Low-Dose Decitabine Compared With Standard Supportive Care in Treating Older Patients With Myelodysplastic Syndrome

Intravenous Low-Dose Decitabine Versus Supportive Care in Elderly Patients With Primary Myelodysplastic Syndrome (MDS) (>10% Blasts or High-Risk Cytogenetics), Secondary MDS or Chronic Myelomonocytic Leukemia (CMML) Who Are Not Eligible for Intensive Therapy: An EORTC-German MDS Study Group Randomized Phase III Study

RATIONALE: Decitabine may help myelodysplasia cells develop into normal stem cells. It is not yet known if decitabine is more effective than standard supportive care in treating myelodysplastic syndrome.

PURPOSE: Randomized phase III trial to compare the effectiveness of low-dose decitabine with that of standard supportive care in treating older patients who have myelodysplastic syndrome.

OBJECTIVES:

• Compare the efficacy of low-dose decitabine vs standard supportive care, in terms of overall survival, of elderly patients with myelodysplastic syndromes.
• Compare the response rate and progression-free survival of patients treated with these regimens.
• Determine the toxicity of decitabine in these patients.
• Assess the duration of hospitalization and number of blood transfusions in patients treated with these regimens.
• Assess the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to cytogenetic risk factors (good vs poor vs intermediate vs unknown), disease (primary myelodysplastic syndrome (MDS) vs secondary MDS), and participating center. Patients with a successful cytogenetic exam are also stratified according to overall International Prognostic Scoring System score (intermediate 1 vs intermediate 2 vs high risk). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive decitabine IV over 4 hours every 8 hours for 3 days. Treatment repeats every 6 weeks for 4-8 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive standard supportive care. Quality of life is assessed at baseline, every 6 weeks during therapy, every 2 months for 1 year, and then every 3 months thereafter.

Patients are followed every 2 months for 1 year and then every 3 months thereafter.

PROJECTED ACCRUAL: A total of 220 patients (110 per treatment arm) will be accrued for this study within 2 years.

DISEASE CHARACTERISTICS:

• Diagnosis of primary or secondary myelodysplastic syndromes (MDS)

  • Any FAB or WHO criteria cellular type allowed

• Bone marrow blast count on aspiration or biopsy of 1 of the following:

  • No more than 10% with poor cytogenetic risk factors (defined as any numerical or structural abnormality of chromosome 7 and/or complex abnormalities)
  • 11-20%
  • 21-30% for patients with acute myeloid leukemia (AML) secondary to MDS (i.e., refractory anemia with excess blasts in transformation by FAB classification)
  • Patients who failed the cytogenetic exam are allowed provided bone marrow blasts are at least 5% and/or 2-3 cytopenias are present

• No rapid progression towards full-blown AML

• No blast crisis of chronic myeloid leukemia

• No t(8;21) alone or in combination with other abnormalities

• Ineligible for intensive chemotherapy (e.g., cytarabine or an anthracycline)

PATIENT CHARACTERISTICS:

Age

• 60 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics

Hepatic

• Bilirubin less than 1.5 times upper limit of normal (ULN)
• Hepatitis B surface antigen negative

Renal

• Creatinine less than 1.5 times ULN

Cardiovascular

• No severe cardiovascular disease
• No arrhythmias requiring chronic treatment
• No congestive heart failure
• No New York Heart Association class III or IV heart disease
• No symptomatic ischemic heart disease

Other

• HIV negative
• No active uncontrolled infection
• No other malignancy within the past 3 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix within the past 2 years
• No prior or concurrent evidence of CNS or psychiatric disorders requiring hospitalization
• No psychological, familial, sociological, or geographical condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 6 weeks since prior growth factors for primary MDS
• No concurrent antiangiogenic drugs (e.g., thalidomide)
• No concurrent interleukin, interferon, or anti-thymocyte globulin

Chemotherapy

• See Disease Characteristics
• More than 6 weeks since prior hydroxyurea for primary MDS
• No other prior chemotherapy for MDS or AML
• Prior chemotherapy for solid tumors or lymphoma (resulting in secondary MDS) allowed

Endocrine therapy

• No concurrent steroids (except as inhalation therapy)

Radiotherapy

• Prior radiotherapy for solid tumors or lymphoma (resulting in secondary MDS) allowed

Surgery

• Not specified

Other

• More than 6 weeks since prior immunosuppressive agents for primary MDS
• No concurrent amifostine
• No concurrent cyclosporine
• No other concurrent experimental therapies