How to treat CML patients in the tyrosine kinase inhibitors era? From imatinib standard dose to second generation drugs front-line: Unmet needs, pitfalls and advantages

Imatinib has revolutionized treatment strategies for chronic myeloid leukemia patients: long-term overall survival was reported to be up to 80% at 8 years of follow-up in respondent patients. Despite the straightforward results obtained, it has been estimated a failure rate per year of 2–4%. Several attempts to improve response have been made with high-dose of imatinib and with combination of standard dose with interferon, but both failed to ameliorate cytogenetic and molecular responses and long-term event-free and overall survival and no advantages were reported in high-risk patients. The introduction of second generation tyrosine kinase inhibitors in clinical practice allowed to rescue more than 50% of patients resistant or intolerant to imatinib. Both dasatinib and nilotinib were tested as single agent in first-line and then tested against imatinib standard dose: the results of phases II and III trials showed early and maintained complete cytogenetic response, rapid reduction of molecular burden and significant reduction of progression rate. At the present time, after FDA approval of both agents in first-line, several points of discussion are still unresolved.

► At the last follow-up of IRIS trial, about 40% of patients did not reach a favorable result.
► High dose imatinib or association with IFN did not improve the results of standard dose imatinib.
► Second generation TKIs used as front-line treatment induced rapid decrease of disease burden, with reduced rate of progression.
► Further researches are needed to identify potential candidates to discontinuation of therapy.