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Chronic Myeloid Leukemia (CML)

Definition

CML is a myeloproliferative neoplasm originating from a pluripotent hematopoietic stem cell. It is defined by a specific molecular lesion: the BCR-ABL fusion gene, which encodes a constitutively active 210 kDa tyrosine kinase. There is no BCR-ABL-negative CML - diseases without this fusion (e.g., "atypical CML," chronic neutrophilic leukemia) are distinct entities.

Goldman-Cecil Medicine, p. 1938; Robbins Pathologic Basis of Disease, p. 583

Molecular Pathogenesis

Feature	Detail
Cytogenetic event	Reciprocal translocation t(9;22)(q34;q11)
Result	Shortened chromosome 22 = Philadelphia (Ph) chromosome; elongated chromosome 9
Fusion gene	BCR::ABL - constitutively active tyrosine kinase (210 kDa)
Frequency	>90% of cases show the Ph chromosome by karyotype; remainder detected by FISH or PCR
Cell of origin	Pluripotent HSC (hence both myeloid and lymphoid blast crisis are possible)

Mechanism: The BCR dimerization domain causes constitutive self-association, activating the ABL kinase moiety. This drives RAS and JAK/STAT signaling - the same pathways activated by normal hematopoietic growth factors - causing granulocytic and megakaryocytic proliferation and premature release of immature cells from the marrow.

Robbins Pathologic Basis of Disease, p. 583

Epidemiology

Peak incidence: 5th-6th decade of life
~4,800 new cases/year in the United States
Occurs in children and adolescents, but primarily an adult disease
Without treatment: median survival ~3 years
With TKI therapy: near-normal age-adjusted lifespan in chronic-phase disease

Disease Phases

Phase	ELN Criteria	WHO Criteria
Chronic	Blasts <15% (peripheral/marrow)	Blasts <10%
Accelerated	Blasts 15-<30% peripheral/marrow	Blasts 10-<20%
Blast crisis	Blasts ≥30%	Blasts ≥20%

75% of patients in developed countries are diagnosed in chronic phase.

Natural progression (untreated):

After ~3 years, ~50% enter accelerated phase (rising anemia, thrombocytopenia, basophilia, new cytogenetic abnormalities - trisomy 8, isochromosome 17q, Ph duplication)
Accelerated phase terminates in blast crisis within 6-12 months
Other 50% progress directly to blast crisis without an accelerated phase
Blast crisis types: 70% myeloid, ~30% lymphoid (pre-B cell) - confirming pluripotent stem cell origin
Goldman-Cecil Medicine, p. 1940; Robbins Pathologic Basis of Disease, p. 583

Morphology

Bone marrow:

Markedly hypercellular with massively increased maturing granulocytic precursors
Elevated proportion of eosinophils and basophils
Increased megakaryocytes (often small, dysplastic)
Characteristic sea-blue histiocytes (scattered macrophages with wrinkled green-blue cytoplasm)
Increased reticulin; overt fibrosis is rare

Peripheral blood:

Leukocytosis often >100,000 cells/µL
Spectrum: neutrophils, band forms, metamyelocytes, myelocytes, eosinophils, basophils
Blasts usually <10% of circulating cells
Thrombocytosis (often marked)

Other:

Massive splenomegaly (extramedullary hematopoiesis, often with splenic infarcts)
Mild hepatomegaly and lymphadenopathy
Robbins Pathologic Basis of Disease, p. 583

Clinical Features

Onset: Insidious
Symptoms: Fatigue, weakness, weight loss, anorexia (hypermetabolism), dragging left upper quadrant sensation from splenomegaly, or acute left upper quadrant pain from splenic infarction
Diagnosis confirmed by: Detection of BCR::ABL fusion gene via karyotype (Ph chromosome), FISH, or PCR

Response Definitions & Monitoring

Response Type	Definition
Hematologic response	Normalization of CBC, no symptoms
Cytogenetic response (CCyR)	No Ph+ metaphases on bone marrow cytogenetics
Major Molecular Response (MMR)	≥3-log reduction in BCR-ABL mRNA (BCR-ABL ≤0.1% on IS)
Deep Molecular Response (MR4/MR4.5)	≥4-4.5 log reduction; prerequisite for treatment-free remission (TFR) attempts

