The prognostic implications of autoimmune hemolytic anemia in chronic lymphocytic leukemia across treatment eras

Approximately 5%-10% of patients with chronic lymphocytic leukemia (CLL) develop autoimmune hemolytic anemia (AIHA). However, its pathogenesis and prognostic significance remain heterogeneous and incompletely defined. This study investigated the clinical and molecular features of CLL-associated AIHA and aimed to clarify its prognostic impact. We retrospectively analyzed baseline characteristics, first-line treatments, and survival outcomes in 1,404 patients with CLL. The incidence of AIHA was 10.4%, with 69.2% of cases classified as warm-antibody AIHA (wAIHA). CLL patients with AIHA were characterized by male predominance, advanced disease stage, IGHV4-34 usage, and other adverse biological features. Among the tested genes, DNMT3A mutations were more frequent in patients with AIHA, while MYD88 mutations were enriched in cold-antibody AIHA (cAIHA). Although AIHA conferred a significantly adverse prognostic impact on CLL outcomes, this effect was markedly attenuated with targeted therapies. Unmutated IGHV status predicted inferior outcomes in the overall CLL cohort, but not among patients with AIHA. Our findings underscore the importance of routine AIHA screening in high-risk CLL and support consideration of targeted therapies to mitigate the adverse impact of AIHA on long-term survival.