Chronic Myeloid Leukemia (CML)
Epidemiology and Pathophysiology
CML is a myeloproliferative neoplasm with an annual incidence of 1-2 cases per 100,000 adults, accounting for approximately 15% of newly diagnosed adult leukemias, with a median age at diagnosis of 60-65 years in Europe. 1
Molecular Basis
CML arises from the balanced translocation t(9;22)(q34;q11.2), creating the Philadelphia chromosome (22q-), which was the first recurrent chromosomal abnormality associated with human malignancy, described in 1960. 1, 2
This translocation fuses the ABL1 gene from chromosome 9 with the BCR gene on chromosome 22, generating the BCR-ABL1 fusion oncogene that produces a chimeric protein with constitutive tyrosine kinase activity. 1, 2, 3
The most common BCR-ABL1 transcripts are e13a2 and e14a2, which encode the p210 protein characteristic of CML. 1
Unusual transcripts include e1a2 (p190, typically seen in Ph+ acute lymphoblastic leukemia) and e19a2 (p230, associated with enhanced neutrophil differentiation). 1
BCR-ABL1 positive cells are genetically unstable and prone to develop additional genomic abnormalities, leading to clonal evolution and disease progression. 1
Disease Phases
Chronic phase (CP) is defined by <15% blasts in blood and bone marrow according to European LeukemiaNet (ELN) criteria, and represents the presentation phase in 90-95% of patients. 1, 4
Accelerated phase (AP) is characterized by 15-29% blasts in peripheral blood or bone marrow, >20% basophils, thrombocytosis or thrombocytopenia unrelated to therapy, or clonal cytogenetic evolution. 1
Blast phase (BP) is defined by ≥30% blasts in blood or bone marrow, or extramedullary blast involvement. 1, 4
Untreated chronic phase CML progresses to accelerated or blast phase within 3-5 years on average. 1, 5
Diagnosis
Clinical Presentation
Most patients (50-60%) are asymptomatic at diagnosis, with CML discovered incidentally on routine blood work. 1
Symptomatic patients present with fatigue, weight loss, night sweats, and abdominal discomfort from splenomegaly. 1, 6
Splenomegaly is present in more than 50% of cases at diagnosis. 1
Laboratory Findings
The characteristic peripheral blood finding is excessive granulocytosis with left shift of granulopoiesis, including immature forms such as myelocytes and metamyelocytes, along with basophilia and eosinophilia. 1, 4
White blood cell counts often exceed 100 × 10⁹/L at presentation, with thrombocytosis also common. 4, 6
Confirmatory Testing
Diagnosis requires demonstration of the Philadelphia chromosome or BCR-ABL1 fusion gene in a patient with characteristic peripheral blood findings. 4, 2
Bone marrow aspirate and biopsy should be performed for morphologic evaluation, cytogenetic analysis to detect the t(9;22) translocation and identify additional chromosomal abnormalities (clonal evolution), and assessment of fibrosis. 1, 4
Conventional cytogenetics detects the Philadelphia chromosome in 90-95% of cases; in the remaining 5%, fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) is required to confirm the BCR-ABL1 fusion. 1, 2
Patients with cryptic Philadelphia chromosome (cytogenetically negative but BCR-ABL1 positive by FISH or RT-PCR) should be treated identically to Philadelphia-positive patients, as therapeutic response is comparable. 1
Quantitative RT-PCR (qPCR) must be performed at baseline to establish the presence of quantifiable BCR-ABL1 mRNA transcripts on the International Scale (IS), which is essential for monitoring treatment response. 1, 4
Qualitative RT-PCR identifies the BCR-ABL1 transcript type (e13a2 or e14a2), which is important for subsequent molecular monitoring. 1, 4
Complete Baseline Workup
History and physical examination should specifically assess for splenomegaly, hepatomegaly, and constitutional symptoms (fever, night sweats, weight loss). 1, 4
Laboratory studies must include complete blood count with differential, comprehensive metabolic panel, hepatitis B panel (required before initiating tyrosine kinase inhibitor therapy), and chemistry profile. 1, 4
Baseline electrocardiogram is mandatory before starting TKI therapy due to potential cardiac toxicities. 7
Differential Diagnosis
Patients with clinical features of CML but no detectable Philadelphia chromosome or BCR-ABL1 rearrangement are classified as atypical CML according to WHO criteria and represent a separate disease entity requiring different management. 1
Atypical CML is BCR-ABL1 negative, lacks basophilia, and shows dysplasia of erythroid, granulocytic, and/or megakaryocytic lineages. 1
Treatment of Chronic Phase CML
First-Line Therapy
Tyrosine kinase inhibitors targeting BCR-ABL1 are the standard of care for newly diagnosed chronic phase CML, with five TKIs approved for frontline therapy: imatinib, dasatinib, nilotinib, bosutinib, and asciminib. 8, 3, 9
Imatinib
Imatinib 400 mg daily was established as the first-line standard based on the landmark IRIS trial comparing imatinib to interferon-alpha plus cytarabine. 1, 10
