Familial Forms of Chronic Lymphocytic Leukemia Have a Worse Prognosis Than Sporadic Forms: an Italian Case-Control Study Open Access

• Familial CLL is associated with more frequent unmutated IGHV status but similar genetic features as sporadic CLL

• Familial CLL is associated with more frequent unmutated IGHV status but similar genetic features as sporadic CLL

Familial chronic lymphocytic leukemia (CLL) constitutes 5-7% of CLL and has previously shown a more aggressive pattern of evolution compared to sporadic CLL, even if no difference in overall survival (OS) has been observed. This multicenter case-control study aimed to compare clinical features, molecular biomarkers, and patient outcomes of familial and sporadic CLL. Adult CLL patients were enrolled from 18 Italian centers, with familial CLL defined as having at least one first-degree relative affected by CLL. Sporadic CLL patients were matched for gender and age at diagnosis within 4 years (1:2 ratio). Kaplan-Meier method was used to evaluate time-to-event outcomes. Of 480 enrolled patients, 160 had familial CLL, 320 sporadic CLL. Significant clinical and molecular differences between familial and sporadic CLL included the presence of lymphadenopathies at diagnosis >5 cm (7.2% vs 2.8%, p=0.027) and unmutated IGHV gene (55.5% vs 36.2% (p<0.001). First-line and second-line treatments were required in 55.6% and 46.1% of familial CLL and 43.1% (p=0.001) and 29.6% (p=0.034) of sporadic CLL, respectively. Both time to first treatment (TTFT) and time to next treatment (TTNT) were shorter for familial CLL than for sporadic CLL [median TTFT 66 months (95% CI: 36.7-95.2); vs 108 months (95% CI: 76.0-140.0), p=0.005; median TTNT 60 months (95% CI: 42.9-77.1) vs 94 months (95% CI: 43.7-144.3), p=0.030, respectively], although familiarity has not emerged as an independent prognostic factor. No difference in OS was observed. Considering the more aggressive course of familial CLL but the similar OS, CLL screening in relatives is not recommended.