Q5 LONG ANSWER 10M ★ High-yield

Discuss the pathogenesis, clinical features, phases, investigations and management of chronic myeloid leukaemia.

General Medicine · Final Professional

Definition

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm arising from a pluripotent haematopoietic stem cell, characterised by uncontrolled proliferation of the granulocytic series with retained capacity for differentiation, and defined by the presence of the Philadelphia chromosome. It accounts for about 15% of adult leukaemias, with a median age at diagnosis of 45–55 years — younger in India than in Western series.

Pathogenesis — the Philadelphia Chromosome

Reciprocal translocation t(9;22)(q34;q11) juxtaposes the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9, producing the shortened chromosome 22 known as the Philadelphia chromosome.
The resulting BCR-ABL1 fusion gene encodes a constitutively active tyrosine kinase (p210), which drives uncontrolled proliferation, reduces apoptosis and impairs stromal adhesion.
This single molecular lesion is both the cause of the disease and the target of treatment — CML is the paradigm of targeted cancer therapy, and its treatment transformed a fatal disease into a chronic manageable one.

Clinical Features

Up to 40–50% are asymptomatic, detected on a routine blood count.
Constitutional: fatigue, weight loss, low-grade fever, night sweats, anorexia.
Massive splenomegaly — the cardinal physical sign, often extending below the umbilicus; causes early satiety, left hypochondrial dragging pain, and may present with acute pain from splenic infarction (with a rub).
Hepatomegaly; sternal tenderness.
Anaemia — pallor, dyspnoea.
Hyperviscosity/leucostasis with very high counts: visual disturbance, headache, confusion, priapism, tinnitus.
Gout and urate stones from high cell turnover.
Bleeding from platelet dysfunction despite normal or raised counts.

Phases

Phase	Blasts	Features
Chronic phase	< 10%	Well controlled with treatment; the phase at which most present; lasts years
Accelerated phase	10–19%	Increasing splenomegaly, worsening counts, basophilia ≥ 20%, new cytogenetic abnormalities, resistance to therapy
Blast crisis	≥ 20%	Behaves as acute leukaemia — two-thirds myeloid, one-third lymphoid; poor response and short survival

Investigations

CBC: marked leucocytosis, frequently > 100 × 10⁹/L; anaemia; platelets normal or raised (thrombocytosis is common — thrombocytopenia suggests advanced disease).
Peripheral smear — highly characteristic: the full spectrum of granulocytic maturation — myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms and neutrophils; BASOPHILIA (a consistent and near-universal finding) and eosinophilia.
Leucocyte alkaline phosphatase (LAP) score — LOW or absent (in contrast to the leukemoid reaction; see below). Largely superseded by molecular testing but still examined.
Bone marrow: markedly hypercellular with myeloid hyperplasia and a raised myeloid:erythroid ratio; reticulin fibrosis in advanced disease; blast percentage determines the phase.
Cytogenetics — Philadelphia chromosome t(9;22) on karyotype.
FISH and RT-PCR for BCR-ABL1 — the definitive diagnostic test, and the basis of quantitative monitoring of response on therapy.
Raised serum uric acid, LDH and vitamin B12 (from raised transcobalamin).

LEUKEMOID REACTION versus CML — A CLASSIC DIFFERENTIATION

A leukemoid reaction is a reactive, non-malignant leucocytosis exceeding 50 × 10⁹/L with a left shift, occurring in response to severe infection (tuberculosis, pneumonia, severe sepsis), disseminated malignancy, severe haemolysis or haemorrhage, burns, corticosteroid therapy, or diabetic ketoacidosis.

Feature	Leukemoid reaction	Chronic myeloid leukaemia
Cause	Reactive to infection, inflammation, malignancy	Clonal neoplasm
LAP score	HIGH	LOW or absent
Philadelphia chromosome / BCR-ABL1	ABSENT	PRESENT — diagnostic
Basophilia	Absent	PRESENT (characteristic)
Eosinophilia	Absent	Present
Splenomegaly	Usually absent or mild	Massive
Toxic granulation, Döhle bodies	Present	Absent
WBC count	Usually < 100 × 10⁹/L	Often > 100 × 10⁹/L
Course	Resolves with treatment of the cause	Progressive without treatment

CLINICAL PEARL

The two features that settle the diagnosis at the bedside and the bench are BASOPHILIA and the LAP SCORE. Basophilia is essentially universal in CML and absent in a reactive leucocytosis; the LAP score is low in CML and high in a leukemoid reaction (a useful memory aid: the malignant cells are "lazy" and produce less enzyme). Confirmation is always by BCR-ABL1.

Management

1. Tyrosine kinase inhibitors (TKIs) — the transformation of this disease

Imatinib — the first-generation agent; a landmark drug that converted a disease with a median survival of 3–5 years into one with near-normal life expectancy.
Second and third generation: dasatinib, nilotinib, bosutinib (for resistance, intolerance, or as first-line in higher-risk disease), and ponatinib for the T315I mutation, which is resistant to all other TKIs.
Adverse effects: oedema and periorbital swelling, myelosuppression, muscle cramps, rash, hepatotoxicity, gastrointestinal upset; agent-specific effects include pleural effusion (dasatinib), vascular occlusive events (nilotinib, ponatinib) and QT prolongation.
Adherence is critical — TKIs are taken indefinitely, and poor adherence is a major cause of loss of response, particularly where cost is a barrier.

2. Monitoring response

Response is assessed at defined milestones by quantitative RT-PCR for BCR-ABL1 transcripts on the International Scale, aiming for successive haematological, cytogenetic and molecular responses. Failure to reach milestones prompts assessment of adherence, mutation analysis, and a switch of TKI. Selected patients with sustained deep molecular response may attempt treatment-free remission under close monitoring.

3. Other treatment

Hydroxyurea — for rapid initial cytoreduction and where TKIs are unaffordable or unavailable.
Leucapheresis — for symptomatic leucostasis and in pregnancy.
Allogeneic stem cell transplantation — the only proven cure, now reserved for TKI failure, T315I mutation without access to ponatinib, accelerated phase and blast crisis.
Blast crisis: treated as acute leukaemia (with a TKI added according to lineage), followed by transplantation where possible; prognosis remains poor.
Supportive: allopurinol and hydration for tumour lysis and gout, and management of anaemia.

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