Imatinib therapy for chronic myeloid leukemia: where do we go now?

The use of imatinib has greatly improved the outcome of patients with chronic myeloid leukemia (CML). The efficacy of imatinib became apparent in the International Randomized Study of Interferon and STI571 (IRIS). One issue with the IRIS study is the number of patients that may have been lost to follow-up. For example, in the most recent update, data is available for only 364 (66%) of the 553 patients treated with imatinib. Because many patients came off study for administrative reasons despite a favorable response once the drug became available after approval from regulatory agencies, the true rates of success and failure are difficult to estimate. In this issue, de Lavallade et al present a series of 204 consecutive patients with newly diagnosed CML treated with standard-dose imatinib, nearly all of them outside of the IRIS study. The main value of this study is to provide independent confirmation of the IRIS study results by an intention-to-treat analysis, with follow-up available for all patients. Despite the shorter follow-up (median, 38 months), the results are very similar to those in the IRIS trial. A complete cytogenetic response (CCyR) was achieved in 77% of patients and the projected 5-year event-free survival at 5 years is 81.3%. With these excellent results, one important question is: Can imatinib be improved on? Or, do we even need to try to improve on imatinib? The answer to the second question is easier. Despite the outstanding results obtained so far, there is still room for improvement. de Lavallade et al report that 26% of all patients have discontinued imatinib, mostly because of resistance, with only a few discontinuing because of intolerance. Using a broader definition of event-free survival that includes failure to achieve major cytogenetic remission (MCyR) and intolerance to imatinib (in addition to the standard definition that includes loss of compete hematologic response, loss of MCyR, increasing WBC count, death resulting from any cause or progression to accelerated or blast phase), the 5-year probability is 63%. Furthermore, we could consider as an event the inability to achieve or the loss of CCyR. Thus, despite the unquestionable outstanding results with imatinib, there is both room and need for improvement. It is more difficult to answer the question of how we will improve on these results. With imatinib, we have a rate of CCyR of approximately 80% and an overall survival near 90% at 5 years. And we now have excellent second-line therapy for patients who have experienced failure with imatinib, with the second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib that have received regulatory approval, and others (bosutinib, INNO-406) possibly also on their way. Thus, patients that do not respond well or are intolerant to imatinib may still have a favorable long-term outcome with these new therapies. Still, several approaches can be considered for improving the long-term outcome of CML patients. One is to use higher doses of imatinib. Initial reports suggested that this strategy might result in more and faster remissions (CCyR, major molecular response [MMR], and complete molecular response [CMR]) compared with what can be expected with standard dose imatinib. Whether these changes result in an improved long-term patient outcome is unknown, but there are randomized trials comparing standardwith high-dose imatinib that may answer this question. A different approach is to use imatinib in combination with other agents. Interferon, cytarabine, and other agents with known clinical activity in CML or that interfere with other pathways important in CML have been found to be synergistic with imatinib. Initial attempts with such combinations were not very successful. Still, there is interest in pursuing combinations that might help eradicate all evidence of leukemia, including the elusive leukemic stem cell. The success with secondgeneration TKIs in treating patients who have experienced failure with prior imatinib therapy paired with their in vitro potency and possibly lower propensity to trigger development of mutations has generated interest in their use as initial therapy for patients with early chronic phase CML. The early results presented to date are very promising, but additional patients and longer follow-up is needed. One could then ask, What would be needed to dethrone imatinib as the standard of care for patients with newly diagnosed CML? Ultimately, we would like to improve survival, but given the excellent survival at 5 years (88% overall; 95% for CML-related deaths), it is unrealistic to expect an improvement in survival in the short term. Improving survival free from transformation is similarly difficult (93% at 6 years). An improvement in event-free survival would be valuable and is a more reachable goal, particularly if we consider a broader definition of event free, as suggested by de Lavallade et al that includes toxicity and failure to achieve (or loss of) MCyR or CCyR. In this case, 5-year probability of event-free survival is 62.7%. However, in CML we have the advantage of having excellent surrogate markers (CCyR) for overall and event-free survival. Thus, improving the rate of CCyR would be desirable. The current overall CCyR rate with imatinib is 77% (de Lavallade et al) to 82% (IRIS). High-dose imatinib and the new TKIs have induced responses in more than 90% of patients, and there is indirect evidence that this may lead to an improved event-free and transformation-free survival. Improving the rate of molecular responses can be pursued; there are data to suggest that patients with MMR have an improved event-free survival and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 20 JULY 1