title: Increased genomic instability may contribute to the development of kinase domain mutations in chronic myeloid leukemia.
abstract: Imatinib resistance in chronic myeloid leukemia (CML) is commonly due to BCR-ABL kinase domain mutations (KDMs). In this single-institution retrospective analysis, patients with KDMs were identified from a cohort of patients treated for CML at our institution. Clinical outcomes were assessed based on the characteristics of the KDMs and results of cytogenetic analysis. In total, we compared 26 patients with KDM to those without; 46 % (n = 12) versus 20 % (n = 57) progressed to advanced phase (P = 0.003). Median overall survival was 22 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations (P = 0.127). KDM patients had a median progression-free survival (PFS) and overall survival of 75 and 109 months; however, neither was reached in the non-mutation cohort (P = 0.0007, P = 0.235). Median PFS in patients with single versus compound or double mutations was not reached versus 10 months (P = 0.014). We conclude that T315I, P-loop, and compound mutations may worsen prognosis in CML.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA, Kendra.Sweet@moffitt.org.
authors.forename: Kendra
authors.initials: K
authors.lastname: Sweet
authors.forename: Najla H
authors.initials: NH
authors.lastname: Al Ali
authors.forename: Samir M
authors.initials: SM
authors.lastname: Dalia
authors.forename: Rami S
authors.initials: RS
authors.lastname: Komrokji
authors.forename: Robert M
authors.initials: RM
authors.lastname: Crescentini
authors.forename: Sara
authors.initials: S
authors.lastname: Tinsley
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Peter R
authors.initials: PR
authors.lastname: Papenhausen
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Javier
authors.initials: J
authors.lastname: Pinilla-Ibarz
mesh_terms: D000328:Adult; D000368:Aged; D020732:Cytogenetic Analysis; D018450:Disease Progression; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D042822:Genomic Instability; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D016044:Fusion Proteins, bcr-abl