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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 41  |  Issue : 2  |  Page : 56-64

Serum monoclonal and polyclonal free light chains in newly diagnosed Egyptian patients with diffuse large B-cell lymphoma: their impact on event-free and overall survival


1 Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Clinical Pathology Department, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission10-Jan-2016
Date of Acceptance17-Jan-2016
Date of Web Publication15-Jul-2016

Correspondence Address:
Tamer A Elbedewy
Department of Internal, Medicine, Faculty of Medicine, Tanta University, 51719 Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1110-1067.186404

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  Abstract 

Background/aim Diffuse large B-cell lymphoma (DLBCL) constitutes the largest subtype of B-cell non-Hodgkin's lymphomas. The prognostic ability of the International Prognostic Index in the era of immunochemotherapy is modest. New prognostic biomarkers are mandatory to provide new insights into the risk stratification of DLBCL. Nowadays, serum-free light chain (sFLC) assay is being applied to hematologic non-plasma cell B-cell lymphoid malignancies. The aim of our work was to investigate the prevalence and prognostic value of elevated sFLC (monoclonal and polyclonal) in DLBCL and their impact on event-free survival (EFS) and overall survival (OS).
Patients and methods This cohort study included 58 patients with DLBCL. Pretreatment serum samples were taken to detect κ and λ sFLCs with enzyme-linked immunosorbent assay. Patients were followed up every 3 months and computed tomographic scan was done every 6 months for 24 months after treatment. EFS and OS were estimated.
Results Twenty-four patients (41.38%) had elevated κ or λ sFLC. Thirteen patients (22.41%) and 11 patients (18.97%) had monoclonal and polyclonal elevated sFLC, respectively. EFS and OS significantly decreased in patients with elevated sFLC and in those with abnormal sFLC ratio (monoclonal elevated sFLC). OS significantly decreased in patients with monoclonal elevated sFLC when compared with those with polyclonal elevated sFLC, but there was no difference between monoclonal and polyclonal elevated sFLC patients as regards EFS.
Conclusion Elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) correlate with disease outcome (EFS and OS). There was no difference between monoclonal and polyclonal elevated sFLC as regards EFS but there was significant difference as regards OS.

Keywords: diffuse large B-cell lymphoma, event-free survival, monoclonal serum-free light chain, overall survival, polyclonal serum-free light chain


How to cite this article:
Elbedewy TA, Baiomy N. Serum monoclonal and polyclonal free light chains in newly diagnosed Egyptian patients with diffuse large B-cell lymphoma: their impact on event-free and overall survival. Egypt J Haematol 2016;41:56-64

How to cite this URL:
Elbedewy TA, Baiomy N. Serum monoclonal and polyclonal free light chains in newly diagnosed Egyptian patients with diffuse large B-cell lymphoma: their impact on event-free and overall survival. Egypt J Haematol [serial online] 2016 [cited 2019 Dec 11];41:56-64. Available from: http://www.ehj.eg.net/text.asp?2016/41/2/56/186404


  Introduction Top


Non-Hodgkin's lymphomas (NHLs) have a large number of subtypes that show different clinical, biologic, cytogenetic, and molecular characteristics [1]. Diffuse large B-cell lymphoma (DLBCL) constitutes the largest subtype of B-cell NHL. The International Prognostic Index (IPI) had been developed as a clinical prognostic score for DLBCL in the era of chemotherapy [2]. At present, the standard line of treatment for newly diagnosed DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) [2],[3]. IPI remains a clinical prognostic score in the era of immunochemotherapy, although its general prognostic ability is modest. Also, because DLBCL has highly variable clinical courses, identification of molecular and biological prognostic biomarkers is mandatory to provide new insights into the risk stratification of DLBCL patients [4].

The vast majority of immunoglobulin light chains are bound to immunoglobulin heavy chains as intact immunoglobulin, but in healthy individuals a small amount of free κ and λ light chains that are not attached to heavy chains are produced by monoclonal and/or polyclonal B-cell populations and are called serum-free light chains (sFLC) [5]. sFLC abnormalities can be polyclonal (increase in one or both sFLCs with a normal κ : λ ratio), monoclonal (elevation of one sFLC that results in an abnormal ratio), or ratio-only FLC abnormality (normal range κ and λ with abnormal sFLC ratio), which is considered normal. The detection of monoclonal sFLC is very useful in the diagnosis and management of patients with monoclonal gammopathies [6]. The polyclonal elevation of sFLC due to generalized B-cell activation in renal impairment as well as in autoimmune, inflammatory, or infective conditions is also important and associated with high mortality rate in different diseases [7]. The sFLC assay is nowadays being applied to hematologic nonplasma cell B-cell lymphoid malignancies. On utilizing this assay one study found monoclonal sFLCs in 13% of patients with a variety of lymphoma types and in 8% of patients with DLBCL [8]. In another study on 295 patients with untreated DLBCL from two independent cohorts, 32% of patients had an elevated sFLC (polyclonal or monoclonal) and 14% were monoclonal [9].

