Page 12 of 19

PA18.1-2 | Chronic Leukaemias — CML & CLL — Part 1

CLINICAL SCENARIO

A 58-year-old man visits his GP for fatigue and early satiety. On examination, the spleen extends 15 cm below the costal margin. His CBC shows a WBC of 180 × 10⁹/L with neutrophils, metamyelocytes, myelocytes, and basophils all present. His colleague jokes: 'Looks like his bone marrow forgot to stop.' You order a LAP score — it comes back at 8. That single number changes the diagnosis from reactive to malignant. Let's find out why.

WHY THIS MATTERS

CML is the proof-of-concept success story of molecular oncology — the first cancer treated by a rationally designed kinase inhibitor. CLL is the commonest leukaemia in the Western elderly world and a model of immune subversion. Together they illustrate how a single genetic event can reprogram a haematopoietic clone. For clinicians, interpreting a blood film, ordering the right molecular test, and recognising blast transformation are practical daily skills.

RECALL

Before proceeding, briefly recall:
• What is a translocation? What distinguishes a balanced from unbalanced translocation?
• What is a tyrosine kinase? Why might constitutive (always-on) kinase activity be dangerous?
• How does the myeloid series mature: blast → promyelocyte → myelocyte → metamyelocyte → band → neutrophil?
• What is the LAP (leukocyte alkaline phosphatase) score and in which cells is the enzyme normally active?

CML: The Philadelphia Chromosome and BCR-ABL1

Diagram showing how t(9;22) forms the Philadelphia chromosome and BCR-ABL1 fusion kinase, activating proliferative and survival pathways in chronic myelogenous leukemia. — **Panel A:** Normal chromosome 9 with ABL1 at q34, normal chromosome 22 with BCR at q11, reciprocal translocation t(9;22)(q34;q11), derivative chromosome 9, shortened derivative chromosome 22, Philadelphia chromosome.. **Panel B:** BCR gene, ABL1 proto-oncogene, BCR-ABL1 fusion gene, constitutively active BCR-ABL1 tyrosine kinase, phosphate activation symbols.. **Panel C:** BCR-ABL1 kinase signaling to RAS/MAPK proliferation pathway, JAK-STAT anti-apoptosis pathway, and PI3K/AKT survival pathway.. **Panel D:** Clonal granulocyte precursor expansion with retained differentiation, increased myeloid cells in blood and marrow, >95% CML detection note, adult ALL prognostic note, Nowell and Hungerford historical callout..

Chronic myelogenous leukaemia (CML) arises from a single molecular event: the Philadelphia chromosome (Ph), a balanced reciprocal translocation between chromosomes 9 and 22 — written t(9;22)(q34;q11). The result is an abnormally small chromosome 22 visible on conventional karyotyping.

The translocation fuses the BCR gene on chromosome 22 with the ABL1 proto-oncogene from chromosome 9, producing the BCR-ABL1 fusion gene. Its protein product is a constitutively active tyrosine kinase — it phosphorylates downstream signalling molecules continuously, without requiring growth-factor stimulation. Key activated pathways include RAS/MAPK (proliferation), JAK-STAT (anti-apoptosis), and PI3K/AKT (survival).

Net effect: uncontrolled myeloid proliferation + blocked apoptosis → clonal expansion of granulocyte precursors that retain differentiation capacity (unlike AML, where maturation is arrested).

The Ph chromosome is detected in >95% of CML cases. It is also found in 20-30% of adult ALL (where it confers a worse prognosis).

IMPORTANT: The Ph chromosome was the first recurrent chromosomal abnormality linked to a specific cancer (Nowell and Hungerford, Philadelphia, 1960).

Three-panel diagram showing the Philadelphia chromosome translocation t(9;22) with normal chromosomes, translocation process, and resulting BCR-ABL1 fusion gene formation. — **Panel A:** Normal chromosome 9 with ABL1 gene and chromosome 22 with BCR gene in their original positions. **Panel B:** Reciprocal translocation process between chromosomes 9 and 22 with directional arrows showing genetic material exchange. **Panel C:** Derivative chromosome 22 (Philadelphia chromosome) containing BCR-ABL1 fusion gene and derivative chromosome 9.

CML: Phases, Clinical Features, and Blood Picture

A three-panel medical diagram shows chronic-phase CML blood smear findings, phase progression, and diagnostic differences from leukemoid reaction. — **Panel A:** Blast, promyelocyte, myelocyte, metamyelocyte, band neutrophil, segmented neutrophil, basophil, eosinophil, platelets, normocytic red cells, marked leukocytosis, left shift. **Panel B:** Chronic phase, accelerated phase, blast crisis, massive splenomegaly, hypermetabolic symptoms, WBC 50-200 x 10^9/L, blasts 10-19%, blasts >=20%. **Panel C:** CML versus leukemoid reaction comparison: WBC count, left shift pattern, basophilia, LAP score.

