Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the uncontrolled proliferation of mature and maturing granulocytes, driven by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome translocation t(9;22).

Chronic Myeloid Leukaemia (CML)

2. Epidemiology

Parameter	Detail
Incidence	1–2 per 100,000 per year ^[4]
Proportion of adult leukaemias	15–20% ^[4]
Peak age	40–60 years (median age at diagnosis ~50 years) ^[1]^[4]
Sex	Male > Female (1.4:1) ^[4]
Childhood	Exceptionally rare — accounts for only ~5% of paediatric leukaemia ^[5]

4. Relevant Anatomy & Haematopoietic Physiology

5. Aetiology & Pathophysiology

5.1 The Philadelphia Chromosome & BCR-ABL1 Fusion Gene

This is the cornerstone of CML pathophysiology and must be understood thoroughly.

The constitutively active BCR-ABL1 tyrosine kinase activates multiple downstream signalling pathways:

Pathway	Effect
RAS-MAPK	Uncontrolled cell proliferation
JAK-STAT	Enhanced survival signalling
PI3K-AKT	Anti-apoptotic signalling (cells resist programmed death)
CRKL/Paxillin	Altered cell adhesion → premature release of immature myeloid cells from BM into blood

The net result at the cellular level:

Uncontrolled proliferation of granulocytic lineage cells
Impaired apoptosis (cells live longer than they should)
Maturation is NOT significantly impaired (unlike acute leukaemia) — hence cells can still differentiate into mature neutrophils
Reduced adhesion to bone marrow stroma → premature release into blood → leukocytosis with a "left shift" showing all stages of granulocyte maturation

In chronic leukaemia: maturation is not impaired + uncontrolled proliferation + impaired apoptosis ^[3]

Since maturation is not impaired, blasts are able to grow to more mature cells ^[3]

6. Classification — Natural History & Disease Phases

CML classically follows a triphasic illness ^[2]^[4]:

Phase	Blast %	Duration (untreated)	Clinical Characteristics
Chronic Phase (CP)	< 10% (WHO) / < 15% (ELN)	3–5 years	~90% of patients present in this phase ^[2]; relatively indolent; most patients asymptomatic or have mild symptoms
Accelerated Phase (AP)	10–19%	~6–18 months	Acquisition of additional molecular lesions ^[2]; increasing symptoms; progressive splenomegaly; rising WBC refractory to therapy; basophils ≥ 20%; PLT < 100 (unrelated to Tx) or > 1000 (unresponsive to Tx); cytogenetic evolution (additional chromosomal abnormalities beyond Ph) ^[4]
Blast Crisis (BC)	≥ 20%	1–2 months (rapidly fatal)	Behaves like acute leukaemia — 2/3 AML, 1/3 ALL ^[2]; often refractory to treatment; extramedullary blastic disease (chloromas) may occur

WHO 2022 Update

The WHO 2022 classification is debating whether to retain the accelerated phase as a distinct entity, because with modern TKI therapy, the AP has less clinical significance — prognosis is still good if managed appropriately ^[3]. The current WHO 5th edition (2022) and ICC classification differ slightly in their approach to AP, but for exam purposes the traditional three-phase model remains the teaching standard.

7. Clinical Features

7.2 Symptoms (with Pathophysiological Basis)

Symptom	Pathophysiological Basis
Loss of weight (LOW)	Massively expanded myeloid clone has enormous metabolic demands → hypermetabolic/catabolic state → "cancer cachexia"
Loss of appetite (LOA)	Combination of circulating cytokines (TNF-α, IL-6) from the tumour burden + mechanical compression of the stomach by massive spleen
Night sweats	Cytokine-mediated thermoregulatory dysfunction (IL-1, TNF-α, IL-6) acting on the hypothalamic thermostat
Fatigue/lassitude	Multifactorial: anaemia + hypermetabolism + cytokine-mediated malaise
Fever	Release of pyrogenic cytokines from the expanded myeloid clone

"Hypercatabolism: bone pain, weight loss, fever, fatigue, sweating" ^[2]

Symptom	Pathophysiological Basis
Left upper quadrant (LUQ) pain/discomfort	Physical distension of the splenic capsule by the massively enlarged spleen
Early satiety	Mechanical compression of the stomach by the spleen → reduced gastric capacity
LUQ dragging sensation	Weight of the massive spleen pulling on its peritoneal attachments
Acute severe LUQ pain	Splenic infarction — when the spleen outgrows its blood supply → ischaemic necrosis of a segment

Symptom	Pathophysiological Basis
Dyspnoea on exertion	Reduced O₂-carrying capacity → tissue hypoxia → compensatory increase in ventilation
Fatigue and lethargy	Inadequate O₂ delivery to muscles and CNS
Palpitations	Compensatory increased cardiac output in response to anaemia

Anaemia occurs in 45–62% of patients ^[4]
Pathogenesis: the massively expanded granulocytic series "crowds out" erythropoiesis in the bone marrow

Hyperleukostasis: blurred vision, SOB, chest pain ^[2]

Symptom	Pathophysiological Basis
Blurred vision	Leukostasis in retinal microvasculature → retinal vein occlusion → haemorrhage/oedema
Dyspnoea	WBC plugging of pulmonary microvasculature → ventilation-perfusion mismatch
Priapism	WBC sludging in the corpora cavernosa → venous outflow obstruction
Confusion/headache	Cerebral microvascular occlusion

Leukostasis occurs when WBC > 100 × 10⁹/L — the massive number of white cells increases blood viscosity and physically obstruct the microcirculation
More common in blast crisis (blasts are larger and stickier than mature cells)

Symptom	Pathophysiological Basis
Bone pain / sternal tenderness	Expansion of the bone marrow cavity by the massively expanded granulocytic clone → periosteal stretching

Symptom	Pathophysiological Basis
Gouty arthritis / renal colic	Rapid turnover of the massive granulocytic clone → breakdown of nucleic acids → increased uric acid production → hyperuricaemia → crystal deposition

7.3 Signs (with Pathophysiological Basis)

"The most apparent physical exam finding in CML is a massive splenomegaly" ^[3]

Sign	Detail & Pathophysiology
Massive splenomegaly	The most characteristic and often the most impressive physical finding in CML. Results from: (1) infiltration of the splenic red pulp by leukaemic granulocytes; (2) extramedullary haematopoiesis — the spleen resumes its fetal role of blood cell production when the bone marrow is overwhelmed; (3) sequestration of blood cells
Splenic rub	A friction rub audible on auscultation over the spleen, indicating splenic infarction — occurs when the massively enlarged spleen outgrows its vascular supply ^[4]
Variable size	"Can be of any size depending on when the leukaemia is diagnosed" ^[4] — ranges from just palpable to crossing the midline into the pelvis

Differential Diagnosis of Massive Splenomegaly

When the spleen crosses the umbilicus, think of the "Big 5" causes:

CML (most classic cause)
Myelofibrosis (primary or secondary)
Malaria (chronic, especially tropical splenomegaly syndrome)
Kala-azar (visceral leishmaniasis)
Gaucher's disease (lysosomal storage disease)

"Huge splenomegaly is not uncommon [in CML]; differential diagnosis includes myelofibrosis" ^[4]

Sign	Pathophysiology
Pallor (conjunctival, palmar)	Reduced haemoglobin → less colour in capillary beds
Tachycardia	Compensatory increase in cardiac output
Flow murmur	Hyperdynamic circulation due to reduced blood viscosity from anaemia

Sign	Pathophysiology
Petechiae, purpura	Qualitative platelet dysfunction ± thrombocytopenia (more common in AP/BC)
Ecchymoses	As above
Retinal haemorrhages	Combination of anaemia, thrombocytopenia, and leukostasis in retinal vessels

Sign	Significance
Lymphadenopathy	Uncommon in chronic phase; extramedullary involvement (LN, skin) is uncommon unless in blastic crisis ^[4]
Skin nodules (leukaemia cutis)	Extramedullary blastic infiltration — suggests blast crisis
Chloromas (granulocytic sarcomas)	Collections of myeloid blasts forming tumour-like masses in soft tissues; a feature of blast crisis

Feature	Chronic Phase	Accelerated Phase	Blast Crisis
Symptoms	Often none / mild constitutional	Increasing constitutional symptoms, increasing LUQ pain	Severe constitutional symptoms, bleeding, infection
Splenomegaly	Present, may be massive	Progressive, refractory	Variable
WBC	↑↑ (often > 100)	Rising, refractory to Tx	Variable, blasts ≥ 20%
Platelets	Often ↑	Variable (may be ↓ or ↑↑)	Usually ↓
Basophils	Mildly ↑	≥ 20%	Variable
Blasts (PB/BM)	< 10%	10–19%	≥ 20%
Extramedullary disease	Rare	Uncommon	Common (LN, skin, CNS)

8. Relevant Peripheral Blood & Bone Marrow Findings (Pre-Diagnosis Section)

Although formal diagnostics will be covered in the next section, understanding what you see on blood film and BM is essential to understanding the clinical presentation:

Parameter	Typical Finding	Explanation
WBC	Markedly elevated (often 50–200 × 10⁹/L, can exceed 500)	Uncontrolled granulocytic proliferation
Differential	"Full spectrum" / complete representation of myeloid maturation	Predominantly neutrophils and myelocytes → bimodal distribution of myelocytes and neutrophils ^[3]; also promyelocytes, metamyelocytes, bands
Basophilia	Present and characteristic ^[3]	Increased basophil production from the neoplastic clone; important diagnostic clue
Eosinophilia	Often present	Part of the pan-granulocytic proliferation
Hb	↓ (anaemia)	Erythropoiesis suppressed by granulocytic expansion
Platelets	Normal or ↑ (thrombocytosis) ^[2]	Megakaryopoiesis is markedly increased ^[3] from the neoplastic clone

"CBC d/c: ↓Hb, ↑WBC (basophilia, myelocyte > metamyelocyte), N/↑ Plt" ^[2]

9. Important Concepts for Understanding CML

This is a commonly tested distinction:

Feature	CML	Leukaemoid Reaction
WBC	Usually > 50 × 10⁹/L	Usually < 50 × 10⁹/L
Basophilia	Present (characteristic)	Absent
Eosinophilia	Often present	Usually absent
LAP/NAP score	Low (neoplastic neutrophils are functionally deficient)	High (activated normal neutrophils)
Toxic granulation/Döhle bodies	Absent	Present
Splenomegaly	Often massive	Absent or mild
Philadelphia chromosome/BCR-ABL1	Positive (definitive)	Negative
Platelet count	Often elevated	Usually normal
Myelocyte:metamyelocyte ratio	Myelocyte > metamyelocyte	Metamyelocyte > myelocyte

CML represents one of the greatest success stories in targeted cancer therapy:

The BCR-ABL1 fusion protein is a constitutively active tyrosine kinase ^[1]^[3]
Specific targeted treatment against the tyrosine kinase → tyrosine kinase inhibitors (TKIs) ^[3]
Imatinib ("i-MATIN-ib" → "matin" relates to mesenchymal/matrix, "-ib" = inhibitor) was the first TKI designed to fit precisely into the ATP-binding pocket of the BCR-ABL1 kinase, blocking its activity
This transformed CML from a fatal disease (median survival 3–5 years) to a chronic manageable condition with near-normal life expectancy

High Yield Summary

Definition: CML is an MPN defined by the Philadelphia chromosome t(9;22) and BCR-ABL1 fusion gene, causing constitutive tyrosine kinase activity → uncontrolled myeloid proliferation with preserved maturation.