The IRIS trial demonstrated cumulative complete hematologic response rate of 98%, major cytogenetic response rate of 92%, complete cytogenetic response rate of 87%, and progression-free survival of 84% at 5-6 years. 1
Annual progression rate was 4% total (including loss of hematologic and cytogenetic response) and 2% to accelerated or blast phase, with gradual decrease over time. 1
Two prospective randomized studies failed to show superiority of higher imatinib doses (600-800 mg) over standard 400 mg dosing for frontline therapy. 1
Second-Generation TKIs
Second-generation TKIs (dasatinib, nilotinib, bosutinib) produce significantly deeper and faster molecular responses compared to imatinib, but have not demonstrated survival prolongation, likely due to the availability of effective salvage therapies. 3, 9
The choice between first-line TKIs should consider patient comorbidities, side effect profiles, and individual risk factors. 3, 9
Nilotinib requires dose adjustments for electrolyte abnormalities (hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, hyponatremia) and carries risks of cardiovascular events, pancreatitis, and hepatotoxicity. 7
Monitoring Treatment Response
Response assessment is critical for determining treatment success and guiding management decisions. 1
Response Definitions
Complete hematologic response (CHR) requires normalization of peripheral blood counts (WBC <10 × 10⁹/L, platelets <450 × 10⁹/L), disappearance of immature granulocytes, and resolution of splenomegaly. 1
Complete cytogenetic response (CCyR) is defined as 0% Philadelphia chromosome-positive metaphases on bone marrow cytogenetics. 1
Major molecular response (MMR) is defined as BCR-ABL1 ≤0.1% on the International Scale (IS), representing a 3-log reduction from baseline. 1
Deep molecular response includes MR4 (BCR-ABL1 ≤0.01% IS) and MR4.5 (BCR-ABL1 ≤0.0032% IS). 1, 7
Monitoring Schedule
Complete blood counts should be performed every 2 weeks for the first 2 months, then monthly thereafter. 7
Quantitative RT-PCR for BCR-ABL1 transcripts should be performed every 3 months during the first year, then every 3-6 months once stable deep molecular response is achieved. 1
Bone marrow cytogenetics should be performed at 6 and 12 months if complete cytogenetic response has not been achieved by qPCR. 1
Electrocardiograms should be obtained at baseline, 7 days after TKI initiation, periodically during therapy, and following dose adjustments. 7
Chemistry panels including electrolytes, calcium, magnesium, liver enzymes, lipid profile, and glucose should be monitored prior to therapy and periodically during treatment. 7
Response Milestones and Treatment Failure
The European LeukemiaNet has established time-dependent response milestones to define optimal response, warning signs, and treatment failure. 1
Optimal Response
- At 3 months: BCR-ABL1 ≤10% IS and/or Ph+ ≤35%
- At 6 months: BCR-ABL1 <1% IS and/or Ph+ 0%
- At 12 months: BCR-ABL1 ≤0.1% IS (MMR)
- Thereafter: BCR-ABL1 ≤0.1% IS 1
Treatment Failure
Treatment failure is defined by lack of complete hematologic response at 3 months, BCR-ABL1 >10% IS at 6 months, BCR-ABL1 >1% IS at 12 months, or loss of previously achieved responses. 1
Development of high-level resistance mutations (particularly T315I), progression to accelerated or blast phase, or development of additional chromosomal abnormalities in Ph+ cells also constitute treatment failure. 1
Management of Treatment Failure or Suboptimal Response
When treatment failure or resistance occurs, compliance must be verified first, followed by BCR-ABL1 kinase domain mutation analysis. 1
Mutation Testing
BCR-ABL1 kinase domain mutations are the most common mechanism of TKI resistance. 1
The T315I "gatekeeper" mutation confers resistance to all first- and second-generation TKIs (imatinib, dasatinib, nilotinib, bosutinib) but remains sensitive to ponatinib, asciminib, and olverembatinib. 3, 9
For mutations with mild resistance (IC50 <5-fold of unmutated BCR-ABL1), imatinib dose escalation to 600-800 mg daily may be attempted. 1
For highly resistant mutations (IC50 >10-fold of unmutated BCR-ABL1), switching to an alternative TKI is required. 1
Second-Line TKI Options
For patients failing first-line imatinib, second-generation TKIs (dasatinib, nilotinib, bosutinib) are the preferred second-line options. 3, 9
For patients with T315I mutation or failure of two or more TKIs, ponatinib or asciminib are the treatment options. 3, 9
Third-generation TKIs targeting the ABL1 kinase domain (olverembatinib, ELVN-001) or the myristoyl pocket (TGRX-678, TERN-701) are under development. 8
Allogeneic Stem Cell Transplantation
Allogeneic hematopoietic stem cell transplantation remains the only curative therapy for CML but is associated with significant treatment-related mortality (historically around 30%) from infection, bleeding, and graft-versus-host disease. 5, 6
