|Year : 2012 | Volume
| Issue : 4 | Page : 240-245
Prognostic significance of serum monoclonal immunoglobulin in B-chronic lymphocytic leukemia
Mona A. El-Hussiny1, Lamiaa Ibrahim1, Emad Azmy2, Sameh Shamaa3
1 Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura, Egypt
2 Clinical Hematology Unit, Mansoura Cancer Institute, Mansoura Faculty of Medicine, Mansoura, Egypt
3 Department of Medical Oncology, Mansoura Faculty of Medicine, Mansoura, Egypt
|Date of Submission||30-May-2012|
|Date of Acceptance||29-Jun-2012|
|Date of Web Publication||21-Jun-2014|
Clinical Hematology Unit, Mansoura Cancer Institute, P.O. Box 61519, Mansoura
Source of Support: None, Conflict of Interest: None
Serum immunoglobulin (Ig) paraprotein can be detected in a subset of patients with chronic lymphocytic leukemia (CLL) by serum protein electrophoresis and immunofixation electrophoresis. CLL with Ig paraproteinemia had an inferior survival compared with patients with CLL without serum paraprotein.
Participants and methods
The present study was carried out on 100 patients with B-CLL (60 men and 40 women) ranging in age from 33 to 75 years. The staging of CLL was performed according to the Binet staging system. Venous blood samples were obtained from B-CLL patients for a complete blood count. Serum was separated for the measurement of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG) levels by ELISA, and Ig paraprotein. Bone marrow aspiration was carried out for all B-CLL cases. Prognostic markers of CD38 and &zgr;-chain-associated protein kinase-70 (ZAP-70) expression were also analyzed.
Twenty-two patients had Ig paraproteinemia of a total of 100 untreated patients with CLL, frequency 22%. There was a highly significant elevation in LDH, β2-MG, CD38, ZAP-70, IgG, and IgM in CLL with monoclonal paraprotein versus CLL without monoclonal paraprotein. There were positive correlations of serum IgG paraprotein and serum IgM paraprotein with advanced Binet stage (P<0.00 and P=0.00), high level of β2-MG (P=0.00 and 0.00) and LDH (P=0.00 and 0.00), CD38 positivity (P=0.00 and 0.02), and ZAP-70 positivity (P=0.00 and 0.01). Also, there was a positive correlation between high serum β2-MG concentration with Binet stage (P=0.00), high level of LDH (P=0.00), CD38 positivity (P=0.00), and ZAP-70 positivity (P=0.02). After a follow-up of 60 months, 15 patients (15%) died. Eight (36.3%) patients with Ig paraproteinemia died during the observation period, whereas among the 78 patients without Ig paraproteinemia, seven (8.9%) died.
β2-MG and Ig paraprotein serve as poor prognostic markers for B-CLL. Patients with CLL with serum Ig paraprotein represent a heterogeneous group with an inferior clinical outcome. Serum Ig paraprotein might be applied for the assessment of prognosis in patients with CLL.
Keywords: chronic lymphocytic leukemia, monoclonal immunoglobulin, paraproteinemia, prognosis
|How to cite this article:|
El-Hussiny MA, Ibrahim L, Azmy E, Shamaa S. Prognostic significance of serum monoclonal immunoglobulin in B-chronic lymphocytic leukemia. Egypt J Haematol 2012;37:240-5
|How to cite this URL:|
El-Hussiny MA, Ibrahim L, Azmy E, Shamaa S. Prognostic significance of serum monoclonal immunoglobulin in B-chronic lymphocytic leukemia. Egypt J Haematol [serial online] 2012 [cited 2017 Aug 16];37:240-5. Available from: http://www.ehj.eg.net/text.asp?2012/37/4/240/134971
| Introduction|| |
B-chronic lymphocytic leukemia (CLL) is a monoclonal expansion of small mature B lymphocytes accumulating in the blood, marrow, and lymphoid organs. Although most patients are asymptomatic at diagnosis, some can have systemic symptoms, hepatosplenomegaly, lymphadenopathy, and cytopenias because of leukemic infiltration of the bone marrow and other organs 1. The natural course of CLL is highly variable. Whereas some patients have aggressive disease with an early need for treatment and significantly shorter overall survival (OS), others have indolent disease without any need for treatment at all and identical survival with their CLL free counterparts of the same age 2.
