Chronic Myeloid Leukemia¶

Chapter 110 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 110

Key Clinical Points¶

CML is defined by the presence of the BCR::ABL1 fusion gene in a patient with a myeloproliferative neoplasm.
The Philadelphia chromosome t(9;22)(q34.1;q11.2) is present in >90% of classical CML cases.
p210BCR::ABL1 is the most common oncoprotein (e13a2/e14a2); p190BCR::ABL1 (e1a2) has a worse prognosis; p230BCR::ABL1 (e19a2) has an indolent course.
TKI therapy has revolutionized treatment, with 10-year survival rates >85% in chronic phase.
Treatment-free remission (TFR) is associated with durable deep molecular response (DMR) for 2+ years (TFR rate ~50%) or 5+ years (TFR rate ~80%+).
Accelerated-phase criteria: ≥15% peripheral blasts, ≥20% basophils, cytogenetic clonal evolution, or thrombocytopenia <100 × 10^9/L.
Blastic-phase criteria: ≥30% peripheral or marrow blasts or sheets of blasts in extramedullary disease.
Resistance to TKIs often involves ABL1 kinase domain mutations (e.g., T315I) preventing binding to the catalytic site.
Second-generation TKIs (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib, asciminib) are used for resistance or intolerance.
Omacetaxine mepesuccinate is indicated for failure of ≥2 tyrosine kinase inhibitors.

1. DEFINITION & OVERVIEW¶

Chronic myeloid leukemia (CML) is a clonal hematopoietic myeloproliferative stem cell neoplasm driven by the BCR::ABL1 chimeric gene from t(9;22)(q34.1;q11.2), known as the Philadelphia chromosome.

Definition (Harrison's 22e): CML is defined by the presence of the BCR::ABL1 fusion gene in a patient with a myeloproliferative neoplasm.

1.1 Disease Course & Phases¶

Untreated CML follows a biphasic/triphasic course: chronic phase → accelerated phase → blastic phase. * Pre-TKI median survival: 3–7 years * Current 10-year survival with TKI: >85% in chronic phase

1.2 Molecular Classification¶

Two main transcripts arise from major BCR breakpoints: * p210BCR::ABL1: Most common; encoded by e13a2 (b2a2) and e14a2 (b3a2) * p190BCR::ABL1: Associated with Ph-positive acute lymphoblastic leukemia (ALL); rarer in CML * p230BCR::ABL1: Rare in CML; associated with an indolent course

2. EPIDEMIOLOGY¶

CML accounts for ~15% of all leukemias, with male predominance (1.6:1). Median age at diagnosis is 55–65 years; <3% are under 20.

2.1 Epidemiology Data¶

Global Incidence: 2/100,000 annually
US Prevalence: Projected to reach ~450,000 by 2040 due to TKI availability

2.2 Risk Factors¶

No familial associations or environmental risk factors (e.g., benzene, radiation)
Ionizing radiation exposure increases risk (peaks 5–10 years post-exposure)
No association with prior chemotherapy/radiation for other cancers

3. ETIOLOGY & PATHOPHYSIOLOGY¶

The t(9;22) translocation juxtaposes ABL1 to BCR, creating the constitutively active p210BCR::ABL1 oncoprotein. This activates multiple pathways (RAS/MAPK, PI3K, STAT) leading to uncontrolled proliferation and reduced apoptosis.

3.1 Breakpoint Variants¶

Major BCR variants: e13a2/e14a2 → p210BCR::ABL1 (most common)
Minor BCR variants: e1a2 → p190BCR::ABL1 (worse prognosis)
Micro-BCR variants: e19a2 → p230BCR::ABL1 (indolent course)

3.2 TKI Mechanism & Resistance¶

TKIs inhibit BCR::ABL1 kinase activity by binding the ATP-binding domain. * Resistance Mechanisms: * ABL1 mutations (e.g., T315I) preventing binding to the catalytic site * Stem cell survival pathways (Wnt, Foxo3a, PP2A) * Asciminib: Targets the myristoyl pocket of BCR::ABL1

3.3 Blastic Transformation¶

Transformation to blastic phase is associated with: * Chromosomal abnormalities: trisomy 8, del(17p), 20q– * Mutations: TP53, RB1, RUNX1, p16 * Impact of TKI: Reduces transformation rates (now <5% at 10 years)

4. CLINICAL FEATURES¶

Most patients present in chronic phase with minimal symptoms (fatigue, splenomegaly). In low-resource settings, high disease burden presents with splenomegaly, anemia, and weight loss.

