BTK Degraders, Chronic Lymphocytic Leukemia
Conditions
Keywords
Chronic Lymphocytic Leukemia, Bruton tyrosine kinase inhibitors, BCL-2 inhibitors, BTK degraders
Brief summary
The aim of the REBELLE cohort - bio-collection is to collect samples from patients with Chronic Lymphocytic Leukemia candidates or those exposed to BTK degraders to evaluate the mechanisms of resistance to these new molecules. To do this, an additional blood or bone marrow sample to those planned in the context of patient care or a residual lymph node biopsy sample will be collected after signing consent.
Detailed description
Chronic Lymphocytic Leukemia (CLL) is a malignant hematological disease of B cells, primarily observed in older adults. Although it is classified among indolent hematological malignancies, CLL exhibits significant heterogeneity, both in terms of its biological characteristics and its disease progression and the therapeutic strategies employed. In patients requiring treatment, the disease can relapse. Until recently, immunochemotherapy remained the standard treatment for this disease, but the last decade has seen the emergence of oral targeted therapies, such as Bruton's tyrosine kinase inhibitors (BKT1s) and BCL-2 inhibitors (BCL-2 inhibitors), which have profoundly altered patient prognosis. While the introduction of these two classes of drugs has led to improved prognosis, a rare but significant subgroup of patients, known as "double refractory," has emerged. These patients, exposed to both BKT and BCL-2 inhibitors and who have become refractory to both treatments, have a poor prognosis. To overcome this problem of resistance, molecules targeting the degradation of the BTK protein (BTKd) are currently under development. The main investigator propose the creation of a cohort and a biobank of samples from CLL patients who are candidates for or have been exposed to BTKd, in order to study the mechanisms of response and resistance to these molecules.
Interventions
OTHERNon-Interventional Sample Collection and Analysis
This study is observational. Biological samples are collected as part of standard care or for research purposes and analyzed to characterize resistance mechanisms. No treatment or intervention is administered as part of the study protocol.
Sponsors
Nantes University Hospital
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient with CLL candidates ou exposed to BTKd * Patient who has provided informed consent to participate in the study. * Patient covered by a social security health insurance plan
Exclusion criteria
* Minor patients. * Adults under guardianship. * Protected persons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Characterization of resistance mechanisms to CLL patients candidates or exposed to BTKd. | Up to 5 years after inclusion | The primary outcome is the in-depth characterization of tumor cells and their microenvironment in CLL patients candidates or exposed to BTKd. Analyses will be performed using cellular biology (e.g., flow cytometry), molecular biology (e.g., RNA sequencing), and bioinformatics (e.g., deconvolution). Functional studies include the development of preclinical ex vivo models (2D/3D culture) and gene editing of primary cells using CRISPR/Cas9 technology, based on the expertise of Team 11 at CRCI²NA. The study will include 60 patients over a 9-year enrollment period. Each participant will be followed for 5 years, resulting in a total study duration of 14 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Development of preclinical ex vivo culture models | Up to 5 years after inclusion | Establishment of 2D and 3D ex vivo culture systems using primary CLL cells to replicate tumor behavior and evaluate functional characteristics. |
| Genetic modification of primary CLL cells | Up to 5 years after inclusion | Application of gene editing technologies (e.g., CRISPR/Cas9) to modify primary chronic lymphocytic leukemia cells in order to investigate gene function and resistance pathways. |
| Genomic data analysis to identify resistance-related genes | Up to 5 years after inclusion | Comprehensive genomic and transcriptomic profiling of CLL samples to identify genetic alterations and expression patterns associated with resistance to BTK degraders. |
| Pharmacological targeting of novel candidate molecules | Up to 5 years after inclusion | Functional validation of newly identified targets through pharmacological inhibition to assess their therapeutic potential in vitro using CLL models. |
| Generation of knockout cell lines for genes of interest | Up to 5 years after inclusion | Creation of gene knockout models in CLL cell lines via CRISPR/Cas9 to explore the biological role of specific resistance-associated genes. |
| Generation of drug-resistant cell lines and comparative RNA sequencing | Up to 5 years after inclusion | Development of CLL cell lines resistant to BTK degraders followed by RNA sequencing analysis to compare gene expression profiles between drug-sensitive lines and resistant cell lines. |
| Reconstruction of the tumor microenvironment using co-culture systems | Up to 5 years after inclusion | Establishment of co-culture models including immune (T lymphocytes, nurse-like cells) and/or stromal cells (from lymph nodes or bone marrow) to mimic the CLL tumor microenvironment. |
Countries
France
Contacts
CONTACTANNE LOK, Dr
CONTACTBenoit Tessoulin, Dr
PRINCIPAL_INVESTIGATORAnne LOK, MD, PhD
Hospital of Nantes
Outcome results
None listed