Infections in Chronic Lymphocytic Leukemia: Evolving Risks and Prevention Strategies

ABSTRACT Infections remain a leading cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), reflecting both intrinsic immune dysfunction and therapy‐related immunosuppression. The pathogenesis of immunodeficiency in CLL is multifactorial: neoplastic B cells impair humoral immunity, T cells are functionally exhausted, and innate immune cells, particularly neutrophils and NK cells, display profound defects. Beyond impaired pathogen defense, these immune alterations actively support leukemic cell survival and promote a tolerogenic microenvironment. The advent of targeted therapies has reshaped the infectious risk profile. Bruton's tyrosine kinase inhibitors (BTKis) and venetoclax have largely replaced chemotherapy, reducing classic opportunistic infections but introducing new challenges. BTKis are associated with invasive fungal infections and increased pneumonia risk in combination regimens, while venetoclax frequently induces profound neutropenia. Anti‐CD20 monoclonal antibodies cause long‐lasting B‐cell depletion and viral reactivation. These evolving risks demand nuanced approaches to prevention. Prophylactic strategies must be individualized. Antiviral prophylaxis is warranted with anti‐CD20 antibodies and BTKis, and Pneumocystis jirovecii pneumonia (PJP) prophylaxis remains essential with fludarabine, cyclophosphamide, and rituximab (FCR) or prolonged corticosteroid therapy. Antifungal prophylaxis is not routinely indicated in CLL but may be considered in high‐risk patients on BTKis or with refractory disease. Immunoglobulin replacement therapy (IgRT) reduces recurrent bacterial infections in patients with hypogammaglobulinemia, while vaccination—though often limited by suboptimal responses—remains the cornerstone of prevention. Timing before therapy or during treatment‐free intervals is critical, and newer formulations, such as conjugate pneumococcal and recombinant zoster vaccines, are preferred. Future directions include developing predictive biomarkers of infection risk and vaccine responsiveness, integrating immune monitoring into clinical trials, and exploring strategies to modulate neutrophil plasticity and restore T‐cell function. Until then, a pragmatic, risk‐adapted approach combining vigilance, prophylaxis, immunoglobulin replacement, and optimized vaccination offers the best safeguard for patients with CLL.