Declining Rates of Adverse Events (AEs), Rare Occurrence of Serious AEs (SAEs), and No Unexpected Long-Term Side Effects at 5 Years in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Initially Treated with Imatinib (IM) in the International Randomized Study of Interferon vs STI571 (IRIS).

The IRIS trial compared interferon alfa + cytarabine (IFN+Ara-C) and imatinib (IM) in patients (pts) with newly diagnosed CML-CP. Among 553 pts randomized to receive 400 mg IM, 157 (28%) discontinued for reasons which included AEs or deaths unrelated to CML and treatment (6%) and unsatisfactory therapeutic effect (11%). Only 2.4% discontinued due to drug-related AEs. The average daily dose was 389±71 mg, suggesting that no major dose modifications were required due to toxicity. In pts still on IM, the average doses was 382±50 mg. Average duration of exposure is 50 mos (median 60 mos). Table 1 summarizes the most frequently reported non-hematologic AEs (regardless of relationship to study drug) in pts who started IM therapy and those who were still on IM at 2 and 4 years (n=456 and 409 respectively).

Hematologic toxicities were the most frequently occurring grade 3/4 AEs (Table 2).

The most frequent reported AEs as well as grade 3/4 hematological and biochemical toxicities were observed at decreasing frequencies throughout therapy. After 4 years, 8% of pts experienced an SAE, compared with 14%, 12%, 7.5%, and 9% during year one through four of therapy. Overall, only 6% of pts had SAEs considered related to study drug (1.5% pts after 4 years of IM). Congestive heart failure/cardiac dysfunction (incl. pulmonary edemas) were reported for 3% of pts (<1% grade 3/4) and pleural effusion in 1% (<1% grade 3/4). Despite much shorter average exposure (12 mos), similar % of these AEs were noted for IFN+Ara-C.

Although it should be considered that pts more likely to experience grade 3/4 events may have discontinued from the study prematurely, the 5-year data with IM in pts with newly diagnosed CML-CP show declining frequencies of AEs and SAEs over time. Occurrence of SAEs and laboratory abnormalities with long-term follow-up was rare. No unexpected long-term side effects were noted. These results confirm the IM tolerability and safety profile for durations exceeding 4 years.