable angina, or - Unstable cardiac arrhythmias Hypersensitivity to the active substance or to any of the excipients of the drug product 7. Pregnant or lactating females 8. Unwilling or not capable to use effective means of birth control 9. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule, Part B: 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoint Part A-run-in: Lenalidomide dose level selection - DLT and duration of myelosuppression of induction treatment with or without lenalidomide for each of the distinct predefined dose levels Primary endpoint Part A: Induction - Efficacy - EFS after induction treatment with or without lenalidomide (i.e., time from registration to induction failure, death from any cause or relapse whichever occurs first) Primary endpoint Part B: Maintenance - Efficacy - Cumulative incidence of relapse (CIR) after second randomization (maintenance treatment with lenalidomide or observation only) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints Part A Run-in : Lenalidomide dose level selection - Response (CR and CRi) after induction therapy cycles I and II Secondary endpoints Part A: Induction- Efficacy - EFS in the distinct prognostic subsets (AML good-risk vs. AML intermediate-risk vs. AML poor-risk vs. AML-very poor-risk) and cytogenetically and molecularly defined subgroups of AML - Response (CR and CRi) after induction therapy cycles I and II - Disease-free survival (DFS, measured from time of CR/CRi to day of relapse or death from any cause, whichever occurs first) - OS measured from the time of registration - Outcome of induction treatments in relation to MRD measurements -Evaluation of molecular prognostic markers and gene expression profiles for and overexpression of defined genes (e.g. EVI1, cereblon) for outcome in relation to induction and post induction treatments -Toxicities -Evaluation of MRD after induction and post-induction treatments -Time to hematopoietic recovery (ANC 0.5 and 1.0 x 10^9/L; platelets 50 and 100 x 10^9/L) after each treatment cycle -Number of platelet transfusions and last day of platelet transfusion after each cycle -Impact of the use of lenalidomide on the effectiveness of stem cell mobilization Secondary endpoints Part B: Maintenance - efficacy - OS and DFS measured from 2nd randomization, and also in the distinct prognostic subsets (AML good-risk vs. AML intermediate-risk vs. AML poor-risk vs. AML very poor-risk) and cytogenetically and molecularly defined subgroups of AML - Toxicities - Number of platelet transfusions and last day of platelet transfusion after each cycle - Number of RBC transfusions in relation to maintenance or no maintenance treatment - Evaluation of MRD after 2nd randomization - Time to hematopoietic recovery (ANC 0.5 and 1.0x10 ^ 9/L; platelets 50 and 100x10^9/L) after each treatment cycle | — |
Countries
Netherlands
Outcome results
None listed