Leukemia, Myeloid, Chronic Phase
Conditions
Keywords
CML, Philadelphia positive, Bcr-abl, imatinib mesylate, Chronic myeloid leukemia (CML) in chronic phase
Brief summary
This study investigated the safety and efficacy of 400mg Versus 800mg imatinib in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints.
Interventions
DRUGImatinib mesylate
Imatinib is packaged in bottles as 100mg and 400mg tablets
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis) * Diagnosis of chronic myelogenous leukemia (CML) in chronic phase with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations and presence of Breakpoint cluster region gene-abelson proto-oncogene (Bcr-Abl) * Documented chronic phase CML * Adequate end organ function as defined by: * total bilirubin \< 1.5 x Upper Limit of Normal (ULN) * Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) \< 2.5 x ULN * creatinine \< 1.5 x ULN
Exclusion criteria
* Patients in late chronic phase, accelerated phase, or blastic phase are excluded * Patients who have received other investigational agents * Patients who received Gleevec/Glivec for any duration prior to study entry, with the exception of those patients successfully completing \[CSTI571A2107 (NCT00428909)\] study immediately prior to the participation in this study * Patient received any treatment for CML prior to study entry for longer than 2 weeks with the exception of hydroxyurea and/or anagrelide * Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention * Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential). * Patient with a severe or uncontrolled medical condition (i.e., uncontrolled diabetes,chronic renal disease) * Patient previously received radiotherapy to ≥ 25% of the bone marrow * Patient had major surgery within 4 weeks prior to study entry, or who have not recovered from prior major surgery * Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≥ 3 * Patients with International normalized ratio (INR) or partial thromboplastin time (PTT) \> 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants * Patients with known positivity for human immunodeficiency virus (HIV); baseline testing for HIV is not required * Patients with identified sibling donors where allogeneic bone marrow transplant is elected as first line treatment Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months | 12 months | MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 12, 24, 36, 42 months | Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent. |
| Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 12, 24, 36, and 42 months | Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement. |
| Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 12 , 24, 36 and 42 months | Undetectable levels or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) \<= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline). |
| Time to First Major Molecular Response | 42 months overall | MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally). Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method |
| Time to First Complete Cytogenetic Response | 60 months overall | Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method. |
| Time to First Complete Hematological Response (CHR)] | 60 months overall | Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method. |
| Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 60 months over all | EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
| Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 60 months over all and follow up period | PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
| Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 24, 36 and 42 months | MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally). |
| Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 60 months over all and follow up period | OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
| Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | From First major molecular response to first confirmed loss or censoring | Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
| Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | From first complete cytogenetic response to first confirmed loss or censoring | Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
| Mean Actual Dose Intensity Per Day | start of treatment to Month 36 | The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included) |
| Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12 | Month 12 | Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration |
| Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | 42 months | A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value. |
| Time to First Complete Molecular Response (CMR)] | 48 months overall | Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene. |
| Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes | 12 months | — |
| Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 60 months over all and follow up period | (Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval). |
Countries
Argentina, Australia, Brazil, Canada, Italy, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Imatinib 400 mg Oral dose of 400mg Imatinib once daily (q.d.). All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted, reduced, or escalated based on guidelines defined in protocol. | 157 |
| Imatinib 800 mg Patients randomized to receive 800 mg Imatinib were to receive 400 mg twice daily (b.i.d.) oral administration, in the morning and the evening. All patients received the assigned dose starting on Day 0 (Visit 3). The dose of Imatinib could be interrupted or reduced based on guidelines defined in protocol. | 319 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory Value | 2 | 2 |
| Overall Study | Abnormal Procedure | 0 | 1 |
| Overall Study | Administrative Problem(Study Terminated) | 101 | 174 |
| Overall Study | Adverse Event | 8 | 39 |
| Overall Study | Death | 1 | 3 |
| Overall Study | Lack of Efficacy | 20 | 41 |
| Overall Study | Lost to Follow-up | 2 | 7 |
| Overall Study | No longer requires study drug | 1 | 1 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 15 |
Baseline characteristics
| Characteristic | Imatinib 400 mg | Imatinib 800 mg | Total |
|---|---|---|---|
| Age Continuous | 46.2 years STANDARD_DEVIATION 14.9 | 48.2 years STANDARD_DEVIATION 13.89 | 47.6 years STANDARD_DEVIATION 14.25 |
| Sex: Female, Male Female | 73 Participants | 136 Participants | 209 Participants |
| Sex: Female, Male Male | 84 Participants | 183 Participants | 267 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 157 / 157 | 315 / 316 |
| serious Total, serious adverse events | 42 / 157 | 121 / 316 |
Outcome results
Primary
Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months
MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally).
