• Rate of molecular response as measured by log reduction of Bcr-Abl transcript at 12 months and then annually [ Designated as safety issue: No ]
  

• Rate of hematologic response at 12 months and then annually [ Designated as safety issue: No ]
  
• Rate of complete cytogenetic response at 12 months and then annually [ Designated as safety issue: No ]
  
• Rate of major molecular response at 12 months and then annually [ Designated as safety issue: No ]
  
• Rate of complete molecular response at 12 months and then annually [ Designated as safety issue: No ]
  
• Time to complete cytogenetic response as estimated by time-to-event analysis [ Designated as safety issue: No ]
  
• Time to molecular response as estimated by Kaplan-Meier [ Designated as safety issue: No ]
  
• Time to complete molecular response as estimated by Kaplan-Meier [ Designated as safety issue: No ]
  
• Progression-free survival as measured by time to progression or death for any cause at 5 years [ Designated as safety issue: No ]
  
• Frequency of adverse events and number of abnormal lab values as assessed by NCI CTCAE v.30 [ Designated as safety issue: Yes ]
  
• Quality of life as assessed by Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL -5 domains (EQ-5D) at baseline and at months 1, 3, 6, 9, 12, 18, and 24 [ Designated as safety issue: No ]
  
• Health care resource utilization as measured by frequency and duration of inpatient hospitalization and frequency and type of outpatient visit [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Compare the efficacy of 2 different doses of imatinib mesylate, in terms of molecular response rate at 12 months, in patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP).

Secondary

• Compare the rate of hematologic response in these patients.
• Compare the rate of complete cytogenetic response (CCyR) in these patients.
• Compare the time to CCyR, molecular response, and complete molecular response in these patients.
• Compare the percentage of patients with ≥ 3-log reduction in Bcr-Abl transcripts and with undetectable levels at 12 months and beyond.
• Compare the progression-free survival at 5 years in these patients.
• Compare the safety profile of 2 different doses of imatinib mesylate in these patients.
• Validate molecular response as a prognostic factor for time to progression in these patients.
• Compare the quality of life of these patients and healthcare resource utilization.
• Compare the pharmacokinetic characteristics of 2 different doses of imatinib mesylate in these patients.
• Investigate tumor-specific mutations.
• Assess Bcr-Abl pathway activation, as measured by tyrosine phosphorylation of Bcr-Abl downstream molecules, including Crk1 and STAT-5.
• Correlate Bcr-Abl transcript and Bcr-Abl pathway activation with clinical response.
• Conduct proteomic and pharmacogenomic analyses to identify potential biomarkers that may predict the response to imatinib mesylate, markers of imatinib mesylate effect, and potential markers of toxicity in peripheral blood.
• Compare the actual dose-intensity delivered in patients treated with 2 different doses of imatinib mesylate.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to the Sokal relative risk score (< 0.8 [low-risk] vs 0.8-1.2 [intermediate risk] vs > 1.2 [high-risk]). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral imatinib mesylate twice daily in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral imatinib mesylate once daily in the absence of disease progression or unacceptable toxicity. Patients with unresponsive disease after 3-12 months of treatment may receive imatinib mesylate twice daily in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, every 3 months during study treatment, and at 6 and 12 months after completion of study treatment.

After completion of study treatment, patients are followed every 3 months for up to 5 years.

PROJECTED ACCRUAL: A total of 420 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Cytogenetically confirmed chronic myelogenous leukemia in chronic phase (CML-CP)

  • Philadelphia chromosome (9;22) translocations
  • Presence of Bcr-Abl
  • Diagnosed within the past 6 months

• Chronic phase is defined by all of the following:

  • Less than 15% blasts in peripheral blood and bone marrow
  • Less than 30% blasts plus promyelocytes in peripheral blood and bone marrow
  • Less than 20% basophils in the peripheral blood
  • Platelet count ≥ 100,000/mm³
  • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly
• No late chronic phase, accelerated phase, or blastic phase CML
• No sibling donor available for allogeneic bone marrow transplantation as first-line treatment

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Bilirubin < 1.5 times upper limit of normal (ULN)
• SGOT and SGPT < 2.5 times ULN
• Creatinine < 1.5 times ULN
• INR or PTT ≤ 1.5 times ULN except for patients on treatment with oral anticoagulants
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective barrier contraception during and for up to 3 months after completion of study treatment
• No other primary malignancy except if the malignancy is neither currently clinically significant nor requires active intervention
• No severe or uncontrolled medical condition (i.e., uncontrolled diabetes or chronic renal disease)
• No known HIV positivity
• No significant history of noncompliance to medical regimens

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior imatinib mesylate except for patients who successfully complete clinical trial NOVARTIS-CSTI571A2107 immediately prior to entry into this study
• No prior treatment for CML exceeding 1 month in duration with the exception of hydroxyurea and/or anagrelide
• No prior radiotherapy to ≥ 25% of the bone marrow
• More than 4 weeks since prior major surgery and recovered
• No concurrent grapefruit juice
• No other concurrent investigational agents

• No other concurrent anticancer agents, including chemotherapy or biologic agents

  • Concurrent anagrelide during the first month of study treatment allowed
• Concurrent systemic corticosteroids allowed