title: Clinical impact of ABL1 kinase domain mutations and IKZF1 deletion in adults under age 60 with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL): molecular analysis of CALGB (Alliance) 10001 and 9665.
abstract: Recent studies have identified oncogenic lesions in Philadelphia chromosome-positive (Ph+)  acute lymphoblastic leukemia (ALL) and ABL1 kinase mutations that confer resistance to tyrosine kinase inhibitors. We sought to determine the prevalence and clinical impact of these lesions in patients on CALGB 10001, a previously reported Phase II study of imatinib, chemotherapy, and hematopoietic cell transplant in adult Ph + ALL. Of the 58 enrolled, 22 relapsed. By direct sequencing, an ABL1 kinase mutation known to induce imatinib resistance was present at relapse in 13 of 20. Using quantitative PCR assays, the mutations were detectable at diagnosis or early during treatment in most (62%) relapsed patients. Aberrations in IKZF1, CDKN2A/B, and PAX5 were assessed in 28 samples using SNP arrays and genomic DNA sequencing. Of these, 22 (79%) had IKZF1 deletion. The combination of IKZF1 deletion and p210 BCR-ABL1 (p < 0.0001), high white blood cell count (p = 0.021), and minimal residual disease (p = 0.013) were associated with worse disease-free survival.
authors.affiliation: a Department of Medicine , University of Chicago Medical Center , Chicago , IL , USA ;
authors.forename: Rebecca
authors.initials: R
authors.lastname: DeBoer
authors.affiliation: a Department of Medicine , University of Chicago Medical Center , Chicago , IL , USA ;
authors.forename: Gregory
authors.initials: G
authors.lastname: Koval
authors.affiliation: b Alliance Statistics and Data Center , Duke University Medical Center , Durham , NC , USA ;
authors.forename: Flora
authors.initials: F
authors.lastname: Mulkey
authors.affiliation: c Roswell Park