Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR.

Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.

Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

• Complete cytogenetic response (CCyR) - 0% Ph+ metaphases
• Partial cytogenetic response (PCyR) - >0 to 35% Ph+ metaphases
• Minor cytogenetic response (mCyR) - >35 to 65% Ph+ metaphases
• Minimal - >65 to 95% Ph+ metaphases
• None - >95 to 100% Ph+ metaphases
• Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - >95 to 100% Ph+ metaphases

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Complete Hematological Response (CHR) was defined as

• WBC count <10×109/L
• platelet count <450×109/L
• basophils <5%
• no blasts and promyelocytes in peripheral blood
• myelocytes+metamyelocytes <5% in peripheral blood
• no evidence of extramedullary disease, including spleen and liver
• Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Complete Hematological Response (CHR) was defined as

• WBC count <10×109/L
• platelet count <450×109/L
• basophils <5%
• no blasts and promyelocytes in peripheral blood
• myelocytes+metamyelocytes <5% in peripheral blood
• no evidence of extramedullary disease, including spleen and liver
• Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Complete Hematological Response (CHR) was defined as

• WBC count <10×109/L
• platelet count <450×109/L
• basophils <5%
• no blasts and promyelocytes in peripheral blood
• myelocytes+metamyelocytes <5% in peripheral blood
• no evidence of extramedullary disease, including spleen and liver
• Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier.

Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR.

PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.

PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.

To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value.

Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits.

The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration).

Emerging signs of resistance to nilotinib