Chronic Lymphocytic Leukemia (CLL) — Detailed

Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in Western countries (4-5 per 100,000 incidence, 30-40% lower in Asian populations), comprising 25-30% of all leukemias and characterized by clonal proliferation and accumulation of mature, functionally incompetent CD5-positive B-lymphocytes in peripheral blood, bone marrow, lymph nodes, and spleen. Diagnosis requires absolute B-lymphocyte count >5,000/uL with characteristic immunophenotype (CD5+, CD19+, CD20+ dim, CD23+, CD43+, CD79b dim or absent, surface immunoglobulin dim, kappa or lambda light chain restricted) for at least 3 months. Small lymphocytic lymphoma (SLL) is the same disease as CLL but with predominantly tissue (lymph node, spleen) involvement and circulating lymphocyte count <5,000/uL. Monoclonal B-cell lymphocytosis (MBL) is a precursor state with circulating monoclonal B-cells <5,000/uL without other features (high-count MBL 500-5,000/uL progresses to CLL at 1-2% per year).

Pathobiology and prognostic markers: CLL arises from antigen-experienced mature B-cells with clonal heterogeneity. IGHV (immunoglobulin heavy chain variable region) mutation status — IGHV-mutated (M-CLL, ~50%, derived from post-germinal center B-cells, indolent course, median survival 25+ years), IGHV-unmutated (U-CLL, ~50%, derived from pre-germinal center B-cells, more aggressive, median survival 8-10 years). Cytogenetic abnormalities by FISH (Dohner hierarchical classification): del(13q14) — most common (50-60%), favorable (median survival >9 years); trisomy 12 (15-20%) — intermediate; del(11q22-23) ATM gene loss — adverse (rapid progression, bulky lymphadenopathy); del(17p13) TP53 loss — most adverse (resistance to chemoimmunotherapy, requires novel agents). TP53 mutations (5-10% at diagnosis, 30-40% in relapsed/refractory) — particularly poor prognosis. Other adverse markers: NOTCH1 mutations, SF3B1 mutations, BIRC3 mutations, complex karyotype, elevated beta-2 microglobulin, ZAP-70 expression (correlates with U-CLL), CD38 expression, advanced Rai or Binet stage. International Prognostic Index for CLL (CLL-IPI): age, stage, TP53 status, IGHV status, beta-2 microglobulin — risk stratifies into 4 groups.

Clinical presentation and treatment: 70-80% of patients are asymptomatic at diagnosis with incidental lymphocytosis; symptomatic patients present with B-symptoms (fever, night sweats, weight loss, fatigue), painless lymphadenopathy (cervical, axillary, inguinal), splenomegaly, hepatomegaly, recurrent infections (hypogammaglobulinemia, neutropenia), autoimmune complications (autoimmune hemolytic anemia 5-10%, immune thrombocytopenia 2-5%, pure red cell aplasia, autoimmune neutropenia). Treatment indications (IWCLL 2018 criteria): progressive symptomatic lymphocytosis (lymphocyte doubling time <6 months), progressive massive symptomatic adenopathy or splenomegaly, autoimmune cytopenias unresponsive to standard treatment, B-symptoms (constitutional symptoms), progressive cytopenias from marrow involvement. Asymptomatic stage (Rai 0, Binet A) — observe, no benefit from early treatment. First-line treatment: targeted therapies have largely replaced chemoimmunotherapy due to superior efficacy and tolerability — BTK inhibitors (ibrutinib first-generation, acalabrutinib and zanubrutinib second-generation with improved tolerability and reduced cardiovascular toxicity) for continuous treatment, BCL2 inhibitor venetoclax with obinutuzumab for fixed-duration treatment (12 months) in non-del(17p)/non-TP53 mutated patients. For del(17p)/TP53-mutated CLL, BTK inhibitor or venetoclax-based regimens preferred. Chemoimmunotherapy (FCR — fludarabine, cyclophosphamide, rituximab; BR — bendamustine, rituximab; chlorambucil + obinutuzumab in elderly/unfit) reserved for select cases. Relapsed/refractory disease: switch BTK inhibitor class (covalent to non-covalent like pirtobrutinib), venetoclax retreatment, PI3K inhibitors (idelalisib, duvelisib — toxicity concerns), CAR-T cell therapy (lisocabtagene maraleucel approved 2024), allogeneic stem cell transplantation for fit younger patients with high-risk disease. Richter transformation (3-10% lifetime risk) — transformation to aggressive lymphoma (DLBCL most common, Hodgkin lymphoma rare) — poor prognosis, treated with R-CHOP-like or DLBCL regimens. Supportive care: vaccinations (avoid live), prophylaxis for infections, IVIG for severe hypogammaglobulinemia with recurrent infections, secondary malignancy surveillance, cardiovascular risk management for BTK inhibitors.