CML Resistant to 2nd-Generation TKIs: Mechanisms, Next Steps, and New Directions

Scalzulli, Emilia; Carmosino, Ida; Bisegna, Maria Laura; Martelli, Maurizio; Breccia, Massimo

doi:10.1007/s11899-022-00683-3

Cited by 6 publications

(2 citation statements)

References 48 publications

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“…On the other hand, the low progression rates under TKIs indicate that blast crisis can be prevented [ 21 ]. It is therefore essential to identify predictive tools for a prompt recognition of those patients at higher risk of progression and CML-induced death, worthy of closer molecular monitoring and treatment intensifications—considering potentially the choice of a frontline 2G-TKI or the early switch to a more powerful TKI in following lines or even evaluating the eligibility to an allo-SCT or new agents [ 204 ]. This is also the rationale for the new 2022 World Health Organization (WHO) classification for myeloid neoplasms in which the “CML-AP” as diagnostic category is omitted, putting emphasis on the identification of the high-risk features that, regardless of the historical criteria of AP, are associated with CP progression and poor outcome [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights

Iezza

Cortesi

Ottaviani

et al. 2023

Cells

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The introduction of tyrosine kinase inhibitors (TKIs) has changed the treatment paradigm of chronic myeloid leukemia (CML), leading to a dramatic improvement of the outcome of CML patients, who now have a nearly normal life expectancy and, in some selected cases, the possibility of aiming for the more ambitious goal of treatment-free remission (TFR). However, the minority of patients who fail treatment and progress from chronic phase (CP) to accelerated phase (AP) and blast phase (BP) still have a relatively poor prognosis. The identification of predictive elements enabling a prompt recognition of patients at higher risk of progression still remains among the priorities in the field of CML management. Currently, the baseline risk is assessed using simple clinical and hematologic parameters, other than evaluating the presence of additional chromosomal abnormalities (ACAs), especially those at “high-risk”. Beyond the onset, a re-evaluation of the risk status is mandatory, monitoring the response to TKI treatment. Moreover, novel critical insights are emerging into the role of genomic factors, present at diagnosis or evolving on therapy. This review presents the current knowledge regarding prognostic factors in CML and their potential role for an improved risk classification and a subsequent enhancement of therapeutic decisions and disease management.

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Section: Discussionmentioning

confidence: 99%

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights

Iezza

Cortesi

Ottaviani

et al. 2023

Cells

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“…A complex and intricate process called resistance to target therapy leads to the selection of cancer clones that may resist treatment (14). ABL kinase mutations, aberrant drug transporter activity, the activation of several signaling pathways, epigenetic dysfunction, the survival of leukemia stem cells, and immune system dysregulation are a few instances of resistance mechanisms (15). So, a prompt switch in therapy and the choice of the best therapies are made possible by the quantification of BCR::ABL1 transcripts and the identification of BCR::ABL1 kinase domain (KD) alterations.…”

Section: Introductionmentioning

confidence: 99%

Molecular Biology and Drug Therapies of Chronic Myeloid Leukemia: A Review of Recent Literature

Shahid,

Sabar,

Iqbal

et al. 2023

IJPIHS

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Background: Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder of blood stem cells, which is typically characterized by the presence of a Philadelphia chromosome. Even though there have been several studies on the molecular genetics, pharmacogenomics, pharmacological treatments for CML, and its mechanism is still not fully understood. Objectives: This study is designed to provide new updates and better insights into CML molecular biology and drug therapy, along with their benefits and drawbacks. Methodology: For this review, the recent literature was searched from January 2019 to 2023 through various electronic databases. Results: Review findings further suggested that imatinib mesylate was the first tyrosine kinase inhibitor (TKI) licensed as first-line therapy for affected people with CML in the chronic, blast, and rapid phases. Dasatinib is another second-generation multi-target kinase inhibitor, for imatinib-resistant CML treatment in all stages, which is 325 times more effective than imatinib and 16-fold more effective than nilotinib. Nilotinib received approval from the Food and Drug Administration (FDA) for handling imatinib-resistant patients. Bosutinib and ponatinib are other renowned TKIs taken orally. European Medicine Agency (EMA) and FDA-approved asciminib in moderate to severe, rapid, and blast-phase CML patients intolerant to previous therapies. Conclusion: In conclusion, this study indicated the need to include advanced computational tools in addition to the large sample size of cohort studies, which may result in a better understanding of pathophysiology and better clinical outcomes.

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Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in Chronic myeloid leukemia (CML)

Laganà,

Scalzulli,

Bisegna

et al. 2024

Expert Review of Hematology

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CML Resistant to 2nd-Generation TKIs: Mechanisms, Next Steps, and New Directions

Cited by 6 publications

References 48 publications

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights

Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights

Molecular Biology and Drug Therapies of Chronic Myeloid Leukemia: A Review of Recent Literature

Understanding and overcoming resistance to tyrosine kinase inhibitors (TKIs) in Chronic myeloid leukemia (CML)

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