Other malignancies with monoclonal FLCs
SECTION 4 - Lymphoma, leukaemia and plasmacytoma
|Other malignancies with monoclonal FLCs|
|A number of other malignancies are associated with detectable increases in monoclonal FLCs, these include:|
18.1. Solitary plasmacytoma of bone
These bone tumours represent 3-5% of plasma cell neoplasms and are twice as common in women as men (Figure 18.1). Approximately 50% of tumours progress to multiple myeloma (MM) within 3-4 years, while 30-50% of patients are alive at 10 years. The criteria for the disease are shown below .
|Criteria for the diagnosis of solitary plasmacytoma of bone:|
Immunofixation electrophoresis (IFE) of serum and/or concentrated urine shows a small monoclonal protein in approximately 50% of patients. When present, this is useful for guiding therapy and persistence is associated with worse outcome.
The potential use of serum free light chains (sFLCs) has recently been investigated in two studies. In the first report, 13 patients with solitary plasmacytoma were assessed at diagnosis and during progression to MM . By conventional electrophoretic tests, 5 patients had IgG, 2 had IgA and 3 had FLC-only monoclonal proteins, while two were nonsecretory. In total, 5 of the 13 had monoclonal κ FLCs detectable by electrophoretic methods. However, using the more sensitive sFLC immunoassays, 7 patients had κ and 2 had λ monoclonal proteins, including one of the nonsecretory plasmacytomas that was serum κ positive. There was complete concordance between the κ and λ types identified by the FLC assays and the bound light chain type on the intact monoclonal immunoglobulin identified by IFE. After radiotherapy, 7 patients showed reductions in sFLC concentrations. Three patients who progressed to MM showed no reductions in FLC levels.
In a larger study from the Mayo Clinic, 116 patients were retrospectively investigated . At the time of the analysis, 43 had progressed to MM with a median time of 1.8 years. sFLC ratios were abnormal in 54 (47%) patients at diagnosis and this was associated with a higher risk of progression (P=0.039), ie., 44% at 5 years versus 26% with normal sFLC ratios (Figure 18.2), and the group had a shorter survival time (Figure 18.3). A risk stratification model was then constructed for concentrations of more or less than 5g/L of monoclonal immunoglobulin together with normal or abnormal sFLC ratios. Low, intermediate and high risk groups corresponded to none, 1 or 2 positive risk factors, and these gave a progression rate at 2 years of 13%, 26% and 62% respectively (Figure 18.4). It is of interest that urine studies of FLC excretion also showed a correlation with outcome. The authors commented that sFLC analysis provided an important new prognostic indicator.
18.2. Extramedullary plasmacytoma
This is a plasma cell tumour that arises outside the bone marrow and can occur in any organ, although it is found particularly in the upper respiratory tract. Local tumour irradiation is the treatment of choice and only 15% progress to MM. When present, the monoclonal protein is typically IgA . As with solitary plasmacytoma of bone, sFLC measurements may be helpful in managing some of these patients.
|Criteria for the diagnosis of extramedullary plasmacytoma|
18.3. Multiple solitary plasmacytoma
Up to 5% of patients presenting with solitary plasmacytomas develop multiple lesions in the bone or elsewhere, without evidence of MM . As with solitary plasmacytoma, sFLC measurements may be helpful in managing some of these patients.
|Criteria for the diagnosis of multiple solitary plasmacytomas (± recurrent)|
18.4. Plasma cell leukaemia
Plasma cell leukaemia (PCL) is a rare and aggressive variant of multiple myeloma (MM), accounting for 2-4% of cases, and is defined by the presence of >20% plasma cells in the peripheral blood and/or an absolute plasma cell count >2x109/L . It can occur without evidence of MM (primary PCL, 60-70%), or may develop from leukaemic transformation of a pre-existing myeloma clone (secondary PCL, 30-40%) in 1-2% of advanced and refractory patients .