Epidemiology: 15–20% of adult leukaemias; incidence 1–2/100k; median age 50; M > F; only established RF is ionizing radiation.

Key Pathophysiology:

Philadelphia chromosome = t(9;22)(q34.1;q11.2) → BCR-ABL1 fusion gene → constitutively active tyrosine kinase
→ Uncontrolled proliferation + impaired apoptosis + preserved maturation → massive granulocytosis
< 20% blasts = chronic phase; ≥ 20% = blast crisis (acute leukaemia)

Clinical Features:

50% asymptomatic at diagnosis
Massive splenomegaly (the cardinal sign)
Constitutional symptoms (LOW, LOA, night sweats, fatigue)
Hyperleukostasis (if WBC very high): blurred vision, SOB, priapism
Anaemia (45–62%), thrombocytosis (NOT thrombocytopenia)
Basophilia on CBC is characteristic

Phases: Chronic (blasts < 10%) → Accelerated (10–19%, basophilia ≥ 20%, cytogenetic evolution) → Blast crisis (≥ 20%, acute leukaemia)

Key Distinction: "No t(9;22) = not CML." CML is the only MPN defined by BCR-ABL1.

Active Recall - CML: Definition, Epidemiology, Pathophysiology & Clinical Features

Differential Diagnosis of CML

The differential diagnosis of CML must be considered at two levels:

At presentation — when you encounter marked leukocytosis with a left shift on CBC/PBS and need to distinguish CML from other causes of a very high WBC.
At a specific disease phase — when you encounter a patient in blast crisis and must distinguish it from de novo acute leukaemia.

The thinking framework mirrors the 5-step approach to diagnosis of haematological malignancy (MCICM) ^[5]: you begin with morphology (what does the blood film look like?), then layer on cytochemistry, immunophenotyping, cytogenetics, and molecular genetics to reach the final diagnosis.

2. Differential Diagnoses — Detailed Discussion

This is the most important differential to exclude in everyday clinical practice, because reactive causes of leukocytosis are far more common than CML.

"Leukaemoid reaction to infection: WBC can be as high as 50, but should have ↑LAP score, toxic granulation in neutrophils and a readily identifiable precipitating cause" ^[4]

A leukaemoid reaction is a non-neoplastic, exaggerated granulocytic response to a severe stimulus — typically a severe infection (e.g. pneumonia, sepsis, abscess), severe haemolysis, or metastatic cancer to bone marrow.

Why it mimics CML: Both produce marked leukocytosis with immature myeloid precursors visible on the peripheral blood film (a "left shift"). Both can cause WBC counts in the tens of thousands.

How to distinguish from CML:

Feature	CML	Leukaemoid Reaction
WBC count	Usually > 50 (often > 100)	Usually < 50 (rarely > 100)
Basophilia	Present (almost universal) ^[4]^[8]	Absent
Eosinophilia	Often present (~90%)	Usually absent
LAP/NAP score	Low (neoplastic neutrophils are enzymatically deficient) ^[1]^[4]	High (activated normal neutrophils are enzyme-rich)
Toxic granulation / Döhle bodies	Absent	Present (hallmark of reactive neutrophilia)
Myelocyte:metamyelocyte ratio	Myelocyte > metamyelocyte ("myelocyte bulge") ^[1]	Metamyelocyte > myelocyte (orderly maturation pyramid)
Splenomegaly	Often massive	Absent or mild
Philadelphia chromosome / BCR-ABL1	Positive (definitive) ^[3]^[4]	Negative
Platelet count	Often elevated (thrombocytosis)	Usually normal
Precipitating cause	No identifiable infection/trigger	Identifiable severe infection/stimulus

Neutrophils in CML are morphologically normal but cytochemically abnormal with ↓ leukocyte alkaline phosphatase (LAP) activity, which helps to exclude reactive leukocytosis (leukemoid reaction) due to infection ^[1]

Why is the LAP score low in CML? Because the neoplastic neutrophils, although they look morphologically mature under the microscope, are derived from the BCR-ABL1+ clone and have abnormal enzyme content. In contrast, reactive neutrophils are normal cells that have been activated and degranulated — they are packed with enzymes.

High Yield — Distinguishing CML from Leukaemoid Reaction

The three quickest bedside/lab clues that favour CML over a reactive cause:

Basophilia (almost never seen in reactive leukocytosis)
Low LAP/NAP score
Massive splenomegaly

The definitive distinguishing test is demonstration of BCR-ABL1 / Ph chromosome ^[3]^[4].

CML is the only MPN defined by BCR-ABL1; the other MPNs (PV, ET, PMF) are BCR-ABL1 negative ^[4]^[6].

However, some features overlap:

MPN	Key Feature that Might Mimic CML	How to Distinguish
Polycythaemia Vera (PV)	Can have leukocytosis and splenomegaly; JAK2 V617F positive (100%)	Primary feature is ↑Hb/Hct (not leukocytosis); LAP score is high or normal (not low); BCR-ABL1 negative; erythrocytosis dominates ^[6]^[9]
Primary Myelofibrosis (PMF)	Can cause massive splenomegaly (one of the two main causes alongside CML); can have leukocytosis	Leukoerythroblastic film with tear-drop poikilocytes and nucleated RBCs; "dry tap" on BM aspirate due to fibrosis; JAK2/CALR/MPL positive, BCR-ABL1 negative ^[4]^[6]
Essential Thrombocythaemia (ET)	Can have mild leukocytosis and splenomegaly	Thrombocytosis (PLT ≥ 450) is the dominant feature; BCR-ABL1 negative; JAK2/CALR/MPL positive; bone marrow shows predominantly megakaryocytic proliferation ^[6]^[9]

"Other chronic myeloid neoplasm: MDS, MPN, MDS/MPN, distinguished by genetic testing" ^[4]

Why do we need to distinguish these? Because treatment is completely different. CML is treated with TKIs targeting BCR-ABL1; the other MPNs are treated with hydroxyurea, JAK2 inhibitors (ruxolitinib), aspirin, phlebotomy (PV), etc.

MDS is characterised by ineffective haematopoiesis leading to peripheral blood cytopenia ^[10]

MDS typically presents with cytopenias (low counts), not cytoses (high counts) → this is the key difference from CML
However, some MDS subtypes can have a modestly elevated WBC, and the bone marrow can be hypercellular
Distinguishing features:
- Pancytopenia (not leukocytosis) is the hallmark ^[10]
- Dysplastic cells visible on PBS (pseudo-Pelger-Huët cells, hypogranular neutrophils, ring sideroblasts) ^[10]
- Macrocytic anaemia (↑ MCV) is typical ^[10]
- BCR-ABL1 negative
- Different cytogenetic abnormalities: del(5q), del(7q), del(20q), +8 ^[10]

Feature	CML	MDS
WBC	Markedly elevated	Usually low (cytopenia)
Differentiation	Normal/preserved	Impaired (dysplastic)
PBS	Full myeloid spectrum, basophilia	Dysplastic cells, macrocytosis
Proliferation	Excessive and effective	Excessive but ineffective
BM blasts	< 10% (CP)	< 20% (by definition, else = AML)
Genetic hallmark	BCR-ABL1 / Ph+	del(5q), -7, +8 etc.

CLL is unlikely to be confused with CML if the PBS is examined carefully, but both are "chronic leukaemias" and may appear in differential lists:

Feature	CML	CLL
Cell type	Myeloid (granulocytic)	Lymphoid (mature B cells) ^[2]
PBS	Full myeloid spectrum, basophilia	Smear/smudge cells ^[8]
Demographics	Adults, median 50y	Elderly, median ~70y ^[2]
Splenomegaly	Massive	Moderate
Lymphadenopathy	Uncommon (unless blast crisis)	Common
Defining marker	BCR-ABL1 / Ph+	CD5+, CD19+, CD20+, CD23+ ^[2]

3. Summary — Differential Diagnosis Framework

The differentials can be organised by the presenting clinical scenario:

Differential	Key Distinguishing Feature(s)
Leukaemoid reaction	↑LAP, toxic granulation, identifiable infection, no basophilia, BCR-ABL1 negative
Other MPN (PV, ET, PMF)	Dominant feature is polycythaemia, thrombocytosis, or fibrosis respectively; BCR-ABL1 negative; JAK2/CALR/MPL positive
Atypical CML (BCR-ABL1 neg)	Similar PBS but BCR-ABL1 negative by all methods; classified as MDS/MPN overlap
CMML	Prominent persistent monocytosis; dysplastic features; BCR-ABL1 negative
MDS	Cytopenias (not cytoses); dysplastic morphology; macrocytosis
CNL / CEL	Neutrophilia or eosinophilia without full myeloid spectrum; BCR-ABL1 negative

Differential	Key Distinguishing Feature(s)
CML blast crisis	Prior history of CML; underlying granulocyte series changes; BCR-ABL1 positive; may respond to TKI
De novo AML	No antecedent CML; pancytopenia; lacks characteristic granulocyte series changes; BCR-ABL1 usually negative
Ph-positive ALL	De novo presentation; blast morphology; NO chronic-phase myeloid spectrum; lymphoid markers on flow cytometry; BCR-ABL1 positive but distinct entity
Ph-positive AML	Rare; lacks chronic-phase blood picture

Massive splenomegaly differential ^[6]^[12]:

Cause	Distinguishing Feature
CML	Leukocytosis with full myeloid spectrum, basophilia, BCR-ABL1+
Primary Myelofibrosis	Leukoerythroblastic film, tear-drop cells, dry tap, JAK2/CALR/MPL+
Chronic malaria / tropical splenomegaly	Travel history, thick/thin film, malarial antigens
Visceral leishmaniasis (Kala-azar)	Travel to endemic area, pancytopenia, amastigotes on BM
Gaucher's disease	Lysosomal storage disease, Gaucher cells on BM, acid β-glucosidase deficiency

