Molecular composition, clonality and kinetics of B cell compartment in patients with chronic lymphocytic leukemia during ibrutinib treatment

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to resistance to apoptosis and increased proliferation. This study evaluates the effects of Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells in CLL patients. Employing a multi-omics approach up to 3.5 years of follow-up, we analyzed data from 24 CLL patients, with a specific focus on the nine treated with ibrutinib monotherapy. The study observed clonal stability within the ibrutinib-treated group following an effective initial clinical response, where clonotype frequencies remained high and stable, ranging from 74.9% at 1.5 years to 87.7% at 3.5 years. In contrast, venetoclax-treated patients exhibited substantial reductions in clonal frequencies, approaching molecular eradication. Sequencing of the coding genome revealed minimal genomic progression in the ibrutinib group, maintaining somatic drivers and variant allele frequencies (VAF) above 0.2 throughout treatment. At the single-cell level, inhibition of the NF-κB pathway and apoptotic signals were indicated or even augmented during treatment. These findings highlight ibrutinib's role in stabilizing the genomic landscape of CLL cells, maintaining high clonal burdens, and preventing significant genomic evolution. This stability underscores ibrutinib's potential as a long-term treatment option for CLL but also necessitates ongoing molecular monitoring to optimize the therapeutic strategy.