Based on the first phase I and II trials, imatinib was established as a safe and effective treatment for CML, which led to the regulatory authorities granting approval for the treatment of adult patients with CML in blast crisis, accelerated phase, or in chronic phase after failure of IFN-α therapy. However, it was reasonable to assume that the drug would also be effective in patients who are treated at an earlier stage of the disease. Moreover, inhibition of the bcr-abl kinase is most likely to have antileukemic effects during the chronic phase of CML, since additional chromosomal abnormalities may drive the malignant process during accelerated phase and blast crisis.

Update of the Superiority of Standard-dose Imatinib as a Single Agent over an Interferon-alpha-based Regimen In order to demonstrate the benefit of imatinib over the IFN-α-based regimen, it was decided to set up a large international study. This study (known as the IRIS study—International Randomized Study of IFN-α + Ara-C versus Imatinib) was carried out in newly diagnosed patients with chronic-phase CML to compare the efficacy, safety, and tolerability of imatinib administered as monotherapy with that of standard treatment with IFN-α plus Ara-C as the first-line treatment of the disease. The IRIS study enrolled 553 patients in each arm between June 2000 and January 2001. The trial was designed to allow cross-over for patients who had no response, a loss of response, increasing white blood cell count, intolerance of treatment, and failure to achieve major cytogenetic response (MCyR—fewer than 35% Ph chromosome positive bone marrow cells) at 12 months. Mainly because of intolerance and poor responses, a substantial number of patients crossed over from the IFN-α plus Ara-C arm to the imatinib arm; thus, overall survival analysis based on an intention-to-treat basis was not assessable. The subsequent analysis of the trial confirmed the initial impressive results.^10–12

In the IRIS study, routine follow-up data were collected for all randomized patients, including overall survival. For those who discontinued study treatment, quarterly assessments included whether patients were alive, deceased, lost to follow-up, or had received transplant. By the median five-year cut-off (range 5–5.5 years) after the last patient had been recruited into the study, 57 (10%) of the 553 patients initially randomized to imatinib were documented to have died.