The 5-step diagnostic approach (MCICM) ^[5] is used to systematically narrow the differential:

Step	What It Tells You	CML-Specific Finding
Morphology (PBS/BM)	Cell types, maturation, blasts	Full myeloid spectrum, bimodal peak, basophilia, < 10% blasts (CP)
Cytochemistry	Lineage (myeloid vs lymphoid)	Low LAP score (distinguishes from reactive and PV)
Immunophenotyping	Surface markers for lineage and maturity	Less critical for CML diagnosis; useful in blast crisis to determine myeloid vs lymphoid
Cytogenetics (karyotype/FISH)	Chromosomal abnormalities	Ph chromosome t(9;22) — gold standard ^[3]
Molecular genetics (RT-PCR)	Fusion transcripts, mutations	BCR-ABL1 fusion mRNA — most sensitive; also used for monitoring ^[4]

"The gold standard diagnosis of CML is based on cytogenetics — defined by the presence of the Philadelphia chromosome t(9;22)(q34.1;q11.2)" ^[3]

High Yield Summary — Differential Diagnosis of CML

Most important differential at presentation: Leukaemoid reaction — distinguish by basophilia (present in CML, absent in reactive), LAP score (low in CML, high in reactive), and BCR-ABL1 testing (definitive).
Other chronic myeloid neoplasms (PV, ET, PMF, atypical CML, CMML): all BCR-ABL1 negative; distinguished by dominant haematological abnormality and molecular markers (JAK2, CALR, MPL).
At blast crisis: Must distinguish from de novo AML and Ph+ ALL — look for antecedent chronic-phase features and characteristic granulocyte series changes.
"No BCR-ABL1 = not CML" — this is the single most important diagnostic principle.
Massive splenomegaly DDx: CML and primary myelofibrosis are the two haematological causes of truly massive splenomegaly.

Active Recall - Differential Diagnosis of CML

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — CML section, p.1400–1404 ^[2] Senior notes: Maksim Medicine Notes.pdf — Haematology, CML p.176; CLL p.177; Haematological malignancies overview p.172 ^[3] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf — CML section p.22; Chronic vs acute leukemia p.2 ^[4] Senior notes: Ryan Ho Haemtology.pdf — CML section p.63–66; AML section p.53–54; Leukaemia overview p.51 ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf — Leukemia section p.418 ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf — MPN section p.22; Massive splenomegaly p.8; ET p.29; PV p.27 ^[8] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf — CLL PBS findings p.8 ^[9] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf — PV p.27; ET p.29 ^[10] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf — MDS section p.770–774 ^[11] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf — AML section p.731 ^[12] Senior notes: MBBS Final MB (Surgery) (Felix PY Lai).pdf — Splenomegaly differential p.130

Diagnostic Criteria, Diagnostic Algorithm & Investigations for CML

1. Diagnostic Criteria

The diagnosis of CML rests on two pillars working together — you need both a compatible haematological picture AND the defining genetic abnormality. Neither alone is sufficient.

"The gold standard diagnosis of CML is based on cytogenetics — defined by the presence of the Philadelphia chromosome t(9;22)(q34.1;q11.2)" ^[3]

"No t(9;22), not CML" ^[3]

The diagnostic criteria can be summarised as:

Criterion	Detail
1. Compatible blood / BM picture	Leukocytosis with bimodal distribution of myelocytes and neutrophils, basophilia ^[4]; BM: granulocytic hyperplasia, dwarf megakaryocytes with hypolobulated nuclei ^[4]
2. Demonstration of BCR-ABL1	By ANY of: Ph chromosome t(9;22) on karyotyping (90–95% positive) ^[4], BCR-ABL1 fusion gene on FISH ^[4], or BCR-ABL1 fusion mRNA transcript on RT-PCR ^[4]

Both criteria must be met. Let's unpack why each matters:

Why do we need the blood/BM picture? Because other malignancies can carry the Philadelphia chromosome (Ph+ ALL, rarely Ph+ AML) — a compatible chronic-phase myeloid picture distinguishes CML from these.
Why do we need BCR-ABL1? Because other MPNs and reactive conditions can cause leukocytosis with a left shift — BCR-ABL1 is the definitive and sine qua non marker of CML.

High Yield – Diagnostic Principle

Diagnosis of CML requires: ^[4]

Typical finding in peripheral blood/BM — leukocytosis, bimodal distribution, basophilia; BM: granulocytic hyperplasia, dwarf megakaryocytes with hypolobulated nuclei
Characteristic cytogenetic abnormality — demonstration of Philadelphia chromosome (karyotype) or BCR-ABL1 gene (FISH) or fusion mRNA transcript (RT-PCR)

Once CML is confirmed, you must determine the phase — this dictates prognosis and treatment urgency.

Phase	WHO Criteria ^[1]
Chronic Phase (CP)	Blasts < 10% in PB or BM; does not meet AP or BC criteria
Accelerated Phase (AP)	≥ 1 of: Blasts 10–19% in PB or BM; basophils ≥ 20% in PB; persistent thrombocytopenia < 100 × 10⁹/L unrelated to therapy; thrombocytosis > 1,000 × 10⁹/L unresponsive to therapy; progressive splenomegaly and leukocytosis unresponsive to therapy; cytogenetic evolution (additional chromosomal abnormalities beyond Ph, e.g. trisomy 8, trisomy 19, duplication of Ph, isochromosome 17q → loss of TP53) ^[1]
Blast Crisis (BC)	≥ 1 of: Blasts ≥ 20% in PB or BM; large foci or clusters of blasts on BM biopsy; extramedullary blastic infiltrates (myeloid sarcoma) ^[1]

Why does phase matter? Because:

CP patients → excellent long-term outcomes with TKI alone (> 90% 5-year survival)
AP patients → need more aggressive TKI (often 2nd-gen) ± consideration of allogeneic HSCT
BC patients → treated as acute leukaemia with TKI + induction chemotherapy ± HSCT; prognosis is poor

Cytogenetic Evolution — What Is It?

Cytogenetic evolution means the CML clone has acquired additional chromosomal abnormalities on top of the Philadelphia chromosome. Common ones include trisomy 8, trisomy 19, duplication of Ph chromosome, and isochromosome 17q (which leads to loss of the TP53 tumour suppressor gene on 17p) ^[1]. This signals genomic instability and impending blast transformation — it's a red flag.

3. Investigation Modalities — Detailed Breakdown

The 5-step approach to diagnosis of haematological malignancy (MCICM) applies here ^[5]^[14]:

Morphology → Cytochemistry → Immunophenotyping → Cytogenetics → Molecular genetics ^[5]

This is the first and most accessible investigation. Let's go through each parameter systematically.

Parameter	Typical Finding in CML-CP	Interpretation / Pathophysiological Basis
WBC	Markedly elevated — median ~100 × 10⁹/L, often > 25 (frequently > 100) ^[1]^[4]	Uncontrolled granulocytic proliferation driven by constitutive BCR-ABL1 kinase activity
Differential	All cells of the neutrophil series represented: myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, segmented neutrophils	Maturation is preserved (unlike AML where blasts accumulate). The full spectrum = retained differentiation capacity
	Bimodal distribution: peaks at myelocytes and segmented neutrophils ^[3]^[4]	BCR-ABL1 drives proliferation particularly at the myelocyte stage → "myelocyte bulge" ^[1]
	Myelocyte > metamyelocyte ("myelocyte bulge") ^[1]	This is pathognomonic for CML and distinguishes it from reactive left shift where the maturation pyramid is preserved
	Blasts typically < 2% only ^[1]	In CP, differentiation is intact — blasts can still mature
Basophils	Absolute basophilia — present in virtually all cases ^[1]^[4]	Part of the neoplastic clone proliferation; serves as one of the most useful diagnostic clues
Eosinophils	Absolute eosinophilia in ~90% of cases ^[1]^[4]	Also part of the expanded myeloid clone
Monocytes	Absolute monocytosis not uncommon ^[1]	The neoplastic clone can give rise to monocytic cells too; however, monocytosis is NOT the dominant feature (unlike CMML)
Hb	Normal or decreased (NcNc anaemia in 45–60%) ^[1]^[4]	Erythropoiesis is moderately reduced due to crowding by the expanded granulocytic lineage ^[3]
Platelets	Normal or elevated (thrombocytosis) ^[1]^[2]^[4]	Megakaryopoiesis is markedly increased ^[3]; platelets are derived from the neoplastic clone

Thrombocytopenia = Rethink CML

"Thrombocytopenia should prompt reconsideration of other diagnostic possibilities than CML" ^[1]^[4]. If a patient with suspected CML has a low platelet count at presentation, think about AML, MDS, or myelofibrosis instead. Thrombocytopenia in CML only occurs in blast crisis or accelerated phase.

"Advise bone marrow examination with cytogenetics" ^[15] — this is the standard recommendation when the PBS is suggestive of CML.

Component	Finding	Interpretation
Aspirate — Morphology	Hypercellular for age with marked granulocytic hyperplasia ^[3]^[4]	Massively expanded granulocytic clone fills the marrow, reducing fat spaces
	Moderately reduced erythropoiesis → full maturation is attained ^[3]	Erythroid line is crowded out but not absent
	Predominantly neutrophils and myelocytes → bimodal distribution ^[3]	Same bimodal pattern as in blood
	Basophilia ^[3]	Neoplastic basophils visible
	Megakaryopoiesis is markedly increased, with frequent small hypolobated forms ("dwarf megakaryocytes") ^[3]^[4]	Characteristic — the megakaryocytes are small with fewer nuclear lobes than normal
	Blasts < 10% (in CP) ^[2]	Determines phase
Trephine — Histology	Hypercellular with granulopoietic predominance ^[2]	Confirms marrow cellularity and architecture
	Reticulin fibrosis (variable, may increase with disease progression)	Increased fibrosis suggests progression
	Pattern of involvement	Diffuse, not patchy

Why do we do BM if blood is enough to suspect CML?

