|Year : 2016 | Volume
| Issue : 2 | Page : 70-76
The diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia
Olfat M Hendy MD 1, Mona A El Shafie2, Maha M Allam1, Tawfik A Motalib3, Fatma A Khalaf4, Suzy F Gohar5
1 Department of Clinical Pathology, National Liver Institute, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Microbiology, National Liver Institute, Menoufia, Egypt
4 Department of Biochemistry, National Liver Institute, Menoufia, Egypt
5 Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||19-Oct-2015|
|Date of Acceptance||08-Nov-2015|
|Date of Web Publication||15-Jul-2016|
Olfat M Hendy
Ahmed Elsawy Street, Nasr City, Cairo, 11371
Source of Support: None, Conflict of Interest: None
Background Little is known about the prognostic importance of coexpression of CD49d and CD38 in chronic lymphocytic leukemia (CLL) patients.
Aim This study aimed to investigate the coexpression of both CD38 and CD49d as prognostic and survival markers in CLL patients.
Patients and methods Fifty-two patients with newly diagnosed B-cell CLL were included in the study. Twenty age-matched and sex-matched healthy control participants were also included in the study. Patients were subjected to a clinical examination and abdominal ultrasonography and chest radiography. Laboratory investigations including complete blood count, β2 microglobulin, cytogenetic analysis, and immunophenotyping by flow cytometer (B-lymphocyte markers and the expression of CD38 and CD49d) were performed.
Results There was a significant decrease in hemoglobin concentration and platelet counts in patients who coexpressed CD49d+/CD38+ compared with patients who expressed CD49+ alone, whereas white blood cell and lymphocyte counts, lactate dehydrogenase, and β2 microglobulin were significantly higher. In addition, CD49d+/CD38+ coexpression was significantly high in advanced stages of CLL. A positive correlation was detected between CD49d expression and poor prognostic parameters in CLL. The median treatment-free time was shorter in CD49d+ patients (32 months) compared with CD49d- patients (98 months). The median treatment-free duration was shorter in CD38+ patients (28 months) compared with CD38- patients (102 months). In the concordant cases of CD49d+/CD38+, the median treatment-free survival was shorter (24 months) in patients with CD49+/CD38+ patients compared with disconcordant cases of CD49d+/CD38- patients (62 months).
Conclusion CD38 and Cd49d expressions are considered prognostic markers for CLL patients and they should be assessed to decided on the patient's therapy and to determine disease prognosis. These molecules should also be tested in a large-scale study to determine their potential in preventing frequent relapses and development of resistance to chemotherapy in CLL.
Keywords: CD38, CD49, chronic lymphocytic leukemia, cytogenetic, flow cytometry, imunophenotyping, risk factors
|How to cite this article:|
Hendy OM, El Shafie MA, Allam MM, Motalib TA, Khalaf FA, Gohar SF. The diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia. Egypt J Haematol 2016;41:70-6
|How to cite this URL:|
Hendy OM, El Shafie MA, Allam MM, Motalib TA, Khalaf FA, Gohar SF. The diagnostic and prognostic value of CD38 and CD49d expressions in chronic lymphocytic leukemia. Egypt J Haematol [serial online] 2016 [cited 2019 Apr 19];41:70-6. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/70/186409
| Introduction|| |
Over the past decade, several prognostic markers based on genetic phenotypic or molecular characteristics of chronic lymphocytic leukemia (CLL) B cells have been discovered. The clinical utility of these newer prognostic indicators, alone or in combination with each other and the clinical prognostic systems, is still being analyzed .
The neoplastic transformation in CLL cells resulting from the microenvironment operate synergistically by enhancing proliferation and/or inhibiting apoptosis of CLL cells themselves . These microenvironmental interactions may also correspond with disease progression by promoting proliferation of the malignant clone, and hence the acquisition of additional genetic lesions .
Several publications have reported the prognostic significance of specific immunoglobulin variable heavy-chain (IGHV) gene features in CLL. Because IGHV gene sequencing is a technique usually not available in diagnostic laboratories, many studies have focused on the identification of alternative markers with similar prognostic value and whose expression can be investigated easily by flow cytometry .
Integrins are heterodimer glycoprotein receptors consisting of noncovalently linked α and β chains; they are involved in cell adhesion to extracellular matrix proteins, cell surface ligands, and soluble ligands. Integrins are classified according to their β chain into the very late antigen integrins (β1), leukocyte integrins (β2), cytoadhesin integrins (β3), and additional molecules expressing β4, β5, β6, β7, or β8 .
