ABL1 (ABL proto-oncogene 1)

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.

Such a system, using a digital dashboard, has the potential to enhance oversight and contribute to the enhancement of quality assurance. Nonetheless, the implementation of automated data exchange with electronic medical records, enhanced data completeness, and the augmentation of integration into clinical workflows are imperative prior to the large-scale implementation and the transition toward home-based CML care.

Second-generation and third-generation TKIs further improved outcomes by targeting most imatinib-resistant mutations, with ponatinib-based regimens achieving deep molecular responses and long-term survival in most patients. Concurrently, immunotherapies like blinatumomab and CAR-T cells have enabled potent chemotherapy-free strategies, yielding high molecular response rates and challenging the necessity of allo-HSCT for all patients. Current evidence supports reserving allo-HSCT for high-risk patients, while those with sustained minimal residual disease (MRD) negativity may be cured with TKI and immunotherapy alone. Future progress hinges on optimizing combinations, integrating novel agents like asciminib and venetoclax, and leveraging MRD and genomic profiling for precision medicine.

Thus, reduction in level of ITGB1 in resistant cells leads to activation of ERK and p38MAPK belonging to BCR::ABL1 pathway, despite inactivation of BCR::ABL1, which in turn leads to activation of LYN. Together, these kinases activate members of vital pro-survival pathways, thereby imparting imatinib resistance in CML-BC cells.

There was no evidence of systemic toxicity or organ dysfunction after treatment. These findings demonstrated that PEG-pRAPA is an effective polymeric drug and drug delivery platform and support the hypothesis that nanoparticle-based pharmacotherapy can be an effective treatment strategy for VMs.

P2, N=80, Not yet recruiting, University of Alberta | Initiation date: Mar 2026 --> Jul 2026

Notably, genetic or pharmacological inhibition of PELI1 effectively suppresses the proliferation of both tyrosine kinase inhibitors (TKIs)-sensitive and TKI-resistant CML cells, as well as Leukemia stem cells (LSCs), which consequently ameliorates the disease burden and progression of CML. Collectively, our findings demonstrated that targeting PELI1 is a promising therapeutic strategy for CML that can overcome TKI resistance and eliminates LSCs.

P2, N=17, Active, not recruiting, Baylor College of Medicine | N=100 --> 17 | Recruiting --> Active, not recruiting

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.

By comparison, mechanistic learning achieves comparable or improved combination scores for BCR::ABL1-positive and MRD-positive disease, with scores of 0.81 and 0.71, respectively, using only de-differentiation for BCR::ABL1 and primitive-state persistence together with differentiation-directed exit for MRD. Thus, the mechanistic-learning approach not only preserves predictive performance, but also provides a biological hypothesis for why stemness is predictive of these clinically relevant outcomes.

This led to development of tyrosine kinase inhibitors (TKIs) such as Imatinib, Nilotinib, and Ponatinib. Asciminib does not appear to induce a prothrombotic or proinflammatory state under the conditions studied, which may be advantageous for CML patients. However, the observed increase in thrombin generation over time suggests a potential effect on secondary haemostasis that warrants further investigation in controlled studies.

In this setting, Peg-IFN combined with nilotinib induced higher initial rates of MR4·5 compared to TKI monotherapy, despite additional side effects. The onset of psychiatric events might promote immediate cease of Peg-IFN and psychiatrist advice Whether this early molecular response translates into sustained treatment-free survival should be studied in a randomised trial sufficiently powered for this outcome.