A total of 1,106 patients were randomized from 177 centers in 16 countries, 553 to each arm. Baseline characteristics were well balanced between the two arms. Median age was 51 years (range 18-70 years), with 21.9% of patients > 60 years of age. There were 59% males and 41% females; 89.9% Caucasian and 4.7% Black patients. At the cut-off for this analysis (5 years after last patient had been recruited), the median duration of first line treatment was 60 and 8 months in the Gleevec and IFN arm, respectively. The median duration of second-line treatment with Gleevec was 45 months. 69% of patients randomized to Gleevec are still receiving first-line treatment. In these patients, the average dose of Gleevec was 382 mg ± 50 mg. Overall, in patients receiving first line Gleevec, the median daily dose delivered was 389 mg ± 71 mg. Due to discontinuations and cross-overs, only 3% of patients randomized to IFN were still on first-line treatment. In the IFN arm, withdrawal of consent (14%) was the most frequent reason for discontinuation of first-line therapy, and the most frequent reason for cross over to the Gleevec arm was severe intolerance to treatment (26%) and progression (14%).

The primary efficacy endpoint of the study was progression-free survival (PFS). Progression was defined as any of the following events: progression to accelerated phase or blast crisis (AP/BC), death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate therapeutic management. The protocol specified that the progression analysis would compare the intent to treat (ITT) population: patients randomized to receive Gleevec were compared with patients randomized to receive interferon. Patients that crossed over prior to progression were not censored at the time of cross-over, and events that occurred in these patients following cross-over were attributed to the original randomized treatment. The estimated rate of progression-free survival at 60 months in the ITT population was 83.2% [79, 87] in the Gleevec arm and 64.1% [59, 69] in the IFN arm (p < 0.0001, log-rank test), (Figure 1). With 5 years follow up there were 86 (15.6%) progression events in the Gleevec arm: 35 (6.3%) progression to AP/BC, 28 (5.1%) loss of MCyR, 14 (2.5%) loss of CHR or increase in WBC and 9 (1.6%) CML unrelated deaths. In contrast, there were 155 (28.0%) events in the IFN+Ara-C arm of which 128 occurred during first-line treatment with IFN-Ara-C The estimated rate of patients free of progression to accelerated phase (AP) or blast crisis (BC) at 60 months was 92.9% [90, 96] in the Gleevec arm compared to the 86.2%, [82, 90] (p ≤ 0.001) in the IFN arm, (Figure 2). The annual rates of any progression events have decreased with time on therapy. The probability of remaining progression free at 60 months was 95% for patients who were in complete cytogenetic response with molecular response ( ≥ 3 log reduction in Bcr-Abl transcripts as measured by quantitative reverse transcriptase polymerase chain reaction) at 12 months, compared to 89% for patients in complete cytogenetic response but without a major molecular response and 70% in patients who were not in complete cytogenetic response at this time point (p < 0.001).

Figure 1 Progression Free Survival (ITT Principle)

Sponsor agreed for figure 1 only to change title to “Progression-free survival” – FDA OK

Figure 2 Time 10 Progression to AP or BC (in Principle)

A total of 57 (10.3%) and 73 (13.2%) patients died in the Gleevec and IFN+Ara-C group, respectively. At 60 months the estimated overall survival is 89.4% (86, 92) vs. 85.6% (82, 89) in the randomized Gleevec and the IFN+Ara-C group, respectively (p=0.049 log-rank test). The hazard ratio is 0.71 with 95% CI 0.50-1.00. This time-to-event endpoint may be affected by the high crossover rate from IFN+Ara-C to Gleevec. Major cytogenetic response, hematologic response, evaluation of minimal residual disease (molecular response), time to accelerated phase or blast crisis and survival were main secondary endpoints. Response data are shown in Table 12. Complete hematologic response, major cytogenetic response and complete cytogenetic response were also statistically significantly higher in the Gleevec arm compared to the IFN + Ara-C arm (no cross-over data considered for evaluation of responses). Median time to CCyR in the 454 responders was 6 months (range 2-57 months, 25th to 75th percentiles = 3 to 10 months) with 10% of responses seen only after 22 months of therapy).

Table 12 Response in Newly Diagnosed CML Study (60-Month Data)

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