What is chronic myeloid leukemia (CML)?

Chronic Myeloid Leukemia: Overview

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of the Philadelphia chromosome, which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)] that creates the BCR-ABL1 fusion gene encoding a constitutively active tyrosine kinase protein. 1

Epidemiology

• CML has an annual incidence of approximately 1-2 cases per 100,000 adults in the United States, with an estimated 8,450-9,300 new diagnoses annually 1, 2, 3
• The disease accounts for approximately 15% of all adult leukemias 1, 3
• The median age at diagnosis is 60-67 years, though CML occurs across all age groups 1
• There are no major geographic or ethnic differences in incidence 1
• Prevalence is steadily rising due to substantially prolonged survival achieved with tyrosine kinase inhibitor therapy 1

Molecular Pathogenesis

• The Philadelphia chromosome results from translocation t(9;22)(q34;q11.2), fusing the ABL1 gene from chromosome 9 with the BCR gene on chromosome 22 1, 3, 4
• In most patients (>90%), chromosomal breakpoints occur in intron 13 or 14 of the BCR gene (major breakpoint cluster region; M-BCR) 1
• Splicing typically fuses ABL1 exon 2 with BCR exons 13 or 14, producing e13a2 and e14a2 transcripts that encode the p210 oncoprotein 1
• The BCR-ABL1 oncoprotein has constitutively activated tyrosine kinase activity that transforms hematopoietic stem cells through activation of multiple downstream signaling pathways 1, 5
• Less common variants include e1a2 transcripts encoding p190 (associated with Ph-positive acute lymphoblastic leukemia) and e19a2 encoding p230 (associated with enhanced neutrophil differentiation) 1
• BCR-ABL1-positive cells are genetically unstable and prone to develop additional genomic abnormalities, leading to disease progression 1

Clinical Presentation

• Approximately 40% of patients are asymptomatic at diagnosis, with CML discovered incidentally on routine blood work 1
• When present, symptoms are nonspecific and include weight loss, fatigue, low-grade fever, night sweats, and malaise 1
• Splenomegaly is the primary physical finding, present in slightly more than 50% of patients at diagnosis 1
• The hallmark laboratory finding is leukocytosis with left-shifted granulopoiesis showing all stages of maturation (particularly myelocytes and segmented forms), basophilia, and eosinophilia 1
• White blood cell counts often exceed 100 × 10⁹/L at presentation 6
• Thrombocytosis is common in the initial chronic phase 1, 6

Disease Phases

• Chronic Phase (CP-CML): Characterized by <10-15% blasts in blood or bone marrow, present in 90-95% of patients at diagnosis 1, 6
• Accelerated Phase (AP-CML): Defined by 10-29% blasts in blood or bone marrow, >20% basophils, thrombocytosis or thrombocytopenia unrelated to therapy, or clonal cytogenetic evolution 1
• Blast Phase (BP-CML): Characterized by ≥20-30% blasts in blood or bone marrow (depending on classification system) or extramedullary blast infiltration 1
• Untreated chronic phase CML will progress to accelerated or blast phase in 3-5 years on average 1
• Gene expression profiling shows the bulk of genetic changes in progression occur during the transition from chronic to accelerated phase 1
• Blast phase is predominantly myeloid (70-80%) but can be lymphoid (20-30%) 1, 7

Diagnostic Workup

Essential diagnostic confirmation requires demonstration of the Philadelphia chromosome or BCR-ABL1 fusion gene through cytogenetics, FISH, or molecular testing. 1, 5, 6

Initial Laboratory Evaluation

• Complete blood count with differential showing characteristic left-shifted granulopoiesis with immature forms 1, 6
• Chemistry profile and hepatitis B panel 1, 6
• Bone marrow aspirate and biopsy for morphologic assessment, cytogenetics, and molecular studies 1, 6

Confirmatory Testing

• Conventional cytogenetics to detect t(9;22) translocation and identify additional chromosomal abnormalities (clonal evolution) 1, 6
• FISH with dual probes for BCR and ABL1 genes if bone marrow evaluation is not feasible or cytogenetics shows normal karyotype 1, 5
• Qualitative RT-PCR to identify BCR-ABL1 transcript type (typically e13a2 or e14a2) 1, 6
• Quantitative RT-PCR to establish baseline BCR-ABL1 transcript levels on the International Scale 1, 6

Bone Marrow Histopathology

• Increased cellularity due to granulocytic proliferation at all stages of maturation 1
• Blasts must account for <5% in chronic phase 1
• Megakaryocytes are smaller than normal with hypolobulated nuclei ("dwarf megakaryocytes") 1
• Moderate to marked reticulin fibrosis is present in approximately 30% of cases 1
• Immunohistochemistry with CD34, TdT, and lineage-specific markers helps distinguish myeloid versus lymphoid blast crisis 1

Prognosis and Risk Stratification

• Prognostic scoring systems (Sokal and Hasford scores) based on age, spleen size, and blood cell counts allow discrimination of risk groups, though developed in the pre-tyrosine kinase inhibitor era 1
• With modern TKI therapy, patients in chronic phase achieve 85-95% overall survival at 5 years, approaching age-matched controls 7
• Annual progression rate from chronic to accelerated or blast phase has decreased dramatically to 1-1.5% with TKI therapy from historical rates exceeding 20% 7
• Complete cytogenetic response and molecular response milestones provide important time-dependent prognostic information 1
• Additional chromosomal abnormalities in Philadelphia-positive cells (clonal evolution) have prognostic relevance 1

Treatment Principles

Tyrosine kinase inhibitor therapy targeting BCR-ABL1 is the standard first-line treatment for chronic phase CML, with four FDA-approved options: imatinib, dasatinib, nilotinib, and bosutinib. 1, 7, 3, 4

• Second-generation TKIs (dasatinib, nilotinib) achieve deeper and faster responses compared to imatinib but show no survival advantage due to effective salvage options 7, 3, 4
• Standard imatinib dose is 400 mg daily, with 5-year overall survival exceeding 90% in chronic phase 7
• All TKIs demonstrate equivalent survival outcomes if the goal is survival prolongation 4
• Second-generation TKIs may be preferred for younger patients with high-risk disease or when treatment-free remission is the goal 4
• Allogeneic stem cell transplantation is reserved for patients failing at least two TKIs due to resistance or those with accelerated/blast phase disease 3, 4, 8
• Initial allogeneic transplantation is no longer recommended as first-line therapy due to transplant-related mortality 1

Monitoring and Response Assessment

• Quantitative PCR for BCR-ABL1 transcripts should be performed every 3 months after initiating therapy 7
• Key molecular response milestones include BCR-ABL1 ≤10% at 3 months and ≤1% at 12 months 7
• Complete cytogenetic response should be achieved by 12 months 7
• Medication adherence is critical to maintain treatment responsiveness and prevent resistance 2

Common Pitfalls

• Do not rely solely on peripheral blood findings—bone marrow evaluation with cytogenetics is essential for confirming diagnosis and detecting additional chromosomal abnormalities 1, 6
• Do not miss atypical presentations—approximately 5% of cases are Philadelphia chromosome-negative by conventional cytogenetics and require FISH or RT-PCR for diagnosis 1
• Do not confuse blast phase CML with de novo AML—blast phase CML remains BCR-ABL1 positive, representing transformation of the original CML clone, not a new malignancy 7
• Do not overlook BCR-ABL1 transcript type identification—this is crucial for establishing appropriate quantitative monitoring and detecting atypical transcripts that may affect TKI response 1, 6