Emerging alternatives to tyrosine kinase inhibitors for treating chronic myeloid leukemia

Abstract

BCR-ABL-directed tyrosine kinase inhibitors (TKIs) have revolutionised therapy for chronic myeloid leukemia. However, despite the availability and efficacy of this class of agents, lifelong treatment is still required in a significant proportion of patients Areas covered: We give an overview of the currently available BCR-ABL-directed TKIs and other conventional therapies for CML. We proceed to review the current market and some of the scientific rationale for new drug development before outlining a number of novel therapies, considered broadly as immunotherapies and targeted agents. Published English-language literature was reviewed regarding currently available TKIs; clinical trials repositories were reviewed to identify novel agents recently investigated or under active study. Expert opinion: We recommend discussion with patients and enrolment on an appropriate clinical trial where feasible. In situations where no trials are available, or if patients decline enrolment, we recommend use of an appropriate BCR-ABL directed TKI, selected on the basis of an evaluation of patient risk factors and side effect profile. Allogeneic stem cell transplant continues to have a role though this is generally limited to cases with advanced phases of disease or in cases with resistance-conferring mutations.

Drug-adapted cancer cell lines as preclinical models of acquired resistance

“…Resistance can be "intrinsic" or "upfront", i.e., cancer cells do not respond to therapy from the outset. Many cancer diseases, however, initially respond well to therapy, but after a temporary response resistant cancer cells emerge leading to "acquired" resistance, ultimately resulting in therapy failure and patient death [8][9][10][11][12][13][14][15][16][17][18][19] . Hence, cancer diseases that have become resistant to the available treatment options represent an unmet clinical need.…”

What really matters - response and resistance in cancer therapy

“…Some protein kinase inhibitors (e.g., first-generation epidermal growth factor receptor and BCR-ABL inhibitors) and antibodies interfere more specifically with cancer abnormalities and are characterised by better tolerability. However, resistance formation may be an even bigger issue as cures are rare and resistance formation often inevitable [26,27,[29][30][31][32][33][34][35] . This may be because it is easier for cancer cells to bypass their more selective impact, analogous to the rapid development of resistance to highly specific antiviral therapies; a well-known and recognised phenomenon [36][37][38][39] .…”