Chronic Lymphocytic Leukemia Clinical Trial
Official title:
Evaluation of the Redox Profiles of Healthy and Pathological B Cells in Patients With Chronic Lymphocytic Leukemia
In recent years, considerable progress has been made in understanding the biology of chronic
lymphocytic leukemia (CLL), resulting in the emergence of new therapeutic agents that have
significantly improved the long-term survival of patients. However, LLC is still considered
an incurable disease.
Cytogenetic abnormalities are frequently found in this pathology. Some abnormalities are
associated with a more aggressive disease and a poor prognosis. The deletion of chromosome
17p (del (17p)), in particular, makes leukemic cells more resistant to standard therapy.
Chromosome 17p contains the Tumor Protein 53 gene (TP53) which encodes the tumor suppressor
protein 53 (P53) protein. P53 plays a central role in the regulation of important cellular
functions such as DNA damage response, cell cycle regulation, apoptosis, and drug sensitivity
of chemotherapies. In patients with CLL, the loss of p53 function is a major factor of
chemoresistance and is associated with an adverse prognosis. The deletion (17p) is observed
in approximately 5 to 10% of patients with CLL. In contrast, mutations in the TP53 gene are
observed in approximately 30% of patients with CLL. This means that about one-third of
patients with CLL have p53 dysfunction. TP53 and / or del (17p) mutated LLC cells show marked
mitochondrial dysfunction. This dysfunction is responsible for a deregulation of
intracellular redox phenomena, leading to an increase in oxidative stress and an
overproduction of reactive oxygen derivatives (ROS).
Dimethyl Ampal Thiolester (DIMATE) is an active, competitive and irreversible inhibitor of
aldehyde dehydrogenases (ALDH) 1 and 3. In vitro, DIMATE eradicates human cells from acute
myeloblastic leukemia (AML). In patients with CLL, current treatments, particularly
effective, do not specifically target pathological B cells. This results in chronic B
lymphopenia and hypogammaglobulinemias that provide severe long-term infections, which is the
leading cause of death in patients with CLL.
Through this study, we will study, in vitro, the expression of ALDH 1, 3, 9 but also of
glutathione (GSH) and ROS on tumor B lymphocytes and healthy patients carrying an LLC.
Depending on the differences in expression observed, DIMATE could specifically eradicate
leukemic lymphocyte cells by sparing healthy lymphocytes, a hypothesis that will be tested in
vitro. A special evaluation will be made in patients with del (17) and / or TP53 mutation
whose prognosis is still considered unfavorable despite new therapeutic advances.
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