Elevated serum monoclonal and polyclonal free light chains and interferon inducible protein‐10 predicts inferior prognosis in untreated diffuse large B‐cell lymphoma

Abstract

The detection of serum free light (FLC) is useful in the diagnosis of several hematological diseases. The role and biological relevance of monoclonal or polyclonal FLC elevations in predicting long-term outcome in diffuse large B-cell lymphoma (DLBCL) is unknown. We determined the relationship of the type of FLC elevations to outcome, tumor genotype, and pattern of serum cytokine elevations in 276 patients with untreated DLBCL. Elevated FLC was an adverse prognostic factor through 6 years of follow-up (monoclonal, EFS HR = 3.56, 95% CI: 1.88-6.76, p<0.0001; polyclonal, EFS HR = 2.56, 95% CI: 1.50-4.38, p=0.0006). 73% of DLBCL tumors with monoclonal FLC elevations were activated B-cell type (ABC) vs. 33% from patients with normal FLC. Only ABC-DLBCL lines secreted kappa FLC in vitro and this secretion could be inhibited by the NF-κB inhibitor bortezomib. Patients with monoclonal FLC had significantly (all p<0.001) elevated serum levels of IL-12, sIL-2Rα, IL-1R, and IP-10. Patients with polyclonal elevations of FLC had higher levels of IL-6 (p=0.033), IL-8 (p=0.025), sIL2Rα (p=0.011), and IL-1R1 (p=0.041). The combination of elevated FLC and a CXC superfamily chemokine IP-10 predicted a particularly inferior outcome characterized by late relapse. These elevated abnormal FLC and cytokines are potentially useful biomarkers for prognosis and selecting agents for untreated DLBCL.

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

“…It is evident that FLC abnormalities become more frequent as tumors develop across the spectrum of B‐cell differentiation to mature plasma cells. Within DLBCL we have previously reported that patients with monoclonal FLC abnormalities are more likely to have ABC‐type DLBCL and also have increased serum levels of IL‐12, sIL‐2Ra, IL‐1R, and IP‐10 (all P < 0.001) . In contrast, DLBCL patients with polyclonal FLC elevations had higher levels of IL‐6 ( P = 0.033), IL‐8 ( P = 0.025), sIL2Ra ( P = 0.011), and IL‐1R1 ( P = 0.041).…”

“…In chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) we reported that 49% (165/339) of patients had an abnormal FLC with 15% polyclonal elevations . Both monoclonal and polyclonal FLC elevations were associated with an adverse prognosis in both CLL and DLBCL, independent of established clinical prognostic factors . In Hodgkin lymphoma (HL) 30% had elevated FLC (all polyclonal) and this was an adverse prognostic factor .…”

Associations between elevated pre‐treatment serum cytokines and peripheral blood cellular markers of immunosuppression in patients with lymphoma

“…The prognostic significance of pre‐treatment ALC/AMC ratios and serum cytokine concentrations has been described in both NHL and HL, however, the relationship between these prognostic factors and the underlying mechanisms remain largely unknown. We hypothesized that patients with elevated serum cytokines, either being produced by the tumor cells or originating in the tumor microenvironment, would be more likely to have suppressed ALC/AMC ratios.…”

“…The adverse prognostic implications of suppressed ALC/AMC ratios or elevated cytokines have previously been described in both NHL and HL . However, they have never been studied together.…”

“…The type and prognostic significance of these elevations differ across the lymphoma subtypes. In diffuse large B‐cell lymphoma (DLBCL) elevated IP‐10 concentrations were associated with decreased event‐free (EFS) and overall survival (OS) . In classical HL elevated IL‐2R and IL‐6 concentrations were associated with inferior EFS .…”