Elevated Monoclonal Free Light Chains Are a Serum Marker of ABC Type Diffuse Large B-Cell Lymphoma

Abstract

Abstract 1591 Background:The serum free light chain (FLC) assay quantitates free kappa and free lambda immunoglobulin light chains. We previously showed elevated FLC are present in approximately 1 in 3 diffuse large B cell lymphoma (DLBCL) patients from both a phase II cooperative group clinical trial and a large clinic based epidemiology cohort. Approximately 10% of DLBCL patients had elevated FLC that was monoclonal in these series. Patients with monoclonal elevated FLC have very poor outcome with almost 50% of patients progressing in the first 15 months following initial treatment with immunochemotherapy. Unlike patients with polyclonal FLC elevation, where a variety of host effects may cause a rise in both kappa and lambda, it is likely the excess FLC in monoclonal patients is directly related to the tumor. DLBCL are a heterogenous group of tumors that can be classified into germinal center (GCB) or activated B cell (ABC) groupings using immunohistochemistry (IHC) staining algorithms. Here we examine the association of monoclonal free light chains with ABC vs. GCB DLBCL tumors. Methods:Newly diagnosed DLBCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) or NCCTG clinical trial N0489. Serum FLC was quantitated from enrollment research serum draws using the Freelite FLC assay (The Binding Site, Ltd., Birmingham, UK). Monoclonal elevated FLC was defined as an elevated kappa or lambda with a corresponding abnormal FLC ratio. Immunohistochemistry (IHC) staining was performed on paraffin tissue from research tissue microarrays (TMAs). Results:IHC tissue staining was available from 12 patients with monoclonal elevated FLC unrelated to renal failure. Germinal center markers were predominantly negative: 2 of 11 were LMO2 positive (18%), 1 of 12 was CD10 positive (8%), and zero cases out of 11 were GCET1 positive. FoxP1 was positive in 5 of 9 cases (56%) and MUM1 was positive in 4 of 12 cases (33%). By the Tally algorithm, 10 of 11 cases (91%) were ABC type DLBCL The percentage of ABC patients by the Tally algorithm in the corresponding DLBCL patients without monoclonal FLC was 45% (N=108, p=0.004). Conclusions:Approximately 10% of DLBCL patients have elevated monoclonal FLC and these patients have poor prognosis. Elevated monoclonal FLC may be a serum marker for ABC-type lymphoma, as the tumors from patients are predominantly negative for germinal center stains and ABC by the Tally algorithm. The secretion of light chains by the tumor suggests an activated B cell clone and the poor prognosis is characteristic of ABC type DLBCL and. Given the likelihood of the excess monoclonal FLC being tumor related, the potential exists for tracking of tumor response and progression via serum FLC in these patients. Replication of these findings in an additional cohort of DLBCL patients is planned.Table 1CaseAGEGenderIPISerum KappaSerum LambdaSerum FLC RatioTumor Light Chain RestrictionCD10GCET1MUM1FOXP1LMO2BCL6TallyNCCTG157M13.382.021.67−−+−++ABCNCCTG277M35.570.4313.1−−−+−−ABCNCCTG373M43.681.612.29+−++−−ABCMER176F34.872.112.31kappa−−−−ABCMER242M14.511.572.87−−−−−−ABCMER374M20.935.50.17−−−−+−GCBMER460F143.61.2335.4−−++−−ABCMER580F3130.7916.4kappa−−−+−−ABCMER680M22.831.471.93−−−+−+ABCMER758F25.160.3614.3kappa−−−−MER878M38.34.851.71−−+−−−ABCMER961M31.269.670.13lambda−−−−−ABC Disclosures:No relevant conflicts of interest to declare.