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

• Published in: Nature reviews. Clinical oncology Vol. 6; no. 9; pp. 535 - 543
• Main Authors: Quintás-Cardama, Alfonso, Kantarjian, Hagop, Cortes, Jorge
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2009; Nature Publishing Group
• Subjects: Antineoplastic Agents - therapeutic use; Benzamides; Chronic myeloid leukemia; Clinical Trials as Topic; Disease Progression; Dose-Response Relationship, Drug; Drug therapy; Follow-Up Studies; Health aspects; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Medicine; Medicine & Public Health; Oncology; Patient outcomes; Piperazines - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Protein tyrosine kinase; Pyrimidines - therapeutic use; review-article; Time Factors; Treatment Outcome; United States
• ISSN: 1759-4774; 1759-4782; 1759-4782
• DOI: 10.1038/nrclinonc.2009.112

Imatinib is the standard frontline therapy for patients with chronic myeloid leukemia (CML); however, a substantial number require alternative therapy owing to imatinib intolerance or imatinib resistance. Studies have shown that second-generation tyrosine kinase inhibitors are efficacious in restoring cytogenetic responses in patients who require subsequent therapy. Quintás-Cardama et al . discuss the second-generation and third-generation targeted agents that have restored cytogenetic response in patients unresponsive to imatinib, and the strategies being explored to improve the long-term outcome. 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. Key Points The phase III IRIS trial established imatinib as standard therapy for chronic phase CML; an update indicates that a substantial proportion of patients will require alternative therapy during the course of treatment The second-generation tyrosine kinase inhibitors nilotinib and dasatinib can restore cytogenetic response in patients who have failed imatinib therapy; response duration, however, has not been fully established Nilotinib or dasatinib therapy in the frontline setting seems to provide rapid and improved rates of cytogenetic and molecular response, which could potentially translate into improved long-term outcomes Imatinib discontinuation upon achievement of complete molecular response results in high rates of relapse, probably because of the innate insensitivity of CML stem cells to tyrosine kinase inhibitors There is an urgent need to identify pharmacologic inhibitors of pathways essential for the maintenance of BCR-ABL1-positive leukemic initiating cells Several agents with activity against the highly insensitive BCR-ABL1 T315I mutation are being evaluated in clinical trials