Chapter 110: Chronic Myeloid Leukemia¶
Chapter 110 | Part 4: Oncology and Hematology
KEY CLINICAL POINTS¶
- Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell neoplasm driven by the BCR-ABL1 fusion gene from the t(9;22) translocation.
- TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib) are the cornerstone of therapy, with imatinib as the first-line standard.
- Sokal risk stratification (low, intermediate, high) guides prognosis and treatment decisions, with 10-year survival >85% with TKIs.
- CML progresses through chronic, accelerated, and blastic phases, with transformation criteria including blasts ≥ 15% or basophils ≥ 20%.
- Treatment-free remission (TFR) is achievable in ~50% of patients with durable molecular response (MR4) after ≥ 2 years of TKI therapy.
1. DEFINITION & OVERVIEW¶
Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell neoplasm characterized by the Philadelphia chromosome (t(9;22)(q34.1;q11.2)), which results in the BCR-ABL1 fusion gene. This fusion gene encodes a constitutively active tyrosine kinase, driving uncontrolled myeloid proliferation. CML progresses through three phases: chronic (indolent), accelerated, and blastic (blast crisis).
Table 110-1: Presenting Signs and Symptoms of Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase¶
| PARAMETER | PERCENTAGE |
|---|---|
| Age ‡60 years (median) | 40–50 (55–65) |
| Splenomegaly | 30 |
| Hepatomegaly | 5–10 |
| Lymphadenopathy | 5 |
| Hemoglobin <10 g/dL | 10–15 |
| Platelets >450 × 10n/L | 30–35 |
| White blood cells ‡50 × 10n/L | 35–40 |
| ‡3% blasts | 8–10 |
| ‡7% basophils | 10 |
Sokal Risk Stratification¶
| Risk Category | Percentage |
|---|---|
| Low | 60–65 |
| Intermediate | 25–30 |
| High | 10 |
1.1 Pathogenesis¶
The t(9;22) translocation fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9, creating the BCR-ABL1 oncogene. This fusion protein activates downstream pathways (RAS, MAPK, STAT, PI3K) that promote proliferation and inhibit apoptosis. The BCR-ABL1 kinase activity is inhibited by tyrosine kinase inhibitors (TKIs), which are central to CML management.
1.2 Phases of Disease¶
CML progresses through three phases: chronic (indolent), accelerated (with clonal evolution and resistance), and blastic (blast crisis). The chronic phase is characterized by splenomegaly, leukocytosis, and minimal symptoms. Accelerated phase involves increased blasts and basophils, while blastic phase is marked by ≥ 30% blasts in peripheral blood or marrow.
2. EPIDEMIOLOGY¶
CML accounts for ~15% of all leukemias, with a male predominance (male-to-female ratio 1.6:1). Median age at diagnosis is 55–65 years. Incidence increases with age, peaking after 40–50 years. Annual incidence is 2 per 100,000 individuals, with ~9,000 new cases/year in the U.S. Prevalence is expected to rise due to improved survival with TKIs, reaching ~450,000 by 2040.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
CML is not inherited; no familial associations. The t(9;22) translocation is the sole etiologic factor. The BCR-ABL1 fusion gene produces a constitutively active kinase that disrupts normal hematopoiesis. Different BCR-ABL1 transcripts (p210, p190, p230) have varying clinical implications, with p210 being most common in CML.
4. CLINICAL FEATURES¶
Most patients present in the chronic phase with splenomegaly, fatigue, and anemia. Accelerated phase is marked by increased blasts and basophils, while blastic phase involves ≥ 30% blasts. Symptoms include constitutional symptoms, bleeding diatheses, and organomegaly. The Sokal risk score stratifies prognosis based on age, spleen size, and blast counts.
5. DIFFERENTIAL DIAGNOSIS¶
Differential diagnoses include other myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia), chronic myelomonocytic leukemia, and myelodysplastic syndromes. Atypical CML and chronic neutrophilic leukemia may present with similar features but require distinct molecular testing.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnosis requires confirmation of the Philadelphia chromosome (t(9;22)) via FISH, PCR, or karyotype. Molecular testing for BCR-ABL1 transcripts is critical. Bone marrow biopsy shows hypercellularity with myeloid predominance. Monitoring includes PCR for BCR-ABL1 transcripts and cytogenetic analysis.
7. MANAGEMENT & TREATMENT¶
TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib) are first-line therapy. Allogeneic HSCT is curative but reserved for high-risk patients or TKI-resistant cases. Dose adjustments and second/third-generation TKIs are used for resistance. Treatment-free remission (TFR) is achievable in ~50% of patients with durable molecular response (MR4).
Table 110-2: Medical Therapeutic Options in Chronic Myeloid Leukemia¶
| AGENT (BRAND NAME) | APPROVED INDICATIONS | DOSE SCHEDULE | NOTABLE TOXICITIES |
|---|---|---|---|
| Imatinib mesylate (Gleevec) | All phases | 400 mg daily | See text |
| Dasatinib (Sprycel) | All phases | 100 mg daily | Myelosuppression; pleural effusions; pulmonary hypertension |
| Nilotinib (Tasigna) | All phases except blastic phase | 300 mg twice daily | Diabetes; arterio-occlusive events; pancreatitis |
| Bosutinib (Bosulif) | All phases | 400 mg daily | Diarrhea; liver toxicity; renal dysfunction |
| Ponatinib (Iclusig) | T315I mutation; failure of ‡2 tyrosine kinase inhibitors | 45 mg daily | Skin rashes; pancreatitis; systemic hypertension |
| Asciminib (Scemblix) | Third-line therapy; T315I mutation | 40 mg twice daily | Arterial occlusive events; hypertension |
7.1 TKI Therapy¶
Imatinib (400 mg/day) is first-line. Second-generation TKIs (dasatinib, nilotinib) are preferred for TFR. Third-generation TKIs (ponatinib, asciminib) target T315I mutations. Dose adjustments are made based on molecular response and toxicity.
7.2 Allogeneic HSCT¶
HSCT is considered for high-risk CML or TKI resistance. Cure rates vary by phase (30–50% for chronic phase, ≤ 20% for blastic phase). Myeloablative regimens are used, with risks of GVHD and transplant-related mortality.
8. PROGNOSIS & COMPLICATIONS¶
With TKIs, 10-year survival is >85%, with CML-specific survival ~90%. Complications include resistance, side effects (e.g., myelosuppression, hypertension), and transformation to accelerated/blastic phases. Long-term risks include cardiovascular events and secondary malignancies.
9. SPECIAL CONSIDERATIONS¶
Pregnancy: TKIs (especially imatinib) are contraindicated in the first trimester. Hydroxyurea or leukapheresis may be used. Elderly patients may require lower TKI doses. Comorbidities (e.g., renal/liver dysfunction) influence TKI selection.
10. KEY POINTS & CLINICAL PEARLS¶
- BCR-ABL1 fusion gene is diagnostic and therapeutic target. 2. TKIs are first-line, with imatinib as the standard. 3. Sokal risk stratification guides prognosis. 4. TFR is achievable in ~50% of patients with MR4. 5. Allogeneic HSCT is curative but reserved for high-risk cases. 6. Resistance management involves mutation testing and TKI switching.