Leukemia will affect more than 52,000 people in 2014. Chronic myeloid leukemia accounts for nearly 10% of all new cases of leukemia. Chronic myeloid leukemia is associated with the Philadelphia chromosome, a translocation of chromosomes 9 and 22, resulting in the BCR-ABL gene fusion. The protein product, BCR-ABL1, is a constitutively-active, growth-promoting tyrosine kinase that contributes to the malignant transformation of cells.
While the incidence of chronic myeloid leukemia has grown slightly over the past ten years, mortality has been greatly impacted by the advent of targeted therapies. Since the introduction of the first small molecule BCR-ABL1 inhibitor, imatinib, the five-year survival rate for patients newly diagnosed with chronic myeloid leukemia has nearly doubled. While tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia, many challenges remain. Resistance to first-line TKI therapy and potential adverse events are significant hurdles for clinicians. Emerging data and new agents have helped to further improve patient outcome, requiring doctors to remain updated on the latest trial results in chronic myeloid leukemia therapy
Chronic myeloid leukemia therapy is a rapidly-expanding field that centers around a key set of agents: tyrosine kinase inhibitors (TKIs). These drugs are capable of blocking the activity of the problematic gene product BCR-ABL, the principle driver of chronic myelogenous leukemia.
The TKI imatinib was the first molecule of its kind shown to be highly effective in Philadelphia chromosome-positive chronic myeloid leukemia. In the ensuing decade, the introduction of this agent led to a dramatically-improved standard of care over older systemic first-line therapies. Since then, newer TKIs have been introduced in response to the emergence of resistant disease. Nilotinib, bosutinib, and dasatinib are effective in resistant chronic myeloid leukemia, except in the case of T315I mutation in BCR-ABL. The only TKI with efficacy against the T315I mutant is ponatinib, which is recommended for patients who failed prior TKI therapy.
The adoption of TKIs has benefited patients with chronic myeloid leukemia, but these gains are limited to those patients who are tolerant to TKIs and who have wildtype BCR-ABL or one of a specific subset of mutants. Options are more limited in patients who do not meet these conditions. Recently, a protein synthesis inhibitor, omacetaxine mepesuccinate, has emerged as a valuable tool for therapy in patients who have previously failed TKI therapy due to disease progression or intolerance. Additionally, many large-scale clinical trials have been initiated in recent years to answer questions about monitoring of adverse events, choice of appropriate therapies in each line of treatment, and the best approaches for monitoring patient response to treatment.
As researchers discover new tools, patients with leukemia stand a better chance to see a favorable outcome. It is important that we continue to understand the tumor cell biology underlying chronic myeloid leukemia pathology so we may be able to find newer and better agents for management. While we have made massive strides in just the last decade, the development of chronic myeloid leukemia therapies promises a brighter future for patients seeking a cure.