Tyrosine Kinase Inhibitors in the Treatment of Chronic-Phase CML: Strategies for Frontline Decision-making

Abstract

Extended follow-up of the seminal CML trials has demonstrated the long-term efficacy of TKIs, while also highlighting significant differences in their respective toxicity profiles and potency. Dasatinib and nilotinib generate deeper molecular responses than imatinib, particularly among patients with higher risk disease, but this has not translated into a significant survival advantage. Similar results have been obtained at 1 year with bosutinib; its efficacy and toxicity were well balanced at a dose of 400 mg daily, prompting its recent approval for this indication. Lastly, multiple studies have demonstrated that TKIs can be safely discontinued in select individuals who have maintained deep responses for extended periods, establishing treatment-free remission as a novel goal in CP CML. The careful consideration of parameters such as disease risk, the potency, and toxicity profile of each TKI, as well as each patient's unique comorbidities and preferences, enables truly individualized therapeutic decision-making in CP CML, with the goal of ensuring that a high quality of life accompanies the survival advantage conferred by these agents.

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

“…DASATINIB, nilotinib and bosutinib are second generation BCR-ABL inhibitors [251][252][253][254]. Dasatinib (BMS-354825) was designed by Bristol-Myers Squibb and Otskuka Pharmaceutical Co., Ltd. to inhibit imatinib resistant BCR-ABL mutations in CML but it also works against Src family kinases [255][256][257][258].…”

My journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer

“…Treating cancer with tyrphostins has come to resemble chasing a runaway cart, as second-and third-generation compounds are developed to contend with the emergent mutations. Thus, the Bcr-Abl inhibitor imatinib gave rise to nilotinib, a more selective and more potent derivative that also inhibits some of the kinase point mutants, and these have been joined by the structurally unrelated compounds dasatinib and bosutinib (27). Similarly, the first-generation EGFR inhibitors, gefitinib and erlotinib, were followed by the second-generation afatinib and dacomitinib, and the third-generation osimertinib.…”

Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line

“…1 All the TKIs, with the exception of ponatinib, are now approved as first-line treatments in CML. 2,3 The advances in the treatment of CML with different TKIs have led to a vast decrease in patients who are overall unresponsive or intolerant to therapy, as they may be treated with several different TKIs sequentially. 4 Today, CP CML patients are likely to have a normal life expectancy, but the majority face a life-long exposure to TKIs.…”