The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib.

Blood
Wendy T ParkerSusan Branford

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 resis...Continue Reading

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Citations

Oct 4, 2016·Therapeutic Advances in Hematology·Justine Ellen Marum, Susan Branford
Oct 25, 2017·Pharmacogenomics·Nora S SánchezKenna R Mills Shaw
Nov 16, 2018·Blood·Naranie Shanmuganathan, Timothy P Hughes
Dec 7, 2018·Hematology·Naranie Shanmuganathan, Timothy P Hughes
Feb 3, 2016·Nature Reviews. Clinical Oncology·Peter Sidaway
Feb 1, 2018·Leukemia & Lymphoma·Devendra Hiwase, David Ross
Sep 27, 2019·Frontiers in Oncology·Barbara IzzoSara Galimberti
Mar 8, 2020·European Journal of Haematology·Luigia LucianoGiorgina Specchia
Feb 23, 2020·Blood·Naranie Shanmuganathan, Timothy P Hughes
Mar 12, 2019·Therapeutic Advances in Hematology·Matteo MolicaMassimo Breccia
Nov 20, 2019·Leukemia & Lymphoma·Riad El FakihElias Jabbour
Mar 7, 2020·Frontiers in Genetics·Crescenzio Francesco MinerviniFrancesco Albano
Feb 9, 2021·European Journal of Medicinal Chemistry·Qi LiangJianyou Shi
Nov 26, 2021·Blood·Susan Branford

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