Allogeneic transplantation is recommended for patients with chronic phase CML who have failed at least two TKIs due to resistance (not intolerance), and for all patients with accelerated or blast phase disease. 3, 9
Based on genetic randomization studies, drug treatment is superior to allogeneic transplantation in first-line therapy due to transplant-related mortality; therefore, upfront transplantation is not recommended. 1
Even older patients who have cytogenetic relapse after failure of all available TKIs can maintain long-term survival by continuing the most effective/least toxic TKI, with or without addition of non-TKI agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan). 3, 9
Treatment-Free Remission
Patients who achieve sustained deep molecular response (typically MR4.5 for at least 2 years) may be eligible for treatment discontinuation trials, with approximately 40-50% maintaining treatment-free remission. 7, 8
BCR-ABL1 transcript levels must be monitored monthly for the first year after discontinuation, every 6 weeks for the second year, and every 12 weeks thereafter using an FDA-authorized test with sensitivity of at least MR4.5. 7
Most molecular relapses occur within the first 6 months after TKI discontinuation. 8
Patients who experience molecular relapse after discontinuation typically regain deep molecular response upon TKI resumption. 8
Adverse Effects and Monitoring
Hematologic Toxicity
Myelosuppression is the most common severe toxicity, with Grade 3/4 neutropenia occurring in 13-22% and Grade 3/4 thrombocytopenia in 8-10% of patients on imatinib. 10
Neutropenic and thrombocytopenic episodes typically last 2-4 weeks and can be managed with dose reduction or temporary treatment interruption. 10
Permanent discontinuation due to hematologic toxicity is required in less than 1% of patients. 10
Hepatotoxicity
Severe elevation of transaminases or bilirubin occurs in approximately 5% of CML patients treated with imatinib. 10
Grade 3/4 elevations of ALT and AST are managed with dose reduction or interruption, with median episode duration of approximately 1 week. 10
Permanent discontinuation due to liver abnormalities is required in less than 1% of patients. 10
Cardiovascular and Metabolic Effects
Nilotinib carries risks of cardiovascular events, QT prolongation, and sudden death; baseline and periodic ECG monitoring is mandatory. 7
Lipid profiles and glucose should be monitored periodically during the first year and at least yearly during chronic therapy. 7
If HMG-CoA reductase inhibitors are needed for lipid management, drug-drug interactions must be evaluated as certain statins are metabolized by CYP3A4. 7
Fluid Retention
Severe (Grade 3/4) fluid retention occurs in 2.5-3.9% of patients on TKI therapy. 7
Effusions (pleural, pericardial, ascites) or pulmonary edema occur in 1-2% of patients. 7
Patients should be monitored for unexpected rapid weight gain, swelling, shortness of breath, and signs of respiratory or cardiac compromise. 7
Other Toxicities
Tumor lysis syndrome can occur in patients with high white blood cell counts; adequate hydration and correction of uric acid levels are required before initiating therapy. 7
Serious hemorrhagic events, including fatal events, have been reported; GI hemorrhage occurs in 2.9-5% of patients. 7
Growth retardation has been reported in pediatric patients, particularly those under age 12 at baseline. 7
Special Populations
Pediatric Patients
CML in children is rare, with specific biological and treatment considerations. 1
The overall safety profile in pediatric patients is similar to adults, except musculoskeletal pain is less frequent and peripheral edema is not reported. 10
Nausea and vomiting are the most common adverse reactions in pediatric patients. 10
Growth and development must be monitored closely in pediatric patients receiving TKI therapy. 7
Pregnancy
TKIs can cause fetal harm and are contraindicated during pregnancy; females of reproductive potential must use effective contraception during treatment and for 14 days after the last dose. 7
- Animal studies demonstrated embryo-fetal lethality, fetal edema, skeletal variations, and increased resorptions at clinically relevant exposures. 7
Prognosis
The introduction of TKI therapy has transformed CML from a fatal disease to a chronic condition, with 5-year survival rates exceeding 90% and annual mortality reduced from 10-20% to approximately 1%. 8, 5
The prevalence of CML is steadily rising due to substantial prolongation of survival, with an estimated 150,000 cases in the United States and 5 million cases worldwide in 2025. 1, 8
Prognostic scores based on age, spleen size, and blood cell counts (Sokal and Hasford scores) established in the pre-imatinib era still allow discrimination of risk groups with different response rates and survival outcomes. 1
The degree and timing of hematologic, cytogenetic, and molecular responses provide important prognostic information as time-dependent variables. 1