Chronic Myeloid Leukemia

Additionally, the use of NGS is advised for accurately determining the mutation status of BCR::ABL1 KD, particularly in cases where the allele frequency is low, and for identifying mutations across multiple exons simultaneously. Therefore, the utilization of NGS as a diagnostic platform for this test is very promising to guide therapeutic decision-making.

P2, N=20, Completed, The First Affiliated Hospital of Soochow University | Recruiting --> Completed | Trial completion date: Jun 2025 --> Apr 2024 | Trial primary completion date: Jun 2023 --> Apr 2024

Anlotinib effectively inhibits proliferation and induces apoptosis in MCL both in vitro and in vivo. This inhibition is likely linked to suppressing phosphorylation in the PI3K/Akt/mTOR pathway.

We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment.

P1, N=100, Recruiting, Newave Pharmaceutical Inc | Trial completion date: Aug 2024 --> Oct 2025 | Trial primary completion date: Aug 2024 --> Oct 2025

Most commonly used agents include hydroxyurea, interferon, Janus kinase inhibitors, and hypomethylating agents, though none are disease-modifying. Actionable mutations (NRAS/KRAS, ETNK1) have also been identified, supporting novel agents targeting involved pathways. Preclinical and clinical studies evaluating new drugs (e.g., fedratinib, phase 2) and combinations are detailed.

P2, N=10, Recruiting, Fred Hutchinson Cancer Center | Trial primary completion date: Dec 2024 --> Jun 2024

Molecular dynamics simulations of the M244V substitution implicate stabilization of an active kinase conformation through impact on the -C helix as a mechanism of resistance. These N-lobe mutations may compromise the clinical activity of ongoing combination studies of asciminib with ATP-competitive TKIs.

In conclusion, CSF3R mutations were found at a higher frequency in aCML patients than in previous studies, which might reflect ethnic differences. Additional studies are needed to confirm these findings and the relationship between CSF3R and CEBPA mutations.

Genotyping of ABCB1, ABCG2, and CYP3A5 genes may be considered in the management of patients with CML to tailor therapy and optimize clinical outcomes.

Based on the inclusion criteria, a total of 15 studies were included from which a total of 87 cases were covered. Overall, we identified 38 unique complex three- and four-way translocations across 87 Ph-positive cases and found that 85 patients with complex Ph-positive cytogenetics achieved complete remission upon treatment and did not appear to have a lesser response to TKI therapy.

Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.

Furthermore, FL118 potently induced apoptosis not only in Ba/F3 cells expressing BCR-ABL, but also in those expressing the BCR-ABL T315I mutant, which is resistant to BCR-ABL inhibitors. Collectively, these results revealed that DDX5 is a critical therapeutic target in CML and that FL118 is an effective candidate compound for the treatment of BCR-ABL inhibitor-resistant CML.

The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.

This study contributes to understanding the mechanisms of Imatinib resistance in CML, proposing IL6R and MYC as pivotal targets for therapeutic strategies. Moreover, the utilization of NIADS v2 enhances our capability to analyze apoptosis and drug responses, contributing to a deeper understanding of CML pathogenesis and treatment options.

Our results support other reports involving sFRP1 and methylation dynamics; as well as opening new avenues of exploration. Our data supports the conclusion that re-expression of sFRP1 protein alters the expression of factors that play important roles in the overall methylation patterns in the leukemic cell line K562.

It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. In contrast, the allosteric inhibitor asciminib strongly reduces Abl's activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.

Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

In a murine wound infection with vancomycin-resistant Enterococcus faecalis, a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion...Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.

P=N/A, N=144, Recruiting, Rigshospitalet, Denmark | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2026 --> Dec 2025

P2, N=20, Recruiting, University of Florida | Not yet recruiting --> Recruiting

Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR-mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence.

P=N/A, N=168, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

Therefore, pimozide could be a promising agent to support TKI therapies in ponatinib resistance. This research would help to clarify the role of cytokines in ponatinib resistance and advance the development of new therapeutics to utilize the STAT5 inhibitor pimozide in combination with TKIs.

Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.

P1, N=255, Recruiting, Orca Biosystems, Inc. | Trial completion date: Apr 2028 --> Jul 2026

P=N/A, N=160, Recruiting, University Hospital, Clermont-Ferrand | Unknown status --> Recruiting | N=70 --> 160 | Trial completion date: Sep 2021 --> Feb 2026 | Trial primary completion date: Feb 2021 --> May 2025

We identified six genes that were consistently upregulated in the fly CML model and validated in adult and pediatric CML patients and in a mouse cell line expressing BCR::ABL1T315I. This study provides a comprehensive analysis of gene signatures in BCR::ABL1p210 and BCR::ABL1T315I, laying the groundwork for targeted investigations into the role of these genes in CML pathogenesis.

The development of chronic myeloid leukaemia (CML) subsequent to chronic lymphocytic leukaemia (CLL) is an uncommon occurrence, challenging conventional expectations of disease evolution in chronic leukaemia.Extensive and appropriate testing is necessary to promptly identify secondary CML in CLL patients.Targeted therapy with dasatinib, a tyrosine kinase inhibitor, may demonstrate efficacy in reducing leukocytosis and BCR-ABL1 levels in patients with coexisting CLL and CML.

Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

P=N/A, N=26, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> May 2023 | Trial primary completion date: Dec 2023 --> May 2023

Ex-vivo hemocompatibility and in-vivo-biocompatibility of parenteral-Ivn@MJ-NLC, compared to Ivn-solution, was verified via biochemical-blood analysis, histological and histomorphometric studies of liver and kidney tissues. Our findings highlight Ivn@MJ-NLC as an Ivn/MJ synergistic antileukemic platform, ameliorating possible adverse-effects.

P1/2, N=33, Completed, Prescient Therapeutics, Ltd. | Recruiting --> Completed | Trial completion date: Dec 2021 --> Mar 2024 | Trial primary completion date: Dec 2021 --> Oct 2023

P2, N=31, Active, not recruiting, Roswell Park Cancer Institute | Trial completion date: Aug 2023 --> Aug 2024 | Trial primary completion date: Aug 2022 --> Aug 2023

P2, N=260, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024

P2, N=133, Active, not recruiting, National Cancer Institute (NCI)

P2, N=25, Active, not recruiting, National Cancer Institute (NCI) | N=60 --> 25 | Trial completion date: Jun 2023 --> Dec 2024

P2, N=54, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

CML presenting with hearing loss is rare, believed to be related to the infiltration of leukemic cells in the inner ear or microvascular complications. Treatment with tyrosine kinase inhibitors such as Imatinib can improve hematologic parameters, but the effect on hearing loss is uncertaint.

This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

In this article, we systemically review the structural and molecular properties of the critical domains of BCR::ABL1 and how understanding the essential role of BCR::ABL1 kinase activity has provided a solid foundation for the successful development of molecularly targeted therapy in CML. Comparison of responses and resistance to multiple BCR::ABL1 TKIs in clinical studies and current combination treatment strategies are also extensively discussed in this article.