Lenalidomide in Older Patients With Acute Myeloid Leukemia Without Chromosome 5q Abnormalities

Study Overview
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Brief Summary
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This study is designed to test the safety and efficacy of lenalidomide in older patients (age > 60 years) with untreated acute myeloid leukemia without chromosomal abnormalities involving 5q.

Detailed Description
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The incidence of AML increases with age, and current treatment options for the older patient population with newly diagnosed AML (AML >= 60) is limited, all with poor outcomes. AML >= 60 patients are more likely to have poor-risk cytogenetics abnormalities, and many have a preceding myelodysplastic syndrome (MDS). Traditional induction chemotherapy approaches in AML with cytarabine and anthracyclines yield remissions in 45-60% of AML >= 60, however the vast majority of these patients relapse with a median survival of about 9 months. These patients are rarely candidates for potentially curative allogeneic stem cell transplantation. Many untreated AML >= 60 patients are not candidates for aggressive therapy, and those who do receive therapy have a significant induction mortality of 10-20%, and significant hematologic toxicity occurs in over 30%, with no change in overall survival compared with supportive care. AML >= 60 patients with favorable risk cytogenetics have a modest improvement in prognosis, for example with a 5 year overall survival of  20%, compared with 0% in other cytogenetic categories. Thus, all eligible patients with AML >= 60 should be recommended a clinical trial, regardless of whether they would be offered generally ineffective traditional induction chemotherapy. More effective and less toxic therapies are needed for the treatment of AML in this older patient population, indeed the preferred first line therapy in the national cancer center network (NCCN) guidelines for AML is a clinical trial. In trials of lenalidomide in patients with MDS the dose of lenalidomide has been reduced for myelotoxicity and/or thrombocytopenia. However, current paradigms for the therapy of acute myeloid leukemia are based on using high doses of myelosuppressive chemotherapy and supporting the patient through a 4-5 weeks period of neutropenia/thrombocytopenia in an attempt to eliminate the malignant clone. Based on its efficacy in the related myeloid disorder MDS, and the close relationship between MDS and AML in patients > 60, this trial employs the same paradigm of myelosuppressive therapy using high dose lenalidomide instead of chemotherapy. Importantly, within the MDS trials using low doses of lenalidomide, responses were observed in 3/9 (33%) of patients with excess blasts (RAEB/RAEB-t), which are now classified as evolving into AML or AML. This suggests that the therapeutic effect of lenalidomide occurs in the setting of a large percentage of blasts, such as AML, although the dose and schedule of lenalidomide administration is different. The response of AML >= 60 patients to the proposed high dose lenalidomide regimen is unknown. Following high dose lenalidomide, in those patients that have a response, we propose using a lower dose maintenance strategy similar to the FDA approved dosing for MDS. The maintenance phase will include standard dose reductions for unacceptable toxicities.

Official Title
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Phase II Trial of Lenalidomide in Older Patients (>/= 60 Years) With Untreated Acute Myeloid Leukemia Without Chromosome 5q Abnormalities

