Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia

Leleu, Xavier; Moreau, Anne; Weller, Edie; Roccaro, Aldo M.; Coiteux, Vale Rie; Manning, R.J.; Nelson, Marybeth; Leduc, Renee; Robu, Daniela; Dupire, Sophie; Hatjiharissi, Evdoxia; Burwick, Nicholas; Darre, Stéphane; Hennache, Bernadette; Treon, Steven P.; Facon, Thierry; Gertz, Morie A.; Ghobrial, Irène M.

doi:10.1080/10428190802074619

Cited by 44 publications

(29 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the FLC concentration was higher in patients with increased β2 microglobulin, hypoalbulinemia and anemia. 6,7 Small patient series showed a correlation between FLC, time to treatment and overall survival, 6,8 but larger studies are needed to confirm these findings.…”

Section: Introductionmentioning

confidence: 97%

Molecular pathogenesis of Waldenstrom's macroglobulinemia

et al. 2012

View full text Add to dashboard Cite

Waldenström's macroglobulinemia is an indolent, lymphoproliferative disease, characterized by a heterogeneous lymphoplasmacytic bone marrow infiltrate and high immunoglobulin M production. While technological advances over the past several decades have dramatically improved the possibilities of studying the molecular basis of Waldenström's macroglobulinemia, the pathogenesis of the disease remains fragmented. Undoubtedly, research has been successful in uncovering underlying aberrations and deregulated mechanisms in this disease, providing useful information for identifying biomarkers for disease diagnosis, risk stratification and therapeutic intervention, but there is still a long way to go before the pathogenesis of Waldenström's macroglobulinemia is fully revealed. In addition, the low number of in vitro or in vivo models significantly challenges extensive analysis. In this manuscript, we review the molecular basis of this disease.Key words: WM, NF-kB signaling pathway, Jak/STAT, PI3K/Akt, aCGH, IL-6. Waldenström's macroglobulinemia. Haematologica 2012;97(9):1281-1290. doi:10.3324/haematol.2012 This is an open-access paper. Citation: Braggio E, Philipsborn C, Novak A, Hodge L, Ansell S, and Fonseca R. Molecular pathogenesis of ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o nagreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as fever, night sweats or weight loss. The median survival ranges from five to more than ten years, depending on the series analyzed. 10-13The existence of somatic hypermutation in WM indicates a role for antigenic stimulation in the development of WM. [14][15][16] The IgH variable region genes are commonly mutated and the VH3 gene is often used, suggesting antigen exposure and selection. 14,17 Clonality studies have shown clonal IgH and IgL gene rearrangements. The IgH variable region is commonly mutated in WM, but intraclonal variation is usually absent and IgH switching usually does not occur. 18,19 Environmental and inherited factors may contribute to familial IgM-MGUS/WM clusters. Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased risk for progression to WM. 20 In a population-based study of 1,384 individuals with MGUS, researchers showed an increased risk factor of 46 for developing WM. 20 The rate of progression from IgM-MGUS to WM was further noted to be 1.5-2% a year. [21][22][23] While the development of WM is thought to be sporadic, there are a few studies demonstrating familial linkage and predisposition to the disease. 2,[24][25][26] Both familial clustering of WM and a notable increase (~10 fold) of IgM-MGUS frequency in first-degree relatives of WM patients is suggestive of familial risk. 27 Using the assumption that WM and IgM-MGUS share common susceptibility genes, strong linkages involving chromosomes 1q, 3q, and 4q have been identified. 21 A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested b...

show abstract

Section: Introductionmentioning

confidence: 97%

Molecular pathogenesis of Waldenstrom's macroglobulinemia

et al. 2012

View full text Add to dashboard Cite

show abstract

“…LDH 10.5 g/dl 84 versus 209 months [4] 11.5 g/dl 72 versus 123 months [9] 12 g/dl HR = 1. The prognostic role of the free light chain (FLC) concentration has been evaluated at diagnosis in series of 42 [37] to 98 patients [38]. Symptomatic patients had signifi cantly higher FLC values.…”

