Chronic lymphocytic leukaemia
Description
- Monoclonal mature B cell accumulation in blood, marrow, nodes and spleen
- Same disease as SLL - nodal-predominant with blood B cells <5 x10^9/L
- MBL (monoclonal B lymphocytosis) - clonal B cells <5 x10^9/L, no cytopenia, no nodes
- Precedes essentially all CLL; progresses ~1-2%/yr
- Defining feature is immune failure, not marrow failure
- Hypogammaglobulinaemia, autoimmune cytopenias, second cancers
- Many patients die with CLL rather than of it
Epidemiology
- Commonest leukaemia in the Western world; ~1,400 new cases/yr in Australia
- Median age at diagnosis ~70; M>F ~2:1
- Rare in East Asian populations - persists after migration, so genetic not environmental
- Family history: 5-8x inc risk in first-degree relatives (strongest familial risk of any haematological malignancy)
- ~70-80% diagnosed incidentally on an FBE
Aetiopathogenesis
- Antigen-driven clonal expansion + BCR signalling dependence + BCL2-mediated apoptosis failure
- This is why BTK inhibitors and venetoclax work and why the disease is not proliferative
- IGHV mutation status - the single most important biological division
- Mutated (post-germinal centre) - indolent
- Unmutated - aggressive, higher BCR signalling. Fixed for life - test once
- Cytogenetics (FISH) - hierarchical
| Frequency | Prognosis | |
|---|---|---|
| del(13q) sole | ~55% | Best |
| Normal | ~18% | Intermediate |
| +12 | ~16% | Intermediate |
| del(11q) (ATM) | ~18% | Poor, bulky nodes |
| del(17p) (TP53) | ~7% | Worst; chemoresistant |
- Recurrent mutations: TP53, NOTCH1, SF3B1, BIRC3
- *Repeat FISH + TP53 sequencing before every line of therapy* - clonal evolution under selection pressure
Diagnosis
Definition
- Clonal B lymphocytes >=5 x10^9/L in peripheral blood, sustained >3 months, with a characteristic immunophenotype
- Marrow biopsy is not required to diagnose - flow on peripheral blood is sufficient
Film
- Small mature lymphocytes, condensed chromatin, scant cytoplasm
- Smudge / smear cells - fragile cells crushed on the slide
Immunophenotype
- CD5 + CD19 + CD23 positive, CD200 positive
- CD20, CD79b and surface immunoglobulin all expressed weakly (dim)
- Light chain restricted (kappa or lambda only) = clonality
- CD5 on a B cell is abnormal - only CLL and mantle cell
| CLL | Mantle cell | |
|---|---|---|
| CD5 | + | + |
| CD23 | + | - |
| Cyclin D1 / t(11;14) | - | + |
| SOX11 | - | + |
| CD200 | + | - |
- *Always exclude mantle cell - CD23 alone is not enough, do cyclin D1/FISH*
Baseline workup
- FBE + film, reticulocytes, DAT, LDH, haptoglobin (autoimmune haemolysis at diagnosis)
- Immunoglobulins (hypogammaglobulinaemia), beta-2 microglobulin
- FISH panel + TP53 sequencing (>=10% variant allele frequency), IGHV mutation status
- CT only if it will change management; routine surveillance imaging not indicated
Staging
| Rai | Binet | ||
|---|---|---|---|
| 0 | Lymphocytosis only | A | <3 nodal areas, Hb >100, plt >100 |
| I | + lymphadenopathy | B | >=3 nodal areas, counts preserved |
| II | + spleen/liver | C | Hb <100 or plt <100 |
| III | + Hb <110 | ||
| IV | + platelets <100 |
- Cytopenia must be from marrow infiltration - immune cytopenia does not upstage**
- *Survival figures attached to these stages are chemotherapy-era and now substantially understate outcomes*
CLL-IPI
- TP53 status, IGHV status, beta-2 microglobulin, clinical stage, age
Management
A. When to treat - iwCLL indications
*Stage and lymphocyte count alone are never an indication. There is no benefit to treating early asymptomatic disease.*
- Progressive marrow failure - Hb <100 or platelets <100
- Massive (>=6 cm) or progressive/symptomatic splenomegaly or lymphadenopathy
- Lymphocyte doubling time <6 months (from a baseline >30 x10^9/L)
- B symptoms - weight loss >10% in 6 mo, fevers >2 wk, drenching sweats, extreme fatigue
- Autoimmune cytopenia refractory to corticosteroids
- Symptomatic extranodal involvement
B. First-line therapy
*Chemoimmunotherapy has been removed from frontline care. FCR and bendamustine-rituximab are effectively obsolete* - even in young IGHV-mutated patients, given the risk of therapy-related MDS/AML.
