Based onearly reports suggesting a correlation between minimumserum imatinib concentration achieved and the likelihoodof achievingCCyR and/or MMR,12 the imatinib dose wasescalated to 800 mg daily in patients with trough serumconcentration <1,000 ng/mL.

Cohort 1 patients who failedto achieve any molecular target were escalated to imatinib800 mg daily, and subsequently switched to nilotinib 400mg twice daily if failed to reach the same target 3 monthslater. Cohort 2 patients who failed to achieve any targetwere switched to nilotinib directly, as well as patients withimatinib intolerance. At 2 years, 55% of patients remainedon imatinib and 30% on nilotinib. MMR was achieved in64% at 12 months and 73% at 24 months.

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Overall survival(OS) was 96% and transformation-free survival was95% at 3 years. TIDEL-II represents a novel, interestingapproach for the first-line management of CML-CP basedon HD imatinib and selective, early switch to 2G-TKI.13

In 2011, Gafter-Gvili et al published a systematic review and meta-analysis of randomized controlled trials comparing frontline therapy with imatinib 400 mg daily vs higher doses (≥600 mg daily) in patients with CML-CP.14

The search encompassed four trials (European LeukemiaNet [ELN], TOPS, SPIRIT, and CML-Study IV), randomizing 1,673 patients. Three trials included patients of all prognostic risk groups, whereas one trial (ELN) included only high-risk patients. For risk assessment, the Euro score was used in one case (TOPS) and the Sokal score in remaining three.

The assigned imatinib dose in the HD arm was 800 mg daily in three trials and 600 mg daily in one trial. Subjects in the standard dose arm of all four trials were allocated 400 mg of imatinib daily. The TOPS and ELN trials had notably shorter median follow-up (17 and 26 months, respectively) than the CML-Study IV and the SPIRIT study (28–43 months and 47 months, respectively). The primary outcomes of the study were CCyR and MMR rates at 12 months.

In both cases, risk ratio (RR) > 1 favored the HD imatinib arm. The CCyR rate was significantly higher at 12 months in the HD arm (RR 1.17, 95% confidence interval [CI] 1.08–1.26, four trials, I2=33%), as well as MMR (RR 1.26, 95% CI 1.12–1.42, four trials, I2=0%).

However, there was no difference in all-cause mortality or disease progression to AP/BP at the end of follow-up. The study evaluated also safety outcomes: grade 3/4 hematologic and nonhematologic adverse events. In that case, RR < 1 favored HD imatinib.

Adverse events requiring treatment discontinuation were more common in the HD arm (RR 1.98, 95% CI 1.20–3.26, three trials, I2=0%), as were grade 3/4 neutropenia and thrombocytopenia (RR 1.56, 95% CI 1.15–2.12 and RR 1.86, 95% CI 1.28–2.70, respectively).14

Results of the aforementioned studies show that HD imatinib compared with standard dose significantly improves CCyR and MMR at 12 months.

However, there was no significant difference in OS and progression-free survival (PFS) at the time of publication of the studies (Table I).15–18 Thus, the evidence to support the routine use of HD imatinib as frontline treatment for CML-CP is currently insufficient.

Table I – Summary of selected randomized clinical trials evaluating high-dose imatinib in newly diagnosed patients with CML-CP
Clinical Study Imatinib Complete cytogenetic Major molecular response rate Estimated dosage PFS/OS
European LeukemiaNet study15 400 mg/day
800 mg/day
At 12 months 58%
At 12 months 64%
At 12 months 33.3%
At 12 months 39.8%
At 3 years PFS: 86%/OS: 84%
At 3 years PFS: 88%/OS: 91%
TOPS study16 400 mg/day
800 mg/day
At 12 months 66%
At 12 months 70%
At 12 months 40.1%
At 12 months 46.4%
At 18 months PFS: 95%/OS: 98.7%
At 18 months PFS: 97%/OS: 98.2%
SPIRIT17 400 mg/day + IFN-α
600 mg/day
At 12 months 66%
At 12 months 65%
At 12/24 months 57%/64%
At 12/24 months 49%/53%
At 2 years PFS: 96.8%/OS: NA
At 2 years PFS: 96.9%/OS: NA
German Study Group IV18 400 mg/day + IFN-α
800 mg/day
At 3 years 78.5%
At 3 years 85.2%
At 3 years 63%
At 3 years 79%
At 3 years PFS: 94%/99%/OS: 93/99% (for ,1% and $ 1% of BCR-ABL, respectively)
At 2 years PFS: 80.3%/ at 5 years OS: 91%
Abbreviations: CML-CP, chronic phase chronic myeloid leukemia; IFN-α, interferon-alpha; NA, not available; OS, overall survival; PFS, progression-free survival.