CML has three recognised phases:

1. Chronic phase (3-5 years untreated): Patients are often asymptomatic or have fatigue, weight loss, night sweats (hypermetabolic symptoms), and massive splenomegaly due to extramedullary haematopoiesis. WBC is markedly elevated (often 50-200 × 10⁹/L).

Blood film hallmarks of chronic-phase CML:
• Marked leucocytosis with the full myeloid spectrum — blasts, promyelocytes, myelocytes, metamyelocytes, bands, and neutrophils (a 'left shift' extending all the way to blasts)
• Basophilia (raised basophil count — a characteristic and diagnostically useful finding)
• Eosinophilia (often)
• Thrombocytosis (platelet count may be elevated)
• Anaemia (normocytic)
• Low LAP score (≤20) — mature neutrophils in CML are functionally abnormal and lack normal alkaline phosphatase activity

CML blood smear showing full myeloid spectrum with labeled cell types alongside comparison table distinguishing CML from leukaemoid reaction — **Panel A:** CML peripheral blood smear showing blasts, myelocytes, metamyelocytes, band forms, segmented neutrophils, and increased basophils with morphological annotations. **Panel B:** Comparative diagnostic table highlighting WBC elevation, left shift patterns, basophilia, and LAP score differences between CML and leukaemoid reaction.

2. Accelerated phase (months): Increasing blasts (10-19% in blood/marrow), worsening thrombocytopenia, additional cytogenetic abnormalities ('clonal evolution'), splenomegaly worsening despite treatment.

3. Blast crisis (transformation to acute leukaemia): Blasts ≥20% in blood or marrow. 70% myeloid, 30% lymphoid (B-ALL). Prognosis is very poor — median survival weeks to months.

CML vs Leukaemoid Reaction: The LAP Score Distinction

Side-by-side comparison of CML and leukaemoid reaction showing blood film differences, basophilia, Philadelphia chromosome status, and low versus high LAP score. — **Panel A:** CML smear with full myeloid spectrum, basophilia, low LAP score <=20, Philadelphia chromosome t(9;22), and BCR-ABL1 present.. **Panel B:** Leukaemoid reaction smear with neutrophilia dominated by bands and metamyelocytes, toxic granulation, Dohle bodies, high LAP score >100, and Philadelphia chromosome absent.. **Panel C:** Central LAP/NAP diagnostic scale and comparison table highlighting left shift pattern, basophilia, LAP score, and Philadelphia chromosome status..

A leukaemoid reaction is a benign, reactive, very high white cell count (>50 × 10⁹/L) in response to a severe stimulus (sepsis, disseminated TB, metastatic carcinoma). It can mimic CML on a blood film.

The key discriminator is the LAP score (also called NAP — neutrophil alkaline phosphatase score):

Feature	CML	Leukaemoid Reaction
WBC	Markedly elevated	Very elevated
Left shift	Full myeloid spectrum	Mainly bands/metamyelocytes
Basophilia	Present	Absent
LAP score	Low (≤20)	High (>100)
Ph chromosome	Present	Absent
BCR-ABL1	Present	Absent
Cause	Clonal neoplasm	Reactive to infection/tumour

The LAP score measures enzyme activity in 100 neutrophils; each is graded 0-4, maximum score 400. In reactive conditions, mature neutrophils are 'activated' and have high LAP. In CML, the neoplastic neutrophils lack this enzyme upregulation.

Comparison table showing diagnostic differences between CML, CLL, and Leukaemoid Reaction across WBC count, morphology, LAP score, molecular markers, and clinical features. — **Panel A:** Three-column comparison table showing WBC ranges (CML: >50×10⁹/L, CLL: variable, Leukaemoid: <50×10⁹/L), cell morphology illustrations, LAP scores (low, normal, high), molecular markers (BCR-ABL1, CD19/CD5, reactive), and key clinical clues for differential diagnosis.

SELF-CHECK

A 52-year-old man has WBC 120 × 10⁹/L. His blood film shows myelocytes, metamyelocytes, and increased basophils. The LAP score is 12. Which investigation will confirm the diagnosis?

A. Bone marrow trephine biopsy for blast percentage

B. BCR-ABL1 fusion gene detection by PCR or FISH

C. Cytochemical myeloperoxidase staining of blasts

D. Flow cytometry for CD19/CD5 co-expression

Reveal Answer

Answer: B. BCR-ABL1 fusion gene detection by PCR or FISH

The low LAP score plus basophilia and full myeloid spectrum points to CML. BCR-ABL1 detection (by RT-PCR or FISH for the Philadelphia chromosome) is the confirmatory molecular test. Bone marrow biopsy is useful to assess blast percentage/phase, but it is not the confirmatory test for CML. CD19/CD5 is used to diagnose CLL. Myeloperoxidase staining evaluates AML blasts.