Primary and secondary PCL have distinct clinical and biological features. The median age of primary PCL patients is approximately 10 years younger than the general myeloma population and secondary PCL . Primary PCL also has a more aggressive clinical presentation, with a higher tumour burden and an increased incidence of extramedullary and light-chain only disease (26-44%) .
Monoclonal proteins are present in the majority of patients. A combination of serum protein electrophoresis (SPE) and sFLC analysis has been shown to be an effective screen for MM, including PCL , and sFLC analysis should form part of the initial diagnostic work up of these patients .
As there are no specific response criteria for assessing response to treatment in PCL, the IMWG recommend the application of general MM response criteria . Such criteria incorporate sFLC analysis in the definitions of stringent complete response (sCR) for all patients, and very good partial response (VGPR) and PR for patients whose monoclonal protein is not measurable by serum and urine electrophoresis (Chapter 25).
A number of reports highlight the utility of monitoring PCL with sFLCs . Goyal et al., describe a 40-year old patient who showed a markedly elevated level of λ sFLCs (3527 mg/L) at diagnosis. After treatment with RVd (lenalidomide, bortezomib and dexamethasone), the patient achieved a complete response (CR) which was accompanied with a normalisation of the sFLC ratio .
18.5. Waldenström's macroglobulinaemia
Waldenström's macroglobulinaemia (WM) is a low-grade, lymphoproliferative disorder that is associated with the production of monoclonal IgM. The incidence is 5-10% that of MM, with approximately 1,500 new cases per year in the USA and 300 in the UK. The median age of presentation is 65 years. Median survival is 5 years, but over 20% of patients live for more than 10 years and many die from unrelated causes. Typically, patients present with high concentrations of IgM and infiltration of the bone marrow, spleen and lymph nodes with plasmacytoid lymphocytes and mast cells. Patients may have suppression of bone marrow function, enlarged spleen, liver and lymph nodes, hyperviscosity syndrome, cryoglobulinaemia, neuropathy or AL amyloidosis. All aspects of WM have been reviewed in the April 2003 edition of Seminars in Oncology . The diagnostic criteria for WM are shown below.
|Proposed criteria for the diagnosis of WM|
Serum IgM quantification is important for both diagnosis and monitoring. Unfortunately, nephelometric determinations may be unreliable because polymerisation of the IgM molecules distorts the results. At high concentrations in particular, accurate measurements require the use of SPE and scanning densitometry. At low concentrations no method is accurate because the inclusion of normal IgM leads to overestimation of the monoclonal IgM concentrations. IFE is more sensitive than SPE for detecting low concentrations of IgM but is non-quantitative. In addition, the presence of cryoglobulins or cold agglutinins affects IgM measurements by all methods, so serum samples may need to be assessed under warm conditions .
Another laboratory assessment criterion is the presence of FLC proteinuria. This occurs in approximately 50% of patients and may exceed 1 g/day. However, the amounts excreted are usually low and do not relate particularly well to changes in tumour burden .
Since FLC proteinuria occurs in many patients, it is likely that sensitive sFLC assays show abnormal results more frequently. Figure 18.5 shows sFLC concentrations in 37 patients (21 IgMκ, 15 IgMλ and one biclonal) at the time of plasma exchange for hyperviscosity syndrome. All but one had abnormal FLC concentrations and/or abnormal κ/λ ratios. The non-tumour FLCs were not elevated in any of the patients, indicating no significant renal impairment, but occasionally renal failure does occur .
Since sFLCs are elevated in nearly all patients this may be clinically useful. Their short half-life and the large clinical range should provide a sensitive marker for treatment responses. Also, FLCs do not cryoprecipitate and are not affected by other factors that can make IgM measurements difficult.
They found the following:
- sFLCs were higher in WM (36 mg/L; range 16-140) than in IgM MGUS (20 mg/L; range 16-33): p<0.0003, and sFLC ratios were abnormal in 76.5% of WM patients compared with 23.5% of IgM MGUS patients (p<0.001).
