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

• Time to MER [ Time Frame: From randomization to the documented date of MER, assessed up to 16 weeks ] [ Designated as safety issue: No ]
  Time to MER will be compared between lenalidomide monotherapy and combined treatment of lenalidomide and epoetin alfa in MER responders, using a one-sided log-rank test at the significance level of 0.025.
• Duration of MER defined as the time interval between the documented date of MER and the earliest date of resumption of RBC transfusions > 2 units a reduction in hemoglobin concentration >= 2 g/dL in the absence of acute infection [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Summarized by Kaplan-Meier method for patients who achieve MER by treatment arms.
• Rate of MER [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  The 90% confidence interval of the rate of MER to salvage combination therapy will be computed in patients who fail to achieve an MER with lenalidomide monotherapy and cross over to the combination therapy.
• Minor erythroid response rate [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
  Compared between treatment arms by Fisher's exact test.
• Cytogenetic response rate [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  Calculated by treatment arm among patients with cytogenetic abnormalities, along with its 90% confidence interval.
• Bone marrow response (complete response and partial response) rate [ Time Frame: Up to 6 months ] [ Designated as safety issue: No ]
  90% confidence Interval will be calculated by treatment arm.

• Time to MER [ Designated as safety issue: No ]
• Duration of MER [ Designated as safety issue: No ]
• Rate of MER to salvage combination therapy [ Designated as safety issue: No ]
• Minor erythroid response rate [ Designated as safety issue: No ]
• Cytogenetic response rate [ Designated as safety issue: No ]

This randomized phase III trial is studying lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cell. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia

PRIMARY OBJECTIVES:

I. To compare the rate of major erythroid response (MER) in patients with low- or intermediate-1-risk myelodysplastic syndromes treated with lenalidomide with vs without epoetin alfa.

SECONDARY OBJECTIVES:

I. To compare the time to MER in patients treated with these regimens. II. To evaluate the duration of MER in patients treated with these regimens. III. To estimate the frequency of MER to salvage combination chemotherapy in patients who fail to experience an MER after treatment with lenalidomide alone.

IV. To evaluate and compare the frequency of minor erythroid response in patients treated with these regimens.

V. To investigate the mechanism and target of lenalidomide action in patients with chromosome 5q31.1 deletion.

VI. To evaluate the frequency of cytogenetic response and progression, and the relationship between cytogenetic pattern and erythroid response.

VII. To evaluate the frequency of bone marrow response (complete response and partial response) in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to erythropoietin level (≤ 500 mU/mL vs > 500 mU/mL) and prior erythropoietic growth factor (yes vs no). Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype are assigned to treatment arm I.

ARM I: Patients receive oral lenalidomide once daily on days 1-21.

ARM II: Patients receive oral lenalidomide once daily on days 1-21 and epoetin alfa subcutaneously once weekly.

In both arms, treatment repeats every 28 days for 4 courses. Patients who achieve a major erythroid response (MER) may continue treatment beyond 4 courses in the absence of disease progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients in arm I who fail to achieve MER or who achieve MER but relapse after 16 weeks of treatment with lenalidomide may crossover and receive treatment in arm II.

After completion of study treatment, patients are followed for 6 months.

• Anemia
• Chronic Myelomonocytic Leukemia
• de Novo Myelodysplastic Syndromes
• Previously Treated Myelodysplastic Syndromes

• Drug: lenalidomide
  Given orally
  Other Names:

  • CC-5013
  • IMiD-1
  • Revlimid
• Biological: epoetin alfa
  Given subcutaneously
  Other Names:

  • EPO
  • Epogen
  • Eprex
  • erythropoietin
  • Procrit
• Other: laboratory biomarker analysis
  Correlative studies

• Active Comparator: Arm I (lenalidomide)
  Patients receive oral lenalidomide once daily on days 1-21.
  Interventions:

  • Drug: lenalidomide
  • Other: laboratory biomarker analysis
• Experimental: Arm II (lenalidomide, epoetin alfa)
  Patients receive oral lenalidomide once daily on days 1-21 and epoetin alfa subcutaneously once weekly.
  Interventions:

  • Drug: lenalidomide
  • Biological: epoetin alfa
  • Other: laboratory biomarker analysis

Inclusion Criteria:

• Documented diagnosis of 1 of the following:

  • Myelodysplastic syndromes (MDS) lasting ≥ 3 months according to WHO criteria

    • Disease must not be secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases
  • Non-proliferative chronic myelomonocytic leukemia (WBC < 12,000/mm³)

• International prognostic scoring system (IPSS) category of low- or intermediate-1-risk MDS as determined by cytogenetic analysis

  • Cytogenetic analysis required if current bone marrow biopsy is a dry tap

  • Patients with cytogenetic failure and < 10% marrow blasts are eligible

    • Patients with cytogenetic failure must have prior cytogenetic results (FISH is nota substitute) within 6 months after completion of the last type of MDS treatment (in this case, growth factors are not considered a type of MDS treatment).
• Must have symptomatic anemia with hemoglobin < 9.5 g/dL* (transfusion-independent or RBC transfusion-dependent [i.e., ≥ 2 units/month]) within the past 8 weeks

• For patients without the deletion 5q 31.1, must have failed treatment with an erythropoietic growth factor OR have a low probability of response to rhu-erythropoietin, as defined by the following:

  • Prior erythropoietin failure: requires ≥ 40,000 units epoetin alfa/week for 8 weeks or equivalent dose of darbepoetin alfa for 8 weeks and failed to achieve transfusion independence (in transfusion-dependent patients) or failed to achieve ≥ 2 g rise in hemoglobin sustained for ≥4 weeks (in transfusion-independent patients)
  • Low erythropoietin response profile: rhu-erythropoietin and epoetin alfa-naive patients receiving ≥ 2 U pRBC/month for ≥ 8 weeks and serum erythropoietin ≥ 500 mU/mL in the 8 weeks prior to study randomization for a hemoglobin < 9.5 g/dL
• ANC ≥ 500/mm^3 (myeloid growth factor support independent)
• Platelet count ≥ 50,000/mm^3 (platelet transfusion independent)
• Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
• Creatinine clearance ≥ 30 mL/min
• AST and ALT ≤ 2.0 times ULN
• Serum total bilirubin < 3.0 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective double-method contraception for ≥ 4 weeks before, during, and for 4 weeks after completion of study treatment
• No uncontrolled seizures or uncontrolled hypertension
• No history of other malignancy (except basal cell or squamous cell skin carcinoma or carcinoma in situ of the cervix or breast) unless the patient has been confirmed disease-free for ≥ 3 years
• No serious medical condition or any other unstable medical comorbidity, or psychiatric illness that would preclude informed consent or put the patient at unacceptable risk during study treatment
• No thromboembolic events within the past 3 years
• No known allergic reaction to epoetin alfa (Procrit®) or human serum albumin
• No prior desquamating (blistering) rash from thalidomide
• No prior allergic reactions to thalidomide ≥ grade 3
• No known HIV-1 seropositivity

• No documented iron deficiency

  • Must have documented bone marrow iron stores (if marrow iron stain is not available, transferrin saturation must be > 20% or serum ferritin > 100 ng/mL)
• No clinically significant anemia resulting from iron, B_12, or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding
• Concurrent steroids for adrenal failure, hormones for noncancer-related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic allowed
• No prior lenalidomide
• Prior thalidomide allowed
• More than 8 weeks since prior cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS

• At least 28 days since prior non-transfusion therapy, including all types of growth factors, for MDS

  • Concurrent prophylactic hydrocortisone to prevent transfusion reaction allowed