Time frame: 12 months
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imatinib 400 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months | 38.9 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 12 Months | 45.1 Percentage of participants |
Secondary
Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms
EFS on treatment was defined as time between randomization and either (1) death due to any cause during study treatment, (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment, (3) loss of complete hematological response (CHR), or (4) loss of major cytogenic response (MCyR) while on treatment. Estimated rate of EFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: 60 months over all
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 12 Months | 95.3 Percent probability |
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 24 Months | 94.6 Percent probability |
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 36 Months | 92.3 Percent probability |
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 42 Months | 92.3 Percent probability |
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 48 Months | 92.3 Percent probability |
| Imatinib 400 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 60 Months | 90.3 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 48 Months | 93.6 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 12 Months | 98.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 42 Months | 94.1 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 24 Months | 95.3 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 60 Months | 93.6 Percent probability |
| Imatinib 800 mg | Estimated Rate of Event Free Survival (EFS) in Two Treatment Arms | 36 Months | 94.5 Percent probability |
Secondary
Estimated Rate of Overall Survival (OS) in Two Treatment Arms
OS was defined as time between randomization and death due to any cause during study treatment or during follow-up after discontinuation of treatment. Estimated rate of OS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: 60 months over all and follow up period
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 12 Months | 98.7 Percent probability |
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 24 Months | 97.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 36 Months | 96.1 Percent probability |
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 42 Months | 94.7 Percent probability |
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 48 Months | 94.0 Percent probability |
| Imatinib 400 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 60 Months | 94.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 48 Months | 93.4 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 12 Months | 99.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 42 Months | 94.8 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 24 Months | 97.8 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 60 Months | 93.4 Percent probability |
| Imatinib 800 mg | Estimated Rate of Overall Survival (OS) in Two Treatment Arms | 36 Months | 95.5 Percent probability |
Secondary
Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms
PFS on study which was defined as time between randomization and either (1) death due to any cause on treatment of during follow-up after discontinuation of treatment or (2) progression to accelerated phase (AP) or blast crisis (BC) on treatment during follow-up after discontinuation of study treatment. Estimated rate of PFS was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: 60 months over all and follow up period
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 12 Months | 97.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 24 Months | 95.9 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 36 Months | 94.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 42 Months | 94.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 48 Months | 94.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 60 Months | 94.4 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 48 Months | 95.8 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 12 Months | 98.7 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 42 Months | 96.3 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 24 Months | 97.5 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 60 Months | 95.8 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression Free Survival (PFS) in Two Treatment Arms | 36 Months | 96.7 Percent probability |
Secondary
Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms
(Accelerated Phase/Blast Crisis) AP/BC was defined as time between randomization and either (1) (Chronic Myeloid Leukemia) CML-related death (if death was primary reason for discontinuation) or (2) progression to AP or BC (during treatment). Estimated rate of AC/BC was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: 60 months over all and follow up period
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 12 Months | 97.4 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 24 Months | 95.9 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 36 Months | 95.2 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 42 Months | 95.2 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 48 Months | 95.2 Percent probability |
| Imatinib 400 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 60 Months | 95.2 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 48 Months | 97.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 12 Months | 99.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 42 Months | 97.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 24 Months | 97.9 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 60 Months | 97.0 Percent probability |
| Imatinib 800 mg | Estimated Rate of Progression to Accelerated Phase (AC)/Blast Crisis (BC) in Two Treatment Arms | 36 Months | 97.5 Percent probability |
Secondary
Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR)
A Landmark Kaplan-Meier analysis was performed for PFS at 42 months by MMR status at 6, 12, and 18 months to investigate their prognostic value.