Three reasons:

Phase determination — the blast % in BM determines CP vs AP vs BC ^[4]
Cytogenetics — karyotyping requires dividing cells from the marrow aspirate; this is where you detect the Ph chromosome AND any additional chromosomal abnormalities (cytogenetic evolution) ^[2]^[3]
Baseline assessment — for monitoring treatment response later

BM site: typically posterior iliac crest; alternative includes anterior iliac crest and sternum (aspiration only) ^[14]

Test	Finding in CML	Clinical Utility
Leukocyte Alkaline Phosphatase (LAP) / Neutrophil Alkaline Phosphatase (NAP) score	Low ^[1]^[4]	Useful in excluding reactive leukocytosis (leukaemoid reaction) or PV where LAP score is ↑ or normal ^[4]. CML neutrophils look morphologically normal under the microscope but are enzymatically deficient because they come from the abnormal clone
MPO / Sudan Black B	Positive (confirms myeloid lineage)	Less important for CML diagnosis (more useful in AML to confirm myeloid blasts); in CML, the cells are clearly granulocytic on morphology

Why is the LAP score low in CML? The LAP enzyme is a marker of neutrophil maturity and activation. In CML, the neutrophils are derived from the BCR-ABL1+ clone and, despite looking mature, have deficient enzymatic content. In reactive states, normal neutrophils are activated by infection/stress → enzyme content increases → LAP score is high. In PV (another MPN), the neutrophils are activated and LAP is normal-to-high, which helps distinguish PV from CML.

Immunophenotyping is not the primary diagnostic tool for CML in chronic phase — the diagnosis is made on morphology + cytogenetics/molecular genetics.

However, immunophenotyping becomes critical in blast crisis to determine the lineage of the blasts:

Scenario	Role
CP-CML	Not routinely required; flow cytometry may detect basophilia and confirm myeloid lineage
Blast crisis	Essential to determine whether blasts are myeloid (2/3 of cases) or lymphoid (1/3 of cases) ^[2] — this determines treatment approach (myeloid BC → TKI + AML-type chemo; lymphoid BC → TKI + ALL-type chemo)

Flow cytometry markers:

Myeloid blasts: CD34+, CD117+, CD13+, CD33+, HLA-DR+, MPO+
Lymphoid (B-ALL type) blasts: CD19+, CD10+, CD22+, TdT+

3.6 Cytogenetics — The Gold Standard for Diagnosis

"The gold standard diagnosis of CML is based on cytogenetics" ^[3]

Aspect	Detail
Method	Cells from BM aspirate are cultured, arrested in metaphase, and chromosomes are G-banded and examined under light microscopy
Target	Philadelphia chromosome — t(9;22)(q34.1;q11.2) ^[1]^[3]
Sensitivity	Detects the Ph chromosome in ~90–95% of CML cases ^[4]
Additional value	Can detect cytogenetic evolution — additional chromosomal abnormalities (e.g. trisomy 8, trisomy 19, duplication of Ph, isochromosome 17q) ^[1] — which is an AP criterion
Limitations	Requires dividing cells (metaphases); failure rate ~5–10% if marrow is fibrotic or hemodilute; cannot detect submicroscopic rearrangements

Why is karyotyping irreplaceable? Only karyotyping gives you the full chromosomal landscape — it shows ALL chromosomal abnormalities, not just BCR-ABL1. This is essential for detecting cytogenetic evolution and for classification into WHO-defined risk categories.

Aspect	Detail
Method	Fluorescent probes complementary to BCR and ABL1 gene regions are hybridised to interphase or metaphase nuclei; if the two probes co-localise (fusion signal), BCR-ABL1 is present
Target	BCR-ABL1 fusion gene ^[2]^[4]
Sensitivity	Higher than karyotyping (~99%); can detect BCR-ABL1 in Ph-negative CML variants (cryptic translocations)
Advantage	Works on interphase nuclei → does NOT require dividing cells; can be performed on blood samples
Limitations	Only looks at the specific targeted loci — does not provide a full chromosomal picture (cannot replace karyotyping for cytogenetic evolution assessment)

When is FISH especially useful?

When karyotyping fails (insufficient metaphases, fibrotic marrow)
When karyotype is normal but clinical suspicion for CML is high (the ~5% of "Ph-negative" CML cases where the BCR-ABL1 rearrangement is cryptic) ^[4]

Feature	Karyotyping	FISH
Cell requirement	Metaphase (dividing) cells	Interphase or metaphase
Sample source	BM aspirate	BM or peripheral blood
Detects Ph chromosome	Yes	Yes (indirectly via BCR-ABL1)
Detects cytogenetic evolution	Yes — full karyotype	No — only targeted loci
Detects cryptic BCR-ABL1	No	Yes
Turnaround time	1–3 weeks	1–3 days

3.7 Molecular Genetics — RT-PCR and Quantitative PCR (RT-qPCR)

"RT-PCR to demonstrate BCR-ABL1 fusion mRNA transcript (also useful for treatment monitoring)" ^[4]

Aspect	Detail
Method	Reverse-transcription PCR: BCR-ABL1 fusion mRNA is reverse-transcribed to cDNA, then amplified by PCR
Target	BCR-ABL1 fusion mRNA transcript ^[2]^[4]
Sensitivity	Most sensitive diagnostic method — can detect 1 leukaemic cell among 10⁵–10⁶ normal cells
Utility at diagnosis	Confirms BCR-ABL1 in all cases including Ph-negative variants; identifies the specific transcript type (e210 = p210 = most common in CML; e190 = p190 = typical of Ph+ ALL; e230 = p230 = rare CML variant)

Why does transcript type matter? The BCR gene has different breakpoint regions. The exact breakpoint determines the size of the fusion protein:

p210 (major breakpoint, M-bcr): produces a 210 kDa protein → this is the classic CML protein, found in ~95% of CML
p190 (minor breakpoint, m-bcr): produces a 190 kDa protein → more common in Ph+ ALL; occasionally seen in CML (associated with prominent monocytosis)
p230 (micro breakpoint, μ-bcr): rare; associated with a more indolent CML variant (chronic neutrophilic leukaemia-like)

Identifying the transcript type at diagnosis is essential because treatment monitoring by RT-qPCR is transcript-specific — you must know which transcript to track.

RT-qPCR is the most sensitive method for monitoring treatment response ^[2].

Aspect	Detail
Method	Real-time quantitative PCR that measures the amount of BCR-ABL1 mRNA relative to a control gene (usually ABL1)
Expressed as	BCR-ABL1/ABL1 ratio on the International Scale (IS), reported as a percentage
Role at diagnosis	Establishes the baseline BCR-ABL1 level against which all subsequent responses are measured
Role during treatment	Determines the depth of molecular response (MR) — the most sensitive measure of treatment response

Monitoring milestones (ELN criteria) ^[2]:

Timepoint	Optimal Response	What It Means
3 months	BCR-ABL1 ≤ 10% IS	Early response; indicates TKI is working
6 months	BCR-ABL1 ≤ 1% IS (= complete cytogenetic response, CCyR)	No Ph+ metaphases detectable by karyotyping
12 months	BCR-ABL1 ≤ 0.1% IS (= major molecular response, MMR / MR3.0)	3-log reduction from standardised baseline
Any time	BCR-ABL1 ≤ 0.01% IS (MR4.0) or ≤ 0.0032% (MR4.5)	Deep molecular response — prerequisite for potential TKI discontinuation trials

Three Levels of Response Monitoring

CML treatment response is monitored at three levels ^[2]:

Haematological response — normalisation of CBC (WBC, Hb, platelets) → assessed by CBC
Cytogenetic response (CyR) — reduction/elimination of Ph+ metaphases → assessed by karyotyping or FISH
Molecular response (MR) — reduction in BCR-ABL1 mRNA → assessed by RT-qPCR (most sensitive)

The goal of treatment is to achieve progressively deeper levels: haematological → cytogenetic → molecular response.

These are not diagnostic for CML per se, but are important parts of the initial work-up:

Investigation	Finding / Purpose
Serum uric acid	Often elevated (hyperuricaemia) due to massive cell turnover → risk of gout and urate nephropathy; baseline needed before starting cytoreductive therapy (tumour lysis risk)
Serum LDH	Elevated → marker of high cell turnover / disease burden
Serum B12	Often elevated in CML and other MPNs → because of increased transcobalamin III (haptocorrin) production by the expanded granulocytic clone ^[16]
Renal function (Cr, eGFR)	Baseline — hyperuricaemia can cause urate nephropathy; some TKIs are nephrotoxic
Liver function (LFT)	Baseline — TKIs (especially ponatinib) can cause hepatotoxicity
ECG	Baseline — nilotinib can cause QTc prolongation ^[2]
Lipid profile / HbA1c	Baseline — nilotinib is associated with vascular events and metabolic effects
Chest X-ray	Baseline — dasatinib can cause pleural/pericardial effusion ^[2]
HBV serology	Important in Hong Kong context — TKIs can cause reactivation of hepatitis B; screen before treatment

The following table summarises the hierarchy of investigations from first-line to confirmatory:

Priority	Investigation	What It Tells You
1st	CBC with differential + PBS	Raises suspicion: leukocytosis, basophilia, full myeloid spectrum, myelocyte > metamyelocyte
2nd	BM aspirate + trephine with cytogenetics (karyotyping)	Confirms diagnosis (Ph chromosome), determines phase (blast %), provides full chromosomal picture
3rd	FISH for BCR-ABL1 (if karyotype negative or failed)	Detects cryptic BCR-ABL1 rearrangements
4th	RT-PCR (qualitative) for BCR-ABL1	Confirms at molecular level; identifies transcript type
5th	RT-qPCR (quantitative) for BCR-ABL1	Establishes baseline for treatment monitoring
Supportive	LAP score, LDH, uric acid, B12, RFT, LFT, ECG	Exclude reactive causes; baseline for treatment; risk stratification

5. Key Interpretive Principles

PBS Finding	CML	AML	CLL	MDS	Reactive Left Shift
Maturation	Full spectrum preserved	Arrested (blasts predominate)	Mature lymphocytes	Dysplastic cells	Full spectrum preserved
Blasts	< 2% (CP)	≥ 20%	Rare	< 20%	Absent
Basophilia	Present	Usually absent	Absent	Absent	Absent
Myelocyte > metamyelocyte	Yes	N/A	N/A	N/A	No (reversed)
Smear/smudge cells	Absent	Absent	Present ^[8]	Absent	Absent
Toxic granulation	Absent	Absent	Absent	Absent	Present
Auer rods	Absent (unless BC)	May be present	Absent	Absent	Absent
LAP/NAP score	Low	Variable	N/A	N/A	High

"CBP: Hb 9.8, MCV 98.2 (NcNc anaemia), WBC 150.0, Plt 160. Blood film reviewed by pathologist: Features consistent with chronic myeloid leukaemia. Advise bone marrow examination with cytogenetics" ^[15]

This clinical vignette from the molecular pathology lecture illustrates the real-life diagnostic pathway:

Incidental finding of WBC 150 on CBP
Pathologist reviews the film → identifies the characteristic full myeloid spectrum with basophilia
Reports "features consistent with CML"
Recommends BM with cytogenetics → to confirm Ph chromosome and determine phase

High Yield Summary — Diagnosis of CML

Diagnostic criteria: Compatible blood/BM picture (leukocytosis, basophilia, bimodal myelocyte-neutrophil distribution, dwarf megakaryocytes) PLUS demonstration of BCR-ABL1 by karyotype, FISH, or RT-PCR.
Gold standard = cytogenetics (karyotyping) for Ph chromosome detection (90–95%) and assessment of cytogenetic evolution.
Most sensitive test = RT-qPCR for BCR-ABL1 mRNA — used for monitoring, not primary diagnosis.
Phase determination by blast %: CP ( < 10%), AP (10–19% + other features), BC (≥ 20%).
Monitoring levels: Haematological (CBC) → Cytogenetic (FISH/karyotype) → Molecular (RT-qPCR). Optimal: ≤ 10% at 3mo, ≤ 1% at 6mo, ≤ 0.1% at 12mo.
Low LAP score distinguishes CML from reactive leukocytosis (high LAP) and PV (normal/high LAP).
Thrombocytopenia at presentation should prompt reconsideration — CML typically has normal or elevated platelets.

