Association of elevated serumfree light chains with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Alyssa Clay-Gilmour ,Aaron D Norman ,David Murray ,Lynn R Goldin,Alexandra J Greenberg ,James R Cerhan,Timothy G Call,Sara J Achenbach,Tait D Shanafelt,Kari G Rabe,Ola Landgren,Neil E Kay,Nicola J Camp,José F Leis ,Mathew S Maurer ,Susan L Slager,Mary L Mcmaster,Neil E Caporaso,Abdul Rishi ,J Brice Weinberg,S Vincent Rajkumar,Celine M Vachon

doi:10.1038/s41408-019-0220-x

Abstract

Chronic lymphocytic leukemia (CLL) and its precursor, monoclonal B-cell lymphocytosis (MBL), are heritable. Serumfree light-chain (sFLC) measures are a prognostic factor for CLL, but their role in susceptibility to CLL is not clear. We investigated differences between sFLC measurements in pre-treatment serum from five groups to inform the association of sFLC with familial and sporadic CLL: (1) familial CLL (n = 154), (2) sporadic CLL (n = 302), (3) familial MBL (n = 87), (4) unaffected first-degree relatives from CLL/MBL families (n = 263), and (5) reference population (n = 15,396). The percent of individuals having elevated monoclonal and polyclonal sFLCs was compared using age-stratified and age- and sex-adjusted logistic regression models. In age groups >50 years, monoclonal sFLC elevations were increased in sporadic and familial CLL cases compared to the reference population (p’s < 0.05). However, there were no statistically significant differences in sFLC monoclonal or polyclonal elevations between familial and sporadic CLL cases (p’s > 0.05). Unaffected relatives and MBL cases from CLL/MBL families, ages >60 years, showed elevated monoclonal sFLC, compared to the reference population (p’s < 0.05). This is the first study to demonstrate monoclonal sFLC elevations in CLL cases compared to controls. Monoclonal sFLC levels may provide additional risk information in relatives of CLL probands.

Highlights

Chronic lymphocytic leukemia (CLL) has an underlying heritable predisposition, with ~10% of individuals affected with CLL reporting a first-degree relative with CLL or a related lymphoproliferative disorder[1,2,3]
For the first time, we investigated the association of serum-free light-chain (sFLC) levels with risk of CLL using CLL cases, unaffected relatives, and a large comparable reference population
Study participants We identified 302 sporadic CLL cases from Molecular Epidemiology Resource (MER), 154 familial CLL cases, 87 familial Monoclonal Bcell lymphocytosis (MBL) cases, 263 unaffected first-degree relatives from Genetic Epidemiology of CLL (GEC), and 15,396 subjects from the Olmsted County reference population, otherwise referred to as controls

Summary

Introduction

Chronic lymphocytic leukemia (CLL) has an underlying heritable predisposition, with ~10% of individuals affected with CLL reporting a first-degree relative with CLL or a related lymphoproliferative disorder[1,2,3]. Monoclonal Bcell lymphocytosis (MBL), precursor disease to CLL, is an asymptomatic hematologic condition characterized by small absolute levels of blood B-cell clone and no other signs of a lymphoproliferative disorder[3,4,5,6,7]. In 2007, Martin et al.[9] evaluated the frequency of monoclonal serum-free light-chain (sFLC) measurements in patients with other B-cell malignancies and established abnormal sFLCs can be detected in a substantial proportion of patients with NonHodgkin’s lymphoma (NHL) and CLL, and may be a useful clinical tool in the early diagnosis of a B-cell malignancy. A prospective study showed an abnormal rFLC can be detected several years before the actual diagnosis of CLL in a significant percentage of patients[18]. SFLC measurements have been implicated in detection and prognosis of CLL, few studies evaluating sFLCs and risk of CLL (or MBL) have been performed

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Conclusion