- sFLCs correlated with serum IgM (p <0.008) and viscosity (p <0.008) but not bone marrow involvement.
- sFLCs were higher in symptomatic patients (p <0.001), and correlated with other poor prognostic markers of disease activity such as β2-microglobulin, thrombocytopenia and leukopenia.
- sFLCs >60mg/L separated WM from IgM MGUS with >95% specificity.
These authors also investigated the utility of sFLCs in monitoring WM patients . A prospective study of 32 patients with WM showed that using weekly sFLC measurements, response rates could be detected within a month, and earlier than using IgM measurements. They concluded that sFLCs were a sensitive and useful marker for WM management. Itzykson et al.  studied 42 patients and showed that sFLCs >80mg/L were associated with progressive disease and a shorter time to requirement for treatment (Figure 18.6).
These studies now need to be reviewed in relationship to the current clinical response criteria of WM to determine whether improved patient management can be achieved.
In Waldenström’s macroglobulinaemia, sFLCs may be helpful:
- As prognostic markers.
- To distinguish WM from IgM MGUS.
- As an additional criteria for treatment responses or disease relapse.
18.6. B-cell, non-Hodgkin Lymphomas
Non-Hodgkin lymphomas (NHL) represent about 2.6% of all cancer deaths in the UK (approximately twice that of MM) and the incidence is rising by 3-4% per year in all age groups and both sexes. This is largely unexplained but immunosuppression is a well-defined causative factor, leading to a high excess risk. Approximately 80% of lymphoid malignancies are derived from B-lymphocytes at various stages of differentiation (Table 18.1 and Figures 18.7 and 18.8).
Monoclonal immunoglobulins can be identified in the serum of 10-15% of patients using standard electrophoretic methods. The proteins may be IgG, IgA or IgM and are occasionally biclonal. Reports have indicated that monoclonal FLCs can be detected in the urine of 60-70% of patients with B-cell chronic lymphocytic leukaemia (B-CLL) if the urine is highly concentrated , but interpretation may be difficult if there is co-existing proteinuria.
|Precursor B-lymphoblastic leukaemias/lymphomas||<1%|
|Chronic lymphocytic leukaemia (CLL)/B-cell small lymphocytic leukaemia||7%|
|B-cell prolymphocytic leukaemia||<1%|
|Splenic marginal zone B-cell lymphoma||<1%|
|Hairy cell leukaemia||<1%|
|Plasma cell myeloma/plasmacytoma||<1%|
|Extranodal marginal zone B-cell lymphoma (MALT lymphoma)||8%|
|Nodal marginal zone B-cell lymphoma||2%|
|Mantle cell lymphoma||6%|
|Diffuse large B-cell lymphomas (DLC)||33%|
Table 18.1. The REAL/WHO classification of B-cell NHL and their frequency in relation to all NHL .
In order to determine the frequency of abnormal sFLC concentrations in B-cell NHL, frozen sera from the Lymphoma SPORE serum bank at The Mayo Clinic were studied by Martin et al.  For comparison, samples were also tested for monoclonal immunoglobulins by SPE and IFE. Of 208 patients with NHL, a total of 13% (27/208) had abnormal sFLC concentrations (Table 18.2 and Figures 18.9 and 18.10). The highest incidences were in patients with B-cell small lymphocytic leukaemia (24%) and mantle cell lymphoma (36%). The concentrations of the FLCs were typically much lower than those found in patients with MM. Using SPE and IFE, 16% (33/208) of the patients had detectable monoclonal proteins. In 13 patients (6%), monoclonal proteins were detected only by sFLC immunoassays. The authors commented that these results highlighted the potential importance of sFLC tests in monitoring these patients and assessing complete responses to treatment.