Active Recall - CML Diagnostic Criteria, Algorithm & Investigations

References

^[1] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf — CML section, p.1400–1404 ^[2] Senior notes: Maksim Medicine Notes.pdf — Haematology, CML p.176 ^[3] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf — CML section p.22 ^[4] Senior notes: Ryan Ho Haemtology.pdf — CML section p.63–66 ^[5] Senior notes: Adrian Lui Pediatrics Notes.pdf — Leukemia section p.418 ^[6] Senior notes: Block A - Splenomegaly_ common causes of splenomegaly; myeloproliferative diseases.pdf — MPN section p.22; Diagnostic criteria p.24 ^[8] Senior notes: Block A - Introduction to Haematological investigations (CBP, Clotting).pdf — CLL PBS findings p.8; AML/ALL findings p.7 ^[14] Senior notes: Ryan Ho Fundamentals.pdf — High WBC workup p.390–391 ^[15] Lecture slides: Molecular Pathology Seminar 5_Molecular genetic testing for haematological malignancies_Dr ACF Sin.pdf — CML case p.5 ^[16] Senior notes: Block A - Pallor_ diagnosis of anaemia; nutritional anaemia; anaemia of systemic diseases.pdf — B12 and MPN p.19

Management of CML

3. Treatment Modalities — Detailed Discussion

3.1 Immediate / Supportive Measures (All Phases)

Before definitive TKI therapy, patients may need urgent cytoreduction, particularly if they present with very high WBC counts or symptomatic leukostasis.

Aspect	Detail
Drug class	Cytoreductive agent (ribonucleotide reductase inhibitor)
Mechanism	Inhibits ribonucleotide reductase → blocks DNA synthesis → reduces rapidly dividing cells
Indication in CML	Control and maintain WBC count while awaiting confirmatory investigations or when TKI is being initiated ^[4]; commonly used in MPN ^[4]; cytoreduction for symptomatic relief ^[2]
Key limitation	Does NOT reduce the number of BCR-ABL1-positive cells — does not alter the natural history of CML ^[4]. It simply reduces total WBC count non-specifically
Dosing	Typically 1–4 g/day, adjusted to WBC response
Side effects	Bone marrow suppression, macrocytosis, skin hyperpigmentation, leg ulcers (long-term), mucosal dryness

"Hydroxyurea: a type of cytoreductive agent — control and maintain WBC count but does not reduce number of BCR-ABL1 positive cells (does not cure the disease). Usually for those with very high WBC counts but pending investigations to confirm CML" ^[4]

Aspect	Detail
Indication	Symptomatic hyperleukostasis (WBC > 100 × 10⁹/L with end-organ compromise: pulmonary infiltrates, CNS symptoms, priapism)
Mechanism	Mechanical removal of WBCs from the bloodstream via apheresis machine
Role	Temporising measure only — buys time until TKI/hydroxyurea takes effect

Aspect	Detail
Risk	High tumour burden → rapid cell lysis when treatment starts → hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, AKI
Prevention	Allopurinol (xanthine oxidase inhibitor) to prevent uric acid formation; adequate IV hydration; monitor electrolytes closely
When rasburicase?	Consider if uric acid is already very high at presentation or if TLS risk is very high

3.2 Tyrosine Kinase Inhibitors (TKIs) — The Mainstay

TKIs are the cornerstone of CML treatment. ^[2]^[3]^[4] They represent one of the first and most successful examples of rational drug design in oncology — the drug was designed specifically to fit into the ATP-binding pocket of the BCR-ABL1 kinase, blocking its constitutive activity.

Generation	Drug	Key Features
1st generation	Imatinib	The original TKI ("i-MATIN-ib"; "-inib" = kinase inhibitor). Revolutionised CML treatment. Standard dose 400 mg/day. First-line for low/intermediate-risk CP-CML ^[4]
2nd generation	Nilotinib, Dasatinib	More potent BCR-ABL1 inhibition than imatinib; achieve faster and deeper responses. First-line for high-risk CP-CML ^[4]; also used after imatinib failure. Nilotinib: "nil" = related to nitrogen-containing structure. Dasatinib: broader kinase inhibition including SRC family kinases
3rd generation	Ponatinib	Designed specifically to overcome T315I "gatekeeper" mutation — the most common resistance mutation that renders all 1st and 2nd-gen TKIs ineffective ^[2]. Also covers most other BCR-ABL1 mutations
STAMP inhibitor	Asciminib	A novel allosteric inhibitor — binds the myristoyl pocket of BCR-ABL1 (a different site from where ATP-competitive TKIs bind). Effective against T315I when combined with ponatinib; also effective against many TKI-resistant mutations ^[3]

"Specific targeted treatment against the tyrosine kinase → tyrosine kinase inhibitors: Imatinib, Nilotinib, Dasatinib, Ponatinib, Asciminib" ^[3]

Each TKI has a distinct side-effect profile, which guides drug selection and contraindications:

TKI	Key Side Effects ^[2]	Contraindication/Caution
Imatinib	Rash, periorbital oedema, fluid retention, muscle cramps, diarrhoea, nausea, myelosuppression	Generally the best tolerated; caution with hepatic impairment
Nilotinib	↑ QTc prolongation, rash ^[2]; hyperglycaemia, hyperlipidaemia, peripheral arterial occlusive disease (PAOD), pancreatitis, hepatotoxicity	Contraindicated in patients with long QT syndrome, uncontrolled cardiac arrhythmias; must be taken on an empty stomach (food ↑ absorption → ↑ toxicity); avoid with strong CYP3A4 inhibitors
Dasatinib	Pleural/pericardial effusion ^[2], pulmonary arterial hypertension, myelosuppression (especially thrombocytopenia), bleeding risk	Caution in patients with pre-existing pleural effusion or lung disease; dose reduction often needed for effusions
Ponatinib	Thrombosis (arterial and venous), deranged LFTs (hepatotoxicity) ^[2], pancreatitis, hypertension, cardiovascular events (MI, stroke)	Contraindicated in patients with significant cardiovascular risk factors unless no other TKI option; requires careful CV risk assessment
Asciminib	Myelosuppression (thrombocytopenia, neutropenia), pancreatitis, hypertension	Relatively newer agent; monitoring for pancreatic enzymes required

High Yield — TKI Side Effects for Exams

The side effects are commonly tested because they determine which TKI is contraindicated in which patient:

Nilotinib → QT prolongation → avoid in cardiac patients with arrhythmias
Dasatinib → pleural/pericardial effusion → avoid in patients with lung disease
Ponatinib → thrombosis and hepatotoxicity → avoid in patients with high cardiovascular risk

"S/E: rash, ↑QT (nilotinib), pleural/pericardial effusion (dasatinib), thrombosis / dLFT (ponatinib)" ^[2]

Choice of first-line TKI is guided by risk stratification and patient comorbidities ^[4]:

Risk Category	Preferred TKI ^[4]	Rationale
Low / Intermediate risk	Imatinib (1st-gen)	Well tolerated, extensive safety data, generic available (cost-effective); achieves good long-term outcomes
High risk	Nilotinib or Dasatinib (2nd-gen)	Faster and deeper responses; more likely to achieve early optimal milestones; may reduce risk of progression in high-risk patients

"Choice: imatinib [1G] for low-risk, nilotinib, dasatinib [2G] for high-risk" ^[4]

Risk stratification tools:

Score	Components	Purpose
Sokal score	Age, blast cell %, spleen size, PLT count ^[4]	Originally developed in pre-TKI era; still widely used for initial categorisation
Hasford (Euro) score	Age, spleen size, blast %, eosinophil %, basophil %, PLT	Incorporates eosinophils and basophils
EUTOS Long-Term Survival (ELTS) score	Age, spleen size, blast %, PLT	Developed specifically for the TKI era; best predictor of CML-related death

"Prognostic stratification, e.g. Sokal score based on age, blast cell %, spleen size, PLT count" ^[4]

3.3 Phase-Specific Management

This is where the vast majority (~85–90%) of patients present and where TKI therapy produces the best results.