The results among different studies on sFLC in DLBCL cases are limited, with many discrepancies. Therefore, further studies are mandatory to define the role of sFLC as a new, easily measurable prognostic biomarker before its introduction as a routine biomarker in clinical practice for predicting prognosis. Thus the aim of our work was to investigate the prevalence and prognostic value of elevated sFLC (monoclonal and polyclonal) in DLBCL and its impact on event-free survival (EFS) and overall survival (OS).


  Patients and methods Top


Patients

This prospective cohort study included 58 patients with DLBCL. They were selected from the clinical hematology unit, Internal Medicine Department, Tanta University Hospital and Tanta Cancer Center, Egypt, from April 2012 to June 2013. The study was conducted in accordance with the guidelines of the declaration of Helsinki 1975 and its subsequent amendments (1983). Participation in the study was voluntary after written informed consent was obtained from the patients.

Patients with renal impairment, gammopathies, autoimmune disorders, inflammatory disorders, or infective conditions were excluded. Exclusion criteria also included any hematological malignancies other than DLBCL.

Methods

DLBCL was diagnosed on the basis of histopathological examination of lymph nodes and/or extranodal tissue biopsy specimens according to the Revised European-American Lymphoma (REAL) classification criteria of Harris [10]. Patients were staged according to the Ann Arbor staging system with Cotswolds modifications [11]. Ann Arbor staging was determined for all patients at the onset of DLBCL by physical examination, computed tomography (CT) scan (abdomen and pelvis, chest, and neck), and bone marrow examination. Patients' performance status was assessed using Eastern Cooperative Oncology Group (ECOG) performance status [12]. IPI was used for determining the prognosis of DLBCL [2]. The standard treatment protocol for DLBCL in this study was CHOP [intravenous cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1.4 mg/m 2 (maximum dose = 2 mg) on day 1 and oral prednisone 100 mg/day on days 1-5] or R-CHOP (as CHOP plus rituximab at a dose of 375 mg/m 2 on day 1 of each cycle) every 3 weeks for 6-8 cycles [13].

Before the start of the DLBCL treatment, every patient underwent baseline full history taking, complete physical examination including B symptoms (fever > 38°C, drenching sweats especially at night, and unintentional weight loss > 10% of normal body weight over a period of 6 months or less), and routine biochemistry assays including lactate dehydrogenase (LDH) (normal range 105-333 IU/l).

Cheson's criteria were used to define the response to treatment [14]. Patients' response to initial therapy was assessed at mid-treatment, unless response was clinically apparent (3-4 cycles) on CT scan, to identify non-response or progression. Six to eight courses were completed if at least 50% partial remission or complete remission was achieved. The assessment was repeated at the end of therapy. Patients were followed up clinically and by routine investigations every 3 months and by means of a CT scan every 6 months for 24 months after treatment [15]. The follow-up period ranged from 4 months to 24 months (median = 24 months), with 95% confidence interval (18.6-22.1 months).

In the case of relapsed or progressed disease, second-line therapy Ifosfamide/Carboplatin/Etoposide (ICE) (24 h intravenous infusion ifosfamide 5000 mg/m 2 on day 2, intravenous carboplatin using the Calvert formula with maximum 800 mg on day 2, and intravenous etoposide 100 mg/m 2 on day 1-3) every 14 days or Cyclophosphamide/Etoposide/Oncovin(Vincristine)/Prednisone (CEOP) [intravenous cyclophosphamide 750 mg/m 2 on day 1, intravenous etoposide 50 mg/m 2 on day 1 and 100 mg/m 2 orally on days 2 and 3, intravenous vincristine 1.4 mg/m 2 intravenously (maximum dose = 2 mg) on day 1 and oral prednisone 100 mg/m 2 on day 1-10] every 3 weeks was given to patient candidates and non-candidates for high-dose therapy, respectively [15],[16].

Disease progression, retreatment, death, and treatment regimens used were verified through medical records. EFS was defined as the time from diagnosis to disease progression, retreatment, or death due to any cause. OS was defined as the time from diagnosis to death due to any cause. Patients without an event or death were censored at the time of last known follow-up.

