Impact of autoimmune hemolytic anemia on prognosis in chronic lymphocytic leukemia patients: A comprehensive retrospective analysis

Abstract Background: Autoimmune hemolytic anemia (AIHA) complicates 5%-10% of chronic lymphocytic leukemia (CLL) cases, significantly worsening outcomes. While linked to clonal B-cell autoantibodies and immune dysregulation, its precise pathogenesis and prognostic drivers remain incompletely defined, especially in the targeted therapy era and in Asian populations where data are scarce. Methods: We retrospectively analyzed 1404 CLL patients diagnosed (June 1994-July 2024) at the Shengli Oilfield Central Hospital and Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Hematology. All patients underwent a direct antiglobulin (Coombs) test. Baseline clinical characteristics, first-line treatment regimens, and survival data were collected. Results: The incidence of AIHA among CLL patients was 10.40% (146/1404), with warm AIHA (wAIHA) accounting for 69.18% and cold AIHA (cAIHA) for 30.82%. CLL patients with AIHA were predominantly male, presented with advanced-stage disease, and frequently exhibited splenomegaly, lymphadenopathy involving ≥3 regions, high leukocyte counts, elevated IgM, hypoalbuminemia, elevated β2-microglobulin, and positive immunofixation electrophoresis. Trisomy 12 (CEP12) was more common in CLL patients without AIHA. wAIHA patients were more likely to have high CLL-IPI scores and high leukocyte counts. Molecular profiling revealed a significant association between AIHA and IGHV4-34 gene segment usage (particularly in cAIHA). CLL-AIHA patients in the IGHV4-34 group were predominantly mutated for IGHV (M-IGHV), whereas the non-IGHV4-34 group had higher CLL-IPI scores and was more likely to present with lymphadenopathy and high leukocyte counts. Survival analysis demonstrated significantly shorter time to first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) in AIHA patients compared to non-AIHA patients. Among patients without AIHA, those with unmutated IGHV (UM-IGHV) had shorter TTFT, PFS, and OS than those with mutated IGHV (M-IGHV). However, in CLL patients who develop AIHA, the prognostic value of IGHV mutation status disappears, and there is no significant difference in survival between the wAIHA and cold-type AIHA cAIHA groups. When treatment groups were analyzed separately, AIHA was associated with significantly shorter PFS and OS in patients receiving chemotherapy or immunotherapy, whereas it had no adverse effect on survival among those treated with targeted agents. Conclusion: These findings suggest that AIHA is an adverse prognostic factor in CLL, especially in the era of conventional chemotherapy and chemo-immunotherapy, whereas targeted therapies may offset its negative impact. Therefore, AIHA screening should be intensified in Asian patients with high-risk clinical features or IGHV4-34 positivity, and CLL patients who present with AIHA should be considered for targeted treatment first to improve their survival outcomes.