Treatment: Tyrosine Kinase Inhibitors (TKIs)

Six FDA-approved oral BCR::ABL1 TKIs (as of Harrison's 22E, 2025):

Generation	Drug	Dose	Notable Toxicities
1st	Imatinib (Gleevec)	400 mg/day	GI, fluid retention, cytopenias
2nd	Dasatinib (Sprycel)	100 mg/day (1L); 140 mg/day (transformation)	Pleural/pericardial effusions, pulmonary hypertension, cytopenias
2nd	Nilotinib (Tasigna)	See label	Cardiovascular (arterial occlusion), hyperglycemia, QTc prolongation
2nd	Bosutinib (Bosulif)	See label	Diarrhea, hepatotoxicity, cytopenias
3rd	Ponatinib (Iclusig)	See label	Hypertension, arterial/venous thrombosis (VEGFR inhibition)
3rd/STAMP	Asciminib (Scemblix)	See label	Inhibits ABL myristoyl pocket (different MOA); active vs. T315I

Key comparisons:

Nilotinib: structurally similar to imatinib but 30× more potent
Dasatinib: SRC + ABL inhibitor, 300× more potent than imatinib
Bosutinib: SRC + ABL inhibitor, 30-50× more potent than imatinib
Ponatinib + Asciminib: active against T315I "gatekeeper" mutation (resistance to 1st/2nd gen TKIs)
Asciminib: STAMP inhibitor (Specifically Targeting the ABL Myristoyl Pocket) - distinct mechanism

Outcomes with imatinib (chronic-phase):

Complete cytogenetic remission (CCyR): ~60-70%
Major molecular response (MMR): ~50-60%
Overall survival >90%
2nd-generation TKIs achieve higher early response rates and less progression to advanced phases, but without a clear overall survival advantage
Harrison's Principles of Internal Medicine 22E, p. 882

Survival Impact of TKI Era

The figure below from the MD Anderson Cancer Center experience dramatically illustrates the TKI revolution:

CML survival by era - chronic phase (A) and accelerated/blast phase (B)

Panel A (Chronic phase): TKI era (2001-present) achieved ~95% CML-specific survival at 20 years vs. only ~8% in the pre-1982 era
Panel B (Accelerated/Blast phase): TKIs dramatically improved accelerated-phase survival (median 88 months vs. 28 months), but blast-phase benefit remains modest (median 7 vs. 5 months)

Treatment-Free Remission (TFR)

A major evolving goal in CML management. Patients who achieve deep molecular responses (MR4/MR4.5) on TKI therapy can attempt treatment discontinuation. Approximately 40-50% of eligible patients can sustain TFR. Those who lose response typically regain it rapidly on TKI restart.

Resistance & the T315I Mutation

The T315I "gatekeeper" mutation in ABL confers resistance to all 1st and 2nd generation TKIs (imatinib, dasatinib, nilotinib, bosutinib). Ponatinib and asciminib are the agents active against T315I disease. A 2024 systematic review (PMID: 39634261) compared ponatinib vs. asciminib in post-2nd-gen TKI failure.

Differential Diagnosis

Feature	CML	Leukemoid Reaction
WBC	Often >100,000/µL	Usually <50,000/µL
Basophilia	Common	Absent
Ph chromosome / BCR-ABL	Present	Absent
LAP (leukocyte alkaline phosphatase) score	Low/absent	Elevated
Splenomegaly	Marked	Mild/absent

Recent Evidence Note

A 2025 meta-analysis (PMID: 40317312) systematically reviewed patient-reported toxicity during TKI therapy in CML, highlighting that TKI side effects remain a significant quality-of-life burden even with effective disease control.

Sources:

Robbins, Cotran & Kumar Pathologic Basis of Disease (10e), pp. 583-585
Harrison's Principles of Internal Medicine 22E (2025), pp. 881-882
Goldman-Cecil Medicine (International Ed.), pp. 1938-1940

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