Many clinical and laboratory markers have already been tested for their putative prognostic value. Classical and readily available parameters include Rai and Binet stage (on the basis of the number of organs infiltrated by the CLL clone, hemoglobin concentration, and number of platelets) and parameters of cell division (serum level of lactate dehydrogenase (LDH), thymidine kinase, and lymphocyte doubling time) 3.
A number of serologic parameters such as β2-microglobulin (β2-MG) have been shown to provide information on outcome. β2-MG is an extracellular protein associated with the class I major histocompatibility complex. Its serum levels show a correlation with the clinical staging systems 4. Many new prognostic parameters on the basis of molecular biological and phenotypical analyses of B-CLL cells have emerged recently. &zgr;-Chain-associated protein kinase-70 (ZAP-70) is the most promising surrogate marker for the IgVH mutation status 5. The detection of CD38 cell surface expression together with ZAP-70 may prove to be a valuable adjunct in the diagnostic workup of B-CLL patients 6.
Although M-protein secretion is typically a feature of plasma cell dyscrasias, monoclonal gammopathy has been recognized in a wide variety of lymphoproliferative disorders. It has been described in patients with B-CLL 7, well-differentiated lymphoma 8, Burkitt’s lymphoma, and other histological subtypes of lymphomas 9. The WHO classification recognizes that a ‘small M component’ can be found in some patients with CLL; the exact incidence and the precise significance of this association has not been established clearly 10.
The aim of the present work was to study the incidence and prognostic significance of monoclonal protein in B-CLL.
| Patients and methods|| |
The present study was carried out on 100 patients with B-CLL (60 men and 40 women) ranging in age from 33 to 75 years. They were recruited from the oncology center, Mansoura University. The study was approved by the research ethics committee of Mansoura University and consents were obtained from the patients in the study.
The diagnosis of B-CLL was made on the basis of clinical characteristics, peripheral blood and bone marrow morphology, and peripheral blood absolute lymphocyte count of at least 5.0×109/l. Immunophenotyping was carried out as defined in the WHO classification and according to the National Cancer Institute criteria 11.
The immunophenotyping of B-CLL cells was positive for monotypic surface immunoglobulin (Ig) (dim intensity), CD5, CD19, CD20 (dim intensity), and CD23 and usually negative or dimly positive for surface Ig, CD22, CD79b, and FMC-7. The staging of CLL was carried out according to the Binet staging system 12.
Sampling: specimen collection
- One milliliter whole-blood samples were placed in an EDTA-containing tube for complete blood count by an automated cell counter (Sysmex SE 9000; Sysmex Corporation, Kobe, Japan).
- Two milliliter whole blood was placed into an EDTA-containing tube for immunophenotyping. Prognostic testing (ZAP-70 status, CD38 status) was carried out using an EPICS XL flow cytometer (Coulter Electronic, Miami, Florida, USA).
- Two milliliter whole blood was left to clot and serum was separated after centrifugation and stored at −20°C till used for LDH, β2-MG, serum protein electrophoresis and immunofixation, and IgG and IgM concentration analyses.
LDH measurement was carried out using a Dimension RxL Max TM clinical chemistry system (221249-AX; Dade Behring Inc., Siemens, California, USA). The β2-MG level was assayed using a solid-phase enzyme-linked immunosorbent assay (ORGENTEC Diagnostika GmbH 55129, Mainz, Germany).
Serum protein electrophoresis and immunofixation were carried out using a Hellabio Electrophoresis system (0209v4003; Merg Med, Greece) 13,14. Serum IgG and IgM concentration were assayed by quantitative nephelometric determination (Turbox plus, 1020568; Orion Diagnostica, Espoo, Finland) 15.
Detection of ZAP-70 and CD38
For analysis of the CD38 expression level in B-CLL cells, we used the method described by Tinhofer et al. 16. After incubation of a blood sample with a mixture of anti-CD5-FITC, anti-CD19-PerCP-Cy5.5, and anti CD38-PE monoclonal antibodies (Immunotech, Beckman Coulter, Marseille, France) for 15 min, lysis of red blood cells was carried out using IO Test 3 lysing solution (Beckman Coulter, Fullerton, USA). Analysis was carried out using the EPICS XL flow cytometer (Coulter Electronic. After gating on CD5+/CD19+ cells (B cells) and CD5+/CD19− cells (T cells), which were used as an internal positive control, B cells were analyzed for CD38 expression. Isotype controls were run with each sample to distinguish positive from negative cells. The cutoff point for CD38 positivity in CLL cells was more than 30% 17.
