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| ID | Type | Description | Link |
|---|---|---|---|
| 2025-A00697-42 | Other Identifier | ID RCB |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Chronic Lymphocytic Leukemia candidates or those exposed to BTKd | Collection of additional samples of blood and bone marrow or residual lymph node biopsy at the time of inclusion (for diagnosis or relapse), month 6 and relapse. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Non-Interventional Sample Collection and Analysis | Other | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Characterization of resistance mechanisms to CLL patients candidates or exposed to BTKd. | 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. | Up to 5 years after inclusion |
| Measure | Description | Time Frame |
|---|---|---|
| Development of preclinical ex vivo culture models | Establishment of 2D and 3D ex vivo culture systems using primary CLL cells to replicate tumor behavior and evaluate functional characteristics. | Up to 5 years after inclusion |
| Genetic modification of primary CLL cells |
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Inclusion Criteria:
Exclusion Criteria:
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Double refractory CLL patients
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| ANNE LOK, Dr | Contact | 02.40.08.42.11 | anne.lok@chu-nantes.fr | |
| Benoit Tessoulin, Dr | Contact | 02.40.08.23.96 | Benoit.tessoulin@chu-nantes.fr |
| Name | Affiliation | Role |
|---|---|---|
| Anne LOK, MD, PhD | Hospital of Nantes | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU de Angers | Not yet recruiting | Angers | France |
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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. |
| Up to 5 years after inclusion |
| Genomic data analysis to identify resistance-related genes | Comprehensive genomic and transcriptomic profiling of CLL samples to identify genetic alterations and expression patterns associated with resistance to BTK degraders. | Up to 5 years after inclusion |
| Pharmacological targeting of novel candidate molecules | Functional validation of newly identified targets through pharmacological inhibition to assess their therapeutic potential in vitro using CLL models. | Up to 5 years after inclusion |
| Generation of knockout cell lines for genes of interest | Creation of gene knockout models in CLL cell lines via CRISPR/Cas9 to explore the biological role of specific resistance-associated genes. | Up to 5 years after inclusion |
| Generation of drug-resistant cell lines and comparative RNA sequencing | 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. | Up to 5 years after inclusion |
| Reconstruction of the tumor microenvironment using co-culture systems | 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. | Up to 5 years after inclusion |
| CHU de Bordeaux | Not yet recruiting | Bordeaux | France |
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| Institut Bergonié | Not yet recruiting | Bordeaux | France |
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| CHU de Clermont-Ferrand | Not yet recruiting | Clermont-Ferrand | France |
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| CHD Vendée | Recruiting | La Roche-sur-Yon | France |
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| Centre Léon Bernard | Not yet recruiting | Lyon | France |
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| Institut Paoli-Calmettes (Marseille) | Not yet recruiting | Marseille | France |
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| CHU de Montpellier | Not yet recruiting | Montpellier | France |
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| CH Régional Universitaire de Nancy | Not yet recruiting | Nancy | France |
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| University Hospital | Recruiting | Nantes | France |
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| Hôpital Avicenne (AP-HP) | Not yet recruiting | Paris | France |
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| Hôpital Universitaire Pitié Salpêtrière de Paris | Not yet recruiting | Paris | France |
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| CHU de Poitiers | Not yet recruiting | Poitiers | France |
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| Centre Henri-Becquerel de Rouen | Not yet recruiting | Rouen | France |
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| ID | Term |
|---|---|
| D015451 | Leukemia, Lymphocytic, Chronic, B-Cell |
| ID | Term |
|---|---|
| D015448 | Leukemia, B-Cell |
| D007945 | Leukemia, Lymphoid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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