Chronic Lymphocytic Leukaemia (CLL)

See Leukaemias — Overview for the cross-subtype comparison table.

Progressive accumulation of mature malignant CD5+ B-lymphocytes in blood, marrow, spleen and lymph nodes. Most patients are found incidentally on a routine FBC. Many never need treatment.

Demographics: the most common leukaemia in the Western world. Average age at diagnosis 70; extremely rare in children. Lifetime risk about 1 in 200. More common in people of Ashkenazi Jewish ancestry, rare in Japan and China.

Presentation

Most patients are asymptomatic at diagnosis. When symptoms occur they are non-specific.

• Painless lymphadenopathy that fluctuates but does not fully resolve — often cervical, supraclavicular or axillary.
• Unexplained weight loss >10% of body weight over 6 months.
• Fever or severe night sweats without infection (both uncommon).
• Extreme fatigue that stops usual activity.
• Frequent infections, or a first episode of herpes zoster.

Signs:

• Lymphadenopathy — 50–90% of patients.
• Splenomegaly — 25–55%.
• Hepatomegaly — 15–25%.
• Leukaemia cutis is rare.

Blood-test triggers

Investigate CLL as a possible cause of any of these:

• Persistent unexplained lymphocytosis.
• Hypogammaglobulinaemia — present in about a quarter at diagnosis, and becomes more common as the disease progresses.
• Autoimmune haemolytic anaemia.
• Immune thrombocytopenia.

GP work-up

• History and examination, including careful palpation of all node areas, spleen and liver.
• FBC with manual film — smudge cells are typical.
• Flow cytometry on peripheral blood to confirm clonality.
• UEC, uric acid, creatinine, LFTs.
• Serum immunoglobulins and direct antiglobulin (Coombs) test.

Not routinely needed:

• Lymph node biopsy — not required to diagnose CLL even with palpable nodes.
• Imaging — only for local symptoms, compression, or very bulky nodes (e.g. to exclude hydronephrosis or vascular compression).
• Bone marrow aspirate/biopsy — not required for diagnosis.

Have results back and review the patient within two weeks.

Diagnostic criteria

Diagnosis needs >5.0 × 10⁹/L clonal B lymphocytes in peripheral blood for at least three months, with clonality confirmed by light-chain restriction on flow cytometry (CLL International Working Group, updated 2018). Cells typically express CD5, CD19, CD20 and CD23.

A clonal population below 5 × 10⁹/L is monoclonal B-cell lymphocytosis, which progresses to CLL at roughly 1–2% per year and should still be referred.

Staging uses Rai (0–IV) or Binet (A–C); neither predicts early progression well. Routine imaging is not recommended for initial staging.

Referral timing

• Routine — within 2 weeks for most patients. CLL is usually found incidentally in well patients, and urgent work-up is not needed to prevent deterioration.
• Within 72 hours if there is severe or symptomatic thrombocytopenia or anaemia (Hb <70 g/L or platelets <50 × 10⁹/L), or bulky (>5 cm) or locally compressive lymphadenopathy.
• Start investigations promptly where there are severe B symptoms, to exclude more aggressive disease such as lymphoma.

While waiting, explain the slow-growing nature of CLL — intervention is typically not needed for several years, and up to a third of patients never need treatment.

When treatment starts

There is no survival benefit to treating asymptomatic early-stage disease, so observation with 3-monthly clinical review and blood counts is standard. Indications for starting treatment (iwCLL “active disease”) include:

• Constitutional symptoms — fever >38°C for ≥2 weeks without infection, night sweats ≥1 month, weight loss ≥10% over 6 months, extreme fatigue, early satiety.
• Lymphocyte doubling time <6 months, or >50% rise over 2 months.
• Massive or symptomatic splenomegaly (≥6 cm below the costal margin) or nodes ≥10 cm.
• Autoimmune haemolysis or thrombocytopenia unresponsive to corticosteroids.
• Progressive marrow failure — worsening anaemia or thrombocytopenia.
• Recurrent infections.

Treatment

• BTK inhibitors — ibrutinib, acalabrutinib, zanubrutinib.
• BCL-2 inhibitor — venetoclax, often with obinutuzumab as a fixed-duration regimen.
• Chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab) is now largely displaced by targeted agents in first line.
• Allogeneic stem cell transplant is the only curative option and is rarely used.

Ibrutinib starts at 420 mg daily. Watch for bleeding (it impairs platelet activation — assess carefully before combining with anticoagulants or antiplatelets, and withhold 3–7 days either side of high-bleeding-risk surgery), new atrial fibrillation, and hypertension. Avoid CYP3A4 inhibitors such as azole antifungals and macrolides.

Venetoclax starts at 20 mg and is titrated weekly to 400 mg under specialist monitoring because of tumour lysis risk. Take with food at the same time daily — food increases bioavailability 3–5-fold. Severe neutropenia is common.

GP role during treatment

• Adherence. Dose reduction or significant interruption of ibrutinib is associated with worse progression-free survival.
• Vaccination. Give influenza, pneumococcal and COVID-19 vaccines, ideally before any immunosuppressive therapy, since later responses are greatly impaired. Live vaccines including varicella zoster are contraindicated — deaths have occurred.
• Infection. Hypogammaglobulinaemia develops in up to two-thirds of patients. Immunoglobulin replacement can be considered for recurrent severe infection.
• Fertility and pregnancy. Targeted agents are pregnancy category C or D; discuss contraception and refer for fertility discussion before treatment starts.
• Correct vitamin D deficiency; keep dental care up to date.

Prognosis and complications

Survival ranges from 2 to >20 years, median around 10 years, and is improving with targeted agents. Favourable markers: mutated IGHV, del(13q). Unfavourable: del(17p), del(11q), TP53 mutation. CLL-IPI is the usual composite index.

• Richter transformation — 2–10% transform to diffuse large B-cell lymphoma, with fever, rapidly enlarging nodes and a sharply rising LDH.
• Increased risk of second cancers, particularly skin, lung and GI.
• Autoimmune cytopenias.