Time frame: 42 months
Population: Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment. Patients without a valid polymerase chain reaction (PCR) assessment or those who had experienced an event before the landmark were excluded from analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 6 Months | 94.8 Percent probability |
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 12 Months | 100 Percent probability |
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 18 Months | 96.7 Percent probability |
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 6 Months | 100 Percent probability |
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 18 Months | 98.7 Percent probability |
| Imatinib 400 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 12 Months | 93.2 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 18 Months | 99.3 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 6 Months | 95.6 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 12 Months | 94.6 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 12 Months | 99.3 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | No MMR at 18 Months | 97.0 Percent probability |
| Imatinib 800 mg | Estimated Rates of Progression Free Survival (PFS) on Treatment by Major Molecular Response (MMR) | MMR at 6 Months | 99.0 Percent probability |
Secondary
Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12
Imatinib PK trough plasma concentration (Cmin) was defined as any pre-dose Imatinib plasma concentration
Time frame: Month 12
Population: Pharmakokinetic (PK) population consisted of number of patients with a pre-dose PK sample at Month 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib 400 mg | Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12 | 1458.2 mg/mL | Standard Deviation 2259.5 |
| Imatinib 800 mg | Imatinib Pharmacokinetic Trough Plasma Concentration (Cmin) at Month 12 | 739.58 mg/mL | Standard Deviation 1321.09 |
Secondary
Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR)
Duration of CCyR was defined as the time between date of CCyR and the earliest of either (1) loss of CCyR OR (2) (Chronic Myeloid Leukemia) CML-related death or progression to (Accelerated Phase/Blast Crisis) AP/BC during study treatment. Estimated rate of duration of first CCyR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: From first complete cytogenetic response to first confirmed loss or censoring
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 18 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 30 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 12 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 36 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 24 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 42 Months | 98.2 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 6 Months | 99.1 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 42 Months | 95.9 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 6 Months | 99.2 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 12 Months | 97.8 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 18 Months | 97.3 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 24 Months | 96.8 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 30 Months | 96.8 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Complete Cytogenetic Response (CCyR) | 36 Months | 95.9 Percent probability |
Secondary
Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss
Duration of MMR (months) = (date of first confirmed loss or censoring - date of MMR + 1 ) / 30.4375. Estimated rate of duration of first MMR was analyzed by Kaplan-Meier estimate (percent probability and 95% Confidence interval).
Time frame: From First major molecular response to first confirmed loss or censoring
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 18 Months | 92.8 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 6 Months | 98.3 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 21 Months | 90.9 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 12 Months | 95.6 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 24 Months | 89.9 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 3 Months | 100 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 30 Months | 88.5 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 36 Months | 85.1 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 15 Months | 93.8 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 42 Months | 85.1 Percent probability |
| Imatinib 400 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 9 Months | 97.4 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 42 Months | 77.9 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 3 Months | 96.3 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 6 Months | 90.7 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 9 Months | 90.2 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 12 Months | 88.4 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 15 Months | 87.5 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 18 Months | 86.1 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 21 Months | 85.1 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 24 Months | 83.6 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 36 Months | 81.1 Percent probability |
| Imatinib 800 mg | Kaplan-Meier Estimates of Duration of First Major Molecular Response Until Confirmed Loss | 30 Months | 82.5 Percent probability |
Secondary
Mean Actual Dose Intensity Per Day
The mean actual dose intensity per day from start of treatment up to last dose or discontinuation was evaluated up to Month 36. Actual dose intensity (mg/day) = total dose/time on treatment (periods of zero dose are included)
Time frame: start of treatment to Month 36
Population: Safety analysis population (SAP): consisted of all patients who received at least one dose of study medication.Subjects are summarized according to the safety treatment allocation (the dose they actually received).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Imatinib 400 mg | Mean Actual Dose Intensity Per Day | 399.3 mg/day | Standard Deviation 83.84 |
| Imatinib 800 mg | Mean Actual Dose Intensity Per Day | 643.3 mg/day | Standard Deviation 158.63 |
Secondary
Number of Participants With the Effect of Imatinib on the Diabetic Participants With Known Concomitant Type II Diabetes
Time frame: 12 months
Population: Due to the small number of diabetic patients enrolled into the study, the analysis was never done.
Secondary
Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months
Cytogenetic response (CyR)is the percentage of Philadelphia chromosome positive metaphases (among at least 20 metaphase cells in bone marrow (BM)) with Complete Cytogenetic Response (CCyR) being 0 percent.
Time frame: 12, 24, 36, 42 months
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 12 months | 66.9 Percentage of Participants |
| Imatinib 400 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 24 months | 76.4 Percentage of Participants |
| Imatinib 400 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 36 months | 79.0 Percentage of Participants |
| Imatinib 400 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 42 months | 80.3 Percentage of Participants |
| Imatinib 800 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 42 months | 81.5 Percentage of Participants |
| Imatinib 800 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 12 months | 70.2 Percentage of Participants |
| Imatinib 800 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 36 months | 80.6 Percentage of Participants |
| Imatinib 800 mg | Percentage of Participants With Complete Cytogenetic Response (CCyR) Rate at 12, 24, 36, 42 Months | 24 months | 76.8 Percentage of Participants |
Secondary
Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months
Complete Hematologic Response (CHR) is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement.
Time frame: 12, 24, 36, and 42 months
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 12 months | 94.9 Percentage of participants |
| Imatinib 400 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 24 months | 94.9 Percentage of participants |
| Imatinib 400 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 36 months | 96.2 Percentage of participants |
| Imatinib 400 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 42 months | 96.2 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 42 months | 94.4 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 12 months | 93.7 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 36 months | 94.4 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Complete Hematological Response (CHR) Rates at 12, 24, 36, and 42 Months | 24 months | 93.7 Percentage of participants |
Secondary
Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months
MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally).
