Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the Western world.
CLL most commonly occurs in older adults, as the median age of diagnosis is 70 years. The
diagnosis is based on persistent lymphocytosis in blood, bone marrow and lymphatic organs.
With duration of the disease patients develop “B symptoms”, that are characteristic for CLL
progression. Progress of the disease vastly differs between patients, which is usually based on
their individual genetic and cytogenetic characteristics. In asymptomatic stages of CLL
patients do not receive therapy and are closely monitored until the onset of further
complications. While CLL is generally considered incurable, it is commonly treated with
chemoimmunotherapy which combines chemotherapeutics (fludarabine, cyclophosphamide)
and monoclonal antibodies (rituximab). Patients with certain genetic characteristics, such as
del(17p) or TP53 variants do not respond well to chemoimmunotherapy. Targeted therapy
targets individual molecules that play a key role in cell signaling resulting in decreased
proliferation of leukemic cells. Targeted therapy of CLL includes Bruton's tytosine kinase
(BTK) inhibitors (ibrutinib, acalabrutinib), BCL-2 inhibitors (venetoclax) and
phosphatidylinositol 3-kinase (PI3K) inhibitors (idelalisib). Despite improvement in clinical
outcomes a significant percentage of patients develops resistance to targeted therapy.
Resistance most likely occurs as a consequence of genetic variants in a drug's binding site on
the targeted protein. The leading cause of ibrutinib resistance is a BTK variant in the binding-
site for ibrutinib, followed by the PLCG2 variant that causes constant activation of cell
signaling even in the presence of ibrutinib. In the Specialised Haematology Laboratory of the
Clinical Department of Haematology, University Clinical Centre Ljubljana we performed
determination of genetic variants that cause resistance to targeted therapy of CLL in patients
who have been receiving ibrutinib for more than two years. We collected blood samples from
patients following informed consent, performed DNA isolation and analysis by NGS. After
software analysis of the results we determined the presence of multiple genetic variants that
impact prognosis and therapy response in most patients. We found BTK variants in 28,6 % of
observed patients while clinically significant PLCG2 and BCL2 variants weren't found. Genes
that may predict clinical outcome were also analysed (TP53, NOTCH1, SF3B1), where we
found TP53 variants in more than a third of patients, while either NOTCH1 or SF3B1 variants
were found in majority of patients. We have shown that determining specific genetic variants
is crucial for prediction of disease progression and therapeutic response in CLL patients.
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