There is no available data on the clinical benefit of dose escalation for patients with suboptimal response to imatinib, and patients may still improve their response with continuation of therapy at the standard dose as shown in the IRIS trial after 5 years of follow-up. However, there is no data yet regarding the potential benefit of using nilotinib in the group of patients with suboptimal response. In this study, the efficacy of nilotinib 400mg BID will be compared to imatinib 600mg QD.

• Drug: nilotinib
  400 mg twice a day
  Other Name: Tasigna
• Drug: imatinib
  600 mg daily
  Other Name: Gleevec/Glivec

• Nilotinib: Experimental
  nioltinib
  Intervention: Drug: nilotinib
• Imatinib: Active Comparator
  imatinib
  Intervention: Drug: imatinib

Inclusion Criteria:

1. Male or female, aged ≥ 18 years;
2. ECOG Performance Status of 0, 1, or 2 (see Appendix A);

3. Diagnosis of Ph-positive CML in chronic phase (CP) at the start of therapy with imatinib 400mg. CP is defined as follows:

   • <15% blasts in peripheral blood and bone marrow;
   • <30% blasts plus promyelocytes in peripheral blood and bone marrow;
   • <20% basophils in the peripheral blood;
   • ≥100x 109/L (≥ 100,000/mm3) platelets;
   • no evidence of extramedullary leukemia involvement, with the exception of hepatosplenomegaly;

4. Patients with a suboptimal cytogenetic response to 400 mg of imatinib, as follows25 (cytogenetic analysis to document suboptimal response must have been done a maximum of 6 weeks before the first dose of study drug):

   • No partial cytogenetic response at ≥ 6 to <12 months of treatment (and at least 36% to 95% Ph+ metaphases on bone marrow); or
   • No complete cytogenetic response at ≥ 12 to <18 months of treatment (and have at least 1% to 35% Ph+ metaphases on bone marrow);
   • Bone marrow karyotyping (BMK) is required on a minimum of 20 metaphases;
5. Patients receiving 400mg/daily imatinib standard dose for at least 6 months and no more than 18 months;
6. No prior use of imatinib dose higher than 400 mg daily;

Exclusion Criteria:

1. Prior accelerated phase or blast crisis CML;
2. Prior therapy with imatinib in combination to any other drug;
3. More than 18 months (+ 8 weeks) of therapy with 400mg/daily imatinib;
4. Patients receiving imatinib dose of 300 mg daily;
5. Patients with myelotoxicity > Grade 2 (receiving 400mg or less) at the time of randomization,
6. Previously documented T315I mutations;
7. Achieved prior PCyR or CCyR on imatinib and lost that response before entering the study;