Lenalidomide With or Without Epoetin Alfa in Treating Patients With Myelodysplastic Syndrome and Anemia

Inclusion Criteria:

• Age >= 18 years

• NOTE: Results of the bone marrow biopsy and aspirate as well as cytogenetics aremandatory to register subjects onto study, which are indispensable to determineInternational Prognostic Scoring System (IPSS) category needed for eligibility;please note that it is not necessary to wait for the week 16, week 32, or week bonemarrow and cytogenetic results prior to starting the next cycle unless deemednecessary by the treating physician; one example of this exception can include ifthe subject shows signs of progression, such as increased peripheral blood blastpercentage; at that juncture, the treating physician may prefer to await the resultsprior to starting a new cycle; if a cycle is started, and based on the bone marrowresults it is felt by the treating physician that the subject should not continue ontreatment, please be sure to note this information on the case report forms at endof treatment

• Patient must have documented diagnosis of MDS lasting at least three months (MDSduration >= 3 months) according to World Health Organization (WHO) criteria ornon-proliferative chronic myelomonocytic leukemia (CMML) (white blood cell [WBC] < 12,000/mcL)

• Patient must have International Prognostic Scoring System (IPSS) categories of low-or intermediate-1-risk disease; patients must have IPSS score determined bycytogenetic analysis prior to randomization; patients must have cytogenetic analysisdone (to calculate IPSS); if the current bone marrow biopsy is a dry tap, patientswith cytogenetic failure and < 10% marrow blasts will be eligible; subjects withcytogenetic failure must have previous cytogenetic results (fluorescence in situhybridization [FISH] is not a substitute) within the last 6 months post last type ofMDS treatment (in this case, not referring to growth factors as type of MDStreatment)

• Must have symptomatic anemia untransfused with hemoglobin < 9.5 g/dL =< 8 weeksprior to randomization or with red blood cells (RBC) transfusion dependence (i.e., >= 2 units/month) confirmed for =< 8 weeks before randomization

• NOTE: For non-transfusion dependent patients (i.e., receiving < 2 units/4 weeksx 8 weeks pre-study) who receive periodic transfusions, the mean 8 weekpre-transfusion hemoglobin should be used to determine protocol eligibility andresponse reference

• For non-transfusion dependent patients, a minimum of 2 pre-transfusion orun-transfused hemoglobin values are required

• Applies only for patients without the deletion 5q 31.1; patients must have failedtreatment with an erythropoietic growth factor, or have a low probability ofresponse to rhu-erythropoietin; patients with low probability of response torhu-erythropoietin or prior erythropoietin failures are defined as follows:

• Prior erythropoietin failure-requires a minimum trial of >= 40,000 unitsepoetin alfa/week x 8 weeks or equivalent dose of darbepoetin alfa for 8 weekswith failure to achieve transfusion independence in dependent patients or afailure to achieve a >= 2 g rise in hemoglobin sustained for >= 4 weeks innon-transfusion dependent patients

• Low erythropoietin response profile-rhu-erythropoietin and epoetin alfa-naïvepatients receiving >= 2U packed (p)RBC/month for a minimum of 8 weeks, andserum erythropoietin > 500 mU/mL in the 8 weeks prior to randomization for ahemoglobin < 9.5 g/dL

• Patients must be off all non-transfusion therapy for MDS for 28 days prior toinitiation of study treatment, including all types of growth factors; patients mayreceive hydrocortisone prophylactically to prevent transfusion reactions

• Patients must have a serum erythropoietin level documented before randomization and =< 56 days before day 1 of study treatment; NOTE: hemoglobin must be < 9.5 g/dL attime that serum erythropoietin is drawn

• Effective contraception must be used by patients participating in lenalidomidetherapy, and all patients must agree to counseling by a trained counselor every 28days about pregnancy precautions and risks of fetal exposure; females ofchildbearing potential (FCBP) must either commit to continued abstinence fromheterosexual intercourse or begin TWO acceptable methods of birth control: onehighly effective method and one additional effective method AT THE SAME TIME, atleast 28 days before starting lenalidomide, during lenalidomide therapy, during doseinterruptions, and for at least 28 days following discontinuation of lenalidomidetherapy; females of childbearing potential should be referred to a qualifiedprovider of contraceptive methods, if needed; males receiving lenalidomide mustagree to use a latex condom during any sexual contact with females of childbearingpotential even if they have undergone a successful vasectomy

• Platelet count >= 50,000/mcL (50 x 10^9/L) without platelet transfusion (within 56days prior to randomization)

• Absolute neutrophil count (ANC) >= 500 cells/mcL (0.5 x 10^9/L); hence ANC must be >= 500/mcL without myeloid growth factor support (within 56 days prior torandomization)

• Serum creatinine =< 1.5 times upper limit of normal (ULN) (within 56 days prior torandomization)

• Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) orserum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =< 2.0 xULN (within 56 days prior to randomization)

• Serum total bilirubin < 3.0 mg/dL (within 56 days prior to randomization)

• Inclusion criteria for crossover registration from Arm A (lenalidomide alone) to ArmB (lenalidomide and epoetin alfa):

• Patients must have completed 16 weeks of monotherapy with lenalidomide

• Patients must show failure to achieve MER (major erythroid response) or haveachieved MER but relapsed on Arm A

Exclusion Criteria:

• Patients must not have documented iron deficiency; all patients must have documentedmarrow iron stores; if marrow iron stain is not available, the transferrinsaturation must be > 20% or a serum ferritin > 100 ng/mL

• Women must not be pregnant or breastfeeding; females of childbearing potential musthave a negative serum or urine pregnancy test with a sensitivity of at least 25mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 oflenalidomide; a female of childbearing potential (FCBP) is any woman, regardless ofsexual orientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy;or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months; FCBP mustalso agree to ongoing pregnancy testing)

• Patients must not have prior therapy with lenalidomide

• Patients must not have a diagnosis of uncontrolled seizure or uncontrolledhypertension

• Patients must not have proliferative (WBC >= 12,000/mcL) chronic myelomonocyticleukemia (CMML); WBC must be < 12,000/mcL

• Patients must not have MDS secondary to treatment with radiotherapy, chemotherapy,and/or immunotherapy for malignant or autoimmune diseases

• Prior thalidomide therapy is allowed, however, patients must not have prior >=grade-3 allergic reactions to thalidomide

• Patients must not have prior history of desquamating rash from thalidomide at timeof study entry

• Patients must not have clinically significant anemia resulting from iron, B12 orfolate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinalbleeding

• Patients must not have used cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 8 weeksof randomization

• Patients must not have prior history of malignancy other than MDS (except basal cellor squamous skin cell carcinoma or carcinoma in situ of the cervix or breast) unlessthe subject has been confirmed free of disease for >= 3 years

• Patients must not have any serious medical condition or any other unstable medicalco-morbidity, or psychiatric illness that will prevent the subject from signing theinformed consent form or will place the subject at unacceptable risk if he/sheparticipates in the study

• Patients must not have a history of thrombo-embolic events within 3 years prior tostudy randomization

• Patients must not have known human immunodeficiency virus (HIV)-1 seropositivitybecause HIV can be an alternate cause of anemia.

• Patients must not have a known allergic reaction to epoetin alfa (Procrit) or humanserum albumin

• Exclusion criteria for crossover registration from Arm A (lenalidomide alone) to ArmB (lenalidomide and epoetin alfa):

• Patients must not have a limiting unresolved grade 3 or greater toxicity fromlenalidomide monotherapy or drug intolerance preventing continuation of lenalidomidetreatment