Chronic lymphocytic leukemia

01Definition and overview

Chronic lymphocytic leukaemia (CLL) is a cancer of mature B lymphocytes: one clone of small, long-lived B cells that divide at a modest rate but fail to die, so that they build up over years in the blood, marrow, lymph nodes and spleen. The WHO classification (2022) counts CLL and small lymphocytic lymphoma as one disease, separated from its precursor by the size of the clone:

Almost every CLL is preceded by MBL, as myeloma is preceded by a monoclonal gammopathy. Other B-cell lymphomas that spill into the blood can look alike on a film; they belong to the non-Hodgkin lymphomas and are told apart by flow cytometry.

Chronic myeloid leukaemia shares only the word chronic with CLL. It is a different disease, of a different cell line:

02Etiology and pathophysiology

Who gets it

• Age and sex: rare under 40, with a median age at diagnosis of about 70; men are affected nearly twice as often as women.
• Ancestry: commonest in people of European descent. In the United States it is about five times less common in people of Asian or Pacific Islander descent than in White people.
• Family: first-degree relatives have about an eightfold risk of CLL, and a raised risk of other indolent B-cell lymphomas, through many inherited variants of small effect. CLL is familial but not hereditary in the usual sense, so relatives are not tested.
• No environmental cause is firmly established.

How the clone grows

1. 1

   A B cell that will not die

   The clone starts from a mature B cell that has met antigen. Its B-cell receptor, the surface immunoglobulin, signals constantly, driven by self antigens. Many patients share almost identical receptors, a sign that common antigens select the clone.
2. 2

   Signals through BTK

   The signal runs through the kinases SYK, BTK (Bruton tyrosine kinase) and PI3K-delta to NF-kappa-B, which keeps the cell alive and dividing. BTK and PI3K inhibitors block it.
3. 3

   Too much BCL2

   CLL cells carry high levels of BCL2, which blocks the mitochondrial path to apoptosis. One cause is the 13q14 deletion, which removes two microRNAs, miR-15a and miR-16-1, that normally hold BCL2 back. This dependence is why the BCL2 inhibitor venetoclax works so well.
4. 4

   Shelter in nodes and marrow

   In proliferation centres, the cells get help from T cells and stromal cells (through CD40 and the chemokine CXCL12), divide and return to the blood. BTK inhibitors drive them out of these niches, so the blood count rises at first while the nodes shrink.
5. 5

   Evolution

   New lesions build up over the years, under chemotherapy above all: loss of TP53 or ATM, mutations of NOTCH1 and SF3B1, a complex karyotype. They bring resistance and, in a few patients, transformation.

IGHV and the genetic lesions

Each B cell rearranges its own antibody genes, and B cells that pass through a germinal centre then mutate them. The state of the clone's heavy-chain variable genes splits CLL into two diseases:

• Mutated IGHV (less than 98 per cent identical to the germline): from a post-germinal-centre cell; slow progression and long remissions after a fixed course of treatment.
• Unmutated IGHV (98 per cent or more): stronger signalling, faster progression, earlier relapse after time-limited treatment.

IGHV status never changes, so it is tested once, before the first treatment. FISH finds a chromosome lesion in about four in five patients:

TP53 aberrations, a deletion of 17p or a mutation of the gene (often both, one on each copy), are present in 5 to 10 per cent of patients at diagnosis, 10 to 20 per cent at first treatment and up to half later. Chemotherapy kills through p53, so it selects these clones. TP53 is checked by FISH and gene sequencing before every line of treatment. Other mutations and the complex karyotype are not tested routinely.

Immune failure and autoimmunity

The clone crowds out normal B cells and disturbs T cells, neutrophils and complement. Hypogammaglobulinaemia deepens with time and with treatment, bringing infections with encapsulated bacteria, shingles and weak responses to vaccines. Autoantibodies against red cells and platelets are common; most come from normal, polyclonal B cells provoked by the leukaemic cells, not from the clone itself.

03Clinical features

Most patients feel well when a routine blood count shows a lymphocytosis. When there are symptoms, they come from the mass of cells, the crowded marrow and the failing immune system:

• Lymphadenopathy: painless, rubbery, often symmetrical nodes in the neck, axillae and groins.
• An enlarged spleen (discomfort under the left ribs, early fullness) and liver.
• B symptoms: fever without infection, drenching night sweats and weight loss, with marked fatigue.
• Marrow failure: anaemia, and bruising from thrombocytopenia.
• Recurrent chest and sinus infections, and shingles.

Unlike acute leukaemia, CLL rarely causes leukostasis, even with counts of several hundred × 10⁹/L, because its cells are small.