Serological assays

Frozen pretreatment serum samples were assayed to detect κ and λ sFLCs by using human immunoglobulin sFLC κ and λ enzyme-linked immunosorbent assay (ELISA) (Biovendor Research and Diagnostic Products, Candler, North Carolina, USA). The assay separately measures κ sFLC (normal range = 0.225-3.45 mg/dl) and λ sFLC (normal range = 0.45-5.42 mg/dl). In addition, the assay provides the sFLC ratio (normal range = 0.23-1.85). Elevated sFLC was defined as the κ or λ concentrations above the normal range [17].

The test principle

In the BioVendor Human Immunoglobulin sFLC κ and λ ELISA, standards, quality controls, and samples were incubated in microplate wells pre-coated with monoclonal anti-human immunoglobulin sFLC κ or sFLC λ antibody. After 60 min incubation and washing, biotin-labelled secondary monoclonal antibody was added and incubated with the captured antibody sFLC κ or λ complex for 60 min. After another washing, streptavidin horseradish peroxidase conjugate was added. After 30 min incubation and the last washing step, the remaining conjugate was allowed to react with the substrate solution 3,3′, 5, 5′-tetramethylbenzidine. The reaction was stopped by addition of acidic solution, and absorbance of the resulting yellow product was measured. The absorbance was proportional to the concentration of sFLC. A standard curve was constructed by plotting absorbance values against concentrations of standards, and concentrations of unknown samples were determined using this standard curve.

Statistical analysis

The collected data were analyzed using SPSS version 17 software (SPSS Inc., Chicago, Illinois, USA). Comparison of continuous data between two groups was made by using the unpaired t-test for parametric data. Fisher's exact and χ2 -tests were used for comparison between categorical data. Survival analysis was performed using the Kaplan-Meier method, and comparison between two survival curves was made using the log-rank test. The accepted level of significance was 0.05 (P ≤ 0.05 was considered significant).


  Results Top


Fifty-eight DLBCL patients were recruited into this study, comprising 32 men (55.17%) and 26 women (44.83%). At the time of diagnosis, the patients' ages ranged from 28 to 73 years (mean = 50.55 ± 11.001 years) (median = 48.5 years). The demographic clinical and laboratory data of DLBCL patients are shown in [Table 1].
Table 1 Characteristics of the study population


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Twenty-four patients (41.38%) had elevated sFLC [11 patients (18.97%) had elevated κ sFLC and 13 patients (22.41%) had elevated λ sFLC], and none of the patients (0%) had both elevated κ and λ sFLC. Thirteen patients (22.41%) had monoclonal elevated sFLC, and 11 patients (18.97%) had polyclonal elevated sFLC ([Table 1]).

The patients with elevated sFLC had significantly higher incidences of adverse performance status, abnormally high LDH, progression, relapse, and death and a lower incidence of complete remission when compared with patients with normal sFLC ([Table 2]).
Table 2 Comparison between elevated and normal serum-free light chain patients as regards different variables


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The patients with abnormal sFLC ratio (monoclonal elevated sFLC) had a significantly lower percentage of patients with partial remission and a higher percentage of patients with progression, relapse, and death in comparison with the patients with normal sFLC ratio and polyclonal elevated sFLC, but there were no differences as regards complete remission between monoclonal and polyclonal patients ([Table 3]).
Table 3 Comparison between patients with abnormal serum - free light chain ratio (monoclonal elevated serum - free light chain) and those with normal serum - free light chain ratio and those with polyclonal elevated serum - free light chain as regards different variables


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In the analysis of IPI and the line of treatment as independent variables for EFS and OS showed that EFS and OS significantly decreased in patients with higher IPI score (P = 0.000 for EFS and OS) ([Table 4] and [Table 5] and [Figure 1] and [Figure 2]).
Figure 1 Kaplan-Meier analysis of the event-free survival probability

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Figure 2 Kaplan-Meier analysis of the overall survival probability.

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Table 4 Event - free survival probability for different groups of patients


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Table 5 Overall survival probability for different groups of patients


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In the analysis of sFLC, sFLC ratio and the clonality of abnormal sFLC as independent variables for EFS and OS showed that EFS and OS significantly decreased in patients with elevated sFLC, with significant difference, when compared with normal sFLC patients (P = 0.000 and 0.0015, respectively). Also, EFS and OS significantly decreased in patients with abnormal sFLC ratio (monoclonal elevated sFLC), with significant difference when compared with patients with normal sFLC ratio (P = 0.0006 and 0.000, respectively). Also, OS significantly decreased in patients with abnormal sFLC ratio (monoclonal elevated sFLC), with significant difference when compared with that in patients with polyclonal elevated sFLC (P = 0.0125), but there was no difference between monoclonal and polyclonal elevated sFLC patients as regards EFS ([Table 4] and [Table 5] and [Figure 1] and [Figure 2]).


