BCR-ABL1 fusion

In the current case, the BCR-ABL fusion was detected and CML was confirmed after the recurrence of splenomegaly. Subsequent treatment with a combination of flumatinib and ruxolitinib was demonstrated to be safe and effective.

A bone marrow examination after two cycles confirmed the maintenance of hematological remission, and RT-PCR showed reduced minor BCR-ABL mRNA levels. AML with BCR-ABL1 fusion generally has a poor prognosis and has no established treatment, but in this case, treatment with venetoclax and azacitidine successfully induced remission and demonstrated potential efficacy against BCR-ABL fusion-positive clones.

Conversely, RB1 gene mutations were absent in all cases and no direct association between ASS1 gene deletion and imatinib treatment resistance was observed. These findings emphasize the clinical relevance of identifying additional abnormalities alongside BCR/ABL1 translocation for predicting disease progression and guiding treatment strategies in CML.

These findings suggest that resveratrol exerts anti-proliferative and pro-apoptotic effects in CML cells by modulating key genes and induction of DNA fragmentation, highlighting its potential as a therapeutic agent for CML treatment.

We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML.

Moreover, we identified two PABPC1 inhibitors that inhibited BC progression and overcame TKI resistance in murine and human CML. Overall, our work identifies PABPC1 as a selective translation enhancing factor in CML-BC, with its genetic or pharmacological inhibition overcoming TKI resistance and suppressed BC progression.

The FISH technique excels in disease detection with over 98% accuracy and high sensitivity. QRT-PCR is effective for monitoring CML and BCR-ABL1 gene levels, indicating MMR and DMR. CCE, while useful for posttreatment monitoring, is less accurate in measuring treatment response over time.

P1/2, N=11, Terminated, Takeda | Completed --> Terminated; Phase 1 enrollment was terminated due to dose-limiting toxicities, thus the study was terminated by Sponsor.

P2, N=283, Active, not recruiting, Takeda | Trial completion date: Dec 2024 --> Mar 2025

This case contributes to the medical literature by documenting a rare occurrence of extramedullary T-LBL with concurrent CML. The absence of a CML history makes the diagnosis particularly challenging and underscores the need for comprehensive and personalized treatment strategies.

Moreover, this increase disappears in CML patients after treatment with tyrosine kinase inhibitors when the curative effect was satisfactory. We conclude that an increase in the proportion of CD56briCD38+ neutrophil subsets exceeding 2.0 % of total neutrophils serves as a highly sensitive and specific flow cytometry marker, enabling rapid and accurate identification of CML.

We have demonstrated the capability of the SureSeq Myeloid Fusion Complete NGS Workflow Solution to detect known rearrangements in AML. We observed 100% concordance with qPCR and FISH for all samples tested. The NGS data permitted single-exon resolution of breakpoints and revealed the presence of multiple breakpoints which would have remained undetected with FISH.

This review provides insights into existing CML diagnoses, treatment modalities, resistance mechanisms, drugs under trial phases and new potential therapeutic drugs. Furthermore, the review looks ahead to a visionary perspective wherein the CRISPR/Cas9 approach holds the potential to evolve into a prospective curative measure for CML.

The RM was used to evaluate inter-laboratory reproducibility in eight different laboratories, demonstrating that participating laboratories could consistently produce copy concentrations of b3a2 and ABL1-ref, as well as the BCR-ABL1/ABL1 ratio (CV < 2.0%). This work suggests that the RM can be employed in establishing metrological traceability for detecting mutations in the BCR-ABL1 fusion gene, as well as in quality control for testing laboratories.

Asciminib broadens therapeutic choices for patient's refractory or intolerant to 2 prior lines of treatment in a cost-effectiveness manner. The costs of drugs significantly impact the overall cost of the disease, emphasizing the importance of the selected discount rates for each drug. Given the relatively low incidence of CML, the introduction of asciminib has a limited budgetary impact, warranting individualized decisions based on patient`s clinical characteristics.

