Chronic Myeloid Leukemia

Although rare, myeloproliferative neoplasms can involve young patients and pose unique challenges for clinicians in diagnosis and therapy. The paper aims to review the biological markers of MPNs in pediatric populations-a particular group of patients that has been poorly studied due to the low frequency of MPN diagnosis.

We show that PHIP loss phenocopies PHF6 loss, and that PHF6 requires PHIP to occupy chromatin and exert downstream transcriptional effects. Our work unifies PHF6 and PHIP, two disparate leukemia-mutated proteins, into a common functional complex that suppresses AML stemness.

Both cancers were aggressively treated. The patient received autologous stem cell transplantation (ASCT) for multiple myeloma and tyrosine kinase inhibitor for chronic myeloid leukemia concurrently to achieve the complete response.

P=N/A, N=105, Recruiting, Samara State Medical University | Trial completion date: May 2023 --> Sep 2025 | Trial primary completion date: May 2023 --> Sep 2025

Phellifuropyranone A and Meshimakobnol B show significant potency as inhibitors of the T315I-BCR::ABL1 mutant protein, comparable to ponatinib. These compounds may serve as effective alternatives or synergistic agents with ponatinib, potentially overcoming drug resistance and improving treatment outcomes in Chronic Myeloid Leukemia.

P=N/A, N=5000, Recruiting, University of Alabama at Birmingham | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2026

Pharmacological inhibition of PRMT1 activity by MS023 remarkably eliminates LSCs and prolongs the survival of CML mice...PRMT1 augments the global protein synthesis via RPL29 in CML LSCs. Taken together, the findings provide new evidence that histone arginine methylation modification regulates protein synthesis in LSCs and highlight PRMT1 as a valuable druggable target for patients with CML.

P1, N=19, Terminated, M.D. Anderson Cancer Center | Active, not recruiting --> Terminated; Administratively Complete

Additionally, a label-free artificial intelligence-driven flow cytometry successfully identified not only the BCR::ABL1-transduced cells but also peripheral leukocytes from CML patients by assessing mitochondrial morphological alterations. These findings suggested the crucial role of BCR::ABL1-induced mitochondrial fragmentation in driving BCR::ABL1-positive cell proliferation, and the potential use of mitochondrial morphological alterations as a clinical biomarker for the label-free detection of CML cells.

P=N/A, N=100, Recruiting, Carmen Fava

P2, N=38, Completed, Zwi Berneman | Unknown status --> Completed

Several second-generation tyrosine kinase inhibitors (2GTKIs), such as nilotinib, dasatinib, bosutinib, and radotinib (RTB), followed the groundbreaking introduction of imatinib. This review is the first attempt that extensively presents a compilation of data on RTB and describes its therapeutic potential against blood and solid tumors. Further investigations on RTB could expand its chemotherapeutic usage in various solid tumors and enhance the possibility of drug repurposing in cancer therapy.

Our findings showed that progesterone affects its receptor expression on K562 cells. Thus it may influence the performance of K562 cells in addition to its direct effects on these cells (via binding to its receptors).

The patient was started on nilotinib therapy...This case pinpoints the importance of comprehensive study when MDS is present with deletion 20q and a t(9;22), as it can be misdiagnosed as CML. While definitive therapeutic guidelines have yet to be established for this rare presentation of MDS, the use of tyrosine kinase inhibitors is under investigation.

Additionally, WGS can identify unique SVs that may be missed by conventional methods and enables clinical benefits such as HLA typing for potential transplant (alloHCT) or diagnostic refinement by retroviral insertion (e.g. HTLV-1). These findings demonstrate the potential for integration of WGS into clinical practice to enhance personalized treatment strategies.

For patients with AP-CML who progressed while on TKI therapy or those with BP-CML, alloHCT is considered the only curative therapy. Our goal is to review the available data on the therapy of patients with AP-CML and BP-CML.

The selected hit compounds showed ΔG scores ranging from -118.09 to -74.85 kJ/mol in both wildtype and mutant ABL1. Considering all in silico studies performed, it can be inferred that the identified molecules hold promise as potential candidates for drug design aimed at targeting CML.

The results showed that the level of BCR-ABL P210 was upregulated upon transfection of SARS-CoV-2 pseudovirus into blood samples of CML patients. Our results demonstrate that COVID-19 suppresses the immune activity and consequentially elevates the level of BCR-ABL P210 of CML patients.

After key baseline characteristics adjustment, cumulative BCR::ABL1 IS ≤1% and MMR rates were statistically higher with ponatinib than asciminib in patients without a baseline response in most of the comparisons by 12 months. Favorable efficacy outcomes observed in ponatinib vs. asciminib were consistently stronger in the T315I mutation subgroup.

Moreover, CK2 inhibition or genetic ablation of the CK2α catalytic subunit sensitizes T315I-cells towards TKIs. Collectively, our results suggest the potential benefit of inhibiting CK2 in CML characterized by T315I-dependent resistance.

The use of a cryptic splice site in intron 1 of ABL1 led to the generation of an in-frame BCR::ABL1 fusion transcript. The diagnostic difficulties caused by this atypical variant and its implications for diagnostic routine are discussed.

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2024 --> Jun 2025

P2/3, N=76, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Oct 2025

All in all, our results highlight NK cells and innate CD8 T-cells harboring cytotoxic content, as well as global downregulation of PD-1-expression on effector T-cells, as potential predictive functional signatures for successful TFR in CML. Considering innate CD8 T-cells, further investigations are needed to determine whether their possible contributory role in cancer surveillance in CML could be extended to other cancers, and also whether their targeting by immune cheek-point inhibitors could enhance their anti-tumoral functions.

