Genetic Landscape of Chronic Myeloid Leukemia and a Novel Targeted Drug for Overcoming Resistance

Abstract

Tyrosine kinase inhibitors (TKIs) exemplify the success of molecular targeted therapy for chronic myeloid leukemia (CML). However, some patients do not respond to TKI therapy. Mutations in the kinase domain of BCR::ABL1 are the most extensively studied mechanism of TKI resistance in CML, but BCR::ABL1-independent mechanisms are involved in some cases. There are two known types of mechanisms that contribute to resistance: mutations in known cancer-related genes; and Philadelphia-associated rearrangements, a novel mechanism of genomic heterogeneity that occurs at the time of the Philadelphia chromosome formation. Most chronic-phase and accelerated-phase CML patients who were treated with the third-generation TKI for drug resistance harbored one or more cancer gene mutations. Cancer gene mutations and additional chromosomal abnormalities were found to be independently associated with progression-free survival. The novel agent asciminib specifically inhibits the ABL myristoyl pocket (STAMP) and shows better efficacy and less toxicity than other TKIs due to its high target specificity. In the future, pooled analyses of various studies should address whether additional genetic analyses could guide risk-adapted therapy and lead to a final cure for CML.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case–Control Study

“…Chronic myeloid leukemia (CML) has three stages, namely the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC) [ 41 ]. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML, with overall survival of CP-CML comparable to the general population, yet TKIs work well mainly in CP-CML and to some extent in AP-CML, and are less effective in BC-CML, with an average overall survival of less than a year [ 1 , 12 ]. Therefore, the early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities to delay or avoid disease progression.…”

“…Nevertheless, patients in the early progression phase (AP-CML) and advanced progression phase (BC-CML) show resistance to TKIs [ 11 ]. Despite all advancements in the treatment modalities, the average overall survival of BC-CML patients is less than a year, with limited options to treat these patients [ 12 ]. Early recognition of CML patients at risk of disease progression can help to delay or even avoid CML progression by timely interventions with third- and/or fourth-generation TKIs [ 13 ].…”

Multi-Omics Integration for Liver Cancer Using Regression Analysis

“…Certain cancers are characterized by recurrent chromosomal re-arrangements. For example, the chronic myeloid leukemia (CML) blood cancer is characterized by a reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11) [9,10]. This event fuses the BCR gene on chromosome 22 with the ABL gene on chromosome 9 (BCR::ABL), causing constitutive activation of the ABL kinase, which promotes cell division.…”

Next-generation DNA sequencing identifies mutated FANCD2 Gene as a novel Biomarker for monitoring early disease progression and timely therapeutic interventions in advanced phase Chronic Myeloid Leukemia patients

“…Nevertheless, patients in early progression phase (AP-CML) and terminal progression phase (BC-CML) show resistance to TKIs (Takahashi , 2023). Specifically in BC-CML, despite all advancements in treatment modalities, the average overall survival is less than a year, which provides a little time frame for oncologists to clinically intervene CML progression (Yoshimaru & Minami,, 2023). Early detection of CML patients at risk of disease progression can considerably help oncologists to delay or even avoid CML progression by timely treatment decision making specifically with the introduction of third and fourth generation TKIs This preprint research paper has not been peer reviewed.…”