Advances in the treatment of large granular lymphocytic leukemia

Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disease characterized by marked phenotypic, molecular, and clinical heterogeneity. Recent therapeutic advances and emerging clinical data warrant a comprehensive overview of current and evolving treatment strategies. This review summarizes current and future therapeutic approaches in LGLL, including criteria for treatment initiation and response assessment. The literature was identified through a comprehensive search of PubMed up to November 2025. We address the evolving positions of the three main immunosuppressive agents – methotrexate, cyclophosphamide and ciclosporin A – along with other strategies such as chemotherapy, immunotherapy, and hematopoietic stem cell transplantation. In addition, we highlight emerging targeted therapies driven by advances in the understanding of LGLL pathophysiology. Ongoing clinical trials registered on ClinicalTrials.gov and novel agents likely to expand the therapeutic landscape of LGLL are also discussed. LGLL management is undergoing a paradigm shift with the emergence of multiple targeted therapeutic approaches. Future progress will depend on better prognostic stratification, better integration of disease and patient heterogeneity, and the development of personalized treatment strategies, potentially supported by molecular monitoring.