1. The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib
- Author
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Chani Field, Susan Branford, J. Graeme Hodgson, Timothy P. Hughes, Bronte A. Jamison, Victor M. Rivera, Stephanie Lustgarten, Alexandra L. Yeoman, David T Yeung, Haley Altamura, Wendy T Parker, Parker, Wendy T, Yeung, David TO, Yeoman, Alexandra L, Altamura, Haley K, Jamison, Bronte A, Field, Chani R, Hodgson, J Graeme, Lustgarten, Stephanie, Rivera, Victor M, Hughes, Timothy P, and Branford, Susan
- Subjects
0301 basic medicine ,Oncology ,Clinical Trials and Observations ,DNA Mutational Analysis ,Fusion Proteins, bcr-abl ,medicine.disease_cause ,Biochemistry ,Mass Spectrometry ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,0302 clinical medicine ,Neoplasms ,hemic and lymphatic diseases ,tyrosine kinase inhibitors ,Neoplasm ,Aged, 80 and over ,Mutation ,Ponatinib ,Imidazoles ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,chromosome-positive leukemias ,Pyridazines ,Dasatinib ,Leukemia ,Treatment Outcome ,030220 oncology & carcinogenesis ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Immunology ,Antineoplastic Agents ,bcr-abl mutations ,resistance ,Young Adult ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Protein Kinase Inhibitors ,chronic-phase ,Aged ,chronic myeloid-leukemia ,therapy ,business.industry ,Cell Biology ,medicine.disease ,030104 developmental biology ,imatinib ,Nilotinib ,chemistry ,Drug Resistance, Neoplasm ,Multivariate Analysis ,business - 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. Refereed/Peer-reviewed
- Published
- 2016
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