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

The serum free light chain (sFLC) assay represents a predictor of prognosis and therapeutic response in monoclonal gammopathies and multiple myeloma (MM). Since sFLC testing detects and quantifies monoclonal and polyclonal B-cell populations expanding in lymphohemopoietic tissues, we evaluated the potential value of sFLC abnormalities as a novel disease marker for patients (pts) with B-cell non-Hodgkin’s lymphomas (NHL). Frozen (−80°C) serum samples from 354 untreated pts with NHL categorized according to WHO criteria (Table 1) and with normal renal function and serum immunochemistry, were assayed by immunonephelometry (Freelite, The Binding Site, Ltd., Birmingham, UK). After quantitation of serum free k and l concentrations (normal ranges, k: 3.3–19.4 mg/mL; l: 5.71–26.3 mg/mL), FLC ratio was calculated as k/l (free k concentration divided by free l, reference range 0.26–1.65). In cases with a ratio >1.65, k was considered the ‘involved’ (inv.) FLC and l the ‘uninvolved’ FLC, and vice versa if the ratio was less than 0.26. Sera from 45 MM pts, 43 pts with solid tumors and 22 pts with reactive lymphadenopathy (LAD) were also analyzed. Elevated sFLC concentrations, i.e. both k and/or l, were found in 53% to 80% of cases while abnormal FLC (k/l) ratios were detected in a restricted fraction of pts with a histotype-related fashion (Table). Tumors mostly arising from pre-germinal centre (GC) B-cells, i.e. Small Lymphocytic Lymphoma (SLL) and Mantle Cell Lymphoma (MCL), and those deriving from late post-GC cells, i.e. Burkitt lymphoma (BL), displayed the higher rates of abnormal FLC ratio (57%, 42% and 33% for MCL, SLL and BL, respectively), due to free k chain involvement in 86% to >90% of cases. Accordingly, these tumors showed a high median inv. k chain concentration (33.5 to 53 mg/L). In Follicular Cell (FCL) and Diffuse Large B Cell (DLBC) lymphomas the FCL ratio was abnormal in 23% and 25% of pts respectively, due to k FLC involvement in > 90% of cases, and a median serum inv. k concentration of 26 mg/mL in FCL (G1 20.5; G2, 16.3; G3, 16.9; G3b, 23,6 mg/L) and 25 mg/L in DLBCL. Interestingly, 8 cases of localized DLBCL of bone and CNS showed a normal sFLC test. Pts with disseminated Marginal Zone (MZ) lymphoma displayed abnormal FLC ratio in 16% of cases and the highest median inv. k concentration (66.5 mg/L). sFLC testing was positive > 80% of MM pts while no solid tumors and reactive LADs cases displayed abnormal sFLC ratio. In15 NHL pts (FCL, MCL, MZL) given upfront treatment with Rituximab (R) or Zevalin, sFLC test was explored as a tool for therapeutic monitoring. A stepwise decrease in inv. k chains levels was observed in all responders, followed by a rise at relapse. Similarly, disease control in SLL (n=14) and MCL (n=10) pts by first line R-immunochemotherapy was associated to normalization of sFCL test. Our results, on the largest serie reported, indicate that NHL pts display a high frequency of monoclonal sFLC. Differences among WHO histotypes at presentation may mirror specific biologic features, including pre/post-GC derivation and propensity to dissemination. sFCL testing represents a furher tool to dissect biologic heterogeneity of NHL and a new marker for therapeutic monitoring.