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: AML, de novo, secondary to prior therapy, or transformed from MDS, as defined by the International Working Group (except acute promyelocytic leukemia (AML M3). Patients must not have abnormalities of chromosome 5q as assessed by routine cytogenetics or FISH. Diagnosis of AML by WHO criteria (≥20% blasts) is determined by CBC, bone marrow assessment, and immunophenotypic analysis performed within 2 weeks of study enrollment. Intermediate or poor-risk cytogenetics as defined by SWOG criteria Age ≥ 60 years at the time of signing the informed consent form. Understand and voluntarily sign an informed consent form. Able to adhere to the study visit schedule and other protocol requirements. No previous treatment for AML, however hydroxyurea, steroids, and leukopheresis are allowed ECOG performance status of ≤ 2 at study entry. Life expectancy > 2 months Adequate organ function as defined by: Serum creatinine ≤ 1.5X institution upper limit of normal (ULN) Total bilirubin ≤ 2.0 mg/dL AST (SGOT) and ALT (SGPT) ≤ 5 x ULN Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Disease free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. Exclusion Criteria: Received prior treatment for AML Favorable risk cytogenetic abnormalities as defined by SWOG criteria (http://www.bloodjournal.org/cgi/content/abstract/96/13/4075) that include: inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary aberrations, t(8;21) lacking del(9q) or complex karyotype (16). Prior to enrollment, FISH, molecular studies or routine cytogenetics must be completed to rule out these cytogenetic abnormalities. Known CNS leukemia Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study. Use of any other experimental drug or therapy within 30 days of enrollment. Known hypersensitivity to thalidomide.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Lenalidomide 50 mg/day oral for 14 days followed by 30 days of rest. Lenalidomide 50 mg/day oral for 21 days (this is Cycle 1 and Cycle 2). If no progressive disease (PD) then lenalidomide 10 mg/day oral for 28 days for 12 cycles. | Drug: Lenalidomide<br> <br> * Other names: CC-5013;|
| Experimental: Cohort 2<br>Cycle 1: Oral lenalidomide 50 mg/day x 28 days induction therapy. Treatment will then depend on the response to Cycle 1: if patients obtain a complete remission (CR) they will proceed to low dose lenalidomide therapy, if patients have a non-CR they will receive a second high dose cycle of lenalidomide 50 mg/day x 28 days (Cycle 2) Cycle 2 consists of lenalidomide 50mg/day x 28 days Further treatment will depend on the response to Cycle 2: if patients obtain a CR/partial remission (PR)/stable disease (SD) they will proceed to low dose lenalidomide therapy, if patients have PD they will be removed from the study. Low Dose Cycles: low dose lenalidomide therapy consisting of 10 mg daily for a 28 day cycle.be 1) For patients that achieve a CR, 2 cycles of low dose lenalidomide will be administered, and then patients observed off therapy. For patients with PR/SD, low dose lenalidomide will continue for a total of 6 cycles and then patients will be observed off therapy. | Drug: Lenalidomide<br> <br> * Other names: CC-5013;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Remission Rate (CRm + CRi + CRc) | CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count >100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. There is no duration requirement for this designation. CRi = Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells). | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability (Removal From Study Due to Adverse Events) | Toxicity will be scored using CTCAE Version 3.0 for toxicity and adverse event reporting | 4 weeks after last dose of study drug [median duration of therapy was 65 days (range, 3-413 days)] | 
| Response Rate (RR) | RR = as patients obtaining any response (CRm + CRc +CRi + PR). CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count > 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. There is no duration requirement for this designation. CRc = Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells). Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. Partial remission (PR): Requires | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| Morphologic Leukemia Free State | Morphologic leukemia-free state: Defined as < 5% blasts on the BM aspirate with spicules and a count of > 200 nucleated cells and no blasts with Auer rods, and no persistent extramedullary disease. | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| Morphologic Complete Remission Rate (CRm) | CRm = Defined as morphologic leukemia-free state, including <5% blasts in BM aspirate with marrow spicules and a count of > 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC > 1000/uL, platelet count >100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. There is no duration requirement for this designation. | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| Cytogenetics CR Rate (CRc) | Cytogenetic complete remission (CRc): Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells). | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| CR With Complete Blood Counts (CRi) Rate | CRi = Defined as CR with the exception of neutropenia <1000/uL or thrombocytopenia <100,000/ul. | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| Partial Remission Rate (PR) | Partial remission (PR): Requires that the criteria for complete remission be met with the following exceptions: decrease of >50% in the percentage of blasts to 5-25% in the BM aspirate. A value of < 5% blasts in BM with Auer rods is also considered a partial remission. | After 2 cycles of low dose lenalidomide (approximately Day 113 for Cohort 1 and approximately Day 104 for Cohort 2) | 
| Overall Survival (OS) | Overall survival: Defined as the date of first dose of study drug to the date of death from any cause. | 2 years | 
| Event Free Survival (EFS) | Event free survival: Defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, or death due to any cause. | 2 years | 
| Progression-free Survival | Progression-free survival (PFS) denotes the chances of staying free of disease progression for a group of individuals suffering from a cancer after a particular treatment. It is the percentage of individuals in the group whose disease is likely to remain stable (and not show signs of progression) after a specified duration of time. Progression-free survival rates are an indication of how effective a particular treatment is. | 2 years | 
| Relapse Free Survival (RFS) for Complete Responders | This is determined only for patients achieving a complete remission. Defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause. | 2 years | 
| Duration of CR for Complete Responders | Duration of remission: Defined as the interval from the date complete remission is documented to the date of recurrence | 2 years | 
| Changes in NK Cell Number and Function | Peripheral blood mononuclear cells (PBMC) will be viably cryopreserved from patients at baseline (pre-therapy, newly diagnosed AML), during lenalidomide therapy, and posttherapy. Following sample collection, PBMC will be thawed, and flow cytometry will be performed to assess NK cell number (CD56+CD3-), subsets, and phenotype utilizing the Siteman Cancer Center Flow Cytometry / Cell Sorting Core. In addition, NK cell function will be assessed in flow based killing assays using PBMC (containing NK cells) as effectors and NK sensitive cell lines (K562) and/or autologous leukemic blasts as target cells. Thus, analyzing these parameters in patients before, during, and after therapy will provide a comprehensive evaluation of the ability of lenalidomide to modulate NK cells in patients in vivo. | Baseline, during therapy, and posttherapy | 
| Gene Expression Profiles of Bone Marrow and Peripheral Blood | RNA will be made from total bone marrow cells for labeling and evaluations by RNA profiling. Cellular RNA and corresponding biotinylated cRNA targets will be prepared and hybridized with Affymetrix GeneChip® microarrays within the Multiplexed Gene Analysis SCC Core (Dr. Mark Watson, Director). Microarray data (and eventually corresponding gene sequence data) will be integrated an analyzed with state-of-the-art software packages. The pre- and post-treatment RNA profiling studies will be used as a discovery tool. Patterns of gene expression before and after lenalidomide therapy will be compared within each patient's sample to identify genes with altered expression after lenalidomide therapy. In addition, supervised algorithms will be sued to identify genes that can potentially predict clinical outcome and response to lenalidomide therapy. | Pre and post treatment | 
| Plasma Proteins Via Proteomics | Proteomic analysis will be performed within the Siteman Cancer Center proteomics core on pre- and post-treatment plasma samples. This pilot proteomic study will identify candidate proteins of interest with altered expression after treatment with lenalidomide. This approach will provide an unbiased method to assess global changes in serum proteins following lenalidomide therapy. | Pre and post treatment |