4.1 Physical Findings¶

Splenomegaly: 20–70% of patients
Hepatomegaly: 5–10%
Lymphadenopathy: 5%
High basophil counts: May cause pruritus, diarrhea, flushing

4.2 Hematologic & Marrow Findings¶

Leukocytosis: 10–500 imes 10^9/L
Peripheral blood: Neutrophilia with left shift (≤5% blasts)
Thrombocytosis: Common; thrombocytopenia suggests poor prognosis
Bone marrow: Hypercellular, myeloid-to-erythroid ratio 15–20:1

4.3 Table 1 — Presenting Signs and Symptoms (Chronic Phase)¶

Age ≥60 years (median): 40–50 (55–65)
Female gender: 35–45
Splenomegaly: 30%
Hepatomegaly: 5–10%
Lymphadenopathy: 5%
Other extramedullary disease: 2%
Hemoglobin <10 g/dL: 10–15%
Platelets >450 imes 10^9 cells/L: 30–35%
Platelets <100 imes 10^9 cells/L: 3–5%
White blood cells ≥50 imes 10^9 cells/L: 35–40%
Marrow ≥5% blasts: 5%
Marrow ≥5% basophils: 10–15%
Peripheral blood ≥3% blasts: 8–10%
Peripheral blood ≥7% basophils: 10%
Sokal risk Low: 60–65%
Sokal risk Intermediate: 25–30%
Sokal risk High: 10%

5. DIFFERENTIAL DIAGNOSIS¶

Atypical CML, chronic myelomonocytic leukemia, and MDS/MPN must be distinguished from CML:

5.1 Atypical CML¶

CSF3R mutations: 5–10% of cases
SETBP1 mutations: 25% of cases

5.2 MDS/MPN-RS-T¶

SF3B1 mutations: 50–70% (associated with longer survival)

6. INVESTIGATIONS & DIAGNOSIS¶

Diagnosis requires documentation of t(9;22) by G-banding or FISH. Molecular studies confirm BCR::ABL1 transcripts to avoid false-negative PCR results.

6.1 Monitoring Response to Therapy¶

Partial cytogenetic response: ≤35% Ph-positive metaphases (≈BCR::ABL1 IS ≤10%)
Complete cytogenetic response: 0% Ph positivity (≈BCR::ABL1 IS ≤1%)
Major molecular response (MMR): BCR::ABL1 IS ≤0.1%
Deep molecular response (DMR): BCR::ABL1 IS ≤0.01%

6.2 Diagnostic Criteria & Risk Stratification¶

Accelerated-phase criteria: 1. ≥15% peripheral blasts 2. ≥20% basophils 3. Cytogenetic clonal evolution 4. Thrombocytopenia <100 imes 10^9/L

Blastic-phase criteria: 1. ≥30% blasts in blood or marrow 2. Sheets of blasts in extramedullary disease

7. MANAGEMENT & TREATMENT¶

Six FDA-approved TKIs are available: imatinib, nilotinib, dasatinib, bosutinib, ponatinib, and asciminib.

