Q2 LONG ANSWER 10M ★ High-yield

Describe chronic myeloid leukaemia and chronic lymphocytic leukaemia with their clinical features and laboratory findings.

Pathology · 2nd Professional — Para-Clinical

Chronic Myeloid Leukaemia — Definition

Chronic myeloid leukaemia is a myeloproliferative neoplasm of the pluripotent stem cell, characterised by the philadelphia chromosome and by uncontrolled proliferation of the granulocytic series.

Peak age 40 to 50; about 15% of all leukaemias
T(9;22)(q34;q11) — the philadelphia chromosome, present in over 95%; fuses BCR on 22 with ABL on 9, producing a constitutively active tyrosine kinase

Clinical Features and Course

Insidious onset — fatigue, weight loss, night sweats, low-grade fever
Massive splenomegaly is characteristic, often reaching the pelvis; dragging abdominal discomfort, early satiety, and splenic infarcts causing left hypochondrial pain with a rub
Hypermetabolism, gout and priapism from high cell turnover
Three phases — chronic (3–5 years), accelerated, then blast crisis which resembles acute leukaemia (myeloid in 70%, lymphoid in 30%) and is usually rapidly fatal

Laboratory Findings in CML

Test	Finding
White cell count	Markedly raised, often 100,000–500,000/mm3
Peripheral smear	The full spectrum of granulocyte maturation — myeloblasts, promyelocytes, myelocytes, metamyelocytes and mature neutrophils; NO leukaemic hiatus. Basophilia and eosinophilia are characteristic
Leucocyte alkaline phosphatase (lap) score	Low or absent — the classical discriminator
Platelets	Often raised early; fall in the accelerated phase
Bone marrow	Hypercellular with a greatly raised myeloid:erythroid ratio; increased megakaryocytes
Cytogenetics	Philadelphia chromosome; BCR-ABL by fish or RT-PCR
Serum B12 and uric acid	Raised

CLINICAL PEARL

The lap score separates CML from a leukaemoid reaction, and it is counterintuitive. A reactive neutrophilia has high alkaline phosphatase because the cells are normal and activated. CML has a low score because the neoplastic granulocytes are functionally abnormal. Molecular testing for BCR-ABL has largely replaced it, but the principle is still examined.

Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia is a monoclonal proliferation of functionally incompetent mature B lymphocytes, which accumulate because they fail to undergo apoptosis rather than because they divide rapidly.

A disease of the elderly, rare below 40; the commonest leukaemia in adults in the West, though less common in India
Often an incidental finding on a blood count in an asymptomatic person
Symmetrical, painless, generalised lymphadenopathy with hepatosplenomegaly

Test	Finding
Lymphocyte count	Absolute lymphocytosis above 5,000/mm3, often far higher
Peripheral smear	Small mature lymphocytes with scanty cytoplasm; characteristic smudge (smear) cells — fragile cells crushed in making the film
Immunophenotype	CD19, CD20 (weak), CD23 and aberrant CD5 — a B cell expressing a T cell marker, which is the diagnostic combination
Bone marrow	Infiltration by mature lymphocytes
Direct Coombs test	Positive in about 15% — autoimmune haemolytic anaemia
Serum immunoglobulins	HYPOgammaglobulinaemia — the cause of recurrent infection

Comparison of the Chronic Leukaemias

Feature	CML	CLL
Age	40–50	Over 60
Cell	Granulocytic series, all stages	Mature small lymphocytes
Splenomegaly	Massive	Moderate
Lymphadenopathy	Uncommon	Prominent and generalised
Diagnostic marker	Philadelphia chromosome / BCR-ABL	CD5-positive B cells; smudge cells
Characteristic complication	Blast crisis	Autoimmune haemolysis, hypogammaglobulinaemia, richter transformation to high-grade lymphoma
Treatment	Imatinib and other tyrosine kinase inhibitors	Often watchful waiting in early stage; treat when symptomatic

The Other Myeloproliferative Neoplasms

Disorder	Feature	Genetics
Polycythaemia vera	Raised red cell mass with a low erythropoietin; pruritus after a hot bath, plethora, thrombosis, splenomegaly	JAK2 V617F in over 95%
Essential thrombocythaemia	Platelets persistently above 4.5 lakh; thrombosis and paradoxical bleeding	JAK2, CALR or MPL
Primary myelofibrosis	Marrow fibrosis with extramedullary haemopoiesis; massive splenomegaly; tear-drop cells and a leucoerythroblastic film; dry tap on aspiration	JAK2, CALR or MPL
Chronic myeloid leukaemia	As above	BCR-ABL — the one that is Philadelphia positive

All four arise from a single transformed stem cell and may transform into one another or into acute leukaemia
BCR-ABL divides them — CML is Philadelphia positive, the other three are negative and are defined by JAK2, CALR or MPL

Applied Aspects

Imatinib transformed CML from a disease with a median survival of about five years into one with near-normal life expectancy; it is the model of rational targeted therapy, designed against the specific fusion protein
Molecular monitoring of BCR-ABL transcripts guides treatment, and a rising level signals resistance long before the blood count changes
CLL is often not treated at all in early asymptomatic stages, since treatment does not prolong life — a point patients find difficult and which needs careful explanation
Infection is the commonest cause of death in CLL, from hypogammaglobulinaemia; immunoglobulin replacement and vaccination help
Richter transformation — sudden clinical deterioration with rapid nodal enlargement and fever in CLL; carries a poor prognosis
Leukaemoid reaction must always be excluded before diagnosing CML — severe infection, tuberculosis and metastatic carcinoma can all produce counts above 50,000
Hydroxyurea and leucapheresis are used for immediate cytoreduction when the count is dangerously high, before targeted therapy takes effect

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