What are the key differences in presentation between Acute Myeloid Leukemia (AML) and Chronic Myeloid Leukemia (CML)?

Key Differences in Presentation Between AML and CML

AML presents acutely with rapid onset of symptoms over days to weeks and requires immediate intensive treatment, while CML typically presents insidiously over months to years with a chronic, indolent course that may be asymptomatic at diagnosis. 1

Onset and Symptom Timeline

AML Presentation

• Acute onset with symptoms developing over days to weeks, requiring urgent intervention 1
• Patients present with ≥20% blasts in bone marrow at diagnosis, representing an immediate hematologic crisis 2, 1
• Symptoms reflect rapid bone marrow failure: severe fatigue, bleeding manifestations, and recurrent infections 2
• No preceding chronic phase—disease is aggressive from onset 1

CML Presentation

• Insidious onset with symptoms evolving over months to years 1
• Many patients are asymptomatic at diagnosis, with disease detected incidentally on routine blood work 1
• Disease begins in chronic phase (CP) with well-preserved hematopoiesis initially 1
• Without treatment, progression from CP to accelerated phase (AP) or blast phase (BP) occurs over years, not days 1

Clinical Symptoms and Physical Findings

AML Clinical Features

• Severe cytopenias causing profound anemia, thrombocytopenia, and neutropenia 2
• Bleeding complications from thrombocytopenia (petechiae, purpura, mucosal bleeding) 2
• Fever and infections from neutropenia 2
• Bone pain and fatigue from marrow infiltration 2
• Organomegaly is less common than in CML 1

CML Clinical Features

• Marked leukocytosis often >100,000/μL with left-shifted myeloid cells 1
• Splenomegaly present in majority of patients, often massive 1
• Constitutional symptoms: weight loss, night sweats, early satiety from splenomegaly 1
• Patients may remain relatively well despite high white blood cell counts 1
• Hepatomegaly may be present but less prominent than splenomegaly 1

Laboratory and Morphologic Differences

AML Laboratory Features

• Blast percentage ≥20% in peripheral blood or bone marrow is diagnostic 2, 1
• Pancytopenia is typical, with anemia and thrombocytopenia predominating 2
• White blood cell count variable—can be low, normal, or elevated 2
• Auer rods may be present in myeloblasts (pathognomonic when present) 2
• Multilineage dysplasia may be present, especially in secondary AML 2

CML Laboratory Features

• Leukocytosis with full spectrum of myeloid maturation (myeloblasts, promyelocytes, myelocytes, metamyelocytes, bands, neutrophils) 1
• Basophilia and eosinophilia are characteristic findings 1
• Blasts <10% in chronic phase, 10-19% in accelerated phase, ≥20% in blast phase 1
• Thrombocytosis often present in chronic phase 1
• Anemia typically mild or absent in early chronic phase 1

Molecular and Cytogenetic Hallmarks

AML Molecular Profile

• Heterogeneous genetic landscape with no single defining mutation 2
• Common mutations include FLT3-ITD, NPM1, CEBPA, IDH1/2, DNMT3A, and others 2
• Recurrent cytogenetic abnormalities: t(8;21), inv(16), t(15;17) define specific AML subtypes 2
• Secondary AML shows splicing factor mutations (SRSF2, SF3B1, U2AF1) and epigenetic regulator mutations (ASXL1, EZH2) 2
• Philadelphia chromosome (BCR-ABL1) is rare in AML (<1% of cases) and represents a distinct provisional entity 3, 4

CML Molecular Profile

• BCR-ABL1 fusion is present in 95% of cases and is the sole pathogenic driver 1
• Philadelphia chromosome t(9;22)(q34;q11) creates constitutively active tyrosine kinase 1
• Most patients harbor e13a2 or e14a2 fusion transcripts (p210 protein) 2, 1
• Absence of BCR-ABL1 excludes CML diagnosis 1
• Additional mutations accumulate with disease progression to blast phase 2

Disease Trajectory and Prognosis

AML Natural History

• Rapidly fatal without treatment, with survival measured in weeks to months 1
• Requires immediate intensive induction chemotherapy 2, 1
• 5-year survival ranges from 35% in younger fit patients to significantly lower in elderly populations 1
• AML evolving from MDS is more resistant to standard chemotherapy than de novo AML 2

CML Natural History

• With modern TKI therapy, 5-year overall survival exceeds 90% in chronic phase, approaching age-matched controls 1
• Annual progression rate from CP to AP/BP has decreased to 1-1.5% with TKIs (from historical >20% without treatment) 1
• 10-year overall survival ranges from 50-70% depending on risk stratification 1
• Disease is manageable as a chronic condition with oral targeted therapy 1

Critical Diagnostic Pitfalls

Distinguishing CML Blast Phase from De Novo AML

• CML blast phase can mimic AML when presenting with ≥20% blasts 2
• Key distinguishing features for CML-BP: presence of BCR-ABL1 fusion, history of preceding chronic phase symptoms, marked splenomegaly, basophilia/eosinophilia 2, 1
• BCR-ABL1-positive AML is a rare provisional entity (<1% of AML) that requires stringent criteria to differentiate from CML blast crisis 3, 4
• Clinical algorithm: evaluate for prior CBC abnormalities, duration of symptoms, presence of massive splenomegaly, and BCR-ABL1 transcript type 3

Secondary AML Considerations

• History of antecedent hematologic disorder (MDS, MPN) or prior chemotherapy/radiation suggests secondary AML 2
• Multilineage dysplasia and specific mutation patterns (SRSF2, SF3B1, U2AF1, ASXL1, EZH2) indicate secondary AML 2
• Secondary AML has worse prognosis and different treatment considerations than de novo AML 2