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|Title:||Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile|
|Citation:||Blood, 2012; 119(10):2234-2238|
|Publisher:||Amer Soc Hematology|
|Wendy T. Parker, Musei Ho, Hamish S. Scott, Timothy P. Hughes and Susan Branford|
|Abstract:||Specific imatinib-resistant BCR-ABL1 mutations (Y253H, E255K/V, T315I, F317L, and F359V/C) predict failure of second-line nilotinib or dasatinib therapy in patients with chronic myeloid leukemia; however, such therapy also fails in approximately 40% of patients in the chronic phase of this disease who do not have these resistant mutations. We investigated whether sensitive mutation analysis could identify other poor-risk subgroups. Analysis was performed by direct sequencing and sensitive mass spectrometry on 220 imatinib-resistant patients before they began nilotinib or dasatinib therapy. Patients with resistant mutations by either method (n = 45) were excluded because inferior response was known. Of the remaining 175 patients, 19% had multiple mutations by mass spectrometry versus 9% by sequencing. Compared with 0 or 1 mutation, the presence of multiple mutations was associated with lower rates of complete cytogenetic response (50% vs 21%, P = .003) and major molecular response (31% vs 6%, P = .005) and a higher rate of new resistant mutations (25% vs 56%, P = .0009). Sensitive mutation analysis identified a poor-risk subgroup (15.5% of all patients) with multiple mutations not identified by standard screening.|
|Keywords:||Humans; Benzamides; Piperazines; Pyrimidines; Thiazoles; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; Sequence Analysis, DNA; DNA Mutational Analysis; Drug Resistance, Neoplasm; Mutation; Mass Spectrometry; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Imatinib Mesylate; Dasatinib|
|Rights:||Copyright © 2012 by American Society of Hematology|
|Appears in Collections:||Molecular and Biomedical Science publications|
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