Predictive and Prognostic Molecular Biomarkers in Familial Chronic Lymphocytic Leukemia: A Pilot Monocentric Study

Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world and the median age at diagnosis is 70 years. Family history of hemopathies and, more consistently, of CLL is a risk factor to develop the disease. The prevalence of blood diseases, and more specifically of CLL, in relatives of patients with CLL has been estimated at 13% and 7%, respectively. Familial CLL is defined as the presence of at least one first degree relative with CLL. Previous studies hypothesize the phenomenon of anticipation, which is the earlier onset and more aggressive course of a disease in the second generation of relatives, in familial CLL.

Aims: The primary end point is to determine the prevalence of familial CLL in our court of patients with CLL and to confirm the phenomenon of anticipation. The secondary endpoints involve the comparison of the prevalence of clinical features and molecular biomarkers between familial and sporadic CLL; the comparison of the impact of clinical features and molecular biomarkers on patients’ clinical course in terms of time to treatment (TTT), time to next treatment (TTNT), progression-free survival (PFS) and overall survival (OS) between familial and sporadic CLL; the evaluation of response to treatment (ORR) in familial CLL compared to sporadic cases.

Patients and methods: This is a retrospective monocentric study which consists of clinical and biological data collection from all patients with familial CLL. We enrolled 500 patients, which included 46 familial CLL and 454 sporadic CLL cases, diagnosed between January 1987 and April 2022. Patients’ characteristics were described by frequency tables for qualitative variables and position indicators for quantitative variables. The associations with clinical-biological parameters were analyzed using Chi-square or Fisher's exact test for the variables qualitative and Wilcoxon or Kruskal-Wallis test for quantitative variables. Survival was estimated with the Kaplan Meier method and compared by the log rank test.

Results: The prevalence of familial CLL and familiarity for any other hemopathy in our population was 9.4% and 20% respectively. The median age at diagnosis was 65 years old in sporadic and 59 years old in familial CLL (p=0.018). Focusing on patients with familial CLL, our data confirmed the phenomenon of anticipation. In the first generation of patients with familial CLL (including father, mother, and older siblings), the median age at diagnosis was 69 years old (range 50-90), while in the second generation (including children and younger siblings) the median age at diagnosis was 57 years old (range 31-83). The mean difference between the two populations was of 12.6 years (17.5 years lower limit and 7.7 years upper limit), with a 95% confidence interval (p=0.00003). Concerning the IgHV mutational status, sporadic CLL showed mutated IgHV in 65% of the cases and unmutated IgHV in 35%, while familial CLL showed mutated IgHV in 35% of the cases and unmutated IgHV in 65% (p<0.001). No statistically significant difference was instead found for FISH nor for molecular biomarkers, including TP53, NOTHC1, BIRC3 and SF3B1 (Table 1). In our cohort, the time to treatment, time to next treatment and progression free survival for familial CLL appear to be shorter than for the control group, but those results are not statistically significant at the log rank test. Moreover, the overall response rate was significantly lower in patients with familial CLL: this data has never been reported by any study and it further confirms the rather aggressive course of the disease (Table 1). Familial CLL did not show any significant difference in overall survival compared to sporadic CLL.

Conclusions: We confirmed the phenomenon of anticipation in our population. Moreover, we found higher rate of unmutated IgHV in familial CLL compared to sporadic controls, which would underlie a more aggressive course of the disease in this subset of patients. To define the molecular characteristics of familial CLL and to improve the significance of the survival analysis, we need to study a larger population of patients. Our monocentric experience is meant to be a pilot study which will be extended to other centers in Italy and opens the way to a better understanding of CLL clustering in families.

No relevant conflicts of interest to declare.