A Phase III, Randomized, Open-Label Study of 400 Mg Versus 800 Mg of Imatinib Mesylate (IM) in Patients (pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints: 1-Year Results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study

Background: IM 400 mg/d is the standard of care for pts with newly diagnosed CML-CP. Previous reports suggest the rate of major molecular response (MMR), defined as BCR-ABL/control gene (BAC) ratio of ≤ 0.1% on the International Scale, predicts for a benefit in long-term outcomes. Phase 2 trials demonstrated that IM 800 mg/d as initial treatment of CML-CP decreases the time to MMR and increases the depth of molecular response (MR), and may therefore improve long-term outcomes. Methods: TOPS is a prospective, open-label, randomized (2:1) Phase 3 trial that compared IM 800 mg/d to 400 mg/d in CML-CP. Pts were stratified by Sokal risk score. The primary endpoint is MMR rate at 12 months (mo) and secondary endpoints include: rates of complete hematological response, complete cytogenetic response (CCyR), time to CCyR and MMR, progression to accelerated phase (AP) or blast crisis (BC), eventfree survival (EFS), overall survival (OS), IM dose-intensity, pharmacokinetics, and safety. Rates were compared by Fisher’s exact test and time to event outcomes by logrank test. Results: 476 pts were enrolled (800 mg/d, n=319; 400 mg/d, n=157) at 103 sites in 19 countries between 6/05 and 12/06. Median age at diagnosis was 47 yrs, and 24% of pts had high Sokal risk score. Significantly more pts receiving IM 800 mg/d achieved MMR at 3 mo and 6 mo, but not at 12 mo when compared with 400 mg/d (Table 1). Time to MMR was faster in the 800 mg/d arm compared to 400 mg/d; P = .0038. Table 1: MMR rate (%) over time according to randomized dose of IM MMR rate (%) Intent-to-treat (ITT) population Evaluable pts (with polymerase chain reaction assessment) 400 mg (N = 157) 800 mg (N = 319) P-value 400 mg %, (n) 800 mg %, (n) P-value Month 3 3 12 .0011 4 (137) 14 (283) .0011 Month 6 17 34 .0002 20 (135) 39 (276) .0001 Month 9 36 45 .0604 41 (136) 54 (267) .0203 Month 12 40 46 .2035 46 (133) 54 (269) .1386 Achievement of MMR according to average dose over the first 12 mo of treatment was greatest when the intended dose intensity (DI) was achieved (Table 2). Table 2. MMR at 12 mo according to DI (evaluable patients) Randomized Dose MMR DI (first 12 mo) (n) MMR rate, % [95% CI] 400 mg (n =133) 46% ≥ 400 mg (74) 50 [38−62] < 400 mg (59) 41 [28−54] 800 mg (n =269) 54% 800 mg (52) 63 [49−76] 600 – 799 mg (134) 62 [53−70] 400 – 599 mg (69) 38 [26−50] < 400 mg (14) 21 [5−51] CCyR occurred faster in the 800 mg/d arm, indicated by a higher response rate at 6 mo (57% vs. 45%, P = .0146). At 12 mo rates of MMR and CCyR (ITT population) were higher for the 800 mg/d arm but were no longer significantly different (MMR 46% vs. 40%, P= .2035; CCyR 70% vs. 66%, P= .3470). In pts with high Sokal risk scores, rates of MMR at 12 mo were 41% and 26% (P = .1565) for the 800 mg/d and 400 mg/d arms, respectively. Exploratory analysis of MR at 3 mo and its correlation with achievement of MMR at 12 mo follow. Of the pts in the 400 mg arm with BAC ratios >0.1–≤ 1%, >1–≤ 10% or > 10% at 3 mo, 83%, 46%, and 11% later achieved an MMR at 12 mo. In the 800 mg arm 73%, 45% and 21% of the pts with respective BAC ratios achieved an MMR at 12 mo. Based on the BAC ratio at 6 mo, the observed MMR rate at 12 months was 52%, 11%, and 0% in the 400 mg/d arm compared to 46%, 14%, and 18% in the 800 mg/d arm. In the first year of follow-up, 6 pts had documented progression to AP/BC during treatment: 3 (1.9%) in the 400 mg/d arm and 3 (0.9%) in the 800 mg/d arm. At 12 mo, 85% of pts in the 400 mg/d arm were receiving the randomized dose compared to 62% of pts in the 800 mg/d arm. Median DI was 400 mg/d in the 400 mg arm and 750 mg/d in the 800 mg arm. Dose interruptions > 5 days occurred more frequently in the 800 mg/d arm (67% vs 38%). Earlier achievement of MMR correlated with IM plasma trough level at 1 mo for the overall TOPS cohort; pts with IM concentrations < 1165 ng/mL (lowest quartile of the aggregate group) achieved MMR slower than those with concentrations ≥ 1165 ng/mL (p=.0149). The most common grade 3/4 nonhematologic toxicities were rash, diarrhea and myalgia occurring slightly more frequently in the 800 mg/d arm. Grade 3/4 hematologic toxicity occurred more frequently in pts receiving 800 mg/d. Conclusions: TOPS confirms the efficacy and safety of IM in newly-diagnosed CML-CP. MMR occurred earlier in pts treated with 800 mg/d and in patients with plasma IM level above the lowest quartile, reinforcing the utility of IM blood level testing to optimize treatment. DI of IM 800 mg/d was maintained and tolerability was good. Additional follow-up is required to evaluate the effect of dose and MR on long-term clinical outcomes.