Phase Iii Study For Newly Diagnosed Chronic Phase Patients

From June 2000 until January 2001 a phase III study recruited a total of 1106 newly diagnosed patients with CML in CP for a clinical trial referred to as the International Randomized Study of Interferon and STI571 or IRIS (15). Equal numbers of patients received either IM at a dose of 400 mg daily or the combination of interferon-«(IFN) plus cytarabine. The two cohorts were essentially similar with regard to age, starting leukocyte counts, Sokal prognostic scores, and interval from diagnosis. At a median follow-up of 19 months, the estimated rate of major cytogenetic response for the patients who received IM was very much higher than the rate for the patients who received interferon-« and cytarabine (87.1 % vs. 34.7%, P < 0.001); similarly the estimated rates of CCyR were better in the IM-treated patients than in control patients (76.2% vs. 14.5%, P < 0.001). Freedom from progression to advanced phase disease was 97.7% for the imatinib patients and 91.5% for the control patients (P < 0.001). When progression was more broadly defined by any of the following—loss of response to treatment, increasing leukocyte count, onset of advanced phase, or death—the "broad" progression-free survival for IM-treated patients was again very significantly better than that of patients in the control arm. It was also of interest to note that sub-classification of patients into one of three prognostic categories according to criteria established by Sokal et al. (16) separated patients' progression-free survivals in both treatment arms, but progression-free survival for patients in all three Sokal categories was better for IM-treated patients than progression-free survival for patients in the best Sokal category treated with the control combination (P < 0.01).

The most recent analysis of results in the IRIS study was performed at a median follow-up of 60 months from initiation of treatment, at which point 382 (69%) of the 553 patients originally allocated to the IFN/cytarabine arm had crossed over to the IM arm in contrast to crossover in the reverse direction by only 14 (2.5%) patients. Some patients crossed over from the IFN/cytarabine arm on account of intolerance or failure to achieve complete hematologic response or major cytogenetic response by the predetermined target dates, but a major reason for discontinuing treatment with IFN/cytarabine was withdrawal of consent when IM was approved by the Food and Drug Administration (FDA) and other national regulatory agencies and so became available for general use. This high level of discontinuation of treatment in the control arm meant that clinical results could not be analyzed at five years as a conventional prospective study, but analysis of results of primary treatment with IM and comparisons of IM-treated patients with the control arm on an "intention-to-treat" basis were still highly informative. At a median follow-up of five years the clinical results appeared to have improved very substantially in comparison with results reported at 19 months (17). The estimated incidence of CCyR was 87% (Fig. 1); only 7% of patents had progressed to advanced phase. The estimated overall survival for all patients who had received IM as first-line therapy was 89% (Fig. 2), which contrasted with an overall survival of 82% for patients in the control arm, many of whom had actually switched to IM soon after starting the IFN/cytarabine combination to which they had originally been allocated. Landmark analyses performed at 12 and 18 months showed very clearly that the degree to which the total quantity of leukemia in a patient's body had been reduced, as assessed by marrow cytogenetic status and BCR-ABL transcript numbers in the blood at the two time points, was highly predictive of the probability of subsequent survival without progression to advanced phase disease (Fig. 3). Thus patients who had a more than 3-log reduction in BCR-ABL transcript numbers at 18 months compared with a standardized baseline value (see Chapter 4) had 99% survival without progression at five years, whereas patients who had failed to achieve CCyR had a corresponding value of 83%. (P < 0.001). Of even greater interest was the observation that in the IM cohort the annual rate of progression seemed to be diminishing from year one to year five (Table 3), and similarly for patients who achieved CCyR the annual rate of progression to advanced phase seemed to be diminishing from year one to year four (17).

FIGURE 1 Probability of achieving complete hematological response, major cytogenetic response and complete cytogenetic response for 553 patients randomized to receive imatinib mesylate at 400 mg/day as initial treatment for chronic myeloid leukemia in chronic phase in the International Randomized Study of Interferon and STI571 study. The dashed vertical line shows values at one year from start of therapy. Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response.

FIGURE 1 Probability of achieving complete hematological response, major cytogenetic response and complete cytogenetic response for 553 patients randomized to receive imatinib mesylate at 400 mg/day as initial treatment for chronic myeloid leukemia in chronic phase in the International Randomized Study of Interferon and STI571 study. The dashed vertical line shows values at one year from start of therapy. Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response.

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