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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib
Wendy T Parker1, David T O Yeung2, Alexandra L Yeoman3
1Department of Genetics and Molecular Pathology and Australian Cancer Research Foundation Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia;
Abstract:
The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance.
Insights
The number of low-level BCR-ABL1 mutations before ponatinib treatment predicts response in refractory chronic myeloid leukemia (CML). Multiple mutations, especially with T315I, indicate poorer outcomes, but ponatinib may overcome this for some patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Third-generation tyrosine kinase inhibitors (TKIs) like ponatinib are crucial for refractory chronic myeloid leukemia (CML).
- Patient responses to ponatinib vary, and baseline genetic factors influencing outcomes require further investigation.
- Previous studies show low-level BCR-ABL1 mutations impact responses to other TKIs.
Purpose of the Study:
- To investigate the prognostic significance of baseline low-level BCR-ABL1 mutations on ponatinib treatment response.
- To evaluate the impact of mutation burden on outcomes in TKI-resistant CML patients, including those with the T315I mutation.
Main Methods:
- Analysis of 363 TKI-resistant patients from the PONATINIB trial using sensitive mass spectrometry to detect low-level BCR-ABL1 mutations.
- Assessment of mutation status before and during ponatinib treatment.
- Correlation of mutation profiles with treatment response in chronic phase CML (CP-CML).
Main Results:
- Low-level BCR-ABL1 mutations were detected in 15% of patients; most did not expand clonally.
- No single mutation was consistently associated with inferior outcomes.
- The number of detectable mutations, rather than specific mutations, correlated with ponatinib response.
- In CP-CML, patients with T315I and multiple mutations had inferior responses compared to those with T315I as the sole mutation.
- Ponatinib showed potential advantage over other TKIs for CP-CML patients with multiple mutations but without T315I.
Conclusions:
- The mutational landscape detected by mass spectrometry before ponatinib initiation is a significant factor in treatment response.
- The number of low-level mutations is a more critical predictor than individual mutations for ponatinib efficacy.
- Ponatinib may offer a superior therapeutic option for TKI-resistant CML patients with multiple BCR-ABL1 mutations.
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