ABL1 fusion

The introduction of imatinib established proof of principle for oncogene-targeted therapy, leading to sustained survival improvements...More recently, the development of the allosteric inhibitor asciminib introduced a novel mechanism of action and expanded therapeutic options for pretreated patients...Thus, CML represents a unique model of translational oncology, demonstrating how mechanistic insight can drive therapeutic innovation. Future strategies will focus on increasing TFR rates, overcoming resistance, targeting leukemic stem cells, and improving global access to therapy and monitoring, with the ultimate aim of achieving functional cure in the majority of patients.

Thus, an attractive goal in CML, particularly in children with CML, who may need several decades of TKI treatment, is to identify and target immunoregulatory pathways and restoration of immune surveillance mechanisms to promote strong immune responses and TFR success. In this review, we discuss the immunological mechanisms that contribute to the development, progression and control of CML, including supporting evidence of currently approved or investigated therapeutic approaches.

She was started on hydroxyurea, but her platelet count continued to rise, requiring hospitalization for close monitoring, where she was initiated on dasatinib, a tyrosine kinase inhibitor (TKI). As her platelets peaked above 4,000 × 109/L (Reference Range [RR]: 150-450 × 109/L), given the high risk of both thrombotic and bleeding complications, she underwent plateletpheresis, which effectively reduced counts before TKI therapy could achieve disease control. This case highlights the importance of considering the diagnosis of CML in patients with isolated thrombocytosis, particularly in women, and emphasizes the role of plateletpheresis as a potential preventive bridge until TKI therapy takes effect.

Additionally, on mathematical models of the BCR::ABL1 transcripts after initiation of TFR, distinct patterns in the kinetics in sustained and relapsed patients was identified. Our findings support a modified, risk-adapted TFR monitoring strategy for low- and middle-income countries (LMICs) to enhance surveillance while optimizing resource utilization.

This case highlights the limitations of isolated diagnostic modalities in early hematologic malignancy and underscores the importance of integrating clinical, laboratory, morphologic, immunophenotypic, and imaging findings. Persistent clinical suspicion should prompt timely tissue-based evaluation despite initially inconclusive studies to avoid delays in definitive diagnosis and management.

No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without CML-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

Imatinib, the first TKI, demonstrated unprecedented hematologic, cytogenetic, and molecular responses, rapidly becoming the standard of care in CML...Despite these achievements, important challenges remain, including TKI resistance, safety considerations, and the relatively low proportion of patients who achieve and maintain TFR. Newer-generation TKIs, combination strategies, immunomodulatory approaches, and emerging treatment modalities such as degraders offer promising avenues to further improve outcomes, expand TFR eligibility, ensure optimal quality of life, address resistance mechanisms, and render therapy available and affordable to all patients with CML worldwide.

The case also contributes to the limited literature reporting systemic CMV infections associated with dasatinib. In addition, it extends the spectrum of reported dasatinib-associated infections to include Granulicatella adiacens.

The splicing variations mainly occur in ABL1 exon 3 or different exons of BCR, and some are accompanied by intron sequence insertions. Patients with e13a3 type of rare transcripts respond well to TKI treatment, while patients with the e1a3 and e19a2 have poor prognosis.

BCR::ABL1 e6a3 demonstrated enhanced sensitivity to active-state selective inhibitors dasatinib and bosutinib, whereas BCR::ABL1 e6a3/T315I remained resistant. These data show that treatment with asciminib and ponatinib can select for mutations with notably elevated enzymatic activity, effectively targeted by an axitinib-based triple combination. These data highlight the remarkable mutability of the BCR::ABL1 kinase, including through novel isoforms and provides a strong rationale for the clinical assessment of a triple inhibitor combination as a strategy to overcome resistance to dual ponatinib and asciminib therapy.