Treatment of Chronic Myelogenous Leukemia as a Paradigm for Solid Tumors: How Targeted Agents in Newly Diagnosed Disease Transformed Outcomes

Abstract

Overview: Although chronic myelogenous leukemia (CML) is rare, with approximately 5000 new cases in the United States annually, it may be the poster child for the future of oncology. Imatinib mesylate, a selective Bcr-Abl tyrosine kinase inhibitor (TKI), transformed the course of CML from a rapidly fatal disease (median survival, 3 to 6 years) to a functionally curable, indolent disease with an estimated median survival of more than 25 years. This transformation can be attributed to several key factors: the identification of a causal and actionable molecular aberration— BCR-ABL; the development of a potent and selective Bcr-Abl TKI—imatinib; and, importantly the application of imatinib in the earliest phase of CML. In contrast, imatinib, if used in CML blastic phase, improves median survival to only about 1 year. Similar to CML blastic phase, metastatic solid malignancies have undergone genetic evolution, and their molecular aberrations are complex. As a result, resistance is common and eradication is difficult. The key to the dramatic improvement in the survival of patients with CML involved using imatinib in newly diagnosed disease, before blastic transformation. We hypothesize that metastatic solid tumors are analogous to CML blastic phase, and that to achieve improvements in solid tumor outcomes similar to those seen in CML, application of targeted agents to newly diagnosed disease may be required to prevent disease transformation (i.e., metastases). Targeting driver mutations at the time of diagnosis may be critical to the goal of markedly changing the outlook for patients with cancer.