CD49d is the α4 subunit of the very late antigen-4 integrin (α4/β1) and is expressed more widely within the hematopoietic system , in resting CLL cells , and is expressed on pre-B-acute lymphoblastic leukemia cells . CD49d plays a critical role in leukocyte trafficking, activation, and survival , and also facilitates interactions between leukocytes and stromal cells found in the marrow or the germinal center of lymphoid follicles through vascular cell adhesion protein-1 and fibronectin . Notably, in addition to these adhesion functions, CD49d can also serve as a signaling receptor that influences B-cell survival through upregulation of Bcl-2 family members .
CD38 is a highly conserved 45 kDa transmembrane type II glycoprotein, it is expressed in numerous cells types of the hematopoietic system, such as lymphocytes, myeloid cells, natural killer 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 .
CD38 and CD49d are both independent prognostic risk parameters in CLL with important roles in shaping these interactions. 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, little is known about the prognostic importance of CD49d and CD38 coexpression as prognostic and survival markers in CLL patients.
| Aim of the study|| |
This study aimed to assess the diagnostic and prognostic value of CD38 and CD49d expressions in CLL and its impact on survival and future treatment measures.
| Patients and methods|| |
This study included 52 newly diagnosed patients with CLL, 37 men and 15 women, ranging in age from 51 to 76 years. All patients were recruited from the Clinical Oncology Department and National Liver Institute (presenting with splenomegaly) Menoufia University outpatients' clinics between September 2013 and December 2014. In addition, 20 age-matched and sex-matched hematological normal individuals, 16 men and four women, ranging in age from 44 to 62 years, were included in the study as a control group.
The diagnosis of B-CLL was made on the basis of clinical, morphologic, and immunophenotypic criteria. The diagnostic criteria for CLL were as follows: an absolute lymphocyte count more than 5 × 10 6 /l in peripheral blood, and a monoclonal lymphocytic population in peripheral blood, lymph node, or bone marrow (defined as CD5+/CD10-/CD19+/CD22+/CD23+) in more than 30% of lymphocytes . At the time of the study, two patients had stage 0, five patients had stage I, 26 patients had stage II, 12 patients had stage III, and seven patients had stage IV according to the Rai staging system.
Treatments that were administered to patients with progressive disease were highly heterogeneous. Whereas some patients received fludarabine-based treatments - with or without rituximab - others received chlorambucil-based or (C)yclophosphamide, (H)ydroxydaunorubicin, (O)ncovin (vincristine), (P)rednisolone (CHOP)-based regimens.
An informed consent was obtained from all patients before the study and this study was approved by the ethical committee of the Menoufia Faculty of Medicine and the National Liver Institute - Menoufia University.
Clinical and radiological examination
All CLL patients were subjected to a thorough assessment of history, complete physical examination, with a focus on lymphadenopathy, splenomegaly, and hepatomegaly, in addition to abdominal ultrasonography and chest radiography.
From all patients and controls, a peripheral blood sample was obtained; one part was placed in an EDTA-containing vacutainer tube for complete blood count analysis and flow cytometric analysis, the second part was placed in a plain tube for chemistry analysis, and the third part was stored in 3.8% sodium citrate for erythrocyte sedimentation rate (ESR). Bone marrow samples were obtained only from the patients, stained, and examined morphologically; a part of the bone marrow sample was placed in heparinized tubes for molecular cytogenetic analysis.
The following investigations were done: complete blood count was performed on an automatic cell counter, Sysmix-k1000 (Sysmex, Bohemia, NY, USA), with examination of blood smear stained by Leishman stain. ESR and lactate dehydrogenase (LDH) were assessed. Serum β2 microglobulin (β2M) was assessed using the enzyme-linked immunosorbent assay technique.
Cytogenetic abnormalities were detected by interphase fluorescence in-situ hybridization carried out for loci on chromosomes 11, 12, 13, and 17. Isolated blood lymphocytes were washed with Hanks balanced salt solution, and cultured and harvested as described previously by Schlette et al. :fluorescence in-situ hybridization using directly labeled commercial probes (Vysis, London, UK) was used for the following genomic aberrations in CLL: an α satellite DNA probe CEP12, directly labeled with Spectrum Green, was used to detect aneuploidy of chromosome 12. For chromosomes 11, 13, and 17, the following three locus-specific probes were used: LSIp53 for del17p13; LSI-ATM for del11q22-q23 at the site of the ataxia-telangectasia (ATM) gene, 13q14-3 at the probe locus-specific identifier (LSI)-D13S319, which was utilized as an internal control. Slides were viewed under a fluorescent microscope using Pathvision software (Vysis). At least 200 interphase cells were examined for each probe; the karyotype stratification was carried out according to Döhner et al. .
