Medicine chapters
Chronic myeloid and chronic lymphocytic leukaemia
Chronic myeloid leukaemia (BCR-ABL, huge spleen, imatinib) and chronic lymphocytic leukaemia (old patient, smudge cells, CD5+ B cells, watch and wait), side by side.
- CML: a myeloproliferative neoplasm driven by the Philadelphia chromosome t(9;22) making the BCR-ABL tyrosine kinase; huge spleen, very high white count with basophilia and a low LAP score; treat with imatinib.
- CLL: the commonest leukaemia, in the elderly; small mature CD5+ CD23+ B cells, smudge cells, often found by chance; early disease is watched, not treated.
- CLL complications: infections (low immunoglobulins), warm AIHA, ITP and Richter transformation to diffuse large B-cell lymphoma.
On this page
Overview
The chronic leukaemias are clonal blood cancers in which the malignant cells are mature or nearly mature. They progress slowly over years, unlike the acute leukaemias.
- Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm of the granulocyte line, defined by the Philadelphia chromosome.
- Chronic lymphocytic leukaemia (CLL) is a slow build-up of small, mature-looking B lymphocytes, mainly in older people.
Both are common exam topics because each has a "signature" (t(9;22) and imatinib; smudge cells and CD5).
Chronic myeloid leukaemia (CML)
Aetiology and pathogenesis
- A disease of adults, peak age about 40-60 years. It makes up about 14% of leukaemias.
- The cause is an acquired reciprocal translocation t(9;22). The shortened chromosome 22 is the Philadelphia (Ph) chromosome.
- The translocation fuses the ABL gene (chromosome 9) with the BCR gene (chromosome 22). The BCR-ABL fusion protein is a tyrosine kinase that is always switched on, driving myeloid overgrowth.
- The mutation sits in a pluripotent stem cell, so the disease can later turn into either a myeloid or a lymphoid acute leukaemia.
- Ionising radiation is a recognised risk factor.
t(9;22) → BCR-ABL → constant tyrosine kinase activity → imatinib blocks it.
Phases
| Phase | Features |
|---|---|
| Chronic | Most patients present here; may be symptomless; responds well to tyrosine kinase inhibitors |
| Accelerated | Rising blasts and basophils, enlarging spleen, worsening counts despite treatment |
| Blast crisis | Turns into acute leukaemia: mostly myeloid, a minority lymphoid |
Untreated, the disease used to progress through these phases to death within a few years.
Clinical features
- Many are found by chance on a blood count.
- Splenomegaly, often massive, causing left upper quadrant discomfort or early fullness.
- Tiredness and breathlessness from anaemia; weight loss, fever and sweats.
- From a very high white count (hyperleucocytosis/leucostasis): headache, priapism, retinal haemorrhages.
- Lymph node enlargement or a soft-tissue deposit (chloroma) suggests blast crisis.
- High cell turnover can cause raised urate and gout.
Investigations
| Test | Typical finding |
|---|---|
| Full blood count | White count very high (often above 100 × 10⁹/L); Hb normal or low (normocytic); platelets low, normal or high |
| Blood film | Neutrophils plus every stage of maturing myeloid cells (myelocytes, metamyelocytes); basophils and eosinophils raised; few blasts in chronic phase |
| LAP score | Low |
| Bone marrow | Very cellular, with myeloid predominance |
| Cytogenetics / FISH / RT-PCR | t(9;22) or the BCR-ABL transcript; PCR is also used to monitor response |
| Others | High urate, high LDH, raised serum vitamin B12 |
Role of the leucocyte alkaline phosphatase (LAP) score
LAP is an enzyme inside mature neutrophils. The score is:
- Low in CML.
- High in a leukaemoid reaction (reactive neutrophilia from infection, burns or acute illness), and in polycythaemia vera and myelofibrosis.
| Feature | CML | Leukaemoid reaction |
|---|---|---|
| LAP score | Low | High |
| Basophils | Raised | Not raised |
| Toxic granulation, Döhle bodies | Absent | Present |
| t(9;22) / BCR-ABL | Present | Absent |
| Spleen | Large | Usually normal |
A raised LAP score points away from CML. Today the LAP score is largely replaced by BCR-ABL testing, but it is still asked in MCQs.
Diagnosis
Diagnosis rests on the blood count and film plus demonstration of the Philadelphia chromosome or BCR-ABL (cytogenetics, FISH or PCR).
