The potential of serum light chains in diffuse large B-cell lymphoma

A potential new biomarker for diffuse large B-cell lymphoma (DLBCL) should differentiate between high risk and low risk patients at diagnosis and/or provide a measure of tumor burden or activity. Ideally it would also be non-invasive, readily available and easy to interpret. There is a small but growing body of literature examining serum free light chains (FLCs) in lymphoid malignancies. FLC abnormalities have been reported to be associated with outcome in chronic lymphocytic leukemia (CLL) [1,2], Hodgkin lymphoma (HL) [3], mantle cell lymphoma (MCL) [4] and DLBCL [5]; however, outside of CLL, these results are in single studies, and have not yet been replicated. In this issue of Leukemia and Lymphoma, Jardin and colleagues report their experience with serum light chain abnormalities in DLBCL [6]. The importance of this study is two-fold. It provides the first confirmation of previous results in DLBCL. Second, the authors present the first study of serum heavy chain/light chain pairs (HLCs) in lymphoma. Combined, these results provide important insight into the types of light chain abnormalities in DLBCL and how we might apply these findings to future studies and clinical use.

In terms of availability and ease of use, assessment of kappa and lambda FLCs in the serum has become a widely used technique for hematologists in the diagnosis and monitoring of plasma cell dyscrasias. Interpretation of light chain abnormalities in lymphoma is still a work in progress, as the incidence and type of abnormalities vary widely by subtype, and analytical incorporation of the FLC ratio with the absolute concentrations of FLCs has varied by study. There appear to be several types of light chain abnormalities in patients with DLBCL, and it will be important to distinguish these patients for prognostic and management purposes. FLC abnormalities can broadly be grouped into three general categories: polyclonal FLCs (elevation of kappa or lambda with a normal FLC ratio), monoclonal FLCs (elevation of kappa or lambda with an abnormal FLC ratio) and ratio-only FLC abnormalities (non-elevated kappa and lambda with abnormal FLC ratio). Jardin's study suggests that similar groupings can be made using HLC abnormalities.

Most of the current literature has examined general (typically polyclonal) elevation. In DLBCL, 19–32% of patients have elevated FLCs; these patients have poor event-free (EFS) and overall survival (OS). Polyclonal elevation can be due to a varied number of factors including immune stimulation and renal failure, so it is difficult to differentiate whether the poor outcome associated with elevated light chains is tumor related, host related or perhaps a combination of the two. Thus, perhaps the greatest potential of light chain assessment lies in the ability to detect a monoclonal elevation. Barring a known monoclonal gammopathy of unknown significance (MGUS) or other plasma cell disorder, the cause of a monoclonal excess is likely due to secretion from the DLBCL tumor. Hypothetically, this also suggests that the tumor is an activated B-cell (ABC) subtype [7]. From gene expression studies, Jardin and colleagues provide preliminary evidence to support this hypothesis. Our previous study also showed that a rise in monoclonal FLCs was detected prior to scan-based relapse in a patient with DLBCL with monoclonal FLCs at diagnosis, further linking monoclonal light chains with tumor activity and suggesting that monoclonal light chains might have a role as a more specific serum tumor marker than lacatate dehydrogenase (LDH) for monitoring disease status. In terms of outcome, patients with monoclonal light chains have poor EFS and OS, which is presumably tumor related and not due to host factors. This poor outcome also aligns with an ABC tumor subtype. The major limiter of monoclonal FLCs as a biomarker is the low prevalence, as only about 5–10% of patients with DLBCL have a monoclonal FLC elevation at diagnosis. The ability to separately assess kappa and lambda chains in intact antibodies via HLCs will likely increase the utility in DLBCL, as Jardin's study showed a much higher rate of abnormal immunoglobulin M (IgM) kappa:lamba ratios (19%) than abnormal FLC ratios (9%), with little overlap between FLC and IgM abnormalities.

Additional work remains to be done before FLC/HLC assessment can be broadly used clinically as a tumor marker, however. Definitive studies are needed to confirm that excess serum light chains are due to tumor secretion and confirm association with the ABC tumor. Further examination of the relationship between FLC and HLC abnormalities should be performed, as well as formal studies of serial FLC and HLC assessment in relation to disease status. The broad clinical availability of these markers, replicated association of light chain abnormalities with poor outcome, and plausible relationship with tumor activity from an aggressive type of DLBCL suggest that this additional work is warranted for this promising biomarker.

Potential conflict of interest

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