In addition, we observed that e13a2 and e14a2 BCR::ABL1 transcript types could be discriminated based on the mean fluorescence intensity of BCR::ABL1-positive droplets. BCR::ABL1 digital PCR is feasible for DMR quantification in clinical practice and offers an increased sensitivity over RT-qPCR.

These findings highlight dPCR as a sensitive and accurate tool for monitoring MRD in CML patients, providing information for treatment management decisions, and potentially enhancing the selection of candidates for treatment-free remission. Further standardization of dPCR methodologies is warranted to leverage their benefits in clinical practice.

P2, N=25, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2025 --> Apr 2026 | Trial primary completion date: Dec 2024 --> Apr 2025

Predictions of toxicological and pharmacokinetic properties (ADME/Tox) using the top100/base (600 structures), in comparison with the commercial drug imatinib, showed that only nine exhibited the desired properties...Considering future in vitro or in vivo assays, we elaborated the theoretical synthetic routes of the promising compounds identified in the present study. Based on our in silico findings, the selected ligands show promise for future studies in developing chronic myeloid leukemia treatments.

P=N/A, N=415, Active, not recruiting, Mount Sinai Hospital, Canada | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Dec 2025

Ponatinib discontinuation is feasible in patients with CML-CP failing prior TKIs. Patients who achieve sustained MR4.5 for at least 2 years have the highest likelihood of remaining in treatment-free remission following ponatinib discontinuation.

Furthermore discussed about the benefits, possible challenges, viewpoints, comparison with other targeted protein degraders (LYTACs, AUTOTACs) and the most current research results of PROTACs technology in multiple oncology therapies. Abbreviations: PROTACs, Proteolysis Targeting Chimeras; PK, Pharmacokinetic; PD, Pharmacodynamic; MetAP-2, (methionine aminopeptidase 2); BCL6, B-cell lymphoma 6; GCN5, General Control Nonderepressible 5; BKT, Bruton's tyrosine kinase; BET, Bromodomain and extra-terminal; AR, Androgen or Androgen receptor; ER, Estrogen or Estrogen receptor; FDA, Food and Drug Administration; mCRPC, Metastatic castration-resistant prostate cancer; STAT3, Signal Transducer and Activator of Transcription 3; FAK, Focal adhesion kinase; POI, Protein of interest; PEG, Polyethylene glycol; UPS, Ubiquitin-Proteasome System; VHL, Von Hippel-Lindau; CRBN, Cereblon; MDM2, Mouse Double Minute 2 homologue; cIAP, Cellular Inhibitor of Apoptosis; RNF, Ring Finger Protein; BRD, Bromodomain; CDK, Cyclin-dependent kinase; PAMPA, Parallel Artificial Membrane Permeability studies; BRET, Bioluminescence Resonance Energy Transfer; MCL, Mantle cell lymphoma; MCL-1, Myeloid Cell Leukemia 1; BCL-XL, B-cell lymphoma extra-large; TRK, Tropomyosin Receptor Kinase; RTKs, Transmembrane Receptor Tyrosine Kinase; NTRK, Neurotrophic Tyrosine Receptor Kinase; DHT, Dihydrotestosterone; EGFR, Epidermal Growth Factor Receptor; EGFR-TKIs, EGFR tyrosine kinase inhibitors; NSCLC, non-small cell lung cancer; BCR, B-cell receptor; CML, Chronic myelogenous leukemia; TKI, Tyrosine kinase inhibitors; MoA, Mechanism of action; TPD, Targetted protein degraders; LYTACs, Lysosome targeting chimeras; ASGPR, Asialoglycoprotein receptor; AUTOTACs, Autophagy-Targeting Chimeras; ATTECs, Autophagy-tethering compounds; CRISPR-Cas9, Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-associated protein 9; TALEN, Transcription Activator-Like Effector Nuclease; ZFN, Zinc Finger Nuclease.

This was achieved partially by inhibition of ABCG2-mediated excretion of dasatinib from CML cells. Therefore, these findings provide important insights for improving CML treatment and overcoming TKI resistance.

P1, N=0, Withdrawn, Duke University | N=12 --> 0 | Trial completion date: Sep 2027 --> Dec 2029 | Not yet recruiting --> Withdrawn | Trial primary completion date: Sep 2025 --> Dec 2027

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.

This study reveals the potential role of NK cells and macrophages in AML chemoresistance through the analysis of single-cell RNA sequencing data. This provides new ideas and insights into the key mechanisms of immune cells in AML treatment.

The present analyses indicate that hyperoside can target the NRF2/SLC7A11/GPX4 axis to induce ferroptotic CML cell death.

Furthermore, the lack of bisecting GlcNAc modification on c-Kit and transferrin receptor 1 (CD71) suppressed cellular signaling and accelerated the degradation of the CD71 protein, respectively. Our study highlights the critical role of MGAT3 in regulating erythroid differentiation associated with the ERK/MAPK signaling pathway, which may shed light on identifying new differentiation therapy in chronic myelogenous leukemia.

Olverembatinib may provide a viable new treatment option for patients after failure of 2 or more TKIs. ClinicalTrials.gov Identifier: NCT04260022.

P1, N=72, Not yet recruiting, Shenzhen TargetRx, Inc.

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.

P2, N=35, Recruiting, Fred Hutchinson Cancer Center | N=20 --> 35 | Trial completion date: Oct 2026 --> Mar 2027 | Trial primary completion date: Dec 2024 --> Mar 2025

The combination of MST-312 and imatinib shows potential as a CML therapy. However, further research and clinical trials are necessary to validate these findings and determine their clinical relevance.