With more than 10 years of follow-up in IRIS, the long-term outcomes in imatinib-treated patients that we describe here confirm and extend earlier findings. No new safety signals and few drug-related serious adverse events 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 estimated overall survival rate at 10 years with first-line imatinib therapy was 83.3%, which is similar to the rate (84%) reported among patients who were treated with imatinib-based regimens in the CML-IV study, which was initiated shortly after IRIS to further evaluate alternative dosing strategies and drug combinations in patients with newly diagnosed CML in the chronic phase. There are several caveats to these long-term data, including the large number of patients who had an unknown survival status (approximately 20% of the patients in the imatinib group) or who did not have molecular or cytogenetic assessments that could be evaluated (approximately half the patients who completed the trial while taking imatinib had cytogenetic assessments at 10 years that could be evaluated) and the limited collection of long-term safety information. 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 tyrosine kinase inhibitor therapy, when interferon alfa and hematopoietic stem-cell transplantation were the standard therapies. The ability of imatinib to reduce rates of disease progression and CML-related death (and the resulting increase in the rate of overall survival) has made it a model for targeted cancer therapy. Although high rates of response have now also been observed with targeted therapies in patients who have other cancers with well-characterized molecular abnormalities, including BRAF-driven melanoma and epidermal growth factor receptor (EGFR)–mutated lung cancer, the durability of responses observed with targeted therapies for these cancers is much less impressive (and similar to the results with imatinib in patients with CML in blast crisis). These findings are likely to be attributable to CML in the chronic phase being driven solely by BCR-ABL1, whereas solid tumors and the advanced phases of CML may be driven by multiple pathways and complex genomic abnormalities, which further underscores the importance of initiating treatment early in the course of the disease. While the IRIS trial was under way, new recommendations for CML treatment and new BCR-ABL1 inhibitors were developed. Each of the newer agents has a distinct safety and efficacy profile, and two (nilotinib and dasatinib) have been approved as first-line therapies in patients with CML in the chronic phase on the basis of results from phase 3 trials in which they were associated with higher response rates than imatinib (although a higher dose of imatinib may also increase the rates of response). Furthermore, nilotinib resulted in lower rates of progression to the accelerated phase and blast crisis and CML-related death than imatinib. However, despite the better early control of disease observed with second-generation tyrosine kinase inhibitors than with imatinib, it remains to be seen whether they will have similarly favorable long-term safety. Given the long-term safety and efficacy results with imatinib and the increasing availability of generic imatinib, comparative analyses evaluating the available tyrosine kinase inhibitors for first-line therapy are likely to be forthcoming. As experience with imatinib accrued throughout the course of this trial, the treatment of patients who were taking a tyrosine kinase inhibitor improved over time. For example, after issues related to poor adherence to the oral-drug regimens became apparent (more so in routine clinical practice than among patients enrolled in clinical trials), physicians learned to conduct more specific consultations with patients to ensure that they were taking their medication as prescribed. Survival rates in our trial were especially high in certain subgroups of patients, including those who had a major molecular response at 12 months or 18 months and those with low Sokal scores. These results are consistent with previous reports from IRIS and other studies showing that early responses to tyrosine kinase inhibitor therapy are valuable prognostic markers for long-term outcomes and that patients with low risk scores (according to Sokal, Hasford, or European Treatment and Outcome Study scores) at baseline typically have high rates of complete cytogenetic response and overall survival while taking any of the available tyrosine kinase inhibitors. The risk profile of our trial cohort, according to Sokal score, was similar to that in other studies. Imatinib treatment has also allowed for the successful stopping of therapy (for >5 years) in small subgroups of patients with a sustained deep molecular response (molecular response 4 [defined as a reduction of 4 log in the BCR-ABL1 value from the standardized baseline level on the International Scale], molecular response 4.5, or undetectable BCR-ABL1 transcripts), which promotes treatment-free remission as a treatment goal. Approximately 39 to 45% of patients who attempt treatment-free remission after having a durable deep molecular response with imatinib therapy can remain in remission for 3 years or longer. The eligibility rate for an attempt at treatment-free remission has been estimated to be 21.6% after 6 years of imatinib therapy (on the basis of maintenance of a stable deep molecular response for ≥12 months). Thus, the total percentage of imatinib-treated patients who may have a stable treatment-free remission is approximately 10%. Because a greater percentage of patients have deep molecular responses with second-generation tyrosine kinase inhibitors than with imatinib across all risk strata, second-generation agents may enable a larger proportion of patients in all Sokal-score risk groups to be eligible to attempt treatment-free remission. Although long-term survival data were incomplete, the observation that many of the reported deaths in the imatinib group were unrelated to CML is in line with published data showing that patients who have a response to imatinib have a survival rate that is equivalent to that in the general population and are unlikely to die from CML. This trend also highlights the importance of monitoring and managing coexisting conditions in patients with CML in the chronic phase. As the prognosis that is associated with CML in the chronic phase improves and as patients can be expected to live for years or decades, an increasing number of patients will be at risk for death from general health conditions or coexisting conditions rather than from CML. In particular, of the few deaths reported in the low-risk Sokal-score group, most were unrelated to CML (and were likely to be related to the coexisting-condition profile that is typical of this age group). In contrast, patients with a high Sokal score typically died from CML. As is consistent with a previous analysis of the outcomes in patients who crossed over from interferon alfa plus cytarabine to imatinib, the long-term overall survival rate in the group that received interferon alfa plus cytarabine was high, which suggests that second-line imatinib was an effective therapy in many of these patients. Several new questions have arisen, such as the relative benefits and risks of imatinib versus newer tyrosine kinase inhibitors and the role and effect of second-line inhibitor therapy. Approximately half the patients in the imatinib group discontinued the trial early, which suggests that the high rate of overall survival in the imatinib group must be attributed to the use of commercially available imatinib or effective second-line therapies in these patients. Despite these unanswered questions, the long-term results presented here highlight the clinical benefits observed in patients with CML over the past 15 years.