Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Mayo Clinic Systematic Management and Risk-Adapted Therapy for Lymphoid Malignancies (lySMART) Consensus Guidelines 2026.

Chronic lymphocytic leukemia (CLL) is the most frequent leukemia in adults in the United States, with roughly 24,000 new cases expected in 2026 and more than 220,000 people currently living with the disease. During the past 2 decades, advancements in biologic insights and treatment options have significantly enhanced the outcomes for patients with CLL. Treatment paradigms have shifted decisively from chemoimmunotherapy to targeted agents. Bruton tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and anti-CD20 monoclonal antibodies now form the backbone of frontline care, with therapy tailored by genetic risk, comorbidities, and patient preferences. For relapsed or refractory disease, sequencing of covalent and noncovalent Bruton tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and cellular therapies, including chimeric antigen receptor T-cell therapy, has expanded options and improved outcomes in high-risk settings. Richter transformation of CLL represents an area of unmet need as most contemporary series report survival of less than 24 months. These guidelines summarize the Mayo Clinic approach to the diagnosis, risk stratification, and management of patients with CLL, including those with Richter transformation of CLL.