New drugs to overcome meccanisms of resistance in Ph+ leukemia: bosutinib

The outcome for adult with Ph+ leukemias (ALL and CML) has improved dramatically with current therapy including use of Tyrosine Kinase Inhibitors (TKIs), such as imatinib, nilotinib or dasatinib. The complete hematological remission is obtained in about 98% of early chronic phase CML patients treated with TKIs. But the emergence of resistance to imatinib has become a significant problem: the most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. These is an unexpected event in about 4% of CML patients, during first year of TKI therapy. Current approaches to risk classification based not only on well-established clinical parameters such as Sokal’s Score for CML, but including genetic lesions of acute Ph+ leukemia cell at diagnosis, as well as early response parameters are proposed. Several novel agents have been developed showing efficacy in overcoming imatinib resistance: new therapeutic approaches that interfere specifically with mutated forms of Ph+ leukemias and activate specifically the apoptotic pathway on leukemic blast cells are now available, such as Dasatinib, Nilotinib, Bosutinib and we highlights the latter as that may be applicable to the treatment of adult Ph+ leukemias.