For analysis of ZAP-70 expression, blood samples were incubated with anti-CD5-FITC and anti-CD19-PerCP-Cy5.5 (Immunotech, Beckman Coulter) for 15 min; red cells were lysed using IO Test 3 lysing solution (Beckman Coulter, Fullerton, USA). After centrifugation at 200g, fixation and permeabilization of cells were carried out using Intraprep kits reagent (Immunotech, Beckman Coulter); anti-ZAP-70–PE (clone SBZAP) (Beckman Coulter, Fullerton, California, USA) was then added and cells were incubated for 15 min, cells were washed with PBS, and analyzed by flow cytometry. After gating on B cells (CD5+/CD19+), percentages of ZAP-70-positive CLL cells were determined with negative threshold cutoff values set using ZAP-70-stained normal B cells, as well as isotype control-stained CLL cells. The cut-off point for ZAP-70 positivity in CLL cells was more than 20% 18.
Data entry and analyses were carried out using SPSS statistical package version 10 (SPSS Inc., Chicago, Illinois, USA). The quantitative data were presented as mean, SD. Qualitative variables were presented as number and percentage and compared using the χ2-test. The correlation between quantitative variables was determined using the Pearson correlation for parametric data. Kaplan–Meier survival analysis was used to determine overall and disease-free survivals using the log-rank test for comparisons of factor probably affecting survival. A P value less than 0.05 was considered significant.
| Results|| |
[Table 1] shows the clinical characteristics of 22 CLL patients with Ig paraprotein. The present study was carried out on 100 patients with CLL, 22 patients with Ig paraproteinemia from a total of 100 untreated patients with CLL, for a frequency of 22% (eight patients with IgG paraprotein, 10 patients with IgM paraprotein, four patients with both IgG and IgM, and no patient with IgA)[Figure 1]. The frequency of the monoclonal Ig light chain (κ or &lgr;) expressed by the neoplastic cells in all patients with Ig paraproteinemia was κ: 14/22(63.6%) and &lgr;: 8/22 (36.4%).
|Table 1: Isotypes of heavy and light chains among 22 patients with an M protein|
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|Figure 1: Serum immune fixation of B-CLL patients with M protein (both IgG and IgM κ). B-CLL, B-chronic lymphocytic leukemia; IFE, immunofixation electrophoresis; Ig, immunoglobulin.|
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[Table 2] shows a comparison of the studied parameters in CLL with Ig paraprotein and CLL without Ig paraprotein. Significant positive correlations were observed between serum LDH, β2-MG, Binet staging, CD 38%, ZAP 70%, IgG, and IgM. There was a significant increase in the mean values of LDH, β2-MG, CD 38%, ZAP 70%, IgG, and IgM in CLL with M protein in comparison with CLL without M protein (P=0.045, 0.005, 0.002, 0.003, 0.00, and 0.00, respectively).
|Table 2: Characteristics of CLL patients with and without immunoglobulin paraprotein|
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[Table 3] shows the correlations between serum Ig paraprotein and other prognostic factors. The possibility of an interaction between serum Ig paraprotein and other known prognostic factors, such as Binet stages, LDH, and serum level of β2-MG, CD38, and ZAP-70 expression, was analyzed. Significant positive correlations were observed between the serum concentration of IgG paraprotein and advanced Binet stage (r=0.66, P=0.00), serum LDH (r=0.690, P=0.00), serum β2-MG (r=0.511, P=0.01) and CD38 (r=0.634, P=0.00), and ZAP-70 expression (r=0.553, P=0.00). Also, significant positive correlations were observed between serum IgM paraprotein and advanced Binet stage (r=0.570, P=0.00), serum LDH (r=0.710, P=0.00), serum β2-MG (r=0.598, P=0.00) and CD38 (r=0.764, P=0.02), and ZAP-70 expression (r=0.993, P=0.01).
