High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial

Abstract

Background: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown.

Design and methods: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114).

Results: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014).

Conclusions: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).

Figures

Figure 1

Cytogenetic and molecular responses at different time points by intention-to-treat analysis. Major cytogenetic responses (A), complete cytogenetic responses (B) and major molecular responsesIS (C) are shown as response rates at 1.5, 3, 6, 12 and 24 months for the SD arm (arm A; white bars) and the experimental HD arm (arm B; black bars).

Figure 2

Kaplan-Meier survival curves for pre-treated CP CML patients who received SD imatinib (400 mg QD, arm A) or HD imatinib induction (800 mg for 6 months, followed by imatinib 400 mg QD thereafter; arm B). Overall survival (A), progression-free survival (B), event-free survival (C). Events were defined as follows: death from any course during treatment, progression to accelerated phase or blast crisis, loss of a complete haematologic response, loss of a MCyR.

Figure 3

Landmark analyses of PFS and EFS according to CCyR at 6 months. A total of 199 patients (103 patients in arm A and 96 patients in arm B who were still on study treatment and could, therefore, be analyzed by conventional cytogenetics at month 6 after treatment initiation were categorized according to CCyR. The following end-points were analyzed: progression into accelerated phase and blast crisis (A) and EFS (B). Events were defined as follows: death from any cause during treatment, progression to accelerated phase and blast crisis, loss of a complete hematologic response, loss of a MCyR.