Furthermore, our data could serve as a reference for evaluating other K-562 sublines, facilitating the discovery of new K-562 sublines with distinct characteristics. This approach results in the accumulation of K-562 sublines with diverged characteristics and expands the options available, which may help in selecting the most suitable K-562 subline for each experiment.

The introduction of rituximab has improved the outcomes in CD20 positive cases. Other monoclonal antibodies, such as tafasitamab (anti-CD19), obinutuzumab (anti-CD20) and epratuzumab (anti-CD22) have been tested in trials (NCT05366218, NCT04920968, NCT00098839)...In contrast to ATP site inhibitors such as dasatinib and ponatinib, the novel first-in-class selective allosteric ABL myristoyl pocket (STAMP) inhibitor asciminib did not significantly impact ADCC in our settings. Our results suggest that asciminib should be considered in clinical trials.

P2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025

TKIs in combination with transplantation can eliminate the adverse effects of BCR/ABL1 fusion genes on prognosis. Nomogram predictive models were accurate for prognostic prediction and will be useful in clinical practice.

Ocular findings related to CML are rare, with the lowest incidence when compared to other leukemias, and are associated with worse outcomes. Posterior segment findings include intraretinal hemorrhages, Roth spots, and retinal infiltrates. This unique case describes an RRD in CML retinopathy with an aggressive course and poor anatomical result.

P1/2, N=68, Active, not recruiting, Takeda | Trial completion date: Aug 2027 --> Jan 2027 | Recruiting --> Active, not recruiting

No abstract available

We also show that 4DRCA can distinguish BCR-ABL1 fusion transcript positive B-cell acute lymphoblastic leukemia cells with or without CD19 protein expression. The accessibility and extensibility of 4DRCA render it broadly applicable to other cell-based diagnostic workflows, enabling sensitive and accurate single-cell RNA and protein profiling.

The frequency of cancer driver mutations among tissues is non-uniform: for instance, mutations in APC are particularly frequent in colorectal cancer, and 99% of chronic myeloid leukemia patients harbor the driver BCR-ABL1 fusion mutation, which is rarely found in solid tumors. Here, we provide a mechanistic framework that aims to explain how tissue-specific features, ranging from epigenetic underpinnings to the expression of viral transposable elements, establish a molecular basis for selecting cancer driver mutations in a tissue-specific manner.

The findings range from the impact on pathogenesis to the possible use of EVs as medicinal chemical carriers. This review aims to provide for the first time an update on our understanding of EVs as carriers of CML biomarkers for minimal residual disease monitoring, therapy response, and its management, as well as the limited reports on the use of EVs as therapeutic shuttles for innovative treatment approaches.

The content of lipids (1600 cm), nucleic acids (789 cm), and haemoproteins (754, 1130, and 1315 cm), which are crucial in cell metabolism, was indicated as the main source of differentiation between subtypes. Identification of spectroscopic markers of cells with BCR-ABL1 or KMT2A-r may be useful in pharmacological studies to monitor the effectiveness of chemotherapy and further to understand differences in molecular responses between leukemia primary cells and cell lines.

This case highlights the significance of conducting a thorough initial assessment when a patient presents with symptoms suggestive of liver involvement, such as abdominal pain, jaundice and leukocytosis. In this case, the patient's initial symptoms were initially attributed to potential cholangitis due to her clinical presentation, but a peripheral smear unexpectedly revealed blast cells, leading to a diagnosis of B-lymphoblastic leukaemia.The case demonstrates that haematologic malignancies can manifest with various patterns of hepatic involvement, and their presentation can be diverse. In this instance, obstructive jaundice was caused by leukaemic infiltration of the liver, which is a rare initial presentation of acute lymphoblastic leukaemia (ALL).This demonstrates the diagnostic challenges in identifying rare conditions such as leukaemic infiltration of the liver, emphasising the importance of appropriate investigations and consultation with specialists.

Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.

