Chronic lymphocytic leukemia (CLL) is the most common chronic leukemia in adults in Western countries, characterized by clonal proliferation of mature B-lymphocytes (CD5+CD19+CD23+, kappa or lambda restricted) accumulating in peripheral blood (>=5000/microL), bone marrow, lymph nodes, and spleen. Annual incidence is 4-5 per 100,000 with median diagnosis age 70 years; approximately 30% of patients are asymptomatic at diagnosis and identified by incidental lymphocytosis. CLL and small lymphocytic lymphoma (SLL) are the same disease with predominant blood/marrow versus lymph node involvement.
Risk stratification uses Rai (0-IV) and Binet (A-C) clinical staging, plus molecular and biological markers: IGHV mutation status (mutated >=2% deviation from germline = favorable; unmutated = adverse), TP53 mutation or del(17p) (highly adverse), del(11q) ATM deletion (intermediate-adverse), trisomy 12 (intermediate), del(13q) as sole abnormality (favorable), beta-2 microglobulin, CD38 and ZAP-70 expression. CLL International Prognostic Index (CLL-IPI) integrates TP53 status, IGHV mutation, beta-2 microglobulin, clinical stage, and age into 4 risk groups (low, intermediate, high, very high).
Treatment is indicated for active/symptomatic disease per iwCLL criteria (progressive cytopenias, bulky/progressive lymphadenopathy or splenomegaly, B-symptoms, autoimmune complications, lymphocyte doubling time <6 months in advanced stage). Targeted therapy has revolutionized CLL: covalent BTK inhibitors continuous therapy (ibrutinib, acalabrutinib with better cardiotoxicity profile, zanubrutinib with best efficacy/tolerability per ALPINE trial) achieve >85% response rates with sustained remission; fixed-duration combination venetoclax (BCL2 inhibitor) with obinutuzumab (anti-CD20 antibody) for 12 months achieves deep MRD-negative remissions in CLL14 trial. Non-covalent BTK inhibitor pirtobrutinib for resistance to covalent BTK inhibitors. Allogeneic stem cell transplantation reserved for high-risk relapsed disease (TP53-mutated, multiple targeted therapy failures). Richter transformation (3-10% lifetime risk) to diffuse large B-cell lymphoma is treated like de novo DLBCL with chemoimmunotherapy and consideration of allogeneic transplantation.