Treatment approach:

Start TKI (choice based on risk and comorbidities as above)
Monitor BCR-ABL1 by RT-qPCR at defined milestones ^[2]^[3]
Adjust therapy based on response

Monitoring milestones (ELN 2020 recommendations): ^[2]

Timepoint	Optimal	Warning	Failure
3 months	BCR-ABL1 ≤ 10%	BCR-ABL1 > 10%	No CHR or BCR-ABL1 > 10% if confirmed
6 months	BCR-ABL1 ≤ 1%	BCR-ABL1 1–10%	BCR-ABL1 > 10%
12 months	BCR-ABL1 ≤ 0.1% (MMR)	BCR-ABL1 0.1–1%	BCR-ABL1 > 1%
Any time	BCR-ABL1 ≤ 0.1% (MMR or better)	—	Loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, cytogenetic evolution

"Optimal response: ≤10% at 3mo, ≤1% (CyR) at 6mo, ≤0.1% (MMR) at 12mo" ^[2]

Response levels explained:

Level	Abbreviation	BCR-ABL1 IS	What It Means
Complete Haematological Response (CHR)	CHR	—	Normalisation of CBC: WBC < 10 × 10⁹/L, no immature cells, PLT < 450, no palpable spleen
Complete Cytogenetic Response (CCyR)	CCyR	≤ 1%	0% Ph+ metaphases on karyotyping
Major Molecular Response (MMR / MR3.0)	MMR	≤ 0.1%	3-log reduction from standardised baseline — "the amount of BCR-ABL gene in your blood or bone marrow is 1/1000th (or less) of what's expected in someone with untreated CML" ^[3]
Deep Molecular Response (MR4.0)	MR4.0	≤ 0.01%	4-log reduction
Deep Molecular Response (MR4.5)	MR4.5	≤ 0.0032%	4.5-log reduction
Complete Molecular Response (CMR)	CMR	Undetectable	"Complete molecular response DOES NOT MEAN zero → just means lower than the detection limit of the test" ^[3]

"We are aiming for a major molecular response, or better (complete molecular response)" ^[3]

"Monitor the molecular response using quantitative reverse-transcriptase polymerase chain reaction (RT-PCR)" ^[3]

What to do when response is suboptimal or failed:

Check compliance — TKIs are oral medications taken daily; non-compliance is the most common cause of suboptimal response
Check drug interactions — TKIs are metabolised by CYP3A4; concurrent CYP3A4 inhibitors (azoles, macrolides, grapefruit) or inducers (rifampicin, phenytoin) can alter levels
BCR-ABL1 mutation analysis — identifies specific kinase domain mutations that confer resistance to particular TKIs
Switch TKI — guided by the mutation profile

The T315I 'Gatekeeper' Mutation

The threonine at position 315 sits at the "gate" of the ATP-binding pocket. When mutated to isoleucine (T315I), it creates a steric clash that prevents ALL 1st and 2nd-generation TKIs from binding. This is why T315I is called the "gatekeeper" mutation. Only ponatinib (3rd-gen, designed with a carbon-carbon triple bond to bypass the steric clash) and asciminib (binds a completely different site) remain active against T315I ^[2]^[3].

"Accelerated phase: induction TKI followed by HSCT" ^[4]

Step	Treatment
1. Induction	2nd-generation TKI (dasatinib or nilotinib) preferred over imatinib — deeper and faster responses needed
2. Assess response	If good response to TKI → may continue TKI alone with close monitoring
3. Consolidation	Consider allogeneic HSCT, especially if suboptimal TKI response, high-risk features, or donor available

Rationale: AP represents the transition zone where the disease is acquiring additional mutations and becoming harder to control. TKI alone may still work (especially with modern 2nd-gen TKIs), but the window for HSCT should be assessed early.

"Blastic phase: Lymphoid crisis → treat as Ph+ ALL; Myeloid crisis → induction TKI then HSCT" ^[4]

Blast crisis is essentially acute leukaemia arising from the CML clone. Treatment must combine TKI (to target the underlying BCR-ABL1) with intensive chemotherapy (to control the blast population).

BC Type	Proportion	Treatment ^[4]
Myeloid BC	~2/3	TKI + AML-type induction chemotherapy → allogeneic HSCT
Lymphoid BC	~1/3	TKI + ALL-type induction chemotherapy (vincristine, dexamethasone, asparaginase-based) → allogeneic HSCT

Why combine TKI with chemotherapy?

TKI alone is insufficient because blast crisis cells have acquired additional mutations beyond BCR-ABL1 that drive proliferation and block differentiation
Chemotherapy targets the blasts broadly; TKI targets the underlying BCR-ABL1-driven clone
Together, they aim to achieve remission so the patient can proceed to HSCT

Prognosis in BC: Poor even with treatment — median survival 6–12 months. HSCT offers the only chance of long-term survival.

"HSCT very good, but no longer first line → has a very good graft versus tumour effect" ^[3]

Aspect	Detail
Role	Reserved for: (1) patients unresponsive to TKI; (2) patients in blastic phase (BC) ^[3]
Mechanism	Replaces the patient's entire haematopoietic system (including the BCR-ABL1+ clone) with donor stem cells; donor immune cells exert a graft-versus-leukaemia (GVL) effect — donor T cells recognise and destroy residual CML cells
Curative potential	Allogeneic HSCT can be curative ^[4] — the only treatment that can truly eliminate the CML clone
Procedural risk	↑↑↑ Procedural risk — graft-versus-host disease (GVHD), infection, organ toxicity, transplant-related mortality ~10–20% ^[4]
Outcomes	5-year survival ~50–70%; results are better when performed in chronic than in later phases ^[4]
Relapse management	Donor leucocyte infusions (DLI) — especially effective if relapse is diagnosed early by molecular detection ^[4]
Donor	Requires HLA-matched donor (sibling preferred); haplo-identical and unrelated donor options available

Why is HSCT no longer first-line?

TKIs achieve > 90% 5-year survival in CP with an oral medication and minimal toxicity
HSCT carries ~10–20% transplant-related mortality and significant morbidity
The risk-benefit ratio favours TKI in the vast majority of CP patients
HSCT is reserved for patients who have exhausted TKI options or who present in advanced phases

Key Indications for HSCT in CML

Failure of ≥ 2 TKIs (or intolerance to all available TKIs)
T315I mutation not responding to ponatinib/asciminib
Accelerated phase with suboptimal TKI response
Blast crisis (after achieving remission with TKI + chemotherapy)

This represents a potential "functional cure" — stopping TKI in carefully selected patients.

Aspect	Detail
Concept	Patients who maintain a sustained deep molecular response (MR4.0 or MR4.5) for ≥ 2 years may be eligible to stop TKI under close monitoring
Success rate	~40–60% of patients who attempt TFR maintain MMR after stopping; the rest relapse (usually within 6 months) and regain response when TKI is restarted
Monitoring	RT-qPCR monthly for the first year, then every 6–12 weeks
Importance	Eliminates lifelong side effects and cost of TKI; improves quality of life

Why does this work? It is hypothesised that in patients with deep molecular response, the residual BCR-ABL1+ cells are held in check by the patient's immune system (particularly NK cells and T cells). When TKI is stopped, immune surveillance maintains control in some patients but not all.

"Complete molecular response DOES NOT MEAN zero → just means lower than the detection limit of the test" ^[3]

This is why TFR is possible — even with "undetectable" BCR-ABL1, residual leukaemic stem cells likely persist, but immune control prevents expansion.

Phase	First-Line Treatment	Second-Line / Salvage	Role of HSCT
Chronic Phase (low/int risk)	Imatinib 400 mg/day	Switch to 2nd-gen TKI (nilotinib/dasatinib); then ponatinib/asciminib if mutation	If failed ≥ 2 TKIs
Chronic Phase (high risk)	Nilotinib or Dasatinib	Switch to alternative TKI; ponatinib/asciminib for resistant mutations	If failed ≥ 2 TKIs
Accelerated Phase	2nd-gen TKI (dasatinib/nilotinib)	Ponatinib/asciminib; TKI + chemotherapy if blast-like features	Consider after induction TKI
Blast Crisis — Myeloid	TKI + AML-type induction chemo	—	HSCT after achieving remission
Blast Crisis — Lymphoid	TKI + ALL-type induction chemo	—	HSCT after achieving remission

5. Contraindications & Special Considerations

TKI	Absolute/Relative Contraindication	Reason
Nilotinib	Long QT syndrome, concurrent QT-prolonging drugs, uncontrolled arrhythmias	QTc prolongation risk
Dasatinib	Active pleural effusion, severe pulmonary disease	Causes pleural/pericardial effusion
Ponatinib	Active coronary/cerebrovascular/peripheral arterial disease; recent MI or stroke	Arterial thrombosis risk
All TKIs	Pregnancy (teratogenic)	Category D; must use effective contraception; if CML diagnosed in pregnancy, consider interferon-α (safe in pregnancy)

References

Complications of CML

The complications of CML can be organised into three broad categories:

Complications of the disease itself — arising from the biology of CML
Complications of disease transformation — progression to accelerated/blast crisis
Complications of treatment — from TKIs and HSCT

Understanding each complication requires going back to the underlying pathophysiology.

1. Complications of the Disease Itself

The spleen is the organ most affected by CML. Understanding the complications requires recalling why the spleen enlarges: massive splenomegaly results from (1) infiltration of splenic red pulp by leukaemic granulocytes, (2) extramedullary haematopoiesis, and (3) sequestration of blood cells ^[3].

Complication	Pathophysiology	Clinical Features
Splenic infarction	When the massively enlarged spleen outgrows its blood supply → ischaemic necrosis of a segment. The splenic artery branches are end-arteries, so occlusion → wedge-shaped infarct	Acute severe left upper quadrant (LUQ) pain, splenic rub on auscultation (friction between inflamed visceral and parietal peritoneum), fever, left pleural effusion (reactive)
Splenic rupture	Rare but life-threatening; massive splenomegaly makes the capsule taut and vulnerable to minor trauma	Haemodynamic instability, peritoneal signs, surgical emergency
Hypersplenism	The massively enlarged spleen traps and destroys excessive numbers of blood cells (sequestration) → cytopenias disproportionate to marrow findings	Worsening anaemia, thrombocytopenia, or neutropenia beyond what would be expected from marrow disease alone; transfusion requirements increase
Mechanical compression	Massive spleen compresses adjacent structures — stomach (early satiety, weight loss), left kidney (hydronephrosis), diaphragm (left basal atelectasis, dyspnoea)	Abdominal discomfort, early satiety, dyspnoea, dragging sensation

When WBC counts are extremely high (typically > 100 × 10⁹/L, more common in blast crisis where blasts are larger and stickier), the blood viscosity rises and cells physically sludge in the microcirculation.

Organ System	Mechanism	Clinical Features
Pulmonary	WBC plugging of pulmonary microvasculature → V/Q mismatch, pulmonary oedema	Dyspnoea, hypoxia, bilateral infiltrates on CXR
CNS	Cerebral microvascular occlusion ± haemorrhage	Confusion, headache, visual disturbance, stroke-like symptoms, coma
Retinal	Leukostasis in retinal vessels → venous occlusion, haemorrhage	Blurred vision, papilloedema, retinal haemorrhages on fundoscopy
Genital	Sludging in corpora cavernosa → venous outflow obstruction	Priapism (prolonged painful erection — a urological emergency)

Why is leukostasis worse in blast crisis than chronic phase? Because blasts are larger, more rigid, and express more adhesion molecules compared to mature granulocytes — they physically obstruct small vessels more easily.

Aspect	Detail
Pathophysiology	The massively expanded granulocytic clone has enormous cellular turnover → breakdown of nucleic acids (purines) → uric acid production greatly exceeds renal excretion capacity
Clinical consequences	Acute gouty arthritis (crystal deposition in joints), uric acid nephropathy (urate crystals precipitating in renal tubules → AKI), uric acid renal calculi
Prevention	Allopurinol (xanthine oxidase inhibitor) to reduce uric acid formation; adequate hydration; alkalinisation of urine if needed

CML (like all MPNs) predisposes to both thrombosis and bleeding — a seemingly paradoxical combination that makes sense from first principles.