Preliminary analysis of a larger serum bank of Italian patients (n=354) indicated a higher frequency of abnormal FLC ratios (e.g. 57% for mantle cell lymphoma, 33% for Burkitt’s lymphoma and 25% for diffuse large B-cell lymphoma). Concentrations were also measured after treatment and were found to change in accordance with clinical assessments of response and relapse . A smaller study of patients from the UK (n=85) also reported a similar pattern of abnormalities .
A more detailed study of FLC concentrations in 80 patients with diffuse large B-cell lymphoma, found that 29% had elevated (pre-treatment) concentrations of free kappa and 11% had abnormal FLC ratios. Elevated FLC concentrations were associated with worse event-free survival (log rank p=0.006) and overall survival (log rank p=0.009), and concentrations were seen to decrease in response to treatment .
In a case series of 3 patients with primary effusion lymphoma (PEL) or PEL-like lymphoma, changes in FLC concentrations were consistent with changes in treatments and clinical findings, and the authors suggested FLC measurement could be useful for patient monitoring .
HIV-infected patients are at increased risk of developing NHL, and Landgren and colleagues  compared FLC measurements in archived sera from patients who did, or did not, go on to develop NHL. The presence of an abnormal FLC ratio was not found to be prognostic but polyclonal FLC elevations were prognostic (Chapter 21).
|B-cell neoplasm||Number studied||FLC +ve||FLC +ve only||SPE/IFE +ve||SPE/IFE +ve only||Total +ve|
|Small lymphocytic leukemia||25||6 (24%)||2 (8%)||5 (20%)||1 (4%)||7 (28%)|
|Lymphoplasmacytoid||14||2 (14%)||0||4 (29%)||2 (14%)||4 (29%)|
|MALT lymphoma||19||3 (16%)||1 (5%)||7 (37%)||5 (26%)||8 (42%)|
|Follicular, stage I||25||0||0||3 (12%)||3 (12%)||3 (12%)|
|Follicular, stage II||25||2 (8%)||1 (4%)||5 (20%)||4 (16%)||6 (24%)|
|Follicular, stage III||25||1 (4%)||1 (4%)||2 (8%)||2 (8%)||3 (12%)|
|Mantle cell lymphoma||25||9 (36%)||5 (20%)||5 (20%)||1 (4%)||10 (40%)|
|Diffuse large cell||25||2 (8%)||2 (8%)||0||0||2 (8%)|
|Burkitt's lymphoma||17||2 (12%)||1 (6%)||2 (12%)||1 (6%)||3 (18%)|
|Total||208||27 (13%)||13 (6%)||33 (16%)||19 (9%)||46 (22%)|
Table 18.2. Serum monoclonal proteins in B-cell NHL.
B-cell, non-Hodgkin lymphomas complicated by AL amyloidosis
Rarely, AL amyloidosis is associated with NHL. Six patients with this pattern of disease were studied by AD Cohen et al.  and comprised five patients with lymphoplasmacytic lymphoma and one with small lymphocytic lymphoma with plasmacytic features. Organ involvement with amyloid was characterised by bulky lymphadenopathy and visceral deposits but no cardiac disease. Measurements of sFLC concentrations showed elevations at diagnosis and responses to successful treatment. It was concluded that sFLCs were useful for monitoring these patients.
18.7. B-cell, chronic lymphocytic leukaemia
Several reports have suggested that a high percentage of patients with B-CLL may have urine monoclonal proteins . These results are supported by the finding of raised sFLCs in many patients with B-CLL . Of 18 sera studied, 6 patients (33%) had abnormal sFLCs alone (Table 18.3). Using SPE and IFE, only 1 additional patient (6%) had an intact immunoglobulin monoclonal protein. Monoclonal proteins were more commonly found in patients with germline B-CLL (56%) than those with somatic hypermutation (33%). As in patients with B-cell lymphomas, the concentrations of sFLCs were typically much lower than those found in MM (Figure 18.10).
|B-cell CLL type||Number studied||FLC +ve||FLC +ve only||SPE/IFE +ve||SPE/IFE +ve only||Total +ve|
|Germline||9||4 (44%)||3 (33%)||2 (22%)||1 (11%)||5 (56%)|
|Som. Hyper-mutation||9||3 (33%)||3 (33%)||0||0||3 (33%)|
|Total||18||7 (39%)||6 (33%)||2 (11%)||1 (6%)||8 (44%)|
Table 18.3. sFLC concentrations in B-CLL.
