Blast Crisis in CML Management
Immediate Treatment Approach
Initiate a second-generation tyrosine kinase inhibitor (dasatinib or nilotinib) immediately upon BCR-ABL confirmation, combined with phenotype-directed chemotherapy (ALL-type for lymphoid blast crisis, AML-type for myeloid blast crisis), with the goal of achieving second chronic phase and proceeding rapidly to allogeneic stem cell transplantation. 1, 2
Critical Initial Assessment
Determine Blast Phenotype
- Perform bone marrow examination with flow cytometry and immunohistochemistry to classify as lymphoid versus myeloid blast crisis, as this dictates the specific chemotherapy regimen 1, 2
- Blast crisis is defined as ≥30% blasts in blood or bone marrow, or extramedullary blastic infiltration 2
Mutation Analysis
- Obtain BCR-ABL kinase domain mutation analysis at diagnosis before selecting TKI, as resistance-mediating mutations are present in a large proportion of de novo blast crisis cases 1, 3
- Approximately 60% of secondary blast crisis cases harbor tyrosine kinase domain mutations that will determine TKI selection 3
TKI Selection Strategy
De Novo Blast Crisis
- Use second-generation TKI (dasatinib 100 mg daily or nilotinib 300 mg twice daily) as first-line therapy, as these achieve faster and deeper remissions compared to imatinib, which is critical for bridging to transplantation 1, 2
- Never use imatinib as first-line therapy in blast crisis, as second-generation TKIs demonstrate superior activity in advanced-phase disease 1, 2
Mutation-Directed Selection
- If T315I mutation is detected, switch immediately to ponatinib 1, 3
- For other resistance mutations, select between dasatinib or nilotinib based on specific mutation sensitivity patterns 1
- In secondary blast crisis developing during TKI therapy, switching the TKI is strongly recommended 3
Timing of TKI Initiation
- Start TKI immediately upon confirmation of BCR-ABL presence, do not delay for day 15 assessment 3
- Consider dose reduction or discontinuation only in cases of prolonged aplasia after induction treatment 3
Chemotherapy Regimen by Phenotype
Lymphoid Blast Crisis
- Administer ALL-type induction chemotherapy (such as hyperCVAD or similar multi-agent regimen) combined with TKI 1, 2
- Assess bone marrow response at day 15: if blast percentage is <5%, chemotherapy may be terminated and TKI alone continued 3, 1
- If response is not optimal on day 15, use the second half of induction chemotherapy (with anthracyclines) for intensification 3
- Intrathecal chemoprophylaxis is mandatory, continuing monthly as bridging therapy until transplantation 3
- Dasatinib has better CSF penetration than imatinib, though no TKI reaches sufficient CSF concentration to safely prevent CNS disease 3
Myeloid Blast Crisis
- Administer AML-type induction chemotherapy (first induction block following national standards) combined with TKI 3, 1, 2
- Myeloid blast crisis confers worse prognosis than lymphoid in adults, necessitating intensified therapy to induce hematologic response before transplantation 3
Response Monitoring
Assessment Timeline and Methods
- Evaluate response using acute leukemia standards: morphology, cytogenetics, flow cytometry, and molecular MRD markers including BCR-ABL transcripts by real-time PCR 3, 1
- At 3 months, evaluate for cytogenetic response; absence of any cytogenetic response should prompt consideration of alternative therapies 2
- At 6 months, patients achieving major cytogenetic response have significantly better survival compared to those with minor response 2
Distinguishing CML Blast Crisis from Ph+ ALL
- Perform BCR-ABL detection via interphase FISH on neutrophils after major blast reduction (positive in CML blast crisis, negative in Ph+ ALL) 3
- Compare MRD-level (IgG, TCR-rearrangement or flow cytometry) with BCR-ABL transcript level: divergent reduction (MRD declining but BCR-ABL stable) suggests CML blast crisis rather than Ph+ ALL 3
Definitive Therapy: Allogeneic HSCT
Transplant Timing and Eligibility
- Proceed to allogeneic HSCT as soon as second chronic phase is achieved, ideally within 3 months if a donor is available, as this provides the only potentially curative option 1, 4, 5
- Allogeneic HSCT significantly improves 4-year overall survival (46.7% vs 9.7%) and event-free survival (47.1% vs 6.7%) compared to TKI treatment alone 6
- Most long-term survivors are those who have been transplanted; long-term remissions with TKI alone are rare 5
Conditioning Considerations
- In cases of CNS involvement, use TBI-based conditioning regimen with a cranial boost 3
- Reduced-intensity conditioning regimens may be appropriate for older patients to reduce transplant-related mortality 2
Critical Pitfalls to Avoid
TKI Selection Errors
- Never use imatinib as first-line therapy in blast crisis, as second-generation TKIs are superior 1, 2
- Failing to screen for BCR-ABL mutations, particularly T315I, which requires ponatinib rather than dasatinib or nilotinib 1, 2
Treatment Delays
- Delaying treatment initiation, as blast crisis progresses rapidly and immediate therapy is essential 5
- Failing to proceed rapidly to transplantation once second chronic phase is achieved 1, 5
Phenotype-Related Errors
- Overlooking blast phenotype determination, which dictates appropriate chemotherapy regimen 2
- Omitting intrathecal chemoprophylaxis in lymphoid blast crisis, which is as important as in acute leukemia 3
Drug Interactions
- Using ponatinib with asparaginase, as they have overlapping toxicities (pancreatitis and hepatotoxicity) that may preclude concurrent use 3
Supportive Care Measures
Initial Stabilization
- Administer supportive therapy as in acute leukemia, including prevention of tumor lysis syndrome according to institutional standards 3
- In clinically stable patients where definitive diagnosis cannot be established quickly, hydroxyurea may be used 3
- In patients with signs and symptoms of leukostasis, implement lineage-adapted cytoreduction measures according to ALL or AML protocols 3