Thrombotic complications:

Mechanism	Explanation
Hyperviscosity	Very high WBC count → increased blood viscosity → sluggish flow → predisposition to both arterial and venous thrombosis
Abnormal platelet function	Platelets from the neoplastic clone are functionally abnormal and may be hyperreactive
Thrombocytosis	CML is usually associated with thrombocytosis ^[4] — elevated platelet counts increase thrombotic risk

Haemorrhagic complications:

Mechanism	Explanation
Qualitative platelet dysfunction	Despite high numbers, neoplastic platelets may have impaired aggregation, secretion, or adhesion
Acquired von Willebrand Disease (AvWD)	When platelet counts are extremely high ( > 1000 × 10⁹/L), excess platelets consume von Willebrand factor (VWF) → acquired VWF deficiency → bleeding tendency ^[6]. This is the same paradoxical bleeding seen in ET
Thrombocytopenia (in AP/BC)	In advanced phases, BM failure leads to true thrombocytopenia → haemorrhagic risk

"High platelet consumes all the vWF, results in acquired vWD… usually > 1000" ^[6]

2. Complications of Disease Transformation — The Most Important Complication

All forms of MPN share the potential to PROGRESS to myelofibrosis and blastic transformation ^[6]

This is the single most feared complication of CML and historically was the inevitable outcome before TKIs.

Chronic leukaemia will transform into acute leukaemia if left untreated, since leukaemic cells will acquire more and more mutations over time ^[3].

Aspect	Detail
Mechanism	Clonal evolution: the BCR-ABL1+ clone is genomically unstable → additional mutations accumulate (TP53 loss, RB1 deletion, RUNX1, IKZF1, additional Ph copies, isochromosome 17q) → differentiation capacity is lost → blast accumulation
Risk if untreated	> 90% of untreated CML patients will eventually develop blast crisis ^[4]
Risk with TKI	Dramatically reduced — < 5% in patients achieving optimal molecular responses on TKI
Types	2/3 myeloid blast crisis (behaves like AML), 1/3 lymphoid blast crisis (behaves like ALL) ^[2]
Prognosis	Very poor — median survival only 1–2 months without treatment ^[2]; even with TKI + chemotherapy + HSCT, median survival ~6–12 months
Warning signs	Rising blast count, increasing basophilia, cytogenetic evolution, progressive splenomegaly refractory to TKI, new cytopenias

Why can it transform into either AML or ALL? Because CML originates from a pluripotent haematopoietic stem cell — the original BCR-ABL1+ clone has the potential to give rise to both myeloid and lymphoid lineages. When blast crisis occurs, the maturation arrest can happen along either path.

Aspect	Detail
Mechanism	The expanded megakaryocytic population in CML releases fibrogenic cytokines (TGF-β, PDGF, bFGF) → stimulate reticulin/collagen deposition by (non-clonal) fibroblasts → progressive marrow fibrosis
Clinical consequence	Progressive marrow failure (worsening cytopenias), increasing splenomegaly (compensatory extramedullary haematopoiesis), leukoerythroblastic blood picture
Significance	Indicates disease progression; may occur alongside or precede blast crisis

These are not just "side effects" — some are clinically significant and dictate treatment changes.

TKI	Complication	Pathophysiology
Imatinib	Rash ^[2]; periorbital/peripheral oedema; fluid retention; muscle cramps; myelosuppression; hepatotoxicity (rare)	PDGFR inhibition → decreased interstitial fluid reabsorption → oedema; direct dermal toxicity → rash
Nilotinib	QTc prolongation ^[2]; peripheral arterial occlusive disease (PAOD); hyperglycaemia; hyperlipidaemia; pancreatitis	hERG potassium channel inhibition → delayed cardiac repolarisation → QTc prolongation; vascular endothelial toxicity → accelerated atherosclerosis; metabolic effects on glucose/lipid metabolism
Dasatinib	Pleural/pericardial effusion ^[2]; pulmonary arterial hypertension (PAH); severe myelosuppression (thrombocytopenia)	Inhibition of SRC family kinases and PDGFR in pulmonary vasculature/pleural mesothelium → increased vascular permeability → serous effusions
Ponatinib	Arterial and venous thrombosis (MI, stroke, PAOD); hepatotoxicity (dLFT) ^[2]; pancreatitis; hypertension	Broad kinase inhibition including VEGFR, FGFR → vascular endothelial injury → thrombotic events; direct hepatocyte toxicity
Asciminib	Myelosuppression (thrombocytopenia, neutropenia); pancreatitis	Direct effect on normal haematopoiesis (off-target); pancreatic toxicity (mechanism under investigation)

Long-term TKI complications (relevant for lifelong therapy):

Complication	Explanation
Cardiovascular events	Nilotinib and ponatinib accelerate atherosclerosis → MI, stroke, PAOD; require long-term CV risk factor monitoring
Secondary malignancies	Theoretical concern with prolonged immunosuppression; data limited
Reproductive toxicity	All TKIs are teratogenic → impact on family planning, especially for young patients
Metabolic syndrome	Nilotinib → hyperglycaemia, dyslipidaemia → increased CV risk
Bone metabolism	Imatinib inhibits c-KIT and PDGFR in osteoclasts/osteoblasts → altered bone remodelling → may cause hypophosphataemia or bone pain

Aspect	Detail
Pathophysiology	Rapid destruction of the massively expanded leukaemic cell mass (spontaneously or with treatment initiation) → release of intracellular contents: potassium (hyperkalaemia), phosphate (hyperphosphataemia → secondary hypocalcaemia), uric acid (hyperuricaemia)
Risk factors	Very high WBC at presentation, initiation of hydroxyurea or TKI
Clinical consequences	Cardiac arrhythmias (hyperkalaemia), renal failure (uric acid/calcium phosphate precipitation in tubules), seizures (hypocalcaemia), DIC
Prevention	Allopurinol, aggressive IV hydration, close electrolyte monitoring; rasburicase if pre-existing hyperuricaemia

For patients who require HSCT (TKI failure, blast crisis), the transplant carries its own set of significant complications ^[18]:

Early complications (< 1 year):

Complication	Mechanism
Cytopenia-related	Engraftment takes 2–4 weeks; during this period → anaemia, neutropenic infections (bacterial and fungal), bleeding
Neutropenic infections	Profound neutropenia → bacterial (Gram-negative rods, Gram-positive cocci) and fungal (Aspergillus, Candida) infections; febrile neutropenia is a medical emergency ^[17]
Oral and GI mucositis	Conditioning regimen (chemotherapy ± total body irradiation) damages rapidly dividing mucosal epithelium → painful ulceration, inability to eat, diarrhoea
Veno-occlusive disease (VOD) of the liver	Conditioning damages hepatic venous sinusoidal endothelium → thrombosis of hepatic venules → painful hepatomegaly, ascites, jaundice ± fulminant liver failure ^[18]
Graft rejection (host-versus-graft)	Residual host immune cells attack donor cells → engraftment failure
Acute graft-versus-host disease (aGVHD)	Donor T cells recognise host tissues as foreign → attack skin (rash), liver (jaundice), GI tract (diarrhoea). Graded I–IV. Can be life-threatening

Late complications ( > 1 year):

Complication	Mechanism
Chronic GVHD	Donor immune system mounts a chronic autoimmune-like reaction against host tissues → scleroderma-like skin changes, sicca syndrome, bronchiolitis obliterans, hepatic dysfunction ^[18]
Cardiovascular disease	Most common cause of morbidity/non-relapse mortality ^[18] — metabolic effects of immunosuppressants, chronic GVHD-related vascular injury, pre-existing CV risk factors
Endocrine dysfunction	T2DM (3× risk), hypothyroidism, hypogonadism, infertility (conditioning destroys gonads), osteoporosis/AVN (steroid use for GVHD) ^[18]
Second malignancies	Relapse of primary disease; post-transplant lymphoproliferative disease (PTLD, EBV-driven); therapy-related MDS/AML; solid tumours (SCC of skin/oral cavity) ^[18]
Cataracts	From total body irradiation (TBI) used in conditioning ^[18]
Infections	Immunosuppression from GVHD prophylaxis/treatment → susceptibility to CMV, EBV, VZV, Pneumocystis jirovecii; encapsulated bacteria (post-splenectomy/functional hyposplenism)

Allogeneic HSCT: 75% long-term survival, 9.9× mortality of general population (highest years 2–5 post-HSCT) ^[18]

Graft-versus-Leukaemia Effect — The Double-Edged Sword

The same donor immune cells that cause GVHD also attack residual CML cells — this is the graft-versus-leukaemia (GVL) effect. This is why mild GVHD is actually associated with lower relapse rates. If a patient relapses after HSCT, donor leucocyte infusions (DLI) can be given to boost the GVL effect, and this is especially effective if relapse is diagnosed early by molecular detection ^[4].

Category	Complication	Phase Most Relevant	Key Pathophysiology
Disease	Splenic infarction/rupture	CP/AP	Massive splenomegaly outgrowing blood supply
	Hyperleukostasis	CP (extreme WBC) / BC	WBC sludging in microvasculature
	Hyperuricaemia/gout	CP	Massive purine turnover
	Thrombosis	CP/AP	Hyperviscosity, thrombocytosis, dysfunctional platelets
	Acquired VWD	CP (PLT > 1000)	Platelet consumption of VWF
	Infection	CP (functional) / BC (absolute neutropenia)	Dysfunctional neoplastic neutrophils; marrow failure in BC
Transformation	Blast crisis	AP → BC	Clonal evolution, additional mutations; > 90% risk if untreated
	Secondary myelofibrosis	CP/AP	Fibrogenic cytokines from megakaryocytes
TKI-related	QTc prolongation	Any (nilotinib)	hERG channel inhibition
	Pleural effusion	Any (dasatinib)	SRC/PDGFR inhibition → vascular permeability
	Arterial thrombosis	Any (ponatinib)	VEGFR/FGFR inhibition → endothelial injury
	TLS	Treatment initiation	Rapid cell lysis → electrolyte derangement
HSCT-related	GVHD (acute/chronic)	Post-HSCT	Donor T cells attack host tissues
	VOD	Early post-HSCT	Conditioning-damaged hepatic venous endothelium
	Second malignancies	Late post-HSCT	Immunosuppression, conditioning toxicity

High Yield Summary — Complications of CML

Disease complications:

Splenic: infarction (acute LUQ pain + rub), rupture (emergency), hypersplenism (cytopenias)
Hyperleukostasis: pulmonary, CNS, retinal, priapism — worse in blast crisis
Hyperuricaemia: gout, urate nephropathy — prevent with allopurinol
Thrombohaemorrhagic: thrombosis (hyperviscosity, thrombocytosis) AND bleeding (acquired VWD if PLT > 1000)

Transformation — the most feared complication:

Blast crisis: > 90% risk if untreated; 2/3 myeloid, 1/3 lymphoid; median survival 1–2 months without treatment
TKIs have dramatically reduced this risk to < 5% in optimal responders

Treatment complications:

Nilotinib → QTc prolongation, PAOD
Dasatinib → pleural/pericardial effusion
Ponatinib → arterial thrombosis, hepatotoxicity
HSCT → GVHD, VOD, infections, second malignancies, cardiovascular disease (most common cause of non-relapse mortality)

Active Recall - Complications of CML

References

High Yield Summary

Epidemiology: 15–20% of adult leukaemias; incidence 1–2/100k; median age 50; M > F; only established RF is ionizing radiation.