A prospective study that screened 1,003 serum samples from symptomatic patients identified five new patients with B-CLL/ lymphoma . This surprisingly high number of positive samples perhaps reflects the relative frequency of lymphomas compared with MM and has been observed in other studies (Chapter 23). However, the concentrations of monoclonal FLCs were low, supporting the observations shown in Figures 18.9 and 18.10.
Pratt et al.  conducted a retrospective study of sFLC concentrations in samples collected at various time points in 226 CLL patients (183 Stage A, 18 Stage B, 16 Stage C, 9 unknown; mean age 74; male:female ratio 2.2:1) treated at 3 separate hospitals in the UK. sFLC concentrations were similar to those observed previously (Figure 18.11). Of greater interest was the observation that abnormal sFLC ratios were associated with poor outcome. Using Kaplan-Meier survival hazards, abnormal sFLC ratios were a significant indicator of poor survival (n=226, Log rank Mantel-Cox p=0.001) (Figure 18.12). Using Cox regression analysis in 142 patients with complete data sets, disease stage, CD38, Zap-70, IGHV mutation status, sFLC ratio, β2-microglobulin and age were analysed in a forward stepwise analysis. Four independent prognostic variables were identified: Zap-70 (p <0.001), β2-microglobulin (p=0.002), IGHV mutation status (p = 0.003) and sFLC ratio (p=0.009) (Table 18.4).
Thus, abnormal sFLC ratios contributed significantly and independently to the prediction of a worse outcome. Further analysis of patients from the same cohort showed that those with abnormal sFLC ratios and sFLC concentrations >50mg/L had more progressive disease and a shorter time to treatment (median 83 months versus 241 months). As an indicator of time to first treatment, sFLC >50mg/L was independent of stage, Zap-70 and mutational status.
Results supporting the association of an abnormal sFLC ratio with a worse prognosis have also been reported . A study by Shustik et al.  found less significant associations with outcome although the patients in that study had more advanced disease. It appears probable that sFLC measurements have more prognostic value in B-CLL patients with Rai stage I / Binet stage A disease. While many other prognostic factors have been identified in CLL, the ready availability and relatively low cost of sFLC measurement makes it an attractive option. Further studies to investigate the biological rationale for its prognostic associations would be valuable.
In a similar study to that already completed, looking for preceding MGUS in subjects who subsequently developed myeloma , archived sera from subjects who subsequently developed B-CLL were examined . Elevated sFLC levels and abnormal sFLC ratios were observed many years prior to the diagnosis of CLL and the authors suggested that chronic immune stimulation might play a role in CLL pathogenesis.
In B-cell NHL and B-CLL:
- Abnormal sFLC concentrations can be detected in a substantial fraction of patients
- sFLC analysis identifies additional patients to those detected by SPE and IFE
- Studies indicate sFLCs are markers of B-CLL disease activity and are independent prognostic factors for response and survival
|All CLL patients||Normal FLC||Abnormal Kappa||Abnormal Lambda||P value|
|No. of cases||259||159||66||34||N/A|
|Binet Stage A/B/C||209/23/21||135/10/10||50/9/5||24/4/6||N/A|
|Median TTFT (months)||84 (0-266)||117 (0-241)||52 (0-362)||33 (0-192)||0.001|
|Median OS (months)||209 (0-326)||254 (0-292)||201 (0-362)||124 (0-223)||0.002|
|Median Kappa (mg/L)||15.9 (0.32-382)||15 (1.83-55.9)||39.05 (2.73-382)||6.52 (0.32-32.1)||<0.001|
|Median Lambda (mg/L)||16.45 (0.82-216)||17.3 (2.8-57.1)||7.53 (0.82-29.6)||38.4 (8.13-216)||<0.001|
|Median β2M (mg/L)||3.4 (0.13-72.4)||2.95 (1.4-12.5)||4.35 (0.13-17.7)||4.53 (1.74-72.4)||<0.001|
|TTFT: time to first treatment. OS: Overall survival. (Courtesy of G Pratt ).|
Table 18.4. Relationship of disease markers at presentation to outcome in patients with B-CLL.
