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The Diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia. Olfat M. Hendy, Mona A. El Shafie , Maha M. Allam , Tawfik Abdel Motalib, Fatma M. Khalaf , Suzy F. Gohar Presented by: Olfat M. Hendy Professor of Clinical Pathology-NLI- Menoufia University
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The Diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia Olfat M. Hendy, Mona A. El Shafie , Maha M. Allam , Tawfik Abdel Motalib, Fatma M. Khalaf , Suzy F. Gohar Presented by: Olfat M. Hendy Professor of Clinical Pathology-NLI- Menoufia University Egypt
The neoplastic transformation in CLL cells resulting from the micro-environmental interactions. These interactions may correspond with disease progression; hence, the acquisition of additional genetic lesions. Several publications reported the prognostic significance of specific immunoglobulin variable heavy chain (IgHV) genes as well as other many newer prognostic markers in CLL. The clinical utility of these newer markers, alone or in combination with each other and the clinical prognostic systems, is still being analyzed.
CD38 is a transmembrane type II glycoprotein. It is expressed in numerous cells of the hematopoietic system, such as lymphocytes, myeloid cells, NK cells, platelets, and erythrocytes. CD38 has been shown to play a critical role in diverse immune functions: in T cell activation, neutrophil chemotaxis, dendritic cell migration, and monocyte chemokine production.
CD49d is the alpha 4/beta 1 part of the VLA-4 integrin, and it is more widely expressed within the hematopoietic system: it is expressed on pre-B ALL cells, and in resting CLL cells. CD49d plays a critical role in leucocyte trafficking, activation, and surviva. It also facilitates interactions between leucocytes and stromal cells found in the marrow or fount in germinal center of lymphoid follicles. CD49d can also serve as a signaling receptor that influences B-cell survival via upregulation of Bcl-2 family members.
Many previous studies are suggested that, the CD38 and CD49d are independent prognostic risk parameters in CLL. Both are reported to influence CLL cell trafficking between blood and lymphoid organs as well as their survival and proliferation within the lymphoid organs, thereby impacting the pathophysiology of the disease. To date a little is known about the prognostic importance of CD49d and CD38 co-expression as prognostic and survival markers in CLL patients.
Aim of the study So, this study aimed at assessing the diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia and to show its impact on patient survival and future treatment measures.
This study included 52 newly diagnosed patients with CLL, 37 males and 15 females with age ranged from 51 to 76 years. All patients were collected from the clinical oncology department- Menoufia Faculty of Medicine and National Liver Institute (presenting with splenomegaly) Menoufia University. Twenty age and sex matched hematological normal individuals, 16 males and 4 females, age ranged from 44-62 years, were included in the study as a control group
Diagnosis of CLL Diagnostic criteria for CLL was as follows: an absolute lymphocyte count >5 x106/L in peripheral blood; a mono clonal lymphocytic population in peripheral blood, lymph node, or bone marrow (defined as CD19+/CD5+, CD10–,CD22+, CD23+) in >20% of lymphocytes. At the time of the study, two patient had stage 0, 5 had stage I, 26 had stage II, 12 had stage III and 7 had stage IV according to Rai staging system.
Clinical and radiological examination: All CLL cases were subjected to thorough history, complete physical examination stress on lymphadenopathy, splenomegaly, hepatomegaly, in addition to abdominal ultra-sonography and chest X-ray.
Treatment of CLL patients Treatments were given to patients with progressive disease were highly heterogeneous. Whereas some patients received fludarabine-based treatments—with or without rituximab—others had chlorambucil-or CHOP-based regimens. An informed consent was obtained from all patients before the study and this study was approved by the ethical committee of Menoufia Faculty of Medicine and National Liver Institute-Menoufiya University.
Sampling: • Complete blood count (CBC), chemistry analysis, B2 microglobulin and ESR were done. • The bone marrow samples were done for morphological examination, immunophenotyping and molecular cytogenetic analysis. • Cytogenetic analysis: Cytogenetic abnormalities were detected by interphase FISH technique carried out for loci on chromosome 11, 12, 13, and 17.
Immunophenotyping by Flow Cytometer • FCM analysis for BM aspirates were done for the following panel of monoclonal antibodies: B- lymphocyte markers (CD19, CD5, CD23, CD20, CD22, CD79b, CD103, CD123, FMC7, CD38, SmIg, CD10, kappa and lambda light chains). • Expression of CD49d was done on CD19+/CD5+ cells and the mean fluorescence intensity (MFI) were measured. • Samples were considered positive for a marker if >20% of cells expressed that marker; except for CD38 positivity which was considered >30%.
Statistical analysis Data were analyzed using SPSS software, version 21. Survival time distributions between prognostic groups were evaluated using standard Kaplan– Meier methods and were compared using the log-rank test.
Among 39 cases with CD49d+, about 24 cases co-express CD49d+/CD38+ and the remaining 15 cases express CD49d only (CD49d+/CD38-). Table (4) compares between both subgroups .
The median treatment-free time was shorter in CD49d+ CLL patients (32 months) as compared to CD49d- patients (98 months) (p< 0.001, log-rank test) (Fig. 1).
The median treatment- free time was shorter in CD38+ CLL patients (28 months) as compared to CD38- patients (102 months) (p<0.05, log-rank test) (Fig. 2).
The median treatment-free survival was shorter (24 months) in patients coexpress CD49d+/CD38+ patients and was 62 months in CD49d+/CD38- patients (p<0.001, log-rank test) (Fig. 3).
We concluded that , the CD38 and CD49d are more than just markers of an aggressive CLL cell type and that they play functional roles in the pathophysiology of the disease. • The coexpression of both molecule (CD49d+/CD38+) on CLL cells are considered independent risk factors for CLL and they are bad prognostic markers, so they may be integrated into the design of risk-adapted treatment strategies.
Targeting these molecules in large scale study should also be tested for its potential in avoiding the frequent relapses and development resistance for chemotherapy in CLL patients.
