Can we and should we improve on frontline imatinib therapy for chronic myeloid leukemia?

Although imatinib is presently the treatment of choice in newly diagnosed chronic-phase (CP) chronic myeloid leukemia (CML) patients, 8 years from start of the International Randomized Study of Interferon and STI571 (IRIS) trial, 45% of the patients originally enrolled in the imatinib arm (imatinib 400 mg/d) have discontinued this treatment; in 15% of the cases this was due to lack of efficacy and in 5% for safety or intolerance problems. With the aim of improving the results of the standard imatinib 400 mg/d first-line therapy of CML, several trials have been started and are presently ongoing. The purpose of these trials is to test the efficacy of higher dosages of imatinib and of imatinib in combination with other agents, in particular with interferon alpha (IFN). In addition, second-generation tyrosine kinase inhibitors (TKIs), which are now available for treatment of patients resistant or intolerant to imatinib, also have been tested for first-line treatment, in the setting of both single-center and multicenter studies. The results of these trials seem to indicate a superior efficacy of the more potent second-generation TKIs with respect to imatinib, particularly in terms of higher rates of complete cytogenetic responses (CCyR) and of major molecular responses (MMR), that, more importantly, also seem to lead to a decreased number of progressions of the disease. Although these results still need to be fully evaluated after a longer period of follow-up, the use of next-generation agents and modified imatinib-based strategies in the first-line therapy of CML is likely to become a key area of clinical research during the next few years.