Author(s): Parker WT, Ho M, Scott HS, Hughes TP, Branford S
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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.
This article was published in Blood
and referenced in Journal of Antivirals & Antiretrovirals