Treatment
- Imatinib, an oral tyrosine kinase inhibitor (TKI) that blocks BCR-ABL, is the usual first-line drug in chronic phase. It gives complete cytogenetic remission in most patients.
- Side effects of imatinib: nausea, headache, rash, fluid retention and low blood counts.
- Poor response or intolerance: check for kinase mutations and switch to a second-generation TKI (dasatinib, nilotinib, bosutinib).
- T315I mutation: ponatinib.
- Response is followed by quantitative PCR for BCR-ABL. A few patients with a deep, sustained molecular response can stop treatment under close monitoring.
- Accelerated phase or blast crisis: TKI plus intensive chemotherapy, then allogeneic stem cell transplant if possible.
- Hydroxycarbamide (hydroxyurea) can lower a very high count quickly while the diagnosis is confirmed. Give allopurinol to protect against high urate.
"9 and 22 make BCR-ABL; imatinib makes it stop."
Chronic lymphocytic leukaemia (CLL)
Aetiology and pathology
- The commonest leukaemia in Western adults; median age about 70 years; more in men.
- A clonal expansion of small, mature-looking B lymphocytes that fail to die (failure of apoptosis rather than fast division).
- When the same cells are mainly in lymph nodes rather than blood, it is called small lymphocytic lymphoma (SLL).
- It is usually preceded by monoclonal B-cell lymphocytosis (a small clone of under 5 × 10⁹/L B cells), much as MGUS precedes myeloma.
Clinical features
- Most are asymptomatic: a raised lymphocyte count on a routine test.
- Painless lymph node enlargement, often symmetrical and rubbery.
- Splenomegaly and hepatomegaly.
- Recurrent infections from low immunoglobulins (hypogammaglobulinaemia) and poor immune function.
- Anaemia from marrow infiltration or autoimmune haemolysis.
- Bruising from low platelets (infiltration or immune thrombocytopenia).
- Fever, night sweats and weight loss in advanced disease.
Investigations
| Test | Typical finding |
|---|---|
| Blood count | Lymphocytosis (above 5 × 10⁹/L of clonal B cells for diagnosis); Hb and platelets normal or low |
| Blood film | Small mature lymphocytes and smudge (smear) cells, which are fragile cells crushed while making the slide; no blasts |
| Immunophenotype (flow cytometry) | B cells (CD19+) that also carry CD5 and CD23; weak surface immunoglobulin with a single light chain (kappa or lambda) |
| Direct Coombs test | Positive if there is autoimmune haemolysis |
| Immunoglobulins | Low or normal |
| FISH / molecular | 17p deletion (TP53) and 11q deletion mean a worse outlook; isolated 13q deletion is favourable. Must be checked before treatment |
| Bone marrow | Heavily infiltrated by lymphocytes (not essential for diagnosis) |
Mantle cell lymphoma is also CD5-positive, but it is CD23-negative and carries t(11;14) with cyclin D1. CLL is CD5+ and CD23+.
Staging
| Rai stage | Findings | Risk |
|---|---|---|
| 0 | Lymphocytosis only | Low |
| I | + Lymph nodes | Intermediate |
| II | + Spleen and/or liver | Intermediate |
| III | + Anaemia | High |
| IV | + Thrombocytopenia | High |
| Binet stage | Findings |
|---|---|
| A | Fewer than 3 lymphoid areas enlarged |
| B | 3 or more lymphoid areas enlarged |
| C | Anaemia and/or thrombocytopenia |
Lymphoid areas in Binet staging are the cervical, axillary and inguinal nodes, the spleen and the liver.
In both systems, anaemia and low platelets (marrow failure) mark advanced, high-risk disease.
Prognosis
- Median survival is around 10 years but varies widely; many people die with CLL rather than of it.
- Poor features: advanced stage, rapid lymphocyte doubling time, 17p (TP53) or 11q deletion, unmutated IGHV, high CD38 or ZAP-70 expression.
- Infection is the commonest cause of death.
When to treat
Early-stage disease is watched ("watch and wait"); about a third never need treatment. Treat when there is:
- Progressive marrow failure (worsening anaemia or low platelets not due to autoimmunity).
- Massive or progressive spleen or node enlargement.
- Lymphocyte doubling time under 6 months.
- B symptoms: fever, night sweats, weight loss.
