Chronic lymphocytic leukaemia

Definition. A monoclonal proliferation of mature B lymphocytes, defined by ≥5 × 109/L clonal B lymphocytes in peripheral blood persisting for at least 3 months with a characteristic immunophenotype. It is the commonest leukaemia of older adults, with a median age at diagnosis of about 70 years.

Related entities. Small lymphocytic lymphoma (SLL) — same disease with nodal involvement but fewer than 5 × 109/L circulating cells. Monoclonal B-cell lymphocytosis (MBL) — clonal cells without disease, progressing to CLL at 1–2% per year.

Clinical features. Often asymptomatic and detected on a routine blood count. Otherwise painless symmetrical lymphadenopathy, splenomegaly and hepatomegaly, B symptoms (fever, drenching night sweats, weight loss >10%), fatigue, and recurrent infections from hypogammaglobulinaemia.

Complications. Autoimmune haemolytic anaemia and immune thrombocytopenia (direct antiglobulin test positive), pure red cell aplasia, infection — the leading cause of death, second malignancies (especially skin), and Richter's transformation to diffuse large B-cell lymphoma in about 5% (rapid nodal enlargement, rising LDH, B symptoms).

Diagnosis. Peripheral smear shows mature small lymphocytes with smudge (smear) cells. Flow cytometry is diagnostic: CD5+, CD19+, CD23+, CD200+, dim CD20 and dim surface immunoglobulin with kappa or lambda light-chain restriction. Bone marrow examination is not required for diagnosis.

Staging. Rai — 0 lymphocytosis only; I plus lymphadenopathy; II plus spleno/hepatomegaly; III anaemia (Hb <11 g/dL); IV thrombocytopenia (<100 × 109/L). Binet — A fewer than 3 nodal areas; B three or more; C anaemia or thrombocytopenia.

Prognostic markers. Adverse — unmutated IGHV, del(17p) or TP53 mutation (worst, chemotherapy-resistant), del(11q), complex karyotype, high ZAP-70, CD38 and β -microglobulin. Favourable — isolated del(13q) 2 and mutated IGHV. The CLL-IPI combines TP53 status, IGHV, β -microglobulin, clinical stage and age.

Indications to treat (iwCLL 2018). Progressive marrow failure (worsening anaemia or thrombocytopenia), massive or progressive splenomegaly or lymphadenopathy, lymphocyte doubling time under 6 months, autoimmune cytopenia refractory to steroids, and constitutional symptoms. Early asymptomatic disease is not treated — "watch and wait" is the standard of care and treating early does not prolong survival.

Treatment. Targeted agents have replaced chemoimmunotherapy in older adults — continuous BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) or fixed-duration venetoclax (BCL-2 inhibitor) with obinutuzumab for 12 months (CLL14 trial). For del(17p)/TP53 use a BTK inhibitor or venetoclax-based therapy — never FCR. Chlorambucil with obinutuzumab remains an option where targeted agents are unavailable.

Supportive care in the elderly. Annual influenza, pneumococcal and recombinant (non-live) zoster vaccination; prophylactic immunoglobulin if recurrent infection with IgG <400 mg/dL; tumour lysis prophylaxis during venetoclax ramp-up; monitor BTK inhibitors for atrial fibrillation, hypertension and bleeding (avoid combining with warfarin); and use irradiated blood products after purine analogue therapy.

AMPLIFY trial (Brown, NEJM 2025;392:748; FDA approval February 2026) — fixed-duration acalabrutinib plus venetoclax is the first all-oral, time-limited regimen for untreated CLL, with 36-month progression-free survival of 76.5% versus 66.5% for chemoimmunotherapy (HR 0.65). Patients with del(17p)/TP53 were excluded.

Pirtobrutinib, a non-covalent BTK inhibitor (BRUIN trial), is approved after failure of covalent BTK inhibitors, including in BTK C481S resistance. Practice is moving towards MRD-guided fixed-duration therapy instead of indefinite treat-to-progression, which is particularly valuable in older patients wanting time off therapy.