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).
Authors: Kantarjian Hagop M. , Larson Richard A. , Guilhot Francois , O’Brien Stephen G. , Druker Brian J. ,   on Behalf of IRIS Study Group
Published: October 2019

Abstract
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).
Table 1. AEs (≥ 20%) on First-Line Imatinib Therapy AE All grades N= 551 (%) All grades, after 2 yrs N = 456 (%) All grades, after 4 yrs N = 409 (%) Grades 3/4 N= 551 (%) Fluid retention 61.7 20.2 5.6 2.5 – Superficial edema 59.9 18.2 5.1 1.5 – Other fluid retention events 6.9 2.4 0.7 1.3 Nausea 49.5 15.4 3.4 1.3 Muscle cramps 49.2 22.8 7.3 2.2 Musculoskeletal pain 47.0 20.8 6.1 5.4 Diarrhea 45.4 23.0 5.1 3.3 Rash and related terms 40.1 13.8 2.4 2.9 Fatigue 38.8 11.4 2.9 1.8 Headache 37.0 12.1 3.4 0.5 Abdominal pain 36.5 15.4 3.4 4.2 Joint pain 31.4 9.2 2.0 2.5 Nasopharyngitis 30.5 14.3 3.7 0 Hemorrhage 28.9 14.3 5.1 1.8 Myalgia 24.1 4.6 1.5 1.5 Vomiting 22.5 9.2 3.7 2.0 Upper respiratory tract infection 21.2 11.2 2.7 0.2 Cough 20.0 7.7 3.4 0.2
Hematologic toxicities were the most frequently occurring grade 3/4 AEs (Table 2).
Table 2. Grade 3/4 laboratory abnormalities on First-line Imatinib Overall N = 551 (%) After 2 years N= 456 (%) After 4 years N= 409 (%) Hematologic – Neutropenia 16.7 7 1.0 – Thrombocytopenia 8.9 1.5 0.2 – Anemia 4.4 1.8 0.5 Biochemical – ↑ SGOT/SGPT 5.3 0.4 0 – ↑Total bilirubin 1.1 0.4 0.2
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.