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Ibrutinib-Refractory CLL: Focus on B Leukemic Cells

By: Celeste L. Dixon
Posted: Thursday, February 18, 2021

Published in Biomarker Research, results derived from research on leukemic cells’ microenvironment in a patient treated with ibrutinib for chronic lymphocytic leukemia (CLL) may inspire new therapeutic strategies for ibrutinib-refractory patients, according to Sarah Cadot, PhD, of the Université Toulouse III Paul-Sabatier, France, and colleagues. The peripheral blood mononuclear cells of the patient—a 60-year-old man who had more than two previous treatments and a complex karyotype—were monitored during ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology.

An irreversible Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, has been effective in CLL treatment, noted the team, but ibrutinib resistance can emerge. In this patient’s case, a short clinical relapse was “driven by BTK mutation…associated with intraclonal heterogeneity in B leukemic cells and upregulation of common signaling pathways induced by ibrutinib in both B leukemic cells and immune cells.”

In monitoring ibrutinib’s efficacy, Dr. Cadot and colleagues found that the patient’s B leukemic cells and T lymphocytes were drastically reduced after 3 months of treatment; natural killer cells remained stable. Long-term follow-up, however, revealed, “a massive increase” in B leukemic cells, indicative of disease progression on ibrutinib, and a slight increase in T lymphocytes and a decrease in natural killer cells. BTK mutation (87%) was revealed by targeted next-generation sequencing.

The findings of intraclonal heterogeneity in B leukemic cells, upregulation of common signaling pathways induced by ibrutinib, and transcriptional and phenotypic modifications in both B leukemic cells and immune cells offer potential new avenues for clinical options. These alternatives, the researchers wrote, “could be directed to B leukemic cells themselves using venetoclax combined or not with a BRD4 inhibitor or based on immunotherapy using bispecific antibodies or chimeric antigen receptor T-cell [therapy].”

Disclosure: The study authors reported no conflicts of interest.



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