18.8. POEMS syndrome
POEMS syndrome is an acronym for a rare paraneoplastic syndrome that includes Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes, among other manifestations. The disease is usually monoclonal λ restricted.
Drengler et al.  studied 50 patients with newly diagnosed POEMS syndrome using sFLC analysis to determine its role in managing the disease. Fourty-five patients (90%) had an elevated λ sFLC but only 9 had abnormal sFLC ratios. The elevated sFLCs with normal ratios were due to a degree of renal impairment and/or polyclonal activation of the bone marrow, although the underlying mechanisms causing these abnormalities were not apparent.
FLC concentrations are likely to be elevated in many patients with monoclonal cryoglobulinaemia and due to technical difficulties in measuring cryoglobulins, should provide a useful tool. To date, there has been one significant report in patients with hepatitis C virus related lymphoproliferative disorders . This showed that abnormal sFLC ratios were related to both mixed cryoglobulin concentrations and lymphoma development (Chapter 21).
|Chapter 17||Back to Contents Page||Chapter 19|
- ↑ 1.0 1.1 1.2 Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003;121:749–57 PMID: 12780789
- ↑ 2.0 2.1 2.2 2.3 Dingli D, Kyle RA, Rajkumar SV, Nowakowski GS, Larson DR, Bida JP, et al. Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood 2006;108:1979–83 PMID: 16741249
- ↑ Leleu X, Moreau AS, Hennache B, Dupire S, Faucompret JL, Facon T, et al. Serum free light chain immunoassays measurement for monitoring solitary bone plasmacytoma. Haematologica 2005;90:410a
- ↑ 4.0 4.1 4.2 4.3 Fernandez de LC, Kyle RA, Durie BG, A et al. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia 2013;27:780-791 PMID: 23288300
- ↑ Usmani SZ, Heuck, C, Mitchell, A et al. Extramedullary disease portends poor prognosis in multiple myeloma and is over-represented in high-risk disease even in the era of novel agents. Haematologica 2012;97:1761-1767 PMID: 22689675
- ↑ Katzmann JA, Kyle RA, Benson J et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55:1517-1522 19841692 PMID: 19841692
- ↑ van de Donk NW, Lokhorst HM, Anderson KC, Richardson PG. How I treat plasma cell leukemia. Blood 2012;120:2376-2389 22837533 PMID: 22837533
- ↑ Ueda S, Kubo M, Matsuura N et al. Stringent complete remission of primary plasma cell leukemia with reduced-dose bortezomib, lenalidomide and dexamethasone: a case report and review of the literature. Intern Med 2013;52:1235-1238 PMID: 23728562
- ↑ Gozzetti A, Musto P, Defina M et al. Efficacy of bortezomib, lenalidomide and dexamethasone (VRD) in secondary plasma cell leukaemia. Br J Haematol 2012;157:497-498 PMID: 22296516
- ↑ Kruger WH, Kiefer T, Schuler F, Lotze C, Busemann C, Dolken G. Complete remission and early relapse of refractory plasma cell leukemia after bortezomib induction and consolidation by HLA-mismatched unrelated allogeneic stem cell transplantation. Onkologie 2007;30:193–5 PMID: 17396042
