Oncology · 2003
IRIS trial of imatinib versus interferon in CML
International Randomized Study of Interferon and STI571
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. For most patients with CML, the outlook was measured in years.
Imatinib, a small molecule inhibitor of the BCR-ABL tyrosine kinase produced by the Philadelphia chromosome translocation, had emerged from work at Novartis by chemist Nicholas Lydon and subsequent clinical development by Brian Druker at Oregon Health and Science University. Phase II studies in patients who had failed interferon showed cytogenetic response rates that had not been seen with any prior therapy. 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. Major molecular response rates and progression-free survival favored imatinib at every scheduled analysis. Tolerability data were equally decisive: 89% of patients in the interferon arm crossed over to imatinib within 12 months, either because of disease progression or because they could not tolerate the control regimen. Charles Sawyers at Memorial Sloan Kettering contributed to the trial's design and later to understanding resistance mechanisms.
Long-term IRIS follow-up data, reported at 10 years, showed an estimated 83.3% of imatinib-treated patients still in complete cytogenetic response and an overall survival of 83.3%, a figure approaching that of an age-matched general population. Those numbers recast the prognosis of a disease that had previously been understood as chronic and ultimately fatal for most patients who lacked transplant options.
IRIS did more than displace interferon; it demonstrated that targeting a single oncogenic kinase with a small molecule inhibitor could produce durable disease control in a hematologic malignancy. The trial design, comparing a molecularly targeted agent against the existing standard in a disease defined by a specific chromosomal abnormality, became the template for subsequent drug development in other kinase-driven cancers. Second and third-generation BCR-ABL inhibitors, developed in part to address imatinib resistance, were all evaluated against an IRIS-derived benchmark.
Key People
- Brian Druker — Oregon Health and Science University; imatinib development and IRIS lead
- Charles Sawyers — Memorial Sloan Kettering; co-investigator, resistance mechanisms
- Nicholas Lydon — Novartis chemist; synthesized imatinib (STI571)
- Moshe Talpaz — University of Texas MD Anderson; early imatinib clinical trials
N Engl J Med 2003;348:994-1004
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