- Autoimmune haemolysis or thrombocytopenia not responding to steroids.
Treatment options
- Ibrutinib (oral BTK inhibitor): preferred when TP53 is disrupted; can cause atrial fibrillation and bleeding.
- Venetoclax (a BCL-2 inhibitor).
- FCR (fludarabine, cyclophosphamide, rituximab) for younger, fitter patients.
- Anti-CD20 antibody (obinutuzumab or rituximab) with chlorambucil, or bendamustine, for older or frail patients.
- Allogeneic stem cell transplant: occasionally, in fit high-risk patients.
Supportive care:
- Steroids for autoimmune haemolysis or ITP.
- Treat infections early; immunoglobulin replacement for recurrent infection.
- Pneumococcal and influenza vaccines; avoid live vaccines.
- Allopurinol to prevent hyperuricaemia when starting therapy.
Complications
- Infections: bacterial (from hypogammaglobulinaemia), and herpes zoster.
- Warm autoimmune haemolytic anaemia (IgG, Coombs positive) and ITP.
- Richter transformation: change into an aggressive lymphoma, usually diffuse large B-cell lymphoma, in about 5-10% of patients. Suspect it when one node or the spleen grows fast, with fever, weight loss and a rising LDH. The outlook is poor.
"Old man, smudges on the slide, CD5 and 23: CLL."
CML versus CLL at a glance
| Feature | CML | CLL |
|---|---|---|
| Cell line | Myeloid (granulocytes) | Lymphoid (B cells) |
| Age | 40-60 years | Elderly (median about 70) |
| Spleen | Massive | Moderate (can be large) |
| Lymph nodes | Not typical (suggests blast crisis) | Common |
| Film | Whole myeloid series, basophilia | Small lymphocytes, smudge cells |
| Key marker | t(9;22), BCR-ABL | CD5+, CD23+ |
| LAP score | Low | Not used |
| First-line approach | Imatinib | Watch and wait; treat if active |
| Transformation | Blast crisis (acute leukaemia) | Richter (DLBCL) |
Expect: the Philadelphia chromosome t(9;22) and BCR-ABL tyrosine kinase; imatinib as first-line CML treatment and second-generation TKIs for resistance; a low LAP score with basophilia separating CML from a leukaemoid reaction; massive splenomegaly; blast crisis. For CLL: elderly patient with lymphocytosis, smudge cells, CD5+ CD23+ B cells, Rai and Binet staging, watch and wait for early disease, indications for treatment, hypogammaglobulinaemia and infections, warm AIHA and ITP, and Richter transformation. Hairy cell leukaemia (TRAP, dry tap, cladribine) is a common distractor.
Quick revision
- CML: t(9;22) → BCR-ABL tyrosine kinase → imatinib.
- CML film: whole myeloid series, basophils up; LAP score low.
- Leukaemoid reaction: LAP high, toxic granulation, no Ph chromosome.
- CML phases: chronic → accelerated → blast crisis (mostly myeloid).
- CLL: elderly, smudge cells, CD5+ CD23+ B cells.
- Rai III/IV and Binet C (anaemia, low platelets) = advanced.
- Early CLL: watch and wait; treat for marrow failure, bulky or progressive disease, doubling under 6 months, B symptoms.
- CLL death: infection; complications AIHA, ITP, Richter (DLBCL).
- Hairy cell: TRAP+, dry tap, big spleen, cladribine.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Pathoma: Fundamentals of Pathology).
FAQ
What is the Philadelphia chromosome?
It is the small chromosome 22 left after a swap of material between chromosomes 9 and 22, which creates the BCR-ABL gene that drives chronic myeloid leukaemia.
Why is the LAP score low in CML?
The neutrophils in CML come from the malignant clone and carry little alkaline phosphatase, whereas reactive neutrophils in infection have a high score.
What are smudge cells?
They are fragile CLL lymphocytes that burst when the blood film is spread, leaving smeared nuclear remnants on the slide.
Does every patient with CLL need treatment?
No. Early, stable disease is observed; treatment starts only when there is marrow failure, bulky or rapidly growing disease, a short doubling time or B symptoms.
What is Richter transformation?
It is the change of CLL into an aggressive lymphoma, usually diffuse large B-cell lymphoma, shown by rapidly enlarging nodes, B symptoms and a rising LDH.