What is blast cell crisis in leukemia?

What is Blast Crisis in Leukemia

Blast crisis (also called blast phase) is an advanced, aggressive stage of chronic myeloid leukemia (CML) defined by ≥20% blasts in peripheral blood or bone marrow according to WHO criteria, or ≥30% blasts according to European LeukemiaNet criteria, representing transformation to an acute leukemia-like state with poor prognosis. 1

Diagnostic Criteria

The definition varies between classification systems, creating important clinical implications:

• WHO and International Consensus Classification (ICC): ≥20% blasts in blood or bone marrow 1
• European LeukemiaNet: ≥30% blasts in blood or bone marrow, OR extramedullary blastic infiltrates (excluding liver and spleen) 1
• International Bone Marrow Transplant Registry: 30% blasts in blood, marrow, or both, OR extramedullary infiltrates 1

The 20% threshold is clinically significant because patients with 20-29% blasts have significantly better response rates than those with ≥30% blasts. 1

Additional Diagnostic Features

Beyond blast percentage, blast crisis can be diagnosed by:

• Large foci or clusters of blasts in bone marrow biopsy 1, 2
• Extramedullary blast proliferation (myeloid sarcoma, lymphoblastic lymphoma) 1
• Lymphoblasts in peripheral blood or bone marrow, even below 10%, may indicate lymphoid blast phase and warrant further investigation 1

Blast Lineage Classification

Blast crisis is categorized by the predominant blast cell type:

• Myeloid blast crisis: 70-80% of cases 3
• Lymphoid blast crisis: 20-30% of cases (predominantly B-cell lineage; T-cell origin is extremely rare) 1, 3
• Mixed-lineage or biphenotypic: Rare but associated with more aggressive course and poorer prognosis 1

Immunophenotyping is mandatory to characterize blast lineage using flow cytometry and immunohistochemistry with markers for CD34, TdT, myeloid, monocytic, B-lymphoid, and T-lymphoid antigens 1, 3

Key Laboratory and Clinical Features

Peripheral Blood Findings

• Elevated blast percentage (≥20-30% depending on criteria) 1, 2
• Significant basophilia (often ≥20%), more prominent than in de novo acute leukemia 2
• Immature cells including myelocytes and promyelocytes 1, 2
• Thrombocytopenia with persistent platelet count <100 × 10⁹/L unrelated to therapy 2

Bone Marrow Findings

• High blast percentage (≥20-30%) 1, 2
• Large foci or clusters of blasts on biopsy 1, 2
• Dysplastic features in multiple cell lines 2

Molecular and Genetic Features

• BCR-ABL1 tyrosine kinase domain mutations are present in approximately two-thirds of pediatric patients at blast crisis diagnosis (75% in de novo blast crisis, 62% in secondary blast crisis) 1
• Additional chromosomal aberrations (ACAs) and somatic mutations indicate patients at risk for progression 1
• Most patients harbor e13a2 or e14a2 fusion transcripts (>90%), encoding the p210 BCR-ABL1 fusion protein 1

Clinical Presentation and Pathophysiology

Blast crisis represents the terminal phase of CML, characterized by:

• Aggressive clinical course with rapid progression 1
• Genetic instability in BCR-ABL-positive cells driving transformation 3, 4
• Loss of differentiation capacity and increased proliferation 4
• Resistance to therapy, as treatments work far better in chronic phase than blast crisis 4

Extramedullary Involvement

Blast crisis may present with extramedullary disease including:

• Myeloid sarcoma
• T-cell or B-cell acute lymphoblastic lymphoma
• Mixed-lineage blast phase disease 1

Extramedullary involvement, particularly in biphenotypic cases, confers an especially poor prognosis with mortality rates approaching 100% despite aggressive chemotherapy. 5

Critical Diagnostic Workup

When blast crisis is suspected, perform:

• Complete blood count with differential and peripheral blood smear examination 1, 6
• Bone marrow aspiration and biopsy with morphologic evaluation 1, 6
• Flow cytometry for immunophenotyping and lineage determination 1, 3
• Cytogenetic analysis for BCR-ABL translocation t(9;22) and additional chromosomal aberrations 1, 6
• BCR-ABL1 mutation analysis using next-generation sequencing (preferred over Sanger sequencing due to higher sensitivity: 3% vs 20% threshold) to guide TKI selection 1
• Transcript type identification (e13a2, e14a2, or atypical variants) 1

Important Clinical Pitfalls

• Sudden blast crisis can occur even after excellent initial response to tyrosine kinase inhibitors, making careful ongoing monitoring essential 7
• Lymphoblasts at any percentage should raise suspicion for lymphoid blast phase, not just when meeting the 20-30% threshold 1
• Basophilia is a distinguishing feature from de novo acute leukemia and should prompt consideration of CML blast crisis 2
• The accelerated phase category is no longer recognized in current WHO classification; focus is now on chronic phase versus blast phase with attention to genetic risk factors 1

Treatment Context

Imatinib and other tyrosine kinase inhibitors are FDA-approved for CML in blast crisis, with dosing of 600 mg daily for adults 8. However, blast crisis arising from leukemic progenitors (not stem cells) explains why imatinib reduces progression rates 10-fold compared to prior therapies but cannot cure blast crisis, as it depletes progenitors but not leukemic stem cells 9.