State-of-the-art management of CML in 2015 and future prospects

The ABL tyrosine kinase inhibitor (TKI) imatinib mesylate has dramatically changed the treatment of chronic myeloid leukemia (CML). However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. There are several mechanisms underlying imatinib resistance. Notably, point mutations within the ABL kinase domain are the most critical cause of imatinib resistance. It has recently been recognized that adherence to ABL TKIs is very important for resistance. Four second-generation ATP competitive ABL TKIs, i.e., dasatinib, nilotinib, bosutinib and bafetinib, have been developed. The three TKIs other than bafetinib have been approved for CML in Japan. Although bosutinib has not been approved as a first line therapy, dasatinib and nilotinib demonstrated higher efficacy than imatinib for previously untreated CML in the chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harboring T315I. CML treatment is progressing rapidly and further advancements are highly anticipated. Moreover, it was recently reported that some portion of CML patients who achieved a sustained complete molecular response have been able to stop taking TKI agents.