IRIS trial of imatinib versus interferon in CML

Chronic myeloid leukemia had been a manageable but not curable disease through the 1990s. Interferon-alpha combined with low-dose cytarabine produced cytogenetic responses in a fraction of patients and extended survival, but the regimen carried substantial toxicity: fatigue, depression, flu-like symptoms, and injection site reactions that eroded quality of life over months of continuous treatment. Allogeneic stem cell transplantation was the only treatment with curative potential, available only to younger patients with suitable donors and carrying its own serious morbidity. FDA reviewers put the expected median survival on interferon and cytarabine at five to six years.

Imatinib, a small molecule inhibitor of the BCR-ABL tyrosine kinase produced by the Philadelphia chromosome translocation, came out of a kinase inhibitor program that the biochemist Nicholas Lydon set up at Ciba-Geigy, later part of Novartis, and Brian Druker of Oregon Health and Science University took it into the clinic. In a phase II study of 532 patients in whom interferon had failed, published in 2002, imatinib produced major cytogenetic responses in 60% of the 454 with confirmed chronic-phase disease. The IRIS trial, an acronym for International Randomized Study of Interferon and STI571, was designed to provide the head-to-head comparison needed to change the standard of care. It enrolled 1,106 newly diagnosed chronic-phase CML patients at centers across Europe, North America, and Australia.

At 18 months, complete cytogenetic response had occurred in 76% of the imatinib arm versus 15% of the interferon-plus-cytarabine arm. At 18 months, 96.7% of the imatinib group and 91.5% of the combination group had not progressed to accelerated phase or blast crisis. Imatinib was also better tolerated, and by the 10-year analysis 65.6% of patients assigned to interferon and cytarabine had crossed over to imatinib, after a median of 0.8 years on the combination. Stephen O'Brien of the University of Newcastle was first author of the 2003 report, and Druker was its senior author.

The 10-year follow-up, published in 2017 after a median of 10.9 years, estimated overall survival at 83.3% in the imatinib group, and 82.8% of those patients had had a complete cytogenetic response. Serious adverse events attributed to imatinib were uncommon and mostly occurred in the first year, and 48.3% of patients completed the study still taking the drug.

IRIS showed that a small molecule aimed at a single oncogenic kinase could control a hematologic malignancy for years, in a randomized comparison with the existing standard. When dasatinib and nilotinib were tested as first-line drugs in trials published in 2010, the comparator in both was imatinib at the IRIS dose of 400 mg a day. Both newer drugs produced higher rates of complete cytogenetic and major molecular response at 12 months.