Chronic Lymphocytic Leukemia

In this real-world study, early discontinuation was more common in patients initiating a BTKi in contrast to VEN-O. Patients who initiated a BTKi also had high rates of subsequent treatment and hospitalization.

The non-stochastic distribution of the IGKV/LV gene expression in the individual stereotyped subsets was confirmed. Taking into account the complementary role of the light chains in antigen recognition by the clonotypic BCRs, it was suggested that the subsets with the heterogeneous IGK/LV expression might be reclassified and divided into separate subgroups based on the IGHV and IGK/LV association.

Our investigation uncovers that nanomolar concentrations of salinomycin, monensin, nigericin, and narasin (a group of potassium/sodium cation carriers) robustly enhance surface expression of CD20 antigen in B-cell-derived tumor cells, including primary malignant cells of chronic lymphocytic leukemia and diffuse large B-cell lymphoma...The results of RNA-seq, genetic editing, and chemical inhibition delineate the molecular mechanism of CD20 upregulation, at least partially, to the downregulation of MYC, the transcriptional repressor of the MS4A1 gene encoding CD20. Our findings propose the cation carriers as compounds targeting MYC oncogene, which can be combined with anti-CD20 antibodies or adoptive cellular therapies to treat NHL and mitigate resistance, which frequently depends on the CD20 antigen loss, offering new solutions to improve patient outcomes.

The exercise training program used in this study was feasible in people with treatment-naïve CLL who passed pre-trial screening, and we preliminarily conclude that the exercise training program was safe and also resulted in an increase in lean mass. https://doi.org/10.1186/ISRCTN55166064, identifier ISRCTN 55166064.

He was diagnosed with Rai Stage I CLL with del6q, without TP53 mutation, and treated with 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) 6 years prior...The patient received three courses of dexamethasone and acyclovir, leading to successful clearance of the infection, evidenced by the resolution of his B symptoms. Subsequently, he was treated for the CLL recurrence with rituximab and venetoclax, demonstrating a favorable response with significant improvement in adenopathy and resolution of lymphocytosis...Timely administration of antiviral therapy is crucial for HSV lymphadenitis to prevent rapid progression and debilitating symptoms. This case demonstrates the importance of considering atypical viral infection presentations in CLL patients and emphasizes the necessity of timely and adequate biopsies to differentiate between CLL transformation, HSV lymphadenopathy, and other causes of lymphadenopathy while avoiding unnecessarily aggressive lymphoma therapy.

The identified miRNA-gene interactions offer valuable insights for developing targeted therapies for CLL. In addition, we underscored the importance of a practical and robust computational pipeline to ensure the reliability and reproducibility of miRNA sequencing data analysis.

P1, N=24, Recruiting, SIRPant Immunotherapeutics, Inc. | Trial completion date: Mar 2025 --> Dec 2025 | Trial primary completion date: Mar 2025 --> Jun 2025

P2, N=75, Recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

High-BTK subgroup was enriched in replication/repair pathway and transcription machinery. In conclusion, profiling of 5 datasets of ~700 patients revealed unique BTK-associated expression clusters in CLL.

P1, N=58, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Jun 2025

P1/2, N=621, Recruiting, BeiGene | N=466 --> 621

We found higher levels of CXCR4 in patients with progressive disease and the CXCR4hiCD5hi fraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of dividing CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcomes.

Immunophenotypic, cytogenetic, and molecular analyses support that these alterations are secondary events within the CLL clone. This case demonstrates dynamic clonal selection and expansion in response to treatments, which, in turn, contributes to treatment resistance.

The validation cohort of 343 Rai 0 patients confirmed these findings, with UM light chain genes predicting a 7-year treatment free probability of 42.0% versus 73.7% for M genes (p < 0.0001). These results indicate that the mutational status of the light chain genes is an independent predictor of shorter TTFT in early-stage CLL patients.

The two CLL clones have distinct transcriptomes: Numerous genes were differentially expressed, with genes typical for unmutated or mutated CLL showing the expected representation in the two clones. Using PCR, cloning and Sanger sequencing of the IGHV rearrangements we detected both CLL clones over a period of three years without clinical progression of the CLL and thus giving insights into the disease biology of multi-clonal CLL.

There was a statistically significant change in the serum PCT concentration (p < 0.0001), which significantly increased on days 1 to 4 compared to the initial measurement 0. The increases in inflammatory markers shortly after obinotuzumab (anti-CD20 antibody) administration can be significantly high but are most often not related to the onset of infection and do not lead to any ill consequences in the treatment of lymphoproliferative disease.

Furthermore, it decreased microphthalmia-associated transcription factors and induced the suppression of cyclin-dependent kinase 2, hepatocyte growth factor receptor, B-cell/CLL lymphoma 2, and Ras-related proteins. Our findings suggest that the MC extract suppresses tumor survival genes by regulating PAX3, thereby ameliorating melanoma proliferation and invasion.

This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering.

Furthermore, yeast two-hybrid assay results indicated a direct protein-protein interaction between HcIKK and HcCnAα, while no interaction was observed between HcBcl10 and HcCnAα. This study elucidates the specific molecular mechanisms by which HcCnAα regulates the immune response in H. cumingii, providing a foundational basis for further exploration of immune regulation mechanisms and the development of disease prevention strategies in bivalves.

