Thalidomide in Treating Anemia in Patients With Myelodysplastic Syndrome

A Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial Assessing The Safety And Efficacy Of Thalidomide (THALOMID) For The Treatment Of Anemia In Red Blood Cell Transfusion-Dependent Patients With Myelodysplastic Syndromes

RATIONALE: Thalidomide may be an effective treatment for anemia caused by myelodysplastic syndrome.

PURPOSE: Randomized phase II trial to study the effectiveness of thalidomide in treating anemia in patients who have myelodysplastic syndrome.

OBJECTIVES:

• Determine the efficacy of thalidomide for the treatment of anemia in patients with myelodysplastic syndromes.
• Determine whether this drug reduces the frequency of leukemia transformation and decreases bone marrow blast percentage in these patients.
• Determine the effect of this drug on neutrophil and platelet production and the number of episodes of febrile neutropenia in these patients.
• Determine the safety of this drug in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to International Prognostic Scoring System score (low and intermediate-1 vs intermediate-2 and high) and transfusion dependence (yes vs no). Patients are randomized to one of two treatment arms.

• Arm I: Patients receive oral thalidomide once daily on weeks 1-24.
• Arm II: Patients receive oral placebo once daily on weeks 1-24. In both arms, patients who have not progressed to leukemia after 24 weeks of therapy may receive open-label thalidomide for an additional 24 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: A total of 220 patients (110 per treatment arm) will be accrued for this study.

DISEASE CHARACTERISTICS:

• Diagnosis of myelodysplastic syndromes (MDS) of at least 12 weeks duration

  • Refractory anemia (RA)
  • RA with ringed sideroblasts
  • RA with excess blasts
  • Chronic myelomonocytic

• No therapy-related MDS

• No myelosclerosis or myelofibrosis occupying more than 30% of marrow space (or assessed as grade 3+ or greater)

• No transformation to acute myeloid leukemia

• No more than 20% blasts in bone marrow

• No more than 5% blasts in peripheral blood

• Patients with an erythropoietin level 100 mU/mL or less must have failed epoetin alfa treatment (i.e., at least 30,000 units of epoetin alfa weekly for at least 6 weeks)

• Transfusion-dependent (received at least 2 units of packed RBCs or whole blood within the past 8 weeks) OR

• Transfusion-independent (no packed RBC or whole blood transfusions within the past 8 weeks with 2 hemoglobin levels (at least 7 days apart) less than 11 g/dL)

• No iron deficiency (e.g., absent bone marrow iron store)

  • If marrow aspirate is not evaluable, transferrin saturation must be at least 20% and ferritin at least 50 ng/mL

• No uncorrected B12 or folate deficiency

• No other contributing causes of anemia (e.g., autoimmune or hereditary hemolytic disorders or gastrointestinal blood loss)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2 OR
• Zubrod 0-2

Life expectancy:

• At least 6 months

Hematopoietic:

• See Disease Characteristics
• Absolute neutrophil count at least 500/mm^3

Hepatic:

• Bilirubin no greater than 2.0 mg/dL
• AST and ALT less than 2 times upper limit of normal (ULN)
• Hepatitis B surface antigen negative
• Hepatitis C negative

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No uncontrolled hypertension
• No clinically significant, symptomatic, unstable cardiovascular disease unrelated to MDS

Pulmonary:

• No clinically significant, symptomatic, unstable pulmonary disease unrelated to MDS

Neurologic:

• No clinically significant, symptomatic, unstable neurologic disease unrelated to MDS
• No history of epilepsy
• No sustained neurologic deficit (e.g., stroke)
• No grade 2 or greater peripheral neuropathy

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use at least 1 highly effective and 1 additional effective method of contraception for 4 weeks prior to, during, and for 4 weeks after study participation
• HIV negative
• No clinically significant, symptomatic, unstable endocrine, gastrointestinal, or genitourinary disease unrelated to MDS
• No other malignancy within the past 5 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No life-threatening or active infection requiring parenteral antibiotics
• No other serious concurrent illness

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Disease Characteristics
• More than 7 days since prior hematopoietic growth factors (e.g., epoetin alfa, filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-3)
• No prior thalidomide
• No prior agents intended to inhibit vascular endothelial growth factor or tumor necrosis factor alfa (e.g., etanercept or infliximab)
• No concurrent epoetin alfa

Chemotherapy:

• No concurrent chemotherapy that may be active against MDS

Endocrine therapy:

• More than 30 days since prior androgens
• No requirement for ongoing therapy with systemic corticosteroids

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• More than 30 days since prior treatment for MDS except RBC transfusion or epoetin alfa
• More than 30 days since prior participation in another experimental clinical trial
• More than 30 days since prior experimental drugs
• No other concurrent investigational agents or treatments