- ↑ 11.0 11.1 Goyal M, Mohammad N, Palanki SD, Vaniawala SN. Primary plasma cell leukemia with light chain secretion and multiple chromosomal abnormalities: How successfully treated? Indian J Med Paediatr Oncol 2010;31:96-100 PMID: 21206718
- ↑ 12.0 12.1 Owen RG, Treon SP, Al-Katib A, Fonseca R, Greipp PR, McMaster ML, et al. Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003;30:110–5 PMID: 12720118
- ↑ 13.0 13.1 Itzykson R, Le Garff-Tavernier M, Katsahian S, Diemert MC, Musset L, Leblond V. Serum-free light chain elevation is associated with a shorter time to treatment in Waldenstrom's macroglobulinemia. Haematologica 2008;93:793–4 PMID: 18450739
- ↑ Weber D, Treon SP, Emmanouilides C, Branagan AR, Byrd JC, Blade J, Kimby E. Uniform response criteria in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 2003; 30:127–31 PMID: 12720121
- ↑ Blade J, Montoto S, Rosinol L, Montserrat E. Appropriateness of applying the response criteria for multiple myeloma to Waldenstrom's macroglobulinemia? Semin Oncol 2003;30:329–31 PMID: 12720163
- ↑ Bradwell AR, Mead GP, Drayson MT, Carr-Smith HD. Serum immunoglobulin free light chain measurement in intact immunoglobulin myeloma. Blood 2002;100:5054a
- ↑ 17.0 17.1 Leleu X, Hatjiharissi E, Roccaro AM, Moreau AS, Leduc R, Nelson M et al. Serum immunoglobulin free light chain (sFLC) is a sensitive marker of response in Waldenstrom Macroglobulinemia (WM). Blood 2007;110:1486a
- ↑ Leleu X, Moreau AS, Weller E, Roccaro AM, Coiteux V, Manning R et al. Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia. Leuk Lymphoma 2008;49:1104-7 PMID: 18452095
- ↑ 19.0 19.1 Evans LS, Hancock BW. Non-Hodgkin lymphoma. Lancet 2003;362:139–46 PMID: 12867117
- ↑ Deegan MJ, Abraham JP, Sawdyk M, Van Slyck EJ. High incidence of monoclonal proteins in the serum and urine of chronic lymphocytic leukemia patients. Blood 1984;64:1207–11 PMID: 6437461
- ↑ 21.0 21.1 Pezzoli A, Pascali E. Monoclonal Bence Jones proteinuria in chronic lymphocytic leukaemia. Scand J Haematol 1986;36:18–24 PMID: 3952462
- ↑ Pascali E, Pezzoli A. The clinical spectrum of pure Bence Jones proteinuria. A study of 66 patients. Cancer 1988;62:2408–15 PMID: 3179959
- ↑ 23.0 23.1 Martin W, Abraham R, Shanafelt T, Clark RJ, Bone N, Geyer SM et al. Serum-free light chain-a new biomarker for patients with B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Transl Res 2007;149:231-5 PMID:17383597
- ↑ Pinto A, De Filippi R, Iaccarino G, Di Francia R, Distinto M, Frigeri F, et al. Abnormalities in serum free-immunoglobulin light chains show a high and differential frequency among WHO subtypes of B-cell non-Hodgkin's lymphoma (NHL) and may turn of value for therapeutic monitoring: A study of 354 newly diagnosed patients. Blood 2008;112:2813a
- ↑ Mead G, Harding S, Pratt G, Basu S, Jacob A, Beardsmore C, Bradwell AR. Serum immunoglobulin and free light chain abnormalities in non Hodgkin Lymphoma. Ann Oncol 2008;19:315a
- ↑ Maurer MJ, Micallef IN, Katzmann JA, Nikcevich D, Witzig TE. Elevated pre-treatment serum immunoglobulin free light chains (FLC) are associated with poor event-free and overall survival in diffuse large B-Cell lymphoma (DLBCL) Blood 2009;114:136a
