Unfinished Business in Chronic Lymphocytic Leukemia: Translational and Clinical Priorities for a Cure

Remarkable progress in the understanding of disease pathogenesis and treatment across hematologic malignancies has been achieved in the past two decades. Nevertheless, the reliable elimination of disease remains elusive for many cancers. Chronic lymphocytic leukemia (CLL) exemplifies the needs that must be addressed to close the gap between discovery science and remaining clinical challenges. In CLL, targeted therapies have substantially prolonged survival and enabled long-term disease control for many patients. However, curative outcomes remain exceptional, particularly in high-risk groups such as those with TP53 disruption, dual resistance to BTK and BCL2 inhibitors, or transformation to aggressive lymphoma. Recent insights into the interconnection between cancer and immunity have positioned CLL as a model example of cancer-associated immunodeficiency-a realization brought into sharp focus by the SARS-CoV-2 pandemic where CLL patients were at extremely high-risk for infection and poor outcomes. Thus, complications related to infections, autoimmunity and secondary cancers continue to contribute substantially to morbidity and mortality, underscoring the need for research on immune dysfunction in CLL. Furthermore, pronounced heterogeneity in disease progression and therapeutic resistance highlight the need for mechanistic studies to clarify these distinct biological patterns. Advances in these areas not only hold the promise of curative therapy for broader patient subgroups in CLL but will also inform innovation in research on other cancers, particularly in establishing a molecular definition of disease and defining those interactions with the underlying and resultant immune deficiencies.