الفهرس 
CHRONIC LYMPHOCYTIC LEUKEMIAOnly 14 pages are availabe for public view
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Abstract
B
-Chronic lymphocytic leukemia (B-CLL) is characterized by clonal proliferation and accumulation of mature, typically CD5-positive B-cells within the blood, bone marrow, lymph nodes and spleen. Recently, it has been reported that, in CLL, the capacity to generate clonal B-cells might be acquired at the hematopoietic stem cell (HSC) stage, suggesting that the primary leukemogenic event in CLL might involve multi-potent self-renewing HSCs.
CLL is clinically a heterogeneous disease where some patients never require therapy and other patients display an aggressive course with poor response to therapy. Recently, some investigators have tried to develop and validate a 17-gene expression signature that distinguished immunoglobulin heavy-chain variable gene (IgHV)-unmutated patients to identify which of these patients who are likely to achieve durable remissions with fludarabine, cyclophosphamide and rituximab (FCR) chemo-immunotherapy from those who might benefit from alternative front-line regimens.
Dipeptidyl peptidase IV (DPPIV/CD26) is a unique multi-functional 110 kDa membrane-bound glycoprotein that belongs to the serine protease family. It acts as a receptor binding and proteolytic molecule. DPP4 is ubiquitously distributed with the highest expression in kidney, lung, liver and small intestine, whereas low expression is found in brain, heart, and skeletal muscle. It is predominantly found on endothelial and epithelial cells throughout the body, but also found on immune cells like T-cells, activated B-cells, activated natural killer cells and myeloid cells. It plays an important role in immune regulation, signal transduction and apoptosis. In addition, DPP4 has roles in nutrition, metabolism, the immune and endocrine systems, bone marrow mobilization, cancer growth, and cell adhesion.
CD26 plays a regulatory role in the neoplastic transformation and progression of various types of tumors. It is proposed as an important tumor biomarker in different types of cancer, like melanoma, lung and prostate cancer, gastric and colorectal cancer. In hematological malignancies, CD26 expression, was described as a marker of aggressiveness in T-cell malignancies, such as T-acute lymphoblastic leukemia, and was associated with poor prognosis and survival.
Aim of this work is evaluate the prognostic value of CD26 in Egyptian patients with B-CLL, and to assess its correlation to other clinical and laboratory parameters with known prognostic significance.
To fulfill this aim, the present study was conducted on 30 newly-diagnosed CLL patients. They were enrolled from the Hematology¬/Oncology Unit, Internal Medicine Department, Ain-Shams University Hospitals, Ain-Shams Faculty of Medicine, and Misr University for Science and Technology, during the period from July 2018 to July 2019.
In the present study, CD26% expression ranged from 0.2 to 46.0%, with a mean of 19.8 ± 13.5%, and CD26 (MFI) ranged from 0.8-1.9, with mean of 1.1 ± 0.3. CD26% expression was positive in 60% of the studied B-CLL patients. The best cut-off value for CD26% expression that can discriminate the studied B-CLL patients from the control group was sought by constructing receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) = 0.878, 95% CI = 0.779-0.977, p<0.001, cut-off ≥7.0% had perfect specificity but moderate sensitivity.
To study the diagnostic ability of CD26% expression in differentiating the B-CLL patients at high-risk from those with intermediate- or low-risk, a cut-off value of ≥19.5% was sought by Constructing Receiver Operating characteristics (ROC) curve. The area under the ROC curve (AUC) = 0.884, 95% CI = 0.731-1.000, p<0.001.
CD38% expression ranged from 2.5-49%, with a mean of 25.0 ± 17.0 % and CD38% expression was positive in 43.3% of patients. ZAP-70% expression ranged from 0.3-44.3, with a mean of 20.1 ± 15.4, and ZAP-70% expression was positive in 46.7% of CLL patients
In the current work, re-evaluation by FISH analysis revealed, 4 patients (13.3%) were positive for deletion of 11q22 (ATM), 7 patients (23.3%) were positive for del 13q14, 7 patients (23.3%) were positive for del 17p (p53) and 13 patients (16.7%) were positive for +12. The IgHV status was evaluated using PCR technique, 13 patients (43.3%) had mutated IgHV and 17 patients (56.7%) had unmutated IgHV status.
According to Modified Rai staging system, the presently studied B-CLL patients are categorized into 3 classes: low-risk patients 6 (20.0%), intermediate- risk patients 12 (40.0%), and high-risk patients 12 (40.0%). The studied B-CLL patients showed statistically highly significant differences in the high-risk group of patients versus the intermediate- or low-risk groups, as regards serum LDH level (p= 0.003), ZAP-70% (p= 0.033), low smear cells % (p= 0.002) and CD26% expression (p <0.001). CD38% expression had a low statistically significant difference between low-risk group versus high/intermediate risk groups (p= 0.002).
In the present work, B-CLL patients positive for CD26% expression were associated with known poor predicted prognosis. Positive CD26% expression showed statistically significant correlations, with a number of poor clinical and laboratory prognostic parameters: hepatomegaly (p= 0.003), advanced Rai clinical staging (p < 0.001), low hemoglobin level (p= 0.049), low platelets count (p= 0.034), low smear cell % (p <0.001), unmutated IgHV status (p <0.001). Meanwhile atypical lymphocytes (p= 0.049), serum LDH (p= 0.001), CD38% (p <0.001), ZAP-70% (p= 0.007) and IPT score-5 (p <0.001) were statistically significantly higher in CD26% positive expression group of CLL patients.
Finally, in the studied B-CLL patients, CD26% positive expression showed statistically significant positive correlations with serum LDH (p <0,001), CD38% (p <0.001) and ZAP-70% (p= 0.006), as well as, statistically significant negative correlations with hemoglobin (p=0.046), platelets count (p= 0.039) and low smear cell % (p= 0,001).