• Molecular response at 12 months [ Designated as safety issue: No ]
• Hematological response [ Designated as safety issue: No ]
• Cytogenetic response (complete and partial response) measured on bone marrow at baseline, 6 and 12 months [ Designated as safety issue: No ]
• Prognostic effects [ Designated as safety issue: No ]
• Changes in gene expression at pre-treatment and relapse [ Designated as safety issue: No ]
• Frequency and severity of toxic effects [ Designated as safety issue: Yes ]
• Overall and relapse-free survival [ Designated as safety issue: No ]

• Molecular response at 12 months
• Complete hematological response as measured months 1-3, then every 3 months for 6 months
• Cytogenetic response (complete and partial response) measured on bone marrow at baseline, 6 and 12 months

RATIONALE: Imatinib mesylate or dasatinib may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth.

PURPOSE: This randomized phase II trial is studying imatinib mesylate at two different doses and dasatinib to see how well they work in treating patients with previously untreated chronic phase chronic myelogenous leukemia.

OBJECTIVES:

• Compare the rate of molecular response, as measured by the decrease in bcr-abl transcripts after 12 months of treatment, in patients with previously untreated chronic phase chronic myelogenous leukemia treated with imatinib mesylate at standard vs increased dose or dasatinib.
• Test whether increasing doese of imatinib mesylate from 400 mg/day to 800 mg/day increases molecular response rate (as measured by decrese in bcr-abl transcript after 12 months of treatment) in these patients.
• Compare rates of cytogenetic and hematologic response in patients treated with these regimens.
• Compare, preliminarily, the prognostic effects of der(9) and der(22) chromosomal deletions for response in patients treated with these regimens.
• Compare, preliminarily, changes in gene expression at pre-treatment vs at relapse or progression in patients treated with these regimens.
• Compare the frequency and severity of the toxic effects of these regimens in these patients.
• Compare, preliminarily, the overall survival and relapse-free survival of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to Hasford risk category (low vs intermediate vs high). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive oral imatinib mesylate once daily.
• Arm II: Patients receive oral imatinib mesylate twice daily.
• Arm III: Patients receive oral dasatinib twice daily. In all arms, treatment continues for 5 years in the absence of disease progression or unacceptable toxicity.

Patients are followed for up to 5 years.

PROJECTED ACCRUAL: A total of 335 patients will be accrued for this study.

• Drug: dasatinib
• Drug: imatinib mesylate

• Active Comparator: Patients receive oral imatinib mesylate once daily.
• Experimental: Patients receive oral imatinib mesylate twice daily.
• Experimental: Patients receive oral dasatinib twice daily.

DISEASE CHARACTERISTICS:

• Diagnosis of chronic phase chronic myelogenous leukemia (CML) by bone marrow aspiration, biopsy, and peripheral blood counts, meeting criteria for 1 of the following:

  • Philadelphia chromosome-positive* or presence of the variants of the (9;22) translocation by cytogenetics or fluorescent in situ hybridization

    • Secondary chromosomal abnormalities (in addition to the Philadelphia chromosome) allowed
  • bcr-abl positive* by reverse transcription polymerase chain reaction NOTE: *First cytogenetic or molecular analysis performed within the past 180 days to confirm status
• Must be enrolled on SWOG-9007 (SWOG institutions only) and SWOG-S9910

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Zubrod 0-2

Life expectancy

• Not specified

Hematopoietic

• No significant bleeding disorder unrelated to cancer including:

  • Congenital bleeding disorders (e.g., von Willebrand's disease)
  • Acquired bleeding disorder within the past year (e.g., acquired anti-factor VIII antibodies)

Hepatic

• Bilirubin no greater than 2.0 times upper limit of normal (ULN)
• AST or ALT no greater than 2.0 times ULN

Renal

• Not specified

Cardiovascular

• No cardiac symptoms including any of the following:

  • Uncontrolled angina
  • Congestive heart failure or myocardial infarction within the past 6 months
  • Diagnosed or suspected congenital long QT syndrome
  • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
  • Prolonged QTc interval on electrocardiogram (> 450 msec)
  • Uncontrolled hypertension

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer currently in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No other concurrent anticancer biologic agents

Chemotherapy

• No prior chemotherapy for peripheral blood stem cell mobilization

  • Prior collection of unmobilized peripheral blood stem cells allowed

• No other concurrent anticancer chemotherapy

  • Concurrent hydroxyurea and/or anagrelide to control blood counts allowed provided it is only administered during the first 28 days of study therapy and for no more than 28 additional days after study therapy

Endocrine therapy

• Not specified

Radiotherapy

• No concurrent anticancer radiotherapy

Surgery

• More than 28 days since prior major surgery and recovered

Other

• No prior treatment for CML (except hydroxyurea and/or anagrelide)

• No concurrent therapeutic anticoagulation with warfarin

  • Concurrent therapeutic anticoagulation with low-molecular weight heparin allowed
  • Concurrent low-dose warfarin for prophylaxis to prevent catheter thrombosis allowed (arm III only)

• No concurrent drugs* that have a risk of causing Torsades de Pointe including (arm III patients only):

  • Quinidine, procainamide, disopyramide
  • Amiodarone, sotalol, ibutilide, dofetilide
  • Erythromycin, clarithromycin
  • Chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
  • Cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone
  • Halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine NOTE: *Patients who have discontinued any of these medications must have a wash-out period of at least 5 days or at least 5 half-lives of the drug prior to first dose of dasatinib

• No concurrent drugs that irreversibly inhibit platelet function, including any of the following (arm III only):

  • Aspirin

    • Patients who have discontinued aspirin must have a wash-out period of at least 7 days for low-dose aspirin (< 325 mg/day) or 14 days for high-dose aspirin (> 325 mg/day) prior to first dose of dasatinib
  • Dipyridamole
  • Epoprostenol
  • Eptifibatide
  • Clopidogrel
  • Cilostazol
  • Abciximab
  • Ticlopidine
• No other concurrent anticancer agents

• National Cancer Institute (NCI)
• Eastern Cooperative Oncology Group