Staging

Both systems use only the examination and the blood count; Binet is used more in Europe, Rai in North America. Binet counts five areas: the cervical, axillary and inguinal nodes (each counting once, on one side or both), the spleen and the liver. Anaemia or thrombocytopenia counts for staging only when it comes from marrow infiltration: an autoimmune cytopenia does not make a patient Binet C or Rai III or IV.

Complications

• Infections, a leading cause of illness and death at every stage.
• Autoimmune cytopenias, in 5 to 10 per cent, sometimes before the CLL is known: a positive direct antiglobulin test in up to a third of patients, fewer with warm autoimmune haemolytic anaemia; immune thrombocytopenia in 2 to 5 per cent, about 3 in 10 of them with haemolysis too (Evans syndrome); pure red cell aplasia and autoimmune neutropenia in under 1 per cent.
• Richter transformation, in 2 to 10 per cent: an aggressive lymphoma, usually diffuse large B-cell lymphoma, rarely Hodgkin lymphoma.
• Second cancers, skin cancers above all, even before any treatment.
• Prolymphocytic progression: more than 15 per cent of prolymphocytes (larger cells with a prominent nucleolus) in the blood or marrow marks a more aggressive phase.

04Diagnosis and management

Diagnosis

1. Blood film: small, mature lymphocytes with clumped chromatin, and smear cells, fragile CLL cells crushed as the film is spread (typical, not diagnostic).
2. Flow cytometry confirms it: at least 5 × 10⁹/L clonal B cells (CD19) that also carry CD5 (normally a T-cell marker) and CD23, with weak CD20, CD79b and surface immunoglobulin of one light chain, kappa or lambda. CD200 and ROR1 support it.
3. A marrow examination is not needed for the diagnosis, only before treatment when the cause of a cytopenia is unclear.
4. A node biopsy is needed for SLL without blood involvement, or when Richter transformation is suspected.

CD5-positive B cells without CD23 are mantle cell lymphoma until cyclin D1 has been checked.

When to treat

Early-stage CLL without symptoms is watched, with a blood count and examination every 3 to 12 months depending on its pace. Treating early, even with targeted drugs, has not prolonged survival in trials, and a high-risk score is no reason to start. Treatment starts only when an iwCLL criterion of active disease is met:

• progressive marrow failure, with haemoglobin below 100 g/L or platelets below 100 × 10⁹/L from infiltration (a platelet count stable just below 100 need not trigger treatment);
• massive (more than 10 cm across), progressive or symptomatic nodes;
• a massive (more than 6 cm below the left costal margin), progressive or symptomatic spleen;
• a lymphocyte count rising by more than half within 2 months, or doubling in less than 6 months, once other causes (infection, steroids) are excluded;
• autoimmune anaemia or thrombocytopenia that responds poorly to steroids;
• symptomatic disease outside the nodes (skin, kidney, lung, spine);
• disease symptoms: weight loss of more than 10 per cent in 6 months, fatigue that stops work or usual activities, fever above 38.0 °C for 2 weeks or more, or night sweats for over a month, without infection.

haemoglobin below this, from marrow failure

100g/Lhaemoglobin below this, from marrow failure

across, a massive lymph node

10cmacross, a massive lymph node

below the costal margin, a massive spleen

6cmbelow the costal margin, a massive spleen

a lymphocyte doubling time shorter than this

6monthsa lymphocyte doubling time shorter than this

Before treatment: a history of infections, heart disease and medicines; a blood count, direct antiglobulin test, kidney and liver tests, LDH, urate, β2-microglobulin and immunoglobulins; hepatitis B and C and HIV serology; FISH for 17p and TP53 sequencing; IGHV once; an ECG and cardiovascular review before a BTK inhibitor; and CT only before venetoclax, to grade the risk of tumour lysis.

The drugs

Head to head in relapsed CLL, acalabrutinib matched ibrutinib with less atrial fibrillation (9 against 16 per cent), and zanubrutinib kept more patients free of progression at 2 years (78 against 66 per cent) with fewer cardiac events. Patients starting a BTK inhibitor therefore get a second-generation drug; one doing well on ibrutinib need not switch.

First-line treatment

The time-limited combinations licensed in the EU, in cycles of 28 days:

venetoclax with obinutuzumab

12cyclesvenetoclax with obinutuzumab

acalabrutinib with venetoclax, with or without obinutuzumab

14cyclesacalabrutinib with venetoclax, with or without obinutuzumab

ibrutinib with venetoclax

15cyclesibrutinib with venetoclax

venetoclax with rituximab, at relapse

24monthsvenetoclax with rituximab, at relapse

In older patients with other illnesses, a single year of venetoclax with obinutuzumab gave a median of 76 months free of progression (CLL14). In patients without TP53 aberrations who were fit for chemoimmunotherapy, acalabrutinib with venetoclax kept 77 per cent free of progression at 3 years, 83 with obinutuzumab added, against 67 with chemoimmunotherapy (AMPLIFY).

