الفهرس 
Chronic Lymphocytic Leukemia (CLL)
Hereditary and Genetic FactorsOnly 14 pages are availabe for public view
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Abstract
CLL is considered the most common form of leukemia in adults over sixty and rarely occurs below forty. The CLL is a malignant proliferation of monoclonal lymphocytes, most commonly of B-cell origin (B-CLL). It is characterized by an accumulation of small, mature appearing functionally incompetent lymphocytes in BM, PB and lymphoid tissue. The diagnosis of CLL requires a lymphocyte count of 5000 or more per cubic millimeters, and a characteristic cell surface phenotype of clonal B-cells; the presence of CD19, CD5, CD23 and weak expression of CD20, CD79b, and either kappa or lambda immunoglobulin light chain.
The CLL follows an extremely variable clinical course with overall survival times ranging from months to decades. Some patients have no or minimal signs and symptoms during their entire disease course and have a survival time similar to age-matched controls. Other patients experience rapidly deteriorating blood counts, organomegaly and suffer from symptoms at diagnosis or soon thereafter necessitating therapy. This has led to a search for prognostic indicators that correlate better with survival. Potential prognostic indicators include clinical stage, lymphocyte doubling time, IgVH mutation status, cytogenetic abnormalities, leukemia cell CD38 and Zap-70 expression. Expression of Zap-70, the Rai, and Binet staging systems are still widely used in clinical practice, but they do not predict disease progression or response to therapy. To fill these voids in the management of CLL, serum APRIL was measured in B-CLL patients.
APRIL is a TNF family member expressed by myeloid and epithelial cells and engages BAFF-R, TACI, and BCMA on B cells. APRIL, derived primarily from DCs, mediated CD40-independent isotype switching from IgG to IgA, in both human and mouse B cells, by both TACI and BAFF-R. APRIL also augments B-cell antigen presentation, co-stimulates B-cell proliferation, enhances B-cell (normal and malignant) survival, regulates B-cell tolerance, promotes tumor cell proliferation and survival and finally, it may co-stimulate activated T cells. It is also involved in B-lymphocytes differentiation and survival, and plays a role in protecting B-CLL cells from apoptosis.
APRIL is overexpressed in certain tumor tissues and different diseases as SLE, RA, Sjögren’s syndrome, MS, immunodeficiency, solid tumors and hematological diseases.
Evaluation of serum APRIL level was done by different methods. APRIL is measured by ELISA, Flow cytometry analysis, Immunohistochemistry, quantitive polymerase chain reaction (PCR), and Northern blot analysis. In our study serum APRIL level was evaluated by ELISA.
The aim of this study was to evaluate the level of serum APRIL in CLL, assess the prognostic significance of serum APRIL in CLL, correlate the level of serum APRIL with well-established prognostic factors of CLL.
The present study was conducted on 45 adult patients with B-CLL. They were subdivided to 20 untreated and 25 treated B-CLL patients. Their ages ranged between 40-75 years. Untreated CLL patients were 13(65%) males and 7(35%) females with male to female ratio (M: F = 1.9:1), their ages ranged from 69-75 (66.95±5.20). Treated CLL patients were 16 (64%) males and 9 (36%) females with male to female ratio (M: F = 1.8:1), their ages ranged from 40-73 (56.00±10.90). The results of the patients were compared to 20 age and sex matched healthy individuals serving as the control group.
All the patients were subjected to Complete history and clinical examination stressing on the presence of organomegaly (liver and spleen) and lymphadenopathy, complete blood count with examination of Leishman-stained smears, Bone marrow aspiration and examination of Leishman-stained smears, Liver and kidney functions tests, Immunophenotyping using the standard panel for chronic lymphoproliferative disease (LPD) together with CD38 and ZAP-70 and Evaluation of serum APRIL level by ELISA.
All controls were subjected to complete history and clinical examination, Routine laboratory investigations including complete blood count with differential leucocytic count, liver and kidney functions tests and Evaluation of serum APRIL level by ELISA.
Untreated and treated B-CLL patients showed higher TLC and ALC compared to the control group. Untreated and treated B-CLL patients showed lower Hb level and platelet count compared to the control group.
No significant difference was detected between untreated and treated groups regarding gender, incidence of lymphadenopathy, Hb level, platelet count, RAI staging, CD 38 and Zap 70.
In the present study, CLL patients (untreated and treated) showed higher levels of serum APRIL in comparison with the normal control group.
Untreated B-CLL patients showed a positive correlation between serum APRIL level and TLC and ALC, however treated B-CLL patients showed no correlation between serum APRIL level and TLC and ALC.
In our study, untreated and treated B-CLL groups showed no correlation between serum APRIL level and age, Hb level and platelet count.
In untreated B-CLL patients, higher serum APRIL levels were found among patients with lymphadenopathy.
Untreated and treated B-CLL patients, showed higher serum APRIL levels among patients with CD38+ and Zap 70+ than those with CD38- and Zap 70- expression.
On the other hand, treated B-CLL patients showed no association between serum APRIL level and each of splenomegaly and RAI staging. No association was found between serum APRIL level and gender.
In the present study, untreated and treated B-CLL group most patients were included in the high-risk group with lymphocytosis together with anemia or thrombocytopenia.
ROC curve was performed to detect the best cutoff value for serum APRIL that can stratify CLL patients into low and high APRIL levels groups with the best sensitivity (97.78%) and specificity (100%). Accordingly, 9.5 ng/ml was assigned as the best cutoff value for serum APRIL, where CLL patients> 9.5 were considered the APRIL high group and< 9.5 were considered the APRIL low group.
Regarding comparing of serum APRIL level in patients with other prognostic factors of CLL, serum APRIL level was significantly higher among CLL patients older than 65 years, ALC> 30x109/L, with CD38+ and Zap 70+ expression, however no association was found between serum APRIL level and each of gender or RAI stage.
Our findings suggest that patients with high CD38 and Zap 70 expression in conjugation with high serum APRIL level may require aggressive therapeutic approaches. APRIL is a powerful prognostic marker related to parameters of disease activity and staging.