Immunophenotyping by a flow cytometer
Flow cytometry immunophenotyping analysis: bone marrow aspirates or whole peripheral blood samples were collected in an EDTA anticoagulant and processed within 24 h of collection. Samples were acquired on a Coulter EPICS-XL flow cytometer (Coulter Diagnostics, Hialeah, FL, USA).
The following panel of monoclonal antibodies was used: B-lymphocyte markers (CD19, CD5, CD23, CD20, CD22, CD79b, CD103, CD123, FMC7, CD38, SmIg, CD10, κ, and λ light chains), all supplied by Beckman Coulter (Fullerton, California, USA). All antibodies were labeled with either fluorescein isothiocyanate or phycoerythrin. Phycoerythrin-cyanine 5-labeled CD19 was used for gating on B-cells. A negative isotopic control for the nonspecific binding of monoclonal antibodies was used. Samples were considered positive for a marker if more than 20% of cells expressed that marker, except for CD38 positivity, which was considered more than 30%.
The expression of CD49d was assessed by flow cytometric analysis using three-color immune-fluorescence by combining phycoerythrin-conjugated anti-CD49d monoclonal antibodies with phycoerythrin-cyanine 5-conjugated anti-CD19 monoclonal antibodies and fluorescein isothiocyanate-conjugated anti-CD5 monoclonal antibodies. CD19-negative lymphocytes (T cells) were expressed CD49d and served as positive controls.
Briefly, after incubation with monoclonal antibodies for 20 min in the dark at 4°C, erythrocytes were lysed with ammonium chloride (NH 4 Cl; pH 7.2) (PharmLyse; BD Biosciences, San Diego, California, USA) at room temperature for 10 min. The cells were then washed in buffered saline. For the detection of cytoplasmic antigens, cells were fixed and permeabilized using 4% formaldehyde and 0.25% saponin. A total of 200 000 events were acquired for assessment of these investigated antibodies. Data were analyzed using FCS Express software (De Novo Software, Los Angeles, California, USA). Identification of the viable leukemic population was performed using CD45 versus side scatter as an initial gate and nonviable cells, debris, and aggregates were excluded on the basis of forward scatter-height/forward scatter-area. The results were presented as a percentage of neoplastic leukemic cells with expression of each respective antigen. The mean fluorescence intensity ratio was calculated by comparison with the negative control.
Data were analyzed using SPSS software, version 21 (Chicago, Il, USA). Fisher's exact test and the χ2 -test were used for qualitative data. Student's (t) test was used to compare two normally distributed variables and the Mann-Whitney test was used for non-normally distributed variables. Correlation coefficients (r) were calculated using Pearson's correlation analysis. An effect was considered statistically significant at P-value less than 0.05. Survival time distributions between prognostic groups were evaluated using standard Kaplan-Meier methods and were compared using the log-rank test.
| Results|| |
[Table 1] shows the data of the CLL patients. A comparison between CLL patients indicated a significant decrease in hemoglobin concentration and platelet counts in CLL patients compared with the control group, whereas ESR, white blood cells, lymphocyte counts, LDH, β2M, and CD49d (mean fluorescence intensity) were significantly increased in CLL patients ([Table 2]).
|Table 2 Comparison between laboratory data of CLL patients and controls |
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The immunophenotypic criteria of CLL patients, CD19 and CD5/CD coexpression, CD23, and SmIg were positive in a total of 52 CLL patients (100%). CD20 was positive in 49 out of 52 patients (94.2%), CD79b in 38 patients (73%), and FMC7 in 13 patients (25%). The coexpression of κ/CD19 and λ/CD19 were positive in 35 (67.3%) and 17 (32.7%) patients, respectively. The CD38 was positive in 28 patients (53.8%) and CD49d in 39 (75%) CLL patients ([Table 3]).
In terms of the cytogenetic criteria of CLL patients, trisomy 12 was detected in six (11.5%) out of 52 CLL patients, deletion of 17p was detected in four (7.7%) patients, deletion of 11q was detected in 10 patients (19.2%), and deletion of 13q was detected in 31 patients (59.6%). However, CD10, CD103, and CD123 were negative in all 52 CLL patients ([Table 3]).