  Discussion Top


sFLC concentrations are dependent on the balance between production and renal clearance through the proximal tubules, with half-lives of between 2 and 6 h. Under normal circumstances, little protein escapes into the urine and hence sFLC concentrations are a more accurate representation of production levels. When there is increased polyclonal immunoglobulin production and/or renal impairment, both κ and λ sFLC concentrations can increase 30-40-fold with normal κ/λ ratio. In contrast, the production of a monoclonal excess of one FLC type as in patients with plasma cell disorders gives an abnormal serum κ/λ ratio, providing an indicator of clonality [18].

Historically, the laboratory methods for screening for monoclonal gammopathies were serum protein electrophoresis (SPE) and urine protein electrophoresis (UPE), which provide a semiquantitative value for the amount of M-protein. Serum immunofixation electrophoresis is required for confirmation of clonality with an analytical sensitivity of between 500 and 2000 mg/l [19]. A major limitation of SPE is the inability to detect low-level monoclonal proteins, particularly FLCs. Serum immunofixation electrophoresis is ~10-fold more sensitive and may pick up additional monoclonal proteins that are undetected by SPE [20].

In 2001, immunoassays using nephelometry (Freelite, Binding Site, Birmingham, UK) were developed, which provide a more sensitive laboratory quantification of monoclonal sFLC. The sFLC tests provide an independent measurement of κ and λ FLC. The assays are latex-enhanced immunoassays and allow measurement of FLC concentrations as low as 1.5 and 3 mg/l for κ and λ FLCs, respectively [18]. Several groups have developed monoclonal antibodies-based FLC immunoassays using the ELISA [21],[22].

The sFLC assays should not be confused with total κ and λ light chain (TLC) assays, which detect all forms of κ or λ light chains (FLC plus those that form intact immunoglobulins). TLC assays are insensitive for the detection of sFLC and are not recommended by international guidelines [23].

There are several plausible causes for elevated sFLC in patients with DLBCL, such as renal dysfunction, advanced age, immune disruption, or stimulation [7]. The production of sFLC in patients with DLBCL could be derived from microenvironment cells based on stimuli from tumor cells or from the tumor cells themselves. In multiple myeloma, monoclonal plasma cells secrete FLC, whereas in Hodgkin's lymphoma polyclonal FLCs are secreted by benign cells in the tumor microenvironment [24].

In our study, 11 patients (18.97%) had elevated κ sFLC, 13 patients (22.41%) had elevated λ sFLC, no patient (0%) had both elevated κ and λ sFLC, and 24 patients (41.38%) had elevated κ or λ sFLC. Thirteen patients (22.41%) had monoclonal elevated sFLC, and 11 patients (18.97%) had polyclonal elevated sFLC.

Martin et al. [8] showed the frequency of abnormal sFLC ratio in 25 patients with DLBCL to be 8%. A larger study was published by Maurer et al. [9] including two independent cohorts (N0489 and MER with 76 and 219 patients, respectively) of 295 patients with DLBCL in which elevated sFLC concentrations and abnormal sFLC ratio were seen in 34 and 12% of the N0489 group and in 31 and 15% of the MER group, respectively. Elevated FLC or abnormal sFLC ratio was present in 32 and 14% of patients, respectively. In the study by Witzig et al. [25] on 276 patients with DLBCL, 94 patients (34%) had an elevation of sFLC: 68 (25%) polyclonal and 26 (9%) monoclonal. Han et al. [26] showed that the frequency of elevated sFLC and abnormal sFLC ratio was 42.6% (51/108) and 4.6% (5/108) of patients, respectively, in a study of 108 therapy-naοve patients with DLBCL. In the study by Kim et al. [27] on 175 newly diagnosed DLBCL patients, 96 (54.9%) patients had an elevated sFLC. Monoclonal and polyclonal abnormal sFLCs were observed in 34 (19.4%) and 68 patients (38.9%), respectively.

The frequency of elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) varies considerably, from 31 to 54.9% and from 4.6 to 19.4%, respectively, across studies [8],[9],[24],[25],[26]. The discrepancy in the reported incidence of elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) between studies, including our study, can be attributed to several factors. One could be the differences in the sensitivity of the methods used for detection of sFLC (ELISA vs. nephelometry). Other factors may be the number of patients studied, the ethnicity of the studied groups, age of the patients, and differences in renal functions. Our selection of patients with a normal renal function could explain why we had less polyclonal elevations.