Time frame: 24, 36 and 42 months
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 24 months | 53.5 Percentage of participants |
| Imatinib 400 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 36 months | 52.2 Percentage of participants |
| Imatinib 400 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 42 months | 51.6 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 24 months | 50.8 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 36 months | 49.8 Percentage of participants |
| Imatinib 800 mg | Percentage of Participants With Major Molecular Response (MMR) Rates at 24, 36, and 42 Months | 42 months | 50.2 Percentage of participants |
Secondary
Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts
Undetectable levels or Complete molecular response is defined as Bcr-Abl ratio (%) on international scale (IS) \<= 0.0032% (≥ 4.5 log reduction of BCR-Abl transcripts from a standardized baseline).
Time frame: 12 , 24, 36 and 42 months
Population: Intent-to-treat (ITT) population consisted of all patients who were randomized into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Imatinib 400 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 12 Months | 4.5 Percentage of Partcipants |
| Imatinib 400 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 24 Months | 11.5 Percentage of Partcipants |
| Imatinib 400 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 36 Months | 12.7 Percentage of Partcipants |
| Imatinib 400 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 42 Months | 14.6 Percentage of Partcipants |
| Imatinib 800 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 42 Months | 12.5 Percentage of Partcipants |
| Imatinib 800 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 12 Months | 4.7 Percentage of Partcipants |
| Imatinib 800 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 36 Months | 13.2 Percentage of Partcipants |
| Imatinib 800 mg | Percentage of Patients With Undetectable Levels of Bcr-Abl (A Fusion Gene of the Breakpoint Cluster Region [Bcr] Gene and Abelson Proto-oncogene [Abl] Genes) Transcripts | 24 Months | 10.3 Percentage of Partcipants |
Secondary
Time to First Complete Cytogenetic Response
Cytogenetic response (CyR) is the percentage of Philadelphia positive metaphases (among at least 20 metaphase cells in Bone Marrow) with Complete Cytogenetic Response (CCyR) being 0 percent. Time to CCyR (months) = (date of first CCyR or censoring - date of randomization + 1) / 30.4375. Time to first CCyR was evaluated using the Kaplan-Meier method.
Time frame: 60 months overall
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg | Time to First Complete Cytogenetic Response | 10.8 Months |
| Imatinib 800 mg | Time to First Complete Cytogenetic Response | 5.8 Months |
Secondary
Time to First Complete Hematological Response (CHR)]
Complete Hematological Response (CHR) is defined is where all of the following criteria must be present for ≥4 weeks: White Blood Cell (WBC) count \<10 x 109/L, Platelet count \<450 x 109/L, Basophils \<5%, No blasts and promyelocytes in Peripheral Blood (PB), (Myelocytes + metamyelocytes) \< 5% in PB and No evidence of extramedullary involvement. Time to CHR (months) = (date of first CHR or censoring - date of randomization + 1) / 30.4375. Time to first CHR was evaluated using the Kaplan-Meier method.
Time frame: 60 months overall
Population: Intent-to-treat (ITT) population consisted of all patients who are randomized into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg | Time to First Complete Hematological Response (CHR)] | 1.0 Months |
| Imatinib 800 mg | Time to First Complete Hematological Response (CHR)] | 1.0 Months |
Secondary
Time to First Complete Molecular Response (CMR)]
Complete Molecular Response is defined as a Bcr-Abl (a fusion of gene of Bcr and ABl genes) ratio ≤0.0032% on the International Scale Bcr = breakpoint cluster gene Abl = abelson proto-oncogene.
Time frame: 48 months overall
Population: This analysis was not done because no major molecular improvement was observed in the 800mg dose compared to 400mg dose. Hence, analysis for complete molecular response was not necessary.
Secondary
Time to First Major Molecular Response
MMR is defined as Bcr-Abl (A fusion gene of the breakpoint cluster region \[Bcr\] gene and Abelson proto-oncogene \[Abl\] genes) transcript ratio ≤0.1% (≥ 3 log reduction of BCR-ABL transcripts from a standardized baseline), as detected by reverse transcriptase polymerase chain reaction \[RT-PCR\] (performed centrally). Time to MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. Time to first MMR was evaluated using the Kaplan-Meier method
Time frame: 42 months overall
Population: Intent-to-treat (ITT) population consisted of all patients who were randomized to the study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Imatinib 400 mg | Time to First Major Molecular Response | 13.6 Months |
| Imatinib 800 mg | Time to First Major Molecular Response | 8.4 Months |