Key Pathophysiology:

Philadelphia chromosome = t(9;22)(q34.1;q11.2) → BCR-ABL1 fusion gene → constitutively active tyrosine kinase
→ Uncontrolled proliferation + impaired apoptosis + preserved maturation → massive granulocytosis
< 20% blasts = chronic phase; ≥ 20% = blast crisis (acute leukaemia)

Clinical Features:

50% asymptomatic at diagnosis
Massive splenomegaly (the cardinal sign)
Constitutional symptoms (LOW, LOA, night sweats, fatigue)
Hyperleukostasis (if WBC very high): blurred vision, SOB, priapism
Anaemia (45–62%), thrombocytosis (NOT thrombocytopenia)
Basophilia on CBC is characteristic

Phases: Chronic (blasts < 10%) → Accelerated (10–19%, basophilia ≥ 20%, cytogenetic evolution) → Blast crisis (≥ 20%, acute leukaemia)

Key Distinction: "No t(9;22) = not CML." CML is the only MPN defined by BCR-ABL1.

High Yield Summary — Differential Diagnosis of CML

Most important differential at presentation: Leukaemoid reaction — distinguish by basophilia (present in CML, absent in reactive), LAP score (low in CML, high in reactive), and BCR-ABL1 testing (definitive).
Other chronic myeloid neoplasms (PV, ET, PMF, atypical CML, CMML): all BCR-ABL1 negative; distinguished by dominant haematological abnormality and molecular markers (JAK2, CALR, MPL).
At blast crisis: Must distinguish from de novo AML and Ph+ ALL — look for antecedent chronic-phase features and characteristic granulocyte series changes.
"No BCR-ABL1 = not CML" — this is the single most important diagnostic principle.
Massive splenomegaly DDx: CML and primary myelofibrosis are the two haematological causes of truly massive splenomegaly.

High Yield Summary — Diagnosis of CML

Diagnostic criteria: Compatible blood/BM picture (leukocytosis, basophilia, bimodal myelocyte-neutrophil distribution, dwarf megakaryocytes) PLUS demonstration of BCR-ABL1 by karyotype, FISH, or RT-PCR.
Gold standard = cytogenetics (karyotyping) for Ph chromosome detection (90–95%) and assessment of cytogenetic evolution.
Most sensitive test = RT-qPCR for BCR-ABL1 mRNA — used for monitoring, not primary diagnosis.
Phase determination by blast %: CP ( < 10%), AP (10–19% + other features), BC (≥ 20%).
Monitoring levels: Haematological (CBC) → Cytogenetic (FISH/karyotype) → Molecular (RT-qPCR). Optimal: ≤ 10% at 3mo, ≤ 1% at 6mo, ≤ 0.1% at 12mo.
Low LAP score distinguishes CML from reactive leukocytosis (high LAP) and PV (normal/high LAP).
Thrombocytopenia at presentation should prompt reconsideration — CML typically has normal or elevated platelets.

High Yield Summary — Management of CML

First-line treatment: TKIs — imatinib (low risk) or 2nd-gen TKI nilotinib/dasatinib (high risk).

TKI mechanism: Competitive inhibition of BCR-ABL1 tyrosine kinase ATP-binding pocket.

Key side effects to remember:

Nilotinib → QT prolongation
Dasatinib → pleural/pericardial effusion
Ponatinib → arterial thrombosis / hepatotoxicity

T315I gatekeeper mutation: Resistant to all 1st/2nd-gen TKIs → treat with ponatinib or asciminib.

Monitoring: RT-qPCR for BCR-ABL1 at 3, 6, 12 months. Target: ≤ 10% at 3mo, ≤ 1% at 6mo, ≤ 0.1% (MMR) at 12mo.

HSCT: Curative but reserved for TKI failure or blast crisis; 5-year survival ~50–70%.

Hydroxyurea: Cytoreduction for high WBC; does NOT reduce BCR-ABL1+ cells.

TFR: Possible in sustained deep molecular response (MR4.0+) for ≥ 2 years; ~40–60% success.

Blast crisis: TKI + chemotherapy (AML-type for myeloid, ALL-type for lymphoid) → HSCT.

High Yield Summary — Complications of CML

Disease complications:

Splenic: infarction (acute LUQ pain + rub), rupture (emergency), hypersplenism (cytopenias)
Hyperleukostasis: pulmonary, CNS, retinal, priapism — worse in blast crisis
Hyperuricaemia: gout, urate nephropathy — prevent with allopurinol
Thrombohaemorrhagic: thrombosis (hyperviscosity, thrombocytosis) AND bleeding (acquired VWD if PLT > 1000)

Transformation — the most feared complication:

Blast crisis: > 90% risk if untreated; 2/3 myeloid, 1/3 lymphoid; median survival 1–2 months without treatment
TKIs have dramatically reduced this risk to < 5% in optimal responders

Treatment complications:

Nilotinib → QTc prolongation, PAOD
Dasatinib → pleural/pericardial effusion
Ponatinib → arterial thrombosis, hepatotoxicity
HSCT → GVHD, VOD, infections, second malignancies, cardiovascular disease (most common cause of non-relapse mortality)

Chronic Myeloid Leukemia

1. Definition

2. Epidemiology

2.1 Global Epidemiology

2.2 Hong Kong Data

2.3 Prevalence vs Incidence Distinction

3. Risk Factors

4. Relevant Anatomy & Haematopoietic Physiology

4.1 Normal Haematopoiesis

4.2 Role of ABL1 Tyrosine Kinase in Normal Cells

5. Aetiology & Pathophysiology

5.1 The Philadelphia Chromosome & BCR-ABL1 Fusion Gene

5.1.1 The Translocation

5.1.2 The Fusion Gene Product

5.1.3 Downstream Effects of BCR-ABL1

5.1.4 Frequency of Philadelphia Chromosome

5.2 The Neoplastic Clone

5.3 CML Within the MPN Family

6. Classification — Natural History & Disease Phases

6.1 The Three Phases

6.2 Blastic Transformation — Why Does It Happen?

7. Clinical Features

7.1 Overview of Presentation

7.2 Symptoms (with Pathophysiological Basis)

7.2.1 Constitutional Symptoms (Hypercatabolic State)

7.2.2 Symptoms Related to Splenomegaly

7.2.3 Symptoms Related to Anaemia

7.2.4 Symptoms Related to Hyperleukostasis (Very High WBC)

7.2.5 Symptoms Related to Platelet Dysfunction

7.2.6 Bone Pain

7.2.7 Gout/Hyperuricaemia Symptoms

7.3 Signs (with Pathophysiological Basis)

7.3.1 Splenomegaly — The Cardinal Sign

7.3.2 Hepatomegaly

7.3.3 Signs of Anaemia

7.3.4 Signs of Bleeding/Platelet Dysfunction

7.3.5 Signs Suggesting Disease Progression (AP/BC)

7.4 Key Clinical Features Summary Table

8. Relevant Peripheral Blood & Bone Marrow Findings (Pre-Diagnosis Section)

8.1 Complete Blood Count (CBC) with Differential

8.2 Peripheral Blood Film

8.3 Bone Marrow (Aspirate & Trephine)

9. Important Concepts for Understanding CML

9.1 CML vs Reactive (Leukaemoid) Reaction

9.2 CML as Part of the 5-Step Diagnostic Approach to Haematological Malignancy

9.3 Why TKIs Work — The Rational Drug Design Story

Active Recall - CML: Definition, Epidemiology, Pathophysiology & Clinical Features

References

1. The Central Clinical Scenario: Marked Leukocytosis ± Splenomegaly

2. Differential Diagnoses — Detailed Discussion

2.1 Leukaemoid Reaction (Reactive Leukocytosis)

2.2 Other Myeloproliferative Neoplasms (BCR-ABL1–Negative MPNs)

2.3 "Atypical CML" (BCR-ABL1–Negative CML)

2.4 Chronic Myelomonocytic Leukaemia (CMML) — MDS/MPN Overlap

2.5 Myelodysplastic Syndrome (MDS)

2.6 Acute Myeloid Leukaemia (AML) — De Novo

2.7 Other Ph-Positive Malignancies

2.8 Chronic Lymphocytic Leukaemia (CLL)

2.9 Chronic Neutrophilic Leukaemia (CNL) and Chronic Eosinophilic Leukaemia (CEL)

3. Summary — Differential Diagnosis Framework

3A. Patient with Marked Leukocytosis + Left Shift (Chronic Phase Presentation)

3B. Patient with Blasts ≥ 20% (Blast Crisis vs De Novo Acute Leukaemia)

3C. Patient with Massive Splenomegaly

4. Approach to Narrowing the Differential — Key Investigations

Active Recall - Differential Diagnosis of CML

1. Diagnostic Criteria

1.1 WHO / ICC Diagnostic Criteria (Current)

1.2 Phase Determination (Staging at Diagnosis)

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Morphology — CBC with Differential Count

3.2 Morphology — Peripheral Blood Smear (PBS)

3.3 Morphology — Bone Marrow Aspirate & Trephine Biopsy

3.4 Cytochemistry

3.5 Immunophenotyping

3.6 Cytogenetics — The Gold Standard for Diagnosis

3.6.1 Conventional Karyotyping (G-Banding)

3.6.2 Fluorescence In Situ Hybridisation (FISH)

3.6.3 Comparison of Karyotyping vs FISH

3.7 Molecular Genetics — RT-PCR and Quantitative PCR (RT-qPCR)