Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia

Abstract

Summary The measurement of immunoglobulin serum free light chains (sFLC) has prognostic significance in plasma cell dyscrasias but its role in chronic lymphocytic leukaemia (CLL) is unknown. This retrospective study from three UK hospitals analysed sFLC in 181 untreated/pre‐treatment CLL patients and 78 treated CLL patients, with samples taken later in their disease. An abnormal sFLC ratio was significantly associated with poor overall survival for the 181 untreated/pre‐treatment patients (P = 0·0001) and for all patients (P = 0·002), irrespective of cause of death. Using multivariate analysis (n = 194), four independent prognostic variables for overall survival were identified namely Zap‐70 (P = 0·0001), β2M (P = 0·01), IGHV mutation status (P = 0·017) and an abnormal sFLC ratio (P = 0·024). For CLL patients with unmutated IGHV genes, elevated κ/λ ratios were adversely prognostic. For patients with mutated IGHV genes, reduced κ/λ ratios were adversely prognostic and associated with the poor prognostic IGHV3‐21, IGHV3‐48 and IGHV3‐53 subgroups, suggesting an abnormal sFLC ratio may reflect biological subgroups within CLL. Abnormal sFLC ratios need to be studied prospectively in CLL patients and the biological rationale for their abnormality investigated.

Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study

“…Our results are timely given previous studies reporting a 38.6% of abnormal serum FLC ratio based on a retrospective analysis of 259 pretreated/treated CLL patients 6 and that CLL patients with M-proteins 4 and abnormal FLC ratios 6 at CLL diagnosis have a poorer survival than those without. Indeed, the most recent study shows that Zap-70 expression, elevated ␤-2-microglobulin levels, unmutated IGHV genes, and the presence of an abnormal FLC ratio are independent negative prognostic variables for overall survival in CLL.…”

“…4 Furthermore, a recent study including 181 CLL patients found an abnormal free light chain (FLC) ratio to be independently associated with a poor prognosis along with 3 other previously established markers (Zap-70 expression, elevated ␤-2-microglobulin levels, and unmutated IGHV mutational status). 6 These observations suggest that detectable serum protein abnormalities in CLL may reflect biologic heterogeneity, presenting by differential prognostic profiles.…”

“…Indeed, the most recent study shows that Zap-70 expression, elevated ␤-2-microglobulin levels, unmutated IGHV genes, and the presence of an abnormal FLC ratio are independent negative prognostic variables for overall survival in CLL. 6 In addition, in contrast to, for example, flow cytometry and IGHV gene rearrangement analyses, the protein assays applied in our study are easily available in most standard clinical care settings. Further studies with longitudinal follow-up and larger sample size are needed to explore the role of serum protein abnormalities in relation to cytogenetic abnormalities, such as ZAP-70, CD38 expression, and IGHV in the development of CLL, their applications in the early detection of CLL, as well as in disease progression and outcome.…”

Assessment of Monoclonal Gammopathies by Nephelometric Measurement of Individual Immunoglobulin κ/λ Ratios

“…The HLC results support the observation of relative increases in the production of to molecules. This may be linked to an excess of MC-Igs seen in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia (10,20 ).…”

Serum free light chain analysis

“…A prospective study found that FLC levels may be abnormal nearly 10 years before a diagnosis of CLL is made, suggesting that their production may represent an early event in the pathogenesis of the disease [30]. Other emerging data suggest that an abnormal FLC ratio confers a worse prognosis in CLL patients, and may actually identify a biologically distinct subgroup of the disease [31,32]. Elevated serum FLC levels have also recently been shown to independently confer an increased risk of development of non-Hodgkin lymphoma in HIV-infected persons [33].…”