What are the key differences between Chronic Myeloid Leukemia (CML) and Acute Myeloid Leukemia (AML) in terms of progression rates and treatment strategies?

CML vs AML: Key Differences in Progression and Treatment

Chronic Myeloid Leukemia (CML) is fundamentally a chronic, slowly progressive disease driven by the BCR-ABL1 fusion gene with near-normal life expectancy on tyrosine kinase inhibitors, while Acute Myeloid Leukemia (AML) is an aggressive acute leukemia requiring intensive chemotherapy with significantly worse prognosis.

Molecular and Pathophysiologic Differences

CML Characteristics

• CML arises from a specific translocation t(9;22)(q34;q11) creating the Philadelphia chromosome and BCR-ABL1 fusion gene, which produces a constitutively active tyrosine kinase protein 1
• The BCR-ABL1 fusion is present in 95% of cases and is the sole driver of disease pathogenesis 1
• CML begins as a disease of hematopoietic stem cells with a well-understood molecular mechanism 1

AML Characteristics

• AML can arise from multiple cell types through numerous oncogenic drivers and pre-leukemic events, creating substantial genetic and cellular heterogeneity not observed in CML 2
• AML lacks a single defining molecular abnormality and represents a heterogeneous group of diseases 2
• AML may evolve from myelodysplastic syndromes (MDS) and is often more resistant to therapy than de novo AML 1

Disease Progression Rates

CML Progression

• CML has three distinct phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP), with progression occurring over years if untreated 1
• Without treatment, chronic phase lasts 3-5 years before progressing to accelerated phase, then to blast phase within another year 3
• With modern TKI therapy, annual progression rate from CP to AP or BP has decreased dramatically to 1-1.5% from the historical >20% 1, 4
• Blast phase is defined as ≥30% blasts in blood or marrow by ELN criteria or ≥20% by WHO criteria 1

AML Progression

• AML presents acutely with ≥20% blasts in bone marrow at diagnosis, requiring immediate intensive treatment 1
• AML does not have a chronic phase—it is an acute leukemia from onset 1
• Disease progression in AML refers to relapse after treatment or refractory disease, not phase transformation 4

Treatment Strategies

CML First-Line Treatment

• Four TKIs are FDA-approved for first-line CML-CP: imatinib, dasatinib, nilotinib, and bosutinib, with second-generation TKIs (dasatinib, nilotinib) preferred for intermediate/high-risk patients 4, 5, 6
• All four TKIs are equivalent if the goal is survival improvement 6
• Second-generation TKIs achieve deeper and faster molecular responses but do not improve overall survival compared to imatinib, likely due to effective salvage options 5, 7, 6
• Standard imatinib dose is 400 mg daily, with 5-year overall survival exceeding 90% in chronic phase 1, 4, 3

CML Monitoring and Response Milestones

• Monitor with quantitative PCR for BCR-ABL1 transcripts every 3 months after initiating therapy 4
• Key molecular response milestones: BCR-ABL1 ≤10% at 3 months and ≤1% at 12 months 4
• Complete cytogenetic response (CCyR) should be achieved by 12 months 1

CML Resistance Management

• For imatinib resistance, perform BCR-ABL1 kinase domain mutation analysis and switch to second-generation TKI based on mutation profile 4, 5, 7
• The T315I "gatekeeper" mutation confers resistance to all TKIs except ponatinib, asciminib, and olverembatinib 5, 7, 6
• Allogeneic stem cell transplantation is the only curative treatment for CML and is reserved for patients resistant or intolerant to at least two TKIs 1, 4, 5, 7, 6

AML Treatment Approach

• AML requires intensive induction chemotherapy as first-line treatment, not targeted therapy 1
• For fit patients with relapsed AML, salvage chemotherapy followed by allogeneic transplantation is recommended 4
• Repeat mutation analysis for FLT3 and IDH1/2 at relapse is recommended 4
• For FLT3-mutated relapsed AML, gilteritinib improves outcomes compared with standard salvage therapy 4

CML Blast Phase Treatment

• CML-BP has poor prognosis with median survival <1 year despite treatment 1, 3
• Treatment combines TKIs with AML-style induction chemotherapy, followed by allogeneic transplantation if response achieved 1
• In pediatric CML-BP, lymphoid phenotype predominates (70-80% vs 20-30% in adults) 1

Prognostic Differences

CML Prognosis

• With modern TKI therapy, CML patients in chronic phase achieve 85-95% overall survival at 5 years, approaching age-matched controls 4, 3
• 10-year overall survival ranges from 50-70% depending on risk stratification 1
• Treatment-free remission is achievable in 40-50% of patients maintaining complete molecular remission for ≥2 years 4

AML Prognosis

• AML 5-year survival ranges from 35% in younger fit patients to significantly lower in older populations 4
• AML evolving from MDS is more resistant to standard chemotherapy than de novo AML 1
• Median survival for untreated AML is measured in weeks to months, not years 1

Critical Distinctions for Clinical Practice

Diagnostic Pitfalls

• Distinguishing pediatric CML-BP from Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) can be challenging due to predominance of lymphoid phenotype in pediatric CML-BP 1
• CML requires demonstration of Philadelphia chromosome or BCR-ABL1 fusion gene; cases without these are classified as atypical CML or other myeloid neoplasms 1
• Stable cytopenia for at least 6 months (or 2 months with specific karyotype) is required for MDS diagnosis, helping distinguish from acute presentations 1

Treatment Caveats

• All TKIs may prolong QT interval; repleting potassium and magnesium before starting therapy is essential 4
• High-dose imatinib is not recommended as initial therapy due to no demonstrated reduction in disease progression and higher adverse event rates 4
• In CML, continuing the most effective/least toxic TKI even after multiple failures can maintain long-term survival in older patients 5, 7, 6