What are the next steps for a patient with Chronic Myeloid Leukemia (CML) progression on a Tyrosine Kinase Inhibitor (TKI)?

Management of Chronic Myeloid Leukemia Progression on Tyrosine Kinase Inhibitors

For patients with CML progression on a TKI, the next steps should include BCR-ABL1 mutation analysis, consideration of an alternative TKI (preferably ponatinib for patients with resistance to second-generation TKIs), and evaluation for allogeneic stem cell transplantation. 1

Initial Assessment After TKI Failure

• Determine the type of resistance (primary or secondary) and confirm adherence to medication, as poor compliance is a common cause of apparent treatment failure 1
• Perform bone marrow examination to determine CML phase and document any clonal evolution 1
• Conduct BCR-ABL1 kinase domain mutation analysis to guide selection of subsequent TKI therapy 1
• Assess for additional chromosomal aberrations (ACA), which may indicate disease progression 1
• Consider flow cytometry if blast phase is suspected to distinguish between lymphoid and myeloid blast crisis 1

Management Strategy Based on Disease Phase

Chronic Phase CML with Resistance to First-Line TKI

• For imatinib resistance:

  • Switch to a second-generation TKI (dasatinib, nilotinib, or bosutinib) based on mutation profile and patient comorbidities 1
  • Consider patient-specific factors such as cardiovascular risk factors when selecting alternative TKI 1

• For resistance to second-generation TKI (2GTKI):

  • Ponatinib is preferred over changing to another 2GTKI, unless significant cardiovascular risk factors are present 1
  • Initiate donor search for allogeneic stem cell transplantation (allo-SCT) 1

• For patients with T315I mutation:

  • Ponatinib is the agent of choice 1, 2
  • Consider allo-SCT after a trial of ponatinib therapy 1

Accelerated Phase (AP)

• Treat as high-risk patients 1
• Consider intensification of treatment with ponatinib 1
• Proceed to allo-SCT if response is not optimal 1
• Evaluate for allo-SCT early, as outcomes are better when transplant is performed before progression to blast phase 1

Blast Phase (BP)

• Attempt to return patient to second chronic phase (CP2) 1
• Treatment should include:
  • Intensive combination chemotherapy with a TKI based on mutation profile 1
  • For myeloid BP: AML-type regimens (such as dasatinib or ponatinib + FLAG-IDA) 1
  • For lymphoid BP: ALL-type regimens (such as imatinib or dasatinib + hyperfractionated CVAD) 1
• After achieving CP2, proceed to allo-SCT without delay 1
• For patients unable to tolerate intensive chemotherapy, consider less intensive therapy according to immunophenotype 1

Special Considerations

• Survival in blast phase is generally <1 year without successful intervention 1
• Early indicators of progression include appearance of ACA, somatic mutations, and clinical deterioration 1
• Lymphoid BP has more treatment options and better outcomes than myeloid BP 1
• Patients who fail ponatinib are at high risk of progression and should be considered for early allo-SCT 1
• For patients with resistance to multiple TKIs, clinical trials with experimental agents should be considered 1

Monitoring Response to Subsequent Therapy

• Early molecular response (≤10% BCR-ABL1 IS at 3 months) after second-line TKI therapy is prognostic for overall survival 1
• Patients who do not achieve cytogenetic or molecular responses at 3,6, or 12 months after second-line therapy should be considered for alternative therapies or allo-SCT 1
• Regular BCR-ABL1 transcript monitoring by qPCR every 3 months is recommended 1

Common Pitfalls to Avoid

• Failing to check medication adherence before determining true resistance 1
• Delaying allo-SCT evaluation in patients with resistance to multiple TKIs 1
• Not performing mutation analysis before selecting subsequent TKI therapy 1
• Switching to another 2GTKI instead of ponatinib in patients with resistance to a 2GTKI without specific mutations 1
• Overlooking cardiovascular risk factors when prescribing ponatinib 1

By following this structured approach to managing CML progression on TKIs, clinicians can optimize outcomes for patients facing this challenging clinical scenario.