On comparison between coexpression of CD49d+/CD38+ and CD49d+/CD38- patients among CLL patients, there was a significant decrease in hemoglobin concentration and platelet counts in patients who coexpressed CD49d+/CD38+ compared with patients who expressed CD49+ alone, whereas white blood cell and lymphocyte counts, LDH, and β2M were significantly higher in patients who coexpressed the two markers. In addition, the coexpression of CD49d+/CD38+ was significantly high in CLL patients in advanced stages ([Table 4]).
|Table 4 Comparison between CLL patients in terms of coexpression of CD49d and CD38 |
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In the correlation study, there was a positive correlation between the CD49d expression and prognostic parameters in CLL patients: bone marrow lymphocytic count, lymphadenopathy, CLL staging, trisomy 12, chromosomal aberrations (deletion of 17p, 11q, and 13q), and CD38 expression, whereas no correlation was detected with age or sex ([Table 5]).
|Table 5 Correlation between CD49d expression and prognostic parameters in CLL patients |
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Our findings indicated significant differences in the treatment received between CD49d+ and CD49- CLL patients. Our findings indicated significant differences in the treatment received between CD49d+ and CD49d- CLL patients. Where 63.15% of CD49d+ patients had received chemotherapy at the time of study diagnosis (24/38 patients) compared to 21.4% of CD49d- patients (3/14 patients) (P < 0.001, log-rank test). Treatment-free survival was observed (P < 0.01, log-rank test) ([Figure 1]). The median treatment-free duration was shorter in CD49d+ patients (32 months) compared with CD49d- patients (98 months).
|Figure 1 Kaplan-Meier curve for treatment-free survival of patients with CLL in terms of the expression of CD49d. CLL, chronic lymphocytic leukemia|
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Among CD38+ patients, 16 (57.14%) out of 28 CD38+ patients and four (16.7%) of the CD38- patients had received chemotherapy at the time of analysis. Thus, significantly more CD38+ patients required therapy compared with CD38- patients (P < 0.001). On examining the treatment-survival from diagnosis, The median treatment-free duration was shorter in CD38+ patients (28 months) compared with CD38- patients (102 months) (P < 0.05, log-rank test) ([Figure 2]). The median treatment-free duration was shorter in CD38+ patients (28 months) compared with CD38- patients (102 months).
|Figure 2 Kaplan-Meier curve for treatment-free survival in cases of CLL in terms of the CD38 expression. CLL, chronic lymphocytic leukemia|
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The treatment-free duration from diagnosis was assessed between concordant (CD49d+/CD38+) CLL patients (24 cases) and disconcordant CD49d+/CD38- patients (15 cases). The median treatment-free survival was 62 months in CD49d+/CD38- patients and was shorter (24 months) in CD49+/CD38+ patients (P < 0.001, log-rank test) ([Figure 3]).
|Figure 3 Kaplan-Meier curve for treatment-free survival for concordant cases of CLL (CD49d+/CD38+) and disconcordant CD49d+/CD38-. CLL, chronic lymphocytic leukemia|
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| Discussion|| |
Several biological markers can predict disease progression and therapeutic outcomes in patients with early-stage CLL including IGHV mutational status, CD38, and cytogenetic abnormalities . Unfortunately, the large number of novel prognostic markers in CLL, limited information on their prognostic value, and lack of understanding of how to interpret discordant markers are still barriers toward integration of these markers into routine clinical practice .
In the present study, we have investigated the expression of CD49d and CD38 on the surface of CLL cells to assess their prognostic value in CLL patients and the outcome of therapy.
This study showed that the mean expression of CD49d on cell surfaces of CLL patients was significantly higher than that in the controls. Our results are in agreement with those of Buggins et al. , who reported a multimer complex involving CD38, CD49d, MMP9, and CD44 and observed in the majority of the CLL investigated samples. The testing CD49d expression in routine clinical practice emerged as similarly useful in the baseline prognostic assessment of newly diagnosed CLL. Moreover, CD49d was expressed at a higher level in highly proliferative peripheral blood CLL cells .
