A Case‐Driven Multi‐Omics Analysis for Longitudinal Ibrutinib Response Evaluation of Patients With Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) undergoing ibrutinib treatment often experience incomplete response, yet the molecular level underlying clonal inertia remains to be explored. We investigated the molecular and clinical dynamics of CLL during 16 months of ibrutinib monotherapy by analyzing blood samples from two patients who continued having CLL cells in the peripheral blood during treatment. At diagnosis, the clonal burden within the B cell compartment was found to be 55% (pt1) and 86% (pt2) for the dominant clones. At 16 months following treatment these clones still constituted 66% and 89%, respectively. Utilizing multi-omic methodologies at the DNA and RNA levels, including single-cell transcriptomics, we aimed to establish a comprehensive framework for multi-omics analysis for longitudinal ibrutinib response evaluation. The presented study revealed genomically stable disease during ibrutinib treatment, but with intensified expression of genes involved in pathways related to apoptosis, cellular stress response, and canonical NF-κB signaling from diagnosis to 16 months of treatment.