Imatinib and beyond—exploring the full potential of targeted therapy for CML

Abstract

A subset of patients with chronic myeloid leukemia (CML) who receive imatinib therapy will require alternative therapy at some point owing to safety reasons or lack of efficacy. Achieving an early response with imatinib is protective against treatment failure; second-generation tyrosine kinase inhibitors (TKIs; for example, nilotinib, dasatinib, bosutinib), however, have proven to be efficacious at restoring cytogenetic responses in patients who require subsequent therapy. Response duration, however, is yet to be established and a considerable proportion of patients fail to achieve a clinically meaningful response. A third generation of TKIs is currently undergoing clinical testing for use in patients who fail imatinib and a second-generation TKI. Most of these agents are multikinase inhibitors with activity against a wide variety of BCR-ABL1 mutations, including the highly resistant T315I. The use of second-generation TKIs in the frontline setting seems to provide higher rates of early response compared with imatinib. If these results are confirmed in randomized studies, nilotinib and dasatinib could replace imatinib as standard frontline therapy in CML. Despite the activity of all of the above mentioned agents, curing CML will ultimately depend on the development of agents capable of vanquishing BCR-ABL1-positive CML stem cells. Efforts aimed at achieving this goal are ongoing.

EGFR inhibitors exacerbate differentiation and cell cycle arrest induced by retinoic acid and vitamin D3in acute myeloid leukemia cells

“…Interestingly, a large panel of TKIs (some of which exert a biological activity overlapping with that of erlotinib) also favored the differentiation of AML cells in the presence of ATRA and/or VD. These encompass alternative EGFR inhibitors (such as lapatinib), 51 as well as imatinib (targeting BCR-ABL, KIT and platelet-derived growth factor receptor, PDGFR) 52 and dasatinib, 53,54 which has a quite distinct inhibitory spectrum 55 including the SFK LYN. 56 The molecular effects of these TKIs remain to be precisely elucidated.…”

Sudden unilateral visual loss as an initial presentation of chronic myelogenous leukemia

“…Every patient with retinal infiltrates requires a systemic and central nervous system workup. 18 The patient in this case was fortunate to discover her CML early in the chronic phase. Her prognosis is good as she continues with medical management.…”

“…8 Furthermore, some patients do not respond to or tolerate imatinib, thus second generation TKIs (nilotinib, dasatinib, bosutinib) have been developed and shown efficacy in some of these patients. 18 A more severe ophthalmic manifestation worthy of noting is optic nerve leukemic infiltration, which causes decreased vision. This is an ophthalmic emergency and requires prompt radiation therapy to preserve vision.…”

Characterization of the Discoidin Domain Receptor 2 Kinase as a Novel Therapeutic Target for Squamous Cell Lung Cancer

“…Dasatinib was originally designed as an inhibitor of Src and is a multitargeted tyrosine kinase inhibitor (34). Dasatinib treatment is associated with toxicity in patients, including myelosuppression and the development of pleural and pericardial effusions (35,36).…”