The association of CD49d with other poor prognostic parameters in our study implies that there was a significant positive correlation between CD49d expression, higher β2M level, lymphadenopathy, bone marrow lymphocytic count, and CLL staging, where CD49 overexpression is associated with more advanced stage. This result is in agreement with the study of Ibrahem et al. , who reported that high expression of CD49d was significantly associated with the presence of splenomegaly and more advanced stage of Binet and Rai staging, and also in agreement with the studies of Dal Bo et al. , Gattei et al. , and Uzay et al. , who found that high CD49d expression was associated with advanced CLL stage.
In terms of the relationship between CD49 and other cytogenetic abnormalities, there were positive correlations between CD49 overexpression and trisomy 12, deletion of 17p, deletion of 11q, and deletion of 13q and CD38 expression. These results are in agreement with those of Brachtl et al. , who reported a positive correlation between CD49d overexpression and IGHV, ZAP70, and CD38 and other cytogenetic abnormalities.
Both Shanafelt et al.  and Messmer et al.  reported that high CD49d expression acts as an independent prognostic marker, but is highly associated with other risk parameters such as IGHV, ZAP70, CD38, and the presence of chromosomal aberrations. Also, Zucchetto et al.  found that significantly higher percentage of CD49d+ patients (about 90% of patients) showed the presence of trisomy 12.
In the current study, we next evaluated the relationship between CD49d expression and clinical outcomes; there was a significant difference in the treatment received between CD49d+ and CD49- CLL patients. Whereas 24 (63.15%) out of 38 CD49d+ patients had received chemotherapy at the time of study diagnosis, only three (21.4%) out of 14 CD49d- patients had been treated. The median treatment-free duration was shorter in CD49d+ patients (32 months) compared with CD49d- patients (98 months).
These results are in agreement with those of Shanafelt et al. , who reported that the high CD49d expression predicts reduced overall survival and time to first treatment in CLL patients. Also, Gattei et al. , who studied CD49d as an independent prognostic factor in untreated CLL patients, reported that high CD49d expression was associated with shorter overall survival and treatment-free survival.
In contrast, Uzay et al.  found that the patients who were in early disease stage (Rai 0-1) had significantly better overall survival and treatment free periods than those in advanced disease stage (Rai 3-4), irrespective of the level of CD49d expression. Majid et al.  did not find a correlation between CD49d expression and in-vitro resistance to fludarabine in liquid cultures, albeit they still observed a protective adhesion of CD49d high cells to fibronectin-coated plates.
Among CD38+ patients, 16 (57.14%) out of 28 CD38+ patients and four (16.7%) of the CD38- patients had received chemotherapy at the time of analysis. Therefore, significantly more CD38+ patients required therapy than CD38- patients. The median treatment-free duration was shorter in CD38+ patients (28 months) compared with CD38- patients (102 months).
These results are in agreement with those of Del Poeta et al.  and Durig et al. , who reported that patients in the CD38-positive cohort were characterized by an unfavorable clinical course with a more advanced disease stage, poor responsiveness to chemotherapy, short time to initiation of first treatment, and shorter survival.
Also, the coexpression of CD38 and CD49d was identified as part of the signature characterizing B-CLL subgroups with worse prognosis. The median treatment-free duration from diagnosis was determined between concordant CD49d+/CD38+ expression (24 cases) and discordant CD49d+/CD38- expression CLL cases (15 cases). The median treatment-free survival was 62 months in CD49d+/CD38- patients and was shorter (24 months) in CD49+/CD38+ patients, suggesting that CD49d and CD38 expressions were considered prognostic markers for CLL patients and they should be assessed identify patients who need therapy and to determine the prognosis of CLL.
These results are in agreement with those of Pittner et al. , who found that the best prognoses were associated with a CD38 low/CD49d low B-CLL phenotype, whereas patients affected by CD38 high/CD49d high diseases showed significantly shorter survivals. However, patients affected by a disease expressing discordant phenotypes, either CD38 low/CD49d high or CD38 high/CD49d low, had survivals comparable to those of the poor prognosis CD38 high/CD49d high B-CLL subset.
Another study by Uzay et al.  reported that only patients with high levels of coexpression) CD38≥30% and CD49d ≥30%) had short overall survival, with no statistical significance. These findings show that CD38+CD49d+ coexpression had a poor prognostic effect on the course of the disease.
| Conclusion|| |
The expression of CD49d and CD38 are considered poor prognostic markers for CLL patients and they should be assessed to decide whether patients need therapy and to determine the CLL treatment-survival. These molecules should also be tested in a large-scale study for its potential in preventing frequent relapses and development of resistance to chemotherapy in CLL.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]