- ↑ De Filippi R, Iaccarino G, Frigeri F, Di Francia R, Crisci S, Capobianco G, et al. Elevation of clonal serum free light chains in patients with HIV-negative primary effusion lymphoma (PEL) and PEL-like lymphoma. Br J Haematol 2009;147:405-8 PMID: 19681885
- ↑ Landgren O, Goedert J, Rabkin C, Wilson W, Dunleavy K, Kyle R, et al. Risk of AIDS non-Hodgkin’s lymphoma is strongly predicted by elevated levels of circulating immunoglobulin-free light chains. Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal 2009:29a
- ↑ Cohen G, Rudnicki M, Schmaldienst S, Horl WH. Effect of dialysis on serum/plasma levels of free immunoglobulin light chains in end-stage renal disease patients. Nephrol Dial Transplant 2002;17:879–83 PMID: 11981077
- ↑ Pascali E. Bence Jones proteinuria in chronic lymphocytic leukemia. Am J Clin Pathol 1995;103:665–7 PMID: 7741117
- ↑ Bakshi NA, Gulbranson R, Garstka D, Bradwell AR, Keren DF. Serum free light chain (FLC) measurement can aid capillary zone electrophoresis in detecting subtle FLC-producing M proteins. Am J Clin Pathol 2005;124:214–8 PMID: 16040291
- ↑ Pratt G, Harding S, Holder R, Fegan C, Pepper C, Oscier D, Mead G. Abnormal serum free light chain ratios are associated with poor survival in patients with chronic lymphocytic leukaemia. Br J Haematol 2008;141:80a
- ↑ Ruchlemer R, Reinus C, Paz E, Cohen A, Melnikov N, Ronson A, Rudensky B. Free light chains, monoclonal proteins, and chronic lymphocytic leukemia. Blood 2007;110:4697a
- ↑ Yegin ZA, Ozkurt ZN, Yagci M. Free light chain : A novel predictor of adverse outcome in chronic lymphocytic leukemia. Eur J Haematol 2010;84:406-11 PMID: 20059535
- ↑ Matschke J, Eisele L, Sellmann L, Duehrsen U, Duerig J, Nückel H. Abnormal free light chain ratios in chronic lymphocytic leukemia: a new prognostic factor? Blood 2009;114:1237a
- ↑ Shustik C, Harding S, Ding K, Zhu L, Rassenti LZ, Kipps TJ, et al. Analysis of the serum free light chain ratio and its prognostic value in a cohort of patients with chronic lymphocytic leukemia Blood 2009;114:2631a
- ↑ Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood 2006;107:904-6 PMID: 16210333
- ↑ Tsai H-T, Caporaso NE, Kyle RA, Katzmann JA, Dispenzieri A, Hayes RB, et al. Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study. Blood 2009;114:4928-32 PMID: 19828698
- ↑ Pratt G, Harding S, Holder R, Fegan C, Pepper C, Oscier D, Mead G. Abnormal serum free light chain ratios are associated with poor survival in patients with chronic lymphocytic leukemia. Br J Haematol 2009;144:217-22 PMID: 19016722
- ↑ Drengler T, Kumar S, Gertz M, Lacy M, Katzmann J, Hayman S, Buadi F, Rajkumar S, Kyle R, Greipp P, Dispenzieri A. Serum Immunoglobulin Free Light Chain Measurements Provide Insight into Disease Biology in Patients with POEMS Syndrome. Proceeding of Portugese myeloma meeting 2008
- ↑ Terrier B, Sene D, Saadoun D, Ghillani-Dalbin P, Thibault V, Delluc A, et al. Serum-free light chain assessment in hepatitis C virus-related lymphoproliferative disorders. Ann Rheum Dis 2009;68:89–93 PMID: 16040291
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