Advanced molecular techniques are aimed at detecting BCR-ABL1 transcript levels to monitor treatment response. Transcript typing is necessary to detect minimal residual disease and to achieve molecular response by helping to provide selective therapy based on the type of transcript identified, as transcript type is correlated with the disease course.The purpose of this review is to discuss: the role of the BCR-ABL1 fusion gene in the pathogenesis of CML; the role of BCR-ABL1 transcript characterization in the molecular monitoring of CML therapy; the association of BCR - ABL1 transcript types with different CML phenotypes, molecular responses, and treatment responses; and the laboratory techniques employed to detect and characterize BCR - ABL1 transcripts.

Total body irradiation (TBI) + VP16 was administered to 42 and 50 pts in the HYPO and BCRABL groups, respectively, while 18 HYPO and 30 BCRABL pts received non-TBI conditioning (busulfan or treosulfan + fludarabine and thiotepa, as per study protocol)...Notably, 24 out of 143 pts (17%) with HYPO/BCRABL received immunotherapy before HSCT (blinatumomab, inotuzumab ozogamicin, and/or CAR-T cells)... Children receiving HSCT for treatment of BCP-ALL with either hypodiploidy or bcr-abl1 fusion showed outcomes comparable to BCP-ALL pts without these genetic lesions. CIR and EFS reached plateaus beyond 3 y post-HSCT, indicating that approximately two-thirds of these pts can be cured by HSCT with low rates of treatment-related mortality. Pts with BCRABL achieved favorable outcomes without the need for long-term or lifelong TKI therapy.

Conclusion We have demonstrated that NGS has a high sensitivity for identification of RNA fusion genes, is complementary to conventional cytogenetics testing, and has vast clinical impact in terms of diagnosis, prognostication and clinical management. We advocate for the integration of NGS with DNA and RNA sequencing into routine investigation of suspected myeloid malignancies for a more precise and comprehensive diagnostic approach.

Study Design and Methods This is an open label, Phase I/II investigator initiated trial evaluating the addition of venetoclax to dasatinib and steroids (with Rituximab in CD20+ patients)...Newly diagnosed Ph+ ALL or MPAL patients may not have received leukemia-directed therapy other than for steroids or hydrea, and relapsed patients must have not had prior dasatinib exposure...Consolidation phase with blinatumomab plus dasatinib and venetoclax is planned for the cohort expansion group. Enrollment began in September 2022 and is expected to be complete by September 2025. This trial is registered at clinicaltrials.gov (NCT04872790).

In agreement with previous studies, our results suggest that BCR/ABL1 expression under the control of the BCR promoter may not be sufficient to induce Ph + leukemia. In the future, we would like to determine the effect of second hit deletions in vitro and further evaluate their leukemic character in in vivo settings.

P1/2, N=68, Recruiting, Takeda | Active, not recruiting --> Recruiting

In conclusion, the overall prevalence of hematological AEs by TKI type was: dasatinib > bosutinib > imatinib > nilotinib. Study limitations include inability to normalize for dosage and treatment duration.

While the majority of malignancies were found to have a low risk of containing malignant cells in ovarian tissue, further studies are needed to ensure safe implementation of future fertility restoration in clinical practice.

The patient underwent bone marrow transplantation 6 months after his initial diagnosis. Cases of CML in T-ALL BP have been reported, but to our knowledge, no case of extramedullary T-ALL with concurrent CML in AP in BM has been described.

To the best of our knowledge this is the first study to investigate ASXL1 mutation in -TKI-resistant CML patients in Tunisia. Despite the limits of our study, our finding highlights that this truncating ASXL1 mutation may be a potential biomarker for predicting therapeutic efficacy, and a treatment strategy for CML with ASXL1 mutation should be established. Moreover, future studies need to comprehensively identify the landscape and clinical relevance of genetic and epigenetic alterations in CML, which can be used to develop novel therapeutic strategies or to prognosticate treatment response.

With more prolonged and sustained deep molecular responses, it is possible to achieve more durable treatment- free remissions and eventually achieve the definitive discontinuation of TKIs.

The therapeutic equivalence of generic imatinib reinforces its potential as a cost- effective alternative for CML treatment in resource-constrained settings like Libya.

P2, N=17, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting