Autoimmune or Chronic Infectious Disease in B-CLL at Diagnosis: Association with Unmutated VH Gene Status and Unfavorable Cytogenetics.
Authors: Vanura Katrina , Le Trang , Esterbauer Harald , Spaeth Florentin , Porpaczy Edith , Shehata Medhat , Eigenberger Karin , Hauswirth Alexander , Scrabs Cathrin , Kroemer Elisabeth , Schwarzinger Ilse , Streubel Berthold , Fonatsch Christa , Stilgenbauer Stephan , Gaiger Alexander , Jaeger Ulrich 
Published: October 2019

Abstract
It is well known that chronic stimulation of the immune system (chronic infection, autoimmune disease) confers an increased risk of developing cancer. B-CLL represents an interesting model for the association of chronic antigenic stimulation with neoplastic transformation. We investigated the incidence of pre-existing chronic stimulation in patients with B-CLL at diagnosis. Chronic stimulation (CS) was defined as suffering from autoimmune disease or chronic or recurrent infection. The B-CLL control group consisted of patients without known chronic stimulation or concomitant diseases (non-CS). 187 unselected patients with known VH status diagnosed at our department were included in the study. Baseline characteristics were typical for a representative CLL patient cohort. Median age was 63 ranging from 25 to 83 years. Female:male ratio was 1:1,7. 87% of patients were staged Binet A, 13% Binet B or C. 63% of patients had mutated IgVH genes, 37% had unmutated genes (cut-off ≤ 98%). Normal karyotype was found by FISH in 25.8% of patients, 13q− in 46,1%, 11q− in 21,3%, +12 in 18%, and 17p− in 7,9% of patients. Of these 187 patients, 23,5% had a history of chronic stimulation (10,7% AI, 12,8% Inf). Age and Binet stage were similar between CS and non-CS patients. CS patients included a higher percentage of women (43.3 vs. 33.3%), and a higher percentage of CD38 positive (cut-off = 30%) patients (43,8 vs. 27,9%) compared to the non-CS subgroup, although both not statistically different. CS patients had a significantly higher percentage of unmutated clones (53%) compared to non-CS patients (28%) (p=0,002). Unfavorable cytogenetics (11q−, 17p−, +12) were more pronounced in CS patients compared to the non-CS group (77,8% vs 26,4%). The 4 most frequently used VH genes were 1–69, 3–30, 4–34, and 5–51 for the CS group, and 1–69, 2–5, 3–23, and 3–7 for the non-CS group. VH 1-69, the most frequently used VH gene overall, was unmutated in all CS patients, in non-CS patients several mutated cases were found. Several VH genes (2–26, 2–5, 3–7, 3–9) were exclusively unmutated in CS patients while they were mutated in non-CS patients. Several genes were exclusively used in either CS group (3–13, 3–15, 4–31, 4–39, 4–61, 5–51) or non-CS group (3–64, 3–65, 3–71, 3–74, 4–30, 7–4). They were mutated in most cases. Despite the drawbacks of our study (classification based on patients history and medical records), we provide unique and novel data on the frequency of chronic antigenic stimulation in an unselected cohort of newly diagnosed CLL patients. We noted considerable discrepancies between CS and non-CS patients regarding mutational status and VH gene usage. Our data warrant further evaluation of the role of CS in the development and course of B-CLL.