IGH mutation

The primary first-line treatment options for CLL comprise continuous therapies based on the BTK inhibitors ibrutinib, zanubrutinib, or acalabrutinib, or fixed-duration regimens combining the BCL2 inhibitor venetoclax with obinutuzumab or the BTK inhibitors ibrutinib or acalabrutinib (with or without obinutuzumab). Selecting the appropriate targeted therapy requires careful evaluation of a multitude of factors, including molecular disease features (especially del[17p]/TP53 and IGHV mutational status), comorbidities, comedications, and the patient's preferences. Focusing on primary treatment options, we review data from the key controlled trials that support the first-line use of targeted therapies for patients with CLL, consider ongoing trials that may support clinical decision-making in the future, and assess the potential to personalize treatment regimens in CLL based on minimal residual disease status.

Combining ibrutinib with the GPX4 inhibitor RSL3 enhances ferroptosis and improves antileukemic efficacy in vivo. Notably, ACSL1 is selectively upregulated in U-CLL cells and represents a targetable metabolic enhancer of ferroptosis sensitivity, as shown in vivo. Our findings reveal that TFRC and ACSL1 are functionally distinct yet targetable nodes that govern ferroptosis vulnerability in CLL patients and may guide novel therapeutic strategies for high-risk patients.

The transition to targeted therapies has improved outcomes for high-risk CLL patients. Nevertheless, outcomes for high-risk CLL patients remain inferior to those reported in clinical trials, underscoring the need for real-world evidence and improved therapies.

Our data confirmed unfavourable prognostic value of IGLV321 for prediction of progressionfree survival and overall survival in CLL patients with M IGHV genes, regardless of radiation anamnesis.

This survey highlights gaps between international recommendations and Korean real-world practice, emphasizing the need for improved diagnostic availability, timely reimbursement of targeted agents, and development of Korea-specific clinical guidelines tailored to the Korean context.

Pirtobrutinib demonstrated superiority over BendaR in IRC-assessed PFS in treatment-naïve CLL/SLL. OS trends favored pirtobrutinib despite the study design allowing for crossover. Pirtobrutinib was well tolerated, consistent with its known safety profile, and more favorable than BendaR.

P2, N=160, Active, not recruiting, French Innovative Leukemia Organisation | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2026 --> Aug 2025

P3, N=552, Completed, AstraZeneca | Active, not recruiting --> Completed

The I+V regimen is generally manageable and well-tolerated, with toxicities consistent with those reported for single-agent use. Nonetheless, concerns regarding cardiovascular toxicities have been raised, particularly among older patients.

In conclusion, we identified molecular, phenotypical and immunological differences between IGHV1 and IGHV11 CLL clones, which are key to consider for preclinical studies using the TCL1 mouse model. Furthermore, our data suggests that IGHV1 CLL clones model the nodal form of human CLL.

P3, N=735, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Mar 2035 --> Jul 2035 | Trial primary completion date: Mar 2035 --> Jun 2032

SNVs, indels and SVs achieved accuracy >95%. These results establish Duoseq as a genomic profiling tool for blood cancers that can enable laboratories to provide critical diagnostic information in a time and cost-effective manner.