Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia...

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Resistance or intolerance to tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients with somatic variants suggests additional mutations beyond BCR-ABL1 contribute to treatment failure.
• Understanding the broader mutation spectrum is crucial for optimizing CML management.

Purpose of the Study:

• To explore the mutation spectrum beyond BCR-ABL1 in CML patients.
• To identify genetic variants that affect the achievement of molecular responses during TKI therapy.
• To correlate specific mutations with clinical outcomes and response to different TKI therapies.

Main Methods:

• Retrospective evaluation of 151 CML patients undergoing TKI therapy.
• Next-generation sequencing (NGS) analysis of 22 CML patients at diagnosis to identify mutations other than BCR-ABL1.
• Statistical analysis to correlate mutation status with molecular response milestones (MMR, MR4.0, MR4.5) and clinical characteristics.

Main Results:

• ASXL1 mutations were the most frequent (40.9%).
• NOTCH3 and RELN mutations were associated with failure to achieve major molecular response (MMR) at 12 months.
• ASXL1 mutation frequency was higher in patients not achieving MR4.0 at 36 months (p = 0.023).
• Presence of >2 gene mutations adversely impacted achieving MR4.5 at 12 months (p = 0.024).
• Hemoglobin concentration and MMR were independent factors for deep molecular response (DMR).
• Initial 2nd-generation TKI therapy showed better molecular response achievement than 1st-generation TKI therapy.

Conclusions:

• Mutations beyond BCR-ABL1, particularly ASXL1, significantly influence TKI treatment efficacy and molecular response in CML.
• Specific mutations (NOTCH3, RELN) and the number of mutations (>2) are linked to poorer response.
• ELTS and Socal scores show potential for predicting TKI efficacy and non-BCR-ABL1 mutations, respectively.
• Clinical factors like hemoglobin and TKI generation are important for achieving deep molecular response.