Monoclonal Gammopathy and Hypogammaglobulinemia As Prognostic Factors in Patients with Chronic Lymphocytic Leukemia: A Retrospective Multicentric Experience
Authors: Innocenti Idanna , Corbingi Andrea , Piccirillo Nicola , Autore Francesco , Visentin Andrea , Scomazzon Edoardo , Cassin Ramona , Pasquale Raffaella , Morelli Francesca , Sica Simona , Reda Gianluigi , Trentin Livio , Laurenti Luca 
Published: October 2019

Abstract
Introduction. Chronic Lymphocytic Leukemia (CLL) is an indolent B-cell lymphoproliferative disorder. Several prognostic factors such as IGHV mutation status and chromosomal aberrations as trisomy 12, del11q, del13q or del17p have been detected so far. More recent genetic mutations such as BIRC3, SF3B1, NOTCH1 and TP53 stratifies the prognosis and outcome in CLL patients (pts). However all data above reported, because of expensive techniques and experience typical of big laboratories, are not available to all medical centers. Data concerning the prevalence of hypogammaglobulinemia, IgM or IgG monoclonal gammopathy, and the impact on natural history of CLL pts are controversial and contradictory.
The aim of the study is to evaluate the prevalence and the outcome of monoclonal IgM/CLL, IgG/CLL and hypogammaglobulinemia compared with CLL pts with normal immunoglobulin (Ig) levels.
Patients and methods. We collected from three different Italian centers 902 pts diagnosed with typical CLL from 1987 to 2017 with a baseline assessment of serum Ig, immunofixation, chromosomal aberrations and clinical features; evaluating their impact on time to progression (TTP), time to treatment (TTT).
Results. Once assessment was made, pts included in our study who met eligibility criteria were 902. Fifty-one patients showed IgM monoclonal gammopaty (5,6%); 89 showed IgG (9,9%), 103 patients had hypogammaglobulinemia (11,4%), 659 patients (73%) showed normal gamma level.
In the Padova group, the overall prevalence of monoclonal gammopathy is 15.5% of whom 35 pts (10.5%) with IgG/CLL, 17 pts (5%) with IgM/CLL, 45 pts (13.5%) with hypogamma/CLL and 238 pts (71%) with no evidence of paraprotein.
Data from the Rome group showed similar results: monoclonal gammopathy is 15.4% of whom 37 pts (9%) with IgG/CLL, 26 pts (6.4%) with IgM/CLL, 42 pts (10.3%) with hypogamma/CLL and 304 pts (74.3%) with no monoclonal gammopathy revealed.
In the group from Milano, the prevalence of monoclonal gammopathy is 15.7%; 17 pts (10.7%) with IgG/CLL, 8 pts (5%) with IgM/CLL, 16 pts (10%) with hypogamma/CLL and 118 pts (74.3%) with negativity at immunofixation.
Median age was similar in all the groups (66years, range 26-89years) and data gathered from the 3 centers showed an overlapping rate in prevalence of monoclonal gammopathy in CLL and their related subclasses.
Median TTP was 75 months (91 months for patients with normal gamma levels and 54 months for patients with abnormal gamma globulin, P<0,0001). TTP comparison among single groups of patients was showed in the table1.
Median TTT was 79 months (93 months for patients with normal gamma levels and 54 months for patients with abnormal gamma globulin, P<0,0001). TTT comparison among single groups of patients was showed in the table1.
Summary. Our study provided data about incidence and prognosis of monoclonal gammopaty and hypogammaglobulinemia in CLL patients. Twenty-seven percent of patients with CLL showed abnormal gammopaty; these alteration have a negative impact on TTP and TTT in these setting of patients. Finally our data also detected a particular subset of patients with IgM/CLL characterized by a worst TTP and TTT.

Disclosures
Visentin: janssen: Consultancy, Honoraria. Reda:ABBVIE: Consultancy; Gilead: Consultancy; Janssen and Cilag: Consultancy; Celgene: Consultancy. Trentin:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding; Janssen: Research Funding.