With an occurrence of approximately 2500 new cases per year in France, B-cell chronic lymphocytic leukaemia (CLL) is a major public health issue. The clinical management of patients, both in the first line and in relapse, has been revolutionised by the development of targeted therapies, administered orally. Among these therapies, treatments with Imbruvica (ibrutinib) or Venetoclax have brought clear clinical benefit, but induce the appearance of resistance which leads, in the long term, to progression or transformation of the disease into Richter syndrome. These progressions/transformations are mostly related to mutations in the drug targets.

In a first study, we collected blood samples from patients progressing on ibrutinib or venetoclax, or with Richter syndrome. The search for mutations frequently associated with resistance showed that only 60% of patients progressing on targeted therapy carried a mutation that could account for the progression. For these patients, a new therapeutic orientation must be proposed.

Using a high-tech single cell sequencing approach (CITESeq), the DEMETAR project aims to understand the physiological state of normal immune cells and identify molecular signatures in cells resistant to targeted therapies (progression or transformation). This approach is complemented by an extensive search for new mutations (70 genes) and by ex-vivo screening experiments of therapeutic molecules identified from the molecular signatures.

The expected results should provide a better understanding of the evolution of patients under targeted therapies in order to propose a more personalised medicine.

The Comm’in BC project is coordinated by Dr. Loïc YSEBAERT and Dr. Anne QUILLET-MARY. It has received support of €50,000 from the Claudius Regaud Institute / University Cancer Institute of Toulouse-Oncopole.

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