Debating Frontline Therapy in Chronic Myeloid Leukemia

Abstract

The development of tyrosine kinase inhibitors (TKIs) in the early 2000s revolutionized the therapeutic landscape for chronic phase (CP) chronic myeloid leukemia (CML). Interferon alpha was previously the standard treatment for patients with CP CML prior to the development of TKIs; however, survival was dismal, with a median of 5-6 years (1). With the advent of TKI therapy, the estimated 10-year overall survival increased from less than 20% to more than 80% (2). When optimal therapy is instituted with appropriate monitoring, patients with CP CML now live close to normal life spans (3, 4). Imatinib, the first of these revolutionary medications, was approved by the FDA for the treatment of CML after failure of interferon-alpha therapy in 2001 and for newly diagnosed CP CML patients in 2003. Shortly thereafter, following preclinical and clinical data demonstrating increased potency against the BCR-ABL target, frontline approvals for the second-generation TKIs (dasatinib, nilotinib, and bosutinib) soon followed based on the results of their respective clinical trials (DASISION, ENEST and BFORE) (5–7). Each of these trials compared the efficacy of imatinib 400 mg daily with the corresponding second-generation TKI. Notably, no significant survival difference has been demonstrated between imatinib and any of the second-generation inhibitors. Accordingly, the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) practice guidelines recommend choosing a therapeutic agent based on risk scoring, age, and comorbidities (8, 9). Thus, the optimal frontline treatment of CP CML has become the subject of debate. A recently published meta-analysis sought to answer this question by comparing the safety and efficacy of imatinib versus dasatinib, nilotinib, bosutinib and ponatinib for initial treatment of CP CML (10). Secondand third-generation TKIs demonstrated superior clinical outcomes but also increased toxicity. The authors concluded that the choice of frontline therapy should depend on patients’ age and comorbidities. They suggested that patients without comorbidities should receive second-generation TKIs as initial therapy and that imatinib should be the preferred initial therapy for older patients or those with comorbidities. Notably, third-generation TKI (ponatinib) has not been approved nor is recommended as the frontline treatment of CP AML. Herein, we will review this recently published work and present the arguments for and against the use of secondgeneration TKIs as initial therapy for CP CML.