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).

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 responses^IS (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.