Relapse

Relapse is treated only when the iwCLL criteria are met again, and the choice follows what came before:

• After chemoimmunotherapy: venetoclax with rituximab, or a second-generation BTK inhibitor, not chemotherapy again.
• Progression on a covalent BTK inhibitor: a venetoclax combination or pirtobrutinib, never another covalent one, since resistance is shared; after stopping for side effects, another BTK inhibitor can be used.
• After time-limited venetoclax: venetoclax again if more than 2 years have passed since it ended, otherwise a BTK inhibitor.
• Resistant to both classes: pirtobrutinib, idelalisib with rituximab, clinical trials (bispecific antibodies; CAR T cells, which are licensed for CLL in the USA but not in the EU), and an allogeneic stem cell transplant for fit patients with controlled disease, a long remission for about half of them. Targeted treatment is not stopped until the next is ready, as the disease can flare quickly.

Supportive care

• Vaccines, best given before treatment: a pneumococcal conjugate vaccine at diagnosis and the polysaccharide vaccine at least 2 months later, repeated every 5 years; recombinant zoster; influenza and COVID-19 as nationally advised; hepatitis B. Live vaccines are never given (measles, mumps and rubella, yellow fever, oral polio, the old live zoster vaccine).
• Immunoglobulin replacement for recurrent or serious infections needing hospital with an IgG below 4 g/L; subcutaneous preparations are better tolerated. Routine antibiotic prophylaxis is not advised; aciclovir or valaciclovir can follow shingles.
• Warm autoimmune haemolysis: prednisolone, with rituximab if needed, before any CLL treatment unless the CLL needs it anyway; cold agglutinin disease: warmth, and rituximab rather than steroids; immune thrombocytopenia: steroids or intravenous immunoglobulin, then rituximab or eltrombopag.
• Second cancers: skin checks, sun protection, no smoking, national cancer screening.
• After fludarabine or other purine analogues, blood components are irradiated to prevent transfusion-associated graft-versus-host disease.

Richter transformation

An excisional biopsy of the most active node on PET-CT makes the diagnosis, with tests of clonal relation to the CLL and of TP53 (disrupted in 50 to 60 per cent). Clonally unrelated lymphoma is treated as a new diffuse large B-cell lymphoma and does much better. Related disease, about 80 per cent, gets R-CHOP-like chemoimmunotherapy outside trials, with complete remission in 5 to 38 per cent and median survival rarely beyond a year, so trials come first and fit responders proceed to an allogeneic transplant. The Hodgkin type is treated as Hodgkin lymphoma; a flare of nodes after stopping a BTK inhibitor, and accelerated CLL, are treated as CLL.

05Epidemiology

CLL is the commonest leukaemia of adults in Europe and North America, with about 4.7 new cases per 100,000 a year in Europe and 4.8 in the United States, where about 22,800 are expected in 2026. The median age at diagnosis is about 70, and men are affected nearly twice as often as women (6.5 against 3.5 per 100,000 in the United States). Death rates in Western countries have halved over recent decades, to about 1.0 per 100,000 a year. Small CLL-like clones are common: sensitive flow cytometry finds them in up to about 12 per cent of healthy adults, more with age, nearly all low-count MBL.

06Prognosis

The course varies widely: many patients with early-stage disease and mutated IGHV have a near-normal life expectancy, while others need treatment soon and relapse repeatedly. In the chemotherapy era, median survival was about 10 years overall, more than 20 years with mutated IGHV and about 8 with unmutated IGHV. Today about 90 per cent of patients in the United States are alive 5 years after diagnosis, relative to the general population.

The CLL International Prognostic Index (CLL-IPI) adds up five factors:

The index was built from 3,472 patients treated mostly with chemotherapy, so its survival figures are lower than targeted drugs now achieve; it informs counselling, not the decision to treat. TP53 aberrations still shorten remissions, though far less on BTK inhibitors than with chemotherapy, and undetectable residual disease after time-limited treatment predicts a longer remission but does not yet guide routine care. Deaths come from infections, progressive or transformed disease and second cancers, though many older patients die of something else.

Patients under watch and wait are seen every 3 to 12 months and told to report new nodes, sweats, weight loss and infections. Rapid growth of one node, new B symptoms or a falling haemoglobin mean an early review, not the next routine visit.