| Regimen | Duration | Notes |
|---|---|---|
| Venetoclax + obinutuzumab (CLL14) | Fixed 12 months | PBS-listed 1L since 2020. Deep MRD-negative remissions, retreatable |
| Acalabrutinib +/- obinutuzumab | Continuous | PBS-listed 1L 2024 |
| Zanubrutinib | Continuous | First BTKi PBS-listed 1L (2023) |
| Acalabrutinib + venetoclax (+/- obinutuzumab) | Fixed ~14 cycles, all-oral | AMPLIFY; approved 1L 2026 |
| Ibrutinib | Continuous | Superseded by 2nd-gen BTKi - more AF, hypertension, discontinuation |
- del(17p)/TP53-mutated: targeted therapy only - BTKi (continuous, best evidence) or venetoclax-based
- Outcomes now approach those of standard-risk disease; the old del(17p) survival figures predate targeted agents
- Choice axis: fixed-duration vs continuous, cardiovascular/bleeding risk, renal function, adherence
C. Relapsed / refractory
- Switch class: BTKi -> venetoclax-based, or venetoclax -> BTKi
- Retreatment with venetoclax reasonable if remission >2-3 years after fixed-duration therapy
- Pirtobrutinib - non-covalent BTKi, active after BTK C481S resistance
- BTK degraders and CD19 CAR-T (lisocabtagene maraleucel) for double-refractory disease
- Allogeneic SCT - now rare, reserved for young double-refractory or Richter
- Idelalisib largely abandoned - hepatotoxicity, colitis, pneumonitis, fatal infection
D. Drug-specific hazards
BTK inhibitors
- Redistribution lymphocytosis - >50% rise in first weeks. *Not progression - do not stop*
- AF/flutter ~4% (much less with acalabrutinib/zanubrutinib), hypertension, ventricular arrhythmia
- Bleeding - major haemorrhage ~4%; worse with anticoagulant/antiplatelet
- Hold 3-7 days before and after surgery depending on bleeding risk
- Infection incl. PJP, invasive aspergillosis, PML; diarrhoea, arthralgia
- Acalabrutinib: headache (caffeine helps); tablet formulation removed the PPI interaction
Venetoclax
- Tumour lysis syndrome - mandatory 5-week ramp-up 20 -> 50 -> 100 -> 200 -> 400 mg
- TLS risk stratified by node size and lymphocyte count; hydration, allopurinol/rasburicase, inpatient dosing if high risk
- CYP3A4 substrate - strong inhibitors (posaconazole, voriconazole, itraconazole, clarithromycin, ritonavir) contraindicated during ramp-up; dose reduce >=75% once stable
- Neutropenia (common, G-CSF), diarrhoea, nausea
E. Supportive care - the part that changes mortality
- Vaccinate: annual influenza, COVID, pneumococcal, recombinant (not live) zoster
- Give before treatment - responses are poor once on anti-CD20
- IVIG replacement if IgG low and recurrent/severe bacterial infection
- PJP prophylaxis with purine analogues, and with BTKi/venetoclax in many protocols; antiviral prophylaxis with anti-CD20
- Annual skin surveillance - aggressive SCC and melanoma
- Autoimmune cytopenias: corticosteroid first, then rituximab/ciclosporin; *treat the CLL if refractory*
- Fludarabine can precipitate AIHA - avoid
- Irradiated blood products if purine analogue exposed
Associations
- Autoimmune cytopenias (~10-25%) - AIHA (commonest, warm IgG), ITP, pure red cell aplasia, autoimmune granulocytopenia
- Immune, not infiltrative - does not upstage
- Hypogammaglobulinaemia - up to 70%, progressive; recurrent sinopulmonary infection
- Second malignancies - skin (SCC, melanoma), lung, colorectal
- Richter transformation - DLBCL (>90%) or Hodgkin lymphoma
- Monoclonal gammopathy, acquired angioedema, paraneoplastic pemphigus
- Familial clustering; MBL in relatives
Natural history & complications
- Highly variable: some never require treatment; median OS now measured in >10-15 years
- Not curable with current standard therapy (except selected allogeneic SCT)
Adverse prognostic markers
- Unmutated IGHV (no germinal-centre somatic hypermutation -> more aggressive)
- del(17p) / TP53 mutation - chemoresistant
- del(11q), NOTCH1, SF3B1, BIRC3
- inc beta-2 microglobulin, inc LDH, advanced stage, older age
- CD38 and ZAP-70 expression (surrogates for unmutated IGHV)
Richter transformation
- ~2-10% lifetime, ~0.5-1%/yr
- Suspect: sudden B symptoms, rapidly enlarging asymmetric node, marked inc LDH, hypercalcaemia
- PET-directed biopsy - SUVmax >=10 targets the transformed site
- Clonally related DLBCL (~80%): median survival <12 months; clonally unrelated behaves like de novo DLBCL
- NOTCH1 and TP53 aberration predispose
Causes of death
- Infection and second malignancy more often than progressive CLL
- Richter transformation
- Marrow failure in refractory disease
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