7.1 Pharmacologic Therapy¶

First-line options: * Imatinib: 400–800 mg/day * Nilotinib: 300 mg BID (or 400 mg daily) * Dasatinib: 100 mg/day * Bosutinib: 500 mg/day

Second-line / Specialized TKIs: * Ponatinib: 45 mg/day (used for T315I mutation or failure of ≥2 TKIs) * Dosing Note: May consider lower starting doses (e.g., 30 mg daily); reduce to 15 mg daily once a complete cytogenetic response is achieved. * Asciminib: 200 mg BID (targets myristoyl pocket; used for resistant cases)

Salvage Therapy: * Omacetaxine mepesuccinate: 1.2–1.6 mg/kg SC every 8 hours (indicated for failure of ≥2 tyrosine kinase inhibitors) * Note: Alternative dosing: 1.25 mg/m^2 subcutaneously twice daily for 14 days of induction; 7 days of maintenance every month.

7.2 Non-Pharmacologic & Surgical¶

Allogeneic HSCT: Indicated for high-risk patients or those failing TKIs.

8. PROGNOSIS & COMPLICATIONS¶

With TKI therapy, 10-year survival exceeds 85%.

8.1 Clinical Complications¶

Transformation: Risk of transformation to blastic phase is <5% at 10 years.
Cytopenias: May require dose reductions.
Cardiovascular toxicity: Particularly associated with ponatinib.
Second malignancies.

9. SPECIAL CONSIDERATIONS¶

9.1 Pregnancy¶

TKIs are contraindicated in pregnancy; imatinib is preferred if needed.

9.2 Comorbidities¶

Dasatinib: Avoid with lung disease
Nilotinib: Avoid with pancreatitis or diabetes
Bosutinib: Avoid with liver or renal dysfunction

10. KEY PEARLS & CLINICAL TRAPS¶

Differentiation: Use molecular markers (CSF3R, SETBP1) to distinguish CML from atypical CML.
Resistance: T315I is the hallmark mutation for resistance; Ponatinib and Asciminib are key agents for these cases.
TFR Eligibility: Treatment-free remission (TFR) requires durable deep molecular response (DMR) for 2+ years (~50%) or 5+ years (~80%+).
Safety Selection: Select TKIs based on patient comorbidities (e.g., avoid Nilotinib in patients with diabetes).

Reference Tables¶

TABLE 110-1 Presenting Signs and Symptoms of Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia…¶

Harrison's 22e, p.837

PARAMETER	PERCENTAGE
Age ≥60 years (median)	40–50 (55–65)
Splenomegaly	30
Lymphadenopathy	5
Hemoglobin <10 g/dL	10–15
White blood cells ≥50 × 109 cells/L	35–40
Peripheral blood
≥3% blasts	8–10
≥7% basophils	10
Sokal risk
Low	60–65
Intermediate	25–30
High	10

TABLE 110-2 Medical Therapeutic Options in Chronic Myeloid Leukemia¶

Harrison's 22e, p.839

AGENT (BRAND NAME)	APPROVED INDICATIONS	DOSE SCHEDULE	NOTABLE TOXICITIES
Imatinib mesylate (Gleevec)	All phases	400 mg daily	See text
	All phases	First-line: 100 mg daily Salvage: 100 mg daily in chronic phase; 140 mg daily in transformation
Nilotinib (Tasigna)	All phases except blastic phase	First-line: 300 mg twice daily Salvage: 400 mg twice daily	Diabetes; arterio-occlusive events; pancreatitis
	All phases	First line: 400 mg daily Salvage: 500 mg daily
Ponatinib (Iclusig)	T315I mutation; failure of ≥2 tyrosine kinase inhibitors	45 mg daily (may consider lower starting doses, e.g., 30 mg daily; lower the dose to 15 mg daily once a complete cytogenetic response is achieved)	Skin rashes (10–20%); pancreatitis (5%); arterio-occlusive events (10–20%); systemic hypertension (10–15%)
	Third-line therapy; T315I mutation	40 mg twice daily or 80 mg daily; T315I: 200 mg twice daily
Omacetaxine mepesuccinate (Synribo)	Failure ≥2 tyrosine kinase inhibitors	1.25 mg/m2 subcutaneously twice daily for 14 days of induction; 7 days of maintenance every month (consider shorter dose schedules, 7 days of induction, 2–5 days of maintenance)	Myelosuppression