|Table 3: Correlations between serum monoclonal IgG and IgM concentrations and other prognostic factors|
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[Table 4] shows the correlation between serum β2-MG and LDH concentration and other prognostic parameters: There was a significant positive correlation between high serum β2-MG concentration with Binet stage (r=0.778, P=0.00), serum LDH (r=0.545, P=0.00), CD38 (r=0.619, P=0.00), and ZAP-70 expression (r=0.432, P=0.02). Also, there was a significant positive correlation between serum high LDH level and Binet stage (r=0.567, P=0.00), CD38 (r=0.548, P=0.00), and ZAP-70 expression (r=0.538, P=0.00).
|Table 4: Correlations between high serum β2-MG and LDH concentration and other prognostic factors|
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Prognostic impact of serum Ig paraprotein on OS
After a follow-up of 60 months, 15 patients (15%) died. Ig paraproteinemia was associated with a poor outcome. Eight (36.3%) patients with Ig paraproteinemia died during the observation period (three patients with IgG paraprotein, four patients with IgM paraprotein, one patient with both IgG and IgM, respectively), whereas among the 78 patients without Ig paraproteinemia, seven (8.9%) died. Patients with Ig paraproteinemia had significantly shorter survival times than patients without serum Ig paraprotein (P=0.00). Patients with IgG paraproteinemia had significantly shorter survival times than patients without serum IgG paraprotein (P=0.00) [Figure 2]. Patients with IgM paraproteinemia had significantly shorter survival times than patients without serum IgM paraprotein (P=0.05) [Figure 3]. The estimated mean OS of B-CLL patients with and without Ig paraproteinemia was 50.5 months (95% confidence interval, 47.2–54.1 months) and 59.5 months (95% confidence interval, 58.6–60.0 months), respectively. The estimated OS of B-CLL patients with and without IgG paraproteinemia were 49.9 months (95% confidence interval, 44.5–52.2 months) and 58.2 months (95% confidence interval, 56.7–59.8 months), respectively. The estimated OS of B-CLL patients with and without IgM paraproteinemia were 51.5 months (95% confidence interval, 49.0–53.9 months) and 57.3 months (95% confidence interval, 54.5–59.5 months), respectively.
|Figure 2: Overall survival (OS) curve of B-CLL patients with and without IgG paraproteinemia. B-CLL, B-chronic lymphocytic leukemia; Ig, immunoglobulin.|
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|Figure 3: Overall survival (OS) curve of B-CLL patients with and without IgM paraproteinemia. B-CLL, B-chronic lymphocytic leukemia; Ig, immunoglobulin.|
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| Discussion|| |
B-CLL is a heterogeneous disorder characterized by a variable clinical course 19. Some patients have an aggressive disease requiring early therapy, whereas other patients show a more stable, indolent disease with no benefit from palliative chemotherapy 20. Several prognostic markers have been identified during the last two decades to identify patients with a poor prognosis and to facilitate the clinical management of B-CLL 21.
Although M-protein secretion is typically a characteristic of plasma cell dyscrasias, it can be detected with varying frequencies in other B-cell malignancies such as CLL 22.
The present study found that there were 22 B-CLL patients with Ig paraproteinemia out of a total of 100 untreated patients with CLL, for a frequency of 22% (eight patients with IgG paraprotein, 10 patients with IgM paraprotein, four patients with both IgG and IgM, and no patient with IgA). This was in agreement with Deegan et al. 23, who reported that immune-related phenomena are well-known complications of CLL.
Tsai et al. 24 found that 13% of CLL patients have M protein. These rates are markedly higher than the prevalence of abnormal M proteins in the general population of individuals 50 years or older (reportedly 2–3%) 25. Schaffner et al. 26 and Xu and Roberts-Thomson 27 found an association of CLL with serum monoclonal paraprotein, usually IgM.
Sahota et al. 28 and Efremov et al. 29 observed a monoclonal serum IgG paraprotein coexisting with IgM paraprotein in three patients. The presence of both IgM and IgG monoclonal proteins indicates that neoplastic transformation may have occurred at the time of isotype switching from IgM to IgG or that the tumor cells retained their capability of isotype switching, a process independent of Ig heavy chain gene mutation. Sanchez et al. 30 suggested that these additional M components may represent biclonal or triclonal lymphoproliferative disorders or the development of a subclone within the original tumor cells because of clonal evolution.
