Which leukemia typically has a chronic course, but often transforms into an accelerated phase, and then to an acute blast crisis phase if untreated?

Chronic Myeloid Leukemia (CML) is the Leukemia with Triphasic Progression

The answer is A. CML (Chronic Myeloid Leukemia) is the leukemia that most typically has a chronic course but often transforms into an accelerated phase and then to an acute "blast crisis" phase if untreated.

Characteristics of CML's Triphasic Progression

CML is defined by the presence of the Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)], which creates the BCR-ABL fusion gene 1. This genetic abnormality produces a constitutively activated tyrosine kinase that drives the disease.

The disease typically progresses through three distinct phases:

1. Chronic Phase (CP):

   • Initial presentation in >90% of patients 1
   • Characterized by:
     • Leukocytosis with immature granulocytes
     • Basophilia
     • Often splenomegaly
     • <10% blasts in blood or bone marrow 2

2. Accelerated Phase (AP):

   • Defined by:
     • 15-29% blasts in blood or bone marrow 1

     • 20% basophils in blood

     • Thrombocytosis or thrombocytopenia unrelated to therapy
     • Clonal cytogenetic evolution 1

3. Blast Phase/Crisis (BP/BC):

   • Defined by:
     • ≥30% blasts in blood or bone marrow 1
     • Extramedullary blast infiltration 1
     • Resembles acute leukemia (either myeloid in 70-80% or lymphoid in 20-30% of cases) 3

Distinguishing Features from Other Leukemias

• CML: Triphasic progression (chronic → accelerated → blast crisis) with Philadelphia chromosome
• CLL: Typically indolent course without defined accelerated phase or blast crisis transformation
• AML: Presents acutely without preceding chronic phase
• ALL: Presents acutely without preceding chronic phase

Progression Risk and Management

Without effective treatment, CML will naturally progress from chronic phase through accelerated phase to blast crisis 4. The introduction of tyrosine kinase inhibitors (TKIs) like imatinib has dramatically altered this natural history:

• TKI therapy reduces the progression rate 10-fold compared to previous therapies 5
• The 6-year progression-free survival with imatinib is 84% 1
• The 6-year overall survival is 88% 1

Molecular Basis of Progression

Disease progression is driven by:

• Activation of additional oncogenes
• Inactivation of tumor suppressor genes
• Amplification of the BCR-ABL fusion gene
• Development of BCR-ABL kinase domain mutations 1

Clinical Implications

Early identification of progression markers is crucial as outcomes are significantly worse in advanced phases:

• Patients diagnosed in advanced phases have poorer prognosis 6
• Blast count is the most important prognostic factor, with a 20% blast threshold being more clinically relevant than 30% 6
• Additional factors affecting prognosis include age, hemoglobin level, and additional chromosomal aberrations 6

Treatment Approach

The primary goal of therapy in CML is to prevent progression to accelerated phase or blast crisis 7:

• Imatinib 400 mg daily is the standard first-line therapy for chronic phase 8
• Higher doses (600-800 mg daily) may be needed for accelerated phase or blast crisis 8
• Regular monitoring of treatment response through hematologic, cytogenetic, and molecular testing is essential 2

CML is unique among leukemias in its characteristic triphasic progression pattern, which can now be effectively prevented with appropriate TKI therapy.