P1, N=23, Not yet recruiting, City of Hope Medical Center

MRD-guided duration of treatment may improve further outcomes, but longer clinical follow-up is needed before this approach is incorporated in clinical guidelines. The review gives an update on the impact of biological markers on outcomes with novel agents.

In human liver microsomes (n = 20) and primary human hepatocytes (n = 15), venetoclax metabolite formation varied widely between donors and significantly correlated with CYP3A activity (midazolam 1'-hydroxylation) and CYP3A4 protein expression. Differences between the in vitro data, which showed a positive association between venetoclax metabolism, hepatic CYP3A markers, and plasma 4β-HC/cholesterol ratio, and the in vivo findings in patients with CLL could be due to age or other factors regulating plasma 4β-HC/cholesterol and/or venetoclax disposition. Future studies with larger sample sizes are needed to investigate age-related changes in venetoclax metabolism and plasma 4β-HC/cholesterol ratio.

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

Findings that robust CLL cycling associates with progressively decreasing BCL2 protein that directly correlates with decreasing venetoclax susceptibility, combined with past findings that these cycling cells have the greatest potential for activation-induced cytosine deaminase (AICDA)-driven mutations, suggest that venetoclax treatment should be accompanied by modalities that selectively target the cycling compartment without eliciting further mutations. The employment of survivin inhibitors might be such an approach.

P1, N=54, Recruiting, Roswell Park Cancer Institute | N=36 --> 54

Compared to the conventional culture, there was (i) a lower expression of VCAM1 in both materials, (ii) a higher expression of CCL4 in collagen scaffolds, and (iii) a lower expression of CXCR4 and MCL1 (transcript variant 2) in collagen scaffolds, while it was higher in a CMC-PEG gel. Hence, culture in the material can suppress the expression of a pro-apoptotic gene (MCL1 in collagen scaffolds) or replicate certain gene expression patterns attributed to CLL cells in lymphoid organs (low CXCR4, high CCL4 in collagen scaffolds) or blood (high CXCR4 in CMC-PEG).

P2, N=12, Completed, Bnai Zion Medical Center | Active, not recruiting --> Completed

P2, N=120, Active, not recruiting, University Hospital Tuebingen | Recruiting --> Active, not recruiting

P1, N=20, Completed, University Hospital Tuebingen | Active, not recruiting --> Completed

P1, N=106, Recruiting, Umoja Biopharma | Not yet recruiting --> Recruiting

P1, N=3, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Jan 2026 --> Mar 2025

Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.

AVO was highly active and well-tolerated in patients with previously untreated CLL with high-risk CLL, supporting its use as a new standard of care treatment option.

Despite remarkable advances, these markers also retain a differential prognostic and predictive impact in the context of targeted therapies, mandating risk-stratification in frontline management. Furthermore, BTK- and BCL2-targeting agents differ in their adverse event profiles, requiring adjustment of treatment choice based on patient characteristics such as coexisting conditions, comedications, and delivery-of-care aspects.

Base substitution or indel variants were detected in TP53 (28% of cases), KMT2D (25%), CREBBP (14%), EZH2 (8%), MYD88 (8%), TNFRSF14 (8%), ATM (8%), NOTCH1 (7%), ARID1A (6%), B2M (6%), TNFAIP3 (6%), PIM1 (4%), CD79B (3%), BTK (2%, 97% of which were C481X ibrutinib resistance mutations in cases of CLL), MEF2B (2%), BCL2 (1%), and PLCG2 (1%)...Overall, 75% of FLs harbored a canonical IGH : : BCL2 rearrangement and 86% of MCLs harbored a canonical IGH : : CCND1 rearrangement.Conclusions : This analysis of 3,692 samples demonstrated that the F1H assay platform reliably detects a broad landscape of genomic alterations across a range of mature B-cell lymphoma/leukemia subtypes. By detecting all classes of genomic alterations in a single sequencing reaction, F1H provides an important advantage over single-gene and small-panel molecular tests in an era when the diagnosis, prognosis, and treatment of hematological malignancies increasingly rely on assessing the presence, as well as the absence, of numerous genomic alterations.

P1, N=3, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=88 --> 3

HK2 expression in primary human chronic lymphocytic leukemia (CLL) cells was associated with recent proliferation and could be reduced by PI3K inhibition. Our study implicates PI3K-dependent modulation of HK2 in B cell metabolic reprogramming.

P1, N=226, Active, not recruiting, Janssen Research & Development, LLC | Trial primary completion date: Dec 2024 --> Apr 2025

P1, N=45, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2026 --> Apr 2025 | Trial primary completion date: Nov 2024 --> Apr 2025

P1, N=85, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2026 --> Apr 2025 | Trial primary completion date: Apr 2026 --> Apr 2025

P3, N=700, Recruiting, Janssen Research & Development, LLC | Enrolling by invitation --> Recruiting

P1, N=75, Active, not recruiting, Janssen Research & Development, LLC | Trial completion date: Dec 2026 --> Jul 2025