The limitation of clinical staging systems (Rai and Binet staging systems) in CLL, which fail to identify early-stage patients most likely to progress, has led to the search for new prognostic markers with highly predictive capabilities. Several parameters have shown relevance: lymphocyte doubling time, serum LDH, β2-MG, TK1, ZAP-70 and CD38 expression level, cytogenetic aberrations, and mutational status of IGHV 31.
The present study found a significant elevation in the serum β2-MG concentration in B-CLL patients with Ig paraproteinemia when compared with CLL patients without Ig paraproteinemia (P=0.005). Keating et al. 32 reported that B-CLL patients had an increased concentration of β2-MG, which is a poor prognostic factor in lymphoid malignancies. β2-MG is associated with adverse prognostic features at presentation and higher values have been found in CLL patients with a shorter survival. Di Giovanni et al. 33 found that the mean β2-MG value in the CLL group was significantly higher than that in the control group. The elevated β2-MG may be secondary to increased proliferation of lymphoma cells because of stimulation by cytokines, causing an increase in the turnover of the membrane-bound β2-MG 34. Ibrahim et al. 35 have reported that serum levels of β2-MG higher than 4.0 mg/l are adverse prognostic factors in a wide range of lymphoid malignancies, including B-CLL. Fayad et al. 36 have reported that elevated Rai stage and elevated β2-MG correlated with shorter survival in CLL patients.
The present study found a strong positive correlation between serum high LDH level with Binet stage (r=0.567, P=0.00), β2-MG (r=0.545, P=0.00), CD38 (r=0.548, P=0.00), and ZAP-70 expression (r=0.538, P=0.00). Few studies have been published on LDH measurement in CLL. Some authors have reported that the total LDH activity in B-CLL was not significantly different from that of normal B cells 37. However, Dohner et al. 38 have reported that a high level of serum LDH, which is a measure of tumor burden and turnover, is associated with rapid disease progression and worse clinical prognosis in B-CLL. Also, Shen et al. 39 found that the OS time in group of elevation of both LDH and β2-MG levels was shorter than that in group of normal levels of both LDH and β2-MG in CLL.
The present study found unfavorable prognostic significance of serum Ig paraprotein. Ig paraproteinemia was significantly related to adverse prognostic factors. There were positive correlations of the serum Ig paraprotein concentration with advanced Binet stage; high levels of β2-MG, CD38, and ZAP-70 expression were observed. Also, there were positive correlations of serum IgG paraprotein and serum IgM paraprotein with advanced Binet stage (P=0.00 and 0.00), LDH (P=0.00 and 0.00), and high levels of β2-MG (P=0.01 and 0.00) and CD38 (P=0.00 and 0.02), and ZAP-70 expression (P=0.00 and 0.01).
These findings are in agreement with those of Xu et al. 40, who reported strong correlations of serum Ig paraprotein with advanced Binet stage, DAT positivity, high level of β2-MG and TK1, absence of IGHV mutations, ZAP-70+, CD38+, and cytogenetic abnormalities of del(17p13) or del(11q22.3).
In our study, OS was longer in patients without Ig paraproteinemia than in patients with serum Ig paraprotein. After a follow-up 60 months, 15 patients (15%) died. Eight (36.3%) patients with Ig paraproteinemia died during the observation period (three patients with IgG paraprotein, four patients with IgM paraprotein, one patient with both IgG and IgM, respectively), whereas among the 78 patients without Ig paraproteinemia, seven (8.9%) died. Patients with Ig paraproteinemia either IgG or IgM had significantly shorter survival times than patients without serum Ig paraprotein (P=0.00).
There is a debate about the relationship between serum Ig paraprotein and survival in CLL. Bernstein et al. 41 have reported that those with an M protein at diagnosis had a poorer survival than those without (63 versus 103 months, P=0.04), and Xu et al. 40 have reported that OS was longer in patients without Ig paraproteinemia than in patients with serum Ig paraprotein. However, Yin et al. 42 have not confirmed this observation. Therefore, it is still not clear how the serum Ig paraprotein actually affects the survival of CLL patients 9.
| Conclusion|| |
Patients with CLL with serum Ig paraprotein represent a heterogeneous group with an inferior clinical outcome. Serum Ig paraprotein might be applied for the assessment of prognosis in patients with CLL.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]