Early results (published in Leukemia in 2009) from the phase III International Randomized Study of Interferon and STI571 (IRIS) demonstrated that imatinib 400 mg once daily was more active and associated with fewer adverse events (AEs) than a standard regimen of interferon alfa plus cytarabine in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). In a long-term follow-up to the trial, Andreas Hochhaus, MD, from the Jena University Hospital in Germany, and co-authors determined that the efficacy of imatinib persisted over 10 years with acceptable cumulative and late toxic effects.
According to the report, which was published in the New England Journal of Medicine, patients who received imatinib had an estimated overall survival (OS; primary long-term endpoint) rate of 83.3 percent (95% CI 80.1-86.6) at 10 years. In addition, serious AEs (SAEs) were uncommon and occurred most frequently during the first year of treatment.
“[IRIS] fundamentally changed CML treatment and led to marked improvements in prognosis for patients,” Dr. Hochhaus and colleagues wrote, reporting that, in the final analysis of IRIS, “no new safety signals and few drug-related SAEs were observed during the later years of follow-up, and molecular and cytogenetic response rates were high among the patients who could be evaluated.”
The study included 1,106 patients (median age = 50 years; range = 18-70 years) with previously untreated (other than hydroxyurea or anagrelide), Philadelphia chromosome-positive CP-CML that was diagnosed within 6 months prior to trial entry. Patients were enrolled from 177 centers in 16 countries between June 2000 and January 2012.
Patients were randomized to receive:
- imatinib 400 mg administered orally daily (n=553)
- interferon alfa 5 million IU/m2 administered subcutaneously plus cytarabine 20 mg/m2 administered subcutaneously for 10 days each month (n=553)
Crossover was allowed for lack of response (defined as no complete hematologic response by 6 months or no major cytogenetic response by 12 months), disease progression (defined as white cell count >20×109/L), loss of complete hematologic response or major cytogenetic response, unacceptable AEs, or reluctance to continue taking interferon alfa plus cytarabine after the trial results were originally released.
At 7 years, the trial was extended only for those receiving imatinib, and patients receiving interferon alfa plus cytarabine were eligible to cross over to imatinib and continue the trial.
“Because of the high rate of crossover and the subsequent closing of the group of patients receiving interferon alfa plus cytarabine, most long-term analyses (including safety, response rates, and landmark analyses) included only patients who had been randomly assigned to imatinib,” the authors noted.
The high rate of crossover precluded a direct comparison of OS between imatinib and interferon alfa plus cytarabine; however, the authors determined a hazard ratio of 0.74 (95% CI 0.56-0.99), indicating a 26 percent lower risk of death with firstline imatinib, compared with interferon alfa plus cytarabine (p=0.04; see TABLE).
The median duration of follow-up was 10.9 years (range = 0-11.7 years), and 48.3 percent (n=267) of patients treated with imatinib and 1.3 percent (n=7) of patients treated with interferon alfa plus cytarabine completed treatment. A majority of patients (65.6%; n=363) receiving interferon alfa plus cytarabine crossed over to receive imatinib because of disease progression, or lack or loss of response (31.5%), unacceptable AEs (26.2%), or reluctance to continue taking the treatment regimen (8%).
SAEs deemed related to imatinib occurred in 9.3 percent (n=51/551) of patients, the most frequent of which was abdominal pain (0.7%; n=4).
Cardiac SAEs of any cause were reported in 39 patients (7.1%) and SAEs of a second neoplasm were reported in 62 patients (11.3%). “No new safety signals were observed since the 5-year analysis,” the authors noted.
At 10 years, 47 percent of patients (n=260) were alive and still receiving treatment, while 17.4 percent were alive and not receiving treatment.
“Approximately half of the patients in the imatinib group discontinued the trial early, which suggests that the high rate of OS in the imatinib group must be attributed to the use of commercially available imatinib or effective secondline therapies in these patients,” the authors wrote.
At the end of the trial, 89 patients (16.1%) in the imatinib group died; 37 of those deaths were related to CML in patients who had not undergone hematopoietic cell transplantation (HCT). In the interferon alfa plus cytarabine group, 105 patients (19%) died; 48 of those deaths were related to CML in those who had not undergone HCT.
Progression to accelerated phase or blast crisis during the study was less frequent in imatinib-treated patients (6.9% vs. 12.8%), and the estimated freedom from progression at 10 years was 92.1 percent for the imatinib group (p values not reported). Rates of event-free survival at 10 years were also higher in the imatinib group (79.6% [95% CI 75.9-83.2] vs. 56.6% [95% CI 51.5-61.6]).
Survival rates were especially high in those who had a major molecular response at 12 or 18 months and those with low Sokal scores (based on age, spleen size, peripheral blood platelet count, and blast count). Patients with high Sokal scores had an estimated 10-year OS rate of 68.6 percent, compared with 80.3 percent for intermediate scores and 89.9 percent for low scores.
The study results are limited by the large number of patients with unknown survival status (approximately 20% in the imatinib group) or no molecular or cytogenetic assessments (approximately 50% in the imatinib group). Long-term safety information was limited. The trial also was not able to compare the safety and efficacy of imatinib with newer-generation tyrosine kinase inhibitors (TKIs) that became available during the follow-up period.
“Nonetheless, these results highlight the safety and efficacy of imatinib therapy, with a clear improvement over the outcomes that were expected in patients who received a diagnosis of CML before the introduction of TKI therapy, when interferon alfa and HCT were the standard therapies,” Dr. Hochhaus and co-authors wrote.
|TABLE. Analysis of Outcomes According to Molecular Response at 12 and 18 Months After Firstline Treatment With Imatinib|
|Variable||Major Molecular Response or Better||Lack of Major Molecular Response||P Value|
|Number of evaluable patients||153||151|
|Deaths||15 (9.8%)||22 (14.6%)|
|Not related to CML||11 (7.2%)||7 (4.6%)|
|Related to CML||4 (2.6%)||15 (9.9%)|
|Estimated 10-year OS||91.1%
(95% CI 86.5-95.7)
(95% CI 79.5-91.1)
|Estimated 10-year freedom from CML-related death||97.8%
(95% CI 95.4-100)
(95% CI 84.3-94.5)
|Number of evaluable patients||164||89|
|Deaths||12 (7.3%)||13 (14.6%)|
|Not related to CML||12 (7.3%)||4 (4.5%)|
|Related to CML||0||9 (10.1%)|
|Estimated 10-year OS||93%
(95% CI 89.0-97.0)
(95% CI 77.9-93.2)
|Estimated 10-year freedom from CML-related death||100%
(95% CI 100-100)
(95% CI 84.1-96.8)
|CML = chronic myeloid leukemia; OS = overall survival|