Our results found that the group with elevated sFLC had a significantly higher percentage of patients with adverse performance status, abnormally high LDH, progression, relapse, and death and a lower percentage of patients with complete remission when compared with patients with normal sFLC. Also, the group with abnormal sFLC ratio (monoclonal elevated sFLC) had a significantly lower percentage of patients with partial remission and a higher percentage of patients with progression, relapse, and death in comparison with the group with normal sFLC ratio and polyclonal elevated sFLC, but there were no differences as regards complete remission between monoclonal and polyclonal patients.

In our study, EFS and OS significantly decreased in patients with elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) with significant difference when compared with patients with normal sFLC and normal sFLC ratio, respectively. Also, OS significantly decreased in patients with abnormal sFLC ratio (monoclonal elevated sFLC) with significant difference when compared with polyclonal elevated sFLC patients, but there was no difference between monoclonal and polyclonal elevated sFLC patients as regards EFS.

Maurer et al. [9] investigated the association of pretreatment sFLC with EFS and OS and found that patients with elevated sFLC had inferior EFS and OS in both cohorts compared with patients with normal sFLC even after adjusting for the IPI. Abnormal sFLC ratio, however, was modestly associated with EFS and OS in combined groups, with the association only related to a concomitantly elevated sFLC regardless of its being monoclonal or polyclonal in nature. In a multivariate analysis, sFLC proved to have stronger association with EFS and OS compared with the five IPI components. Further, an association was also found between elevated sFLC and stage, and probably with a more aggressive tumor.

Jardin et al. [28] measured sFLC in 409 serum samples of patients with DLBCL and found that patients with an abnormal sFLC ratio more frequently displayed adverse clinical characteristics and had inferior progression-free survival and OS as compared with patients with a normal ratio in the overall cohort and R-CHOP cohort.

Witzig et al. [25] found that in newly diagnosed DLBCL patients receiving immunochemotherapy there was an association between both monoclonal and polyclonal sFLC abnormalities and inferior outcome. They also found that within the abnormal sFLC category patients with monoclonal sFLC elevation were slightly worse compared with patients with polyclonal sFLC elevation.

Han et al. [26] found that patients with elevated sFLC more frequently displayed adverse clinical characteristics, including age and B symptoms. They also found that patients with elevated sFLC but not with abnormal sFLC ratio had an inferior OS and tended to have shorter progression-free survival compared with patients with normal sFLC even after adjusting for IPI.

Kim et al. [27] found that, in multivariate analysis, elevated sFLC was significant for EFS and OS. Monoclonal and polyclonal abnormal sFLCs were also associated with inferior OS and EFS.

Although these results exhibited some differences, it clearly demonstrated that elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) were associated with unfavorable outcomes in patients with DLBCL.

Our study is not without limitation, as it lacked the use of nephelometry as the more sensitive laboratory quantification of sFLC. However, De Kat Angelino et al. [29] demonstrated that κ sFLC concentrations can be measured more accurately by ELISA than by nephelometry and κ sFLC concentrations measured by nephelometry are constitutively and exponentially overestimated, explaining the large error in patients with high serum κ sFLC concentrations. Our study has some obvious limitations as well, such as a small sample size and short follow-up period. However, the strength of our study is that all patients had normal renal function. In addition, we analyzed a more homogenous group of patients with a uniform type of NHL.


  Conclusion Top


The study concluded that elevated sFLC and abnormal sFLC ratio (monoclonal elevated sFLC) correlate with disease outcome (EFS and OS) and can be considered independent prognostic factors for DLBCL. There was no difference between monoclonal and polyclonal elevated sFLC as regards EFS but there was significant difference as regards OS. Clearly, the measurement of sFLCs as potentially useful biomarkers for prognosis may provide additional information to standard laboratory tests, which may be of considerable importance in DLBCL patient treatment and follow-up.

A wider study on a large number of patients is recommended. Also, serial measurements for sFLC during follow-up may give information about the effect of treatment on sFLC values and provide prediction for relapse. Further studies are needed to better understand the mechanisms of elevated FLC in DLBCL. Future studies should correlate monoclonal FLC secretion with DLBCL genotype to confirm or reject this relationship.

Acknowledgements

The authors thank Dr. Hossam Eldin A. Elashtokhy, MD (Tanta Cancer Center), for his help in collection of some materials for this study.

Authors' contributions: Tamer A. Elbedewy: concept, design, definition of intellectual content, statistical analysis and clinical studies; Tamer A. Elbedewy and Nivin Baiomy: literature search, manuscript preparation, manuscript editing, manuscript review, data acquisition, and data analysis; Nivin Baiomy: experimental studies. All authors have been read and approved the final version of the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

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