Safety and efficacy of asciminib treatment in chronic myeloid leukemia patients in real-life clinical practice

Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

Section: Therapeutic Approaches Against Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

“…Thus, asciminib has had success in overcoming resistance due to kinase domain mutations, even in patients with T315I using combination therapy. Significantly, asciminib has reduced toxicity compared with other TKIs due to its high level of target specificity [43,44]. However, in in vitro studies, asciminib-resistant mutations were predicted, especially occurring at the myristoyl-binding pocket that would prevent allosteric inhibitors from binding [7,45].…”

Section: Bcr::abl1 Kinase Domain Mutations and Their Role In Drug Res...mentioning

confidence: 99%

Genomic Mechanisms Influencing Outcome in Chronic Myeloid Leukemia

Fernandes

Shanmuganathan

Branford

2022

Chronic myeloid leukemia (CML) represents the disease prototype of genetically based diagnosis and management. Tyrosine kinase inhibitors (TKIs), that target the causal BCR::ABL1 fusion protein, exemplify the success of molecularly based therapy. Most patients now have long-term survival; however, TKI resistance is a persistent clinical problem. TKIs are effective in the BCR::ABL1-driven chronic phase of CML but are relatively ineffective for clinically defined advanced phases. Genomic investigation of drug resistance using next-generation sequencing for CML has lagged behind other hematological malignancies. However, emerging data show that genomic abnormalities are likely associated with suboptimal response and drug resistance. This has already been supported by the presence of BCR::ABL1 kinase domain mutations in drug resistance, which led to the development of more potent TKIs. Next-generation sequencing studies are revealing additional mutations associated with resistance. In this review, we discuss the initiating chromosomal translocation that may not always be a straightforward reciprocal event between chromosomes 9 and 22 but can sometimes be accompanied by sequence deletion, inversion, and rearrangement. These events may biologically reflect a more genomically unstable disease prone to acquire mutations. We also discuss the future role of cancer-related gene mutation analysis for risk stratification in CML.

“…Similarly, Cortes et al also reported favourable safety and acceptable clinical efficacy in CML patients with the T315I mutation, showing that around 50% of these patients achieve a major molecular response with asciminib treatment [ 39 ]. Moreover, Gutiérrez et al reported that in CML patients who were heavily pretreated with three or more TKIs prior to asciminib treatment, 48% achieved a complete cytogenic response, and 33% achieved a major molecular response [ 40 ]. Pagani et al reported the results of asciminib treatment in a CML patient with an atypical e19a2 BCR::ABL1 transcript, who had previously developed a T315I kinase domain mutation.…”

Section: Bcr::abl1-dependent Mechanisms Of Resistancementioning

confidence: 99%

Mechanisms of Resistance and Implications for Treatment Strategies in Chronic Myeloid Leukaemia

Poudel

Tolland

Hughes

et al. 2022

Tyrosine kinase inhibitors (TKIs) have revolutionised the management of chronic myeloid leukaemia (CML), with the disease now having a five-year survival rate over 80%. The primary focus in the treatment of CML has been on improving the specificity and potency of TKIs to inhibit the activation of the BCR::ABL1 kinase and/or overcoming resistance driven by mutations in the BCR::ABL1 oncogene. However, this approach may be limited in a significant proportion of patients who develop TKI resistance despite the effective inhibition of BCR::ABL1. These patients may require novel therapeutic strategies that target both BCR::ABL1-dependent and BCR::ABL1-independent mechanisms of resistance. The combination treatment strategies that target alternative survival signalling, which may contribute towards BCR::ABL1-independent resistance, could be a successful strategy for eradicating residual leukaemic cells and consequently increasing the response rate in CML patients.