Section: Reviewmentioning

confidence: 99%

“…FLC concentration, expressed as a continuous variable, was higher in patients with B2M more than 3 mg/l treatment [37,38], albumin less than 35 g/l treatment [37] or with hemoglobin concentration less than or equal to 11.5 g/dl [38]. It was found that the FLC and mIgM concentrations were not related to each other [38], but there was a correlation between maximum percentage reduction in involved FLC and mIgM [39]. The FLC value correlated with time to treatment [37,40], and more importantly to OS [40].…”

Section: Reviewmentioning

confidence: 99%

Risk stratification in Waldenström macroglobulinemia

Morel¹,

Merlini

2012

Expert Review of Hematology

View full text Add to dashboard Cite

“…The serum FLC ratio is now a part of the international consensus guidelines for the management of AL amyloidosis [26] The serum FLC assay has also proven to be useful in a variety of hematologic malignancies beyond myeloma. Patients with Waldenströ m's macroglobulinemia who present with an elevated serum FLC ratio carry a worse prognosis and require treatment sooner than those with a normal ratio [27,28]. There is also emerging evidence that serum FLC can be detected in a large fraction of patients with non-Hodgkin lymphoma.…”

Section: Clinical Applicationsmentioning

confidence: 99%

Serum free light chain analysis

2010

View full text Add to dashboard Cite

In a variety of hematologic malignancies, immunoglobulin light chains (LC) are overproduced clonally and circulate without being linked by disulphide bonds to the immunoglobulin heavy chain. The recent development of a robust assay known as j and k ''free'' LC (FLC) to quantify the levels of these unbound LC in the serum, and thereby determine their ratio, has led to an explosion of studies that demonstrate its utility in a wide range of hematologic disorders. This article summarizes laboratory testing for serum FLC, with a particular focus on clinical applications for the test. Am. J. Hematol. 85:787-790, 2010. V V C 2010 Wiley-Liss, Inc. BackgroundHematologic malignancies frequently result in the production of monoclonal immunoglobulin. Detection of both intact immunoglobulin and immunoglobulin free light chains (FLC) in the urine and blood has proven to be valuable in the diagnosis, prognosis, and monitoring of treatment of these diseases. One particularly useful property of serum FLC is their short half-life in the blood (j, 2-4 hrs; k, 3-6 hrs) in comparison to intact immunoglobulin (21 days), which provides an opportunity for real-time monitoring of disease progression and response to treatment.For well over a century, testing for the presence of Bence Jones (BJ) protein in the urine was considered to be the gold standard to assess the clonally abnormal levels of immunoglobulin FLC. This technique can detect FLC down to the range of 10-40 mg/L; however, it can be challenging to obtain an accurate 24 hr urine collection, which is necessary for the test [1]. Moreover, due to the high resorptive capabilities of the proximal tubules of the kidney or reduced renal function, patients with low levels of FLC in the serum may not have detectable amounts in the urine [2]. Quantitative alterations of serum immunoglobulins (Igs) may result from polyclonal or monoclonal disorders. The combination of serum protein electrophoresis (SPEP), immunofixation (IFE), and densitometric analysis permits characterization and quantitation of the monoclonal immunoglobulin; however, the sensitivity of SPEP to detect FLC is poor, with a lower limit of sensitivity of 500-2,000 mg/L. Although the IFE does improve sensitivity for the detection of FLC (lower limit of sensitivity 150-500 mg/L), it is a more time-intensive assay and does not allow for quantification. Technical Aspects, Performance, and LimitationsThe development of an accurate and reproducible serum assay to determine j and k FLC concentration with high sensitivity has been a major challenge. A significant barrier to the development of the test is the fact that the unique epitope that is a marker of FLC is ''hidden'' or concealed in the conformational structure of an intact Ig. This precluded the development of a tool such as a specific antibody to detect the ''hidden epitope'' of FLC. This barrier was overcome in 2001 by Bradwell and coworkers [3], who dissociated the FLC from heavy chains and then raised polyclonal antibodies to detect the unique epitopes on j and k LC. T...

show abstract

Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia

Cited by 44 publications

References 17 publications

Molecular pathogenesis of Waldenstrom's macroglobulinemia

Molecular pathogenesis of Waldenstrom's macroglobulinemia

Risk stratification in Waldenström macroglobulinemia

Serum free light chain analysis

Contact Info

Product

Resources

About