Chronic Myelogenous Leukaemia (CML) - Robbins Pathology

Overview and Classification

Epidemiology

• Primarily a disease of adults, peak incidence in the fifth to sixth decades of life
• Also occurs in children and adolescents
• Approximately 4,800 new cases per year in the United States
• No strong environmental risk factors identified (though prior radiation exposure is one)

Pathogenesis

The Philadelphia Chromosome

• In >90% of cases, it arises from a reciprocal t(9;22)(q34;q11) translocation - the so-called Philadelphia chromosome (Ph)
• ABL (a proto-oncogene encoding a tyrosine kinase) from chromosome 9 fuses with BCR on chromosome 22
• The resulting derivative chromosome 22 carries the BCR::ABL chimeric gene
• In the remaining ~5-10% of cases, the fusion is created by cytogenetically complex or cryptic rearrangements detectable only by FISH or PCR

The BCR-ABL Oncoprotein

1. BCR contains a dimerization domain that causes BCR-ABL to self-associate
2. Dimerization leads to constitutive activation of the ABL kinase moiety
3. The kinase phosphorylates downstream substrates, activating the RAS, JAK/STAT, and AKT pathways - the same pro-growth, pro-survival pathways normally activated by hematopoietic growth factors

Fig. 13.34 (Robbins Cotran) - BCR::ABL fusion and downstream signaling

Cell of Origin

Morphology

Peripheral Blood

• Leukocytosis, often exceeding 100,000 cells/µL
• Predominantly neutrophils and immature granulocytic forms (metamyelocytes, myelocytes, band forms)
• Basophilia and eosinophilia are characteristic
• Thrombocytosis (elevated platelets), often markedly so
• Blasts typically make up <10% of circulating cells in the chronic phase

Fig. 13.35 (Robbins Cotran) - CML peripheral blood smear

Bone Marrow

• Markedly hypercellular due to massively increased maturing granulocytic precursors
• Elevated proportions of eosinophils and basophils
• Megakaryocytes are increased, often including small dysplastic forms
• Erythroid progenitors present in normal or mildly decreased numbers
• Scattered macrophages with abundant wrinkled, green-blue cytoplasm - "sea-blue histiocytes" (characteristic finding)
• Increased reticulin deposition, but overt marrow fibrosis is rare in the chronic phase

Spleen

• Often massively enlarged - up to 2630 g (normal 150-200 g)
• Red pulp resembles bone marrow due to extensive extramedullary hematopoiesis
• Frequently contains splenic infarcts of varying age due to compromised local blood supply

Fig. 13.36 (Robbins Cotran) - Massively enlarged spleen in CML

Clinical Features

Presentation

• Onset is insidious
• Symptoms of hypermetabolism and anaemia: fatigability, weakness, weight loss, anorexia
• A dragging sensation in the left upper abdomen due to splenomegaly is common; acute left upper quadrant pain may occur from splenic infarction
• May be an incidental finding on a routine blood count

Distinguishing CML from Leukemoid Reaction

• Karyotyping (looking for the Philadelphia chromosome)
• Fluorescence in situ hybridization (FISH)
• PCR-based assays

Natural History and Disease Progression

1. Chronic Phase

• Slow progression; without treatment, median survival ~3 years
• Characterised by excessive production of mature granulocytes and platelets
• BCR-ABL is the sole oncogenic driver; differentiation is preserved

2. Accelerated Phase (in ~50% of patients)

• Increasing anaemia and new thrombocytopenia
• Rise in basophil count
• Acquisition of additional cytogenetic abnormalities (trisomy 8, isochromosome 17q, duplication of Ph chromosome)
• Lasts 6-12 months before terminating in blast crisis

3. Blast Crisis

• Resembles acute leukemia
• In the other 50% of patients, blast crisis occurs abruptly without an accelerated phase
• 70% are myeloid blast crises; most of the remainder are lymphoid (pre-B cell) blast crises
• Lymphoid blast crisis: 85% of cases show IKZF1 mutations (Ikaros transcription factor) - the same mutations found in BCR-ABL-positive B-ALL, suggesting shared molecular origin
• Blast crisis is caused by acquisition of mutations in transcriptional regulators that block differentiation (complementing the BCR-ABL tyrosine kinase)

Treatment (Targeted Therapy)

• BCR-ABL kinase inhibitors (imatinib and successors) produce sustained hematologic remissions in >90% of patients with generally tolerable side effects
• These drugs markedly decrease BCR-ABL-positive cells in marrow and blood
• They usually do not extinguish the CML "stem cell," which persists at low levels
• However, they effectively control blood counts and substantially reduce the risk of transformation to accelerated phase and blast crisis - the greatest threats to life
• Proposed mechanism: by reducing the proliferative drive of BCR-ABL-positive progenitors, inhibitors decrease the rate at which these cells acquire additional mutations driving disease progression

Summary Table

4. Differences — Haemoglobinopathy, Thalassaemia & Sickle Cell Anaemia

a. Thalassaemia vs. Haemoglobinopathy (2016, 2015)

Key Concept

Thalassaemias = too little of a normal globin chain. Haemoglobinopathies = normal amount of an abnormal globin chain.

b. Thalassaemia vs. Sickle Cell Anaemia (SCA) (2021)

Shared Features (important to note)

• Both are autosomal recessive
• Both cause haemolytic anaemia with erythroid hyperplasia
• Both produce pigment gallstones and splenomegaly (at least initially)
• Both are most common in populations where falciparum malaria is/was endemic (heterozygote advantage)
• Both can cause extramedullary haematopoiesis in severe disease