Tyrosine Kinase Inhibitors Available for Chronic Myeloid Leukemia: Efficacy and Safety

Abstract

Chronic myeloid leukemia (CML) is currently a disease in which patients can enjoy a near normal life-expectancy. However, since the majority of patients will need to remain on treatment indefinitely, physicians in care of CML patients need be familiar with the indications and toxicities of all approved tyrosine kinase inhibitors (TKI). In clinical practice, there are five TKI (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) that are available in different scenarios and have distinct safety profiles. Decisions regarding first line treatment must be based on CML risk, comorbidities, and patients expectations. Despite the excellent outcome, half of the patients will eventually fail (due to intolerance or resistance) to first line treatment, with many of them requiring a third or even further lines of therapy. When selecting for such patients, it is essential to distinguish between failure and intolerance to previous TKIs. In the present review, we will address all these issues from a practical point of view.

Cardiovascular Toxicity of Tyrosine Kinase Inhibitors Used in Chronic Myeloid Leukemia: An Analysis of the FDA Adverse Event Reporting System Database (FAERS)

“…For instance, the results of the ENESTnd prospective randomized study showed that the incidence of cardiovascular events after 6 years was 10% in patients treated with nilotinib (5% ischemic heart disease, 1.4% ischemic cerebrovascular disease, and 4.3% peripheral arterial disease) as compared to 2.5% in imatinib-treated patients [20]. Consequently, current experts' recommendations advocate against the use of nilotinib in patients with a high-risk cardiovascular profile, whenever possible [21].…”

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…These receptors have specific growth factors as ligands and are involved in several fundamental functions for cell survival and activation, such as growth, differentiation, and apoptosis [13][14][15][16]. The oncogenic role of their alterations is well documented, as well as their possible exploitation as therapeutic targets [17][18][19][20][21][22][23][24][25].…”

The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

“…The development of a BCR/ABL kinase inhibitor, imatinib, was a significant major improvement in CML treatment [24]. However, imatinib, and second and third-generation tyrosine kinase inhibitors' effectiveness is often inadequate as resistant CML stem cells and residual disease persist in many patients [25][26][27]. Genomic sequencing of CML patients has identified additional genetic changes, like mutations of the tumor suppressor genes RB1, TP53, and CDKN2A [28], and highlighted the fact that BCR-ABL kinase mutations are only identified in approximately 50% of patients with poor responses and disease progression [29].…”