What is the immediate treatment for a patient with Chronic Myeloid Leukemia (CML) in de novo blast crisis?

Immediate Treatment for CML De Novo Blast Crisis

For de novo CML blast crisis, immediately initiate a second-generation tyrosine kinase inhibitor (dasatinib or nilotinib) combined with blast phenotype-appropriate chemotherapy (ALL-type for lymphoid, AML-type for myeloid), followed by allogeneic stem cell transplantation once second chronic phase is achieved. 1, 2, 3

Critical Initial Steps

Immediate Diagnostic Workup

• Determine blast phenotype (lymphoid vs. myeloid) through bone marrow examination with flow cytometry and immunohistochemistry, as this dictates the chemotherapy regimen 1, 2, 3
• Perform BCR-ABL kinase domain mutation analysis at diagnosis, as resistance-mediating mutations are present in a large proportion of de novo blast crisis cases and will guide optimal TKI selection 1, 4
• Evaluate for CNS involvement with lumbar puncture, particularly in lymphoid blast crisis where CNS disease is more common 2, 5
• Initiate HLA typing immediately for all potential transplant candidates to avoid delays in proceeding to allogeneic HSCT 2

TKI Selection Strategy

Upfront Second-Generation TKI

• Use a second-generation TKI (dasatinib 100 mg daily or nilotinib 300 mg twice daily) as first-line therapy in de novo blast crisis, as these agents achieve faster and deeper remissions compared to imatinib, which is critical for bridging to transplantation 1, 3
• Select TKI based on mutation profile: if T315I mutation is detected, switch immediately to ponatinib; for other resistance mutations, choose between dasatinib or nilotinib based on specific mutation sensitivity 1, 3
• Consider dasatinib preferentially if CNS involvement is present due to superior CNS penetration, though it remains insufficient as monotherapy for CNS disease 2

Timing of TKI Initiation

• For lymphoid blast crisis, start TKI immediately upon BCR-ABL1 confirmation, concurrent with chemotherapy induction 2
• For myeloid blast crisis, initiate TKI at the end of induction chemotherapy to avoid excessive toxicity and drug interactions 2

Chemotherapy Regimen by Phenotype

Lymphoid Blast Crisis

• Administer ALL-type induction chemotherapy (such as hyperCVAD or Ida-FLAG) combined with TKI to achieve optimal response 1, 2
• Provide mandatory prophylactic intrathecal chemotherapy according to ALL protocols to prevent CNS relapse 2
• For confirmed CNS involvement, intensify intrathecal therapy and continue monthly until transplantation 2

Myeloid Blast Crisis

• Administer AML-type induction chemotherapy according to institutional standards combined with TKI 1, 2, 3
• Include intrathecal prophylaxis according to AML protocols 2

Definitive Therapy: Allogeneic HSCT

Transplant Strategy

• 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 2, 6, 7
• For patients with CNS involvement, use TBI-based conditioning with cranial boost to control CNS disease 2
• Consider alternative donor sources (matched unrelated, haploidentical) if matched sibling donor is unavailable 2

Response Monitoring

• Assess response using acute leukemia standards: morphology, cytogenetics, flow cytometry, and molecular MRD markers 2
• Evaluate bone marrow at day 15 of induction in lymphoid blast crisis; if blast percentage is <5%, chemotherapy may be terminated and TKI continued alone 1
• If inadequate response to second-generation TKI and induction therapy, switch to ponatinib to avoid delaying HSCT 1

Critical Pitfalls to Avoid

• Never use imatinib as first-line therapy in blast crisis, as second-generation TKIs demonstrate superior activity in advanced-phase disease 1, 3
• Do not delay TKI initiation in lymphoid blast crisis—it must start immediately upon BCR-ABL1 confirmation, not after chemotherapy completion 2
• Avoid starting TKI concurrently with chemotherapy in myeloid blast crisis—wait until after induction to minimize toxicity 2
• Never omit CNS prophylaxis, which is mandatory in both phenotypes regardless of documented CNS involvement 2
• Do not delay donor search and transplant evaluation—initiate immediately at diagnosis, as timing is critical for survival 2
• Avoid failing to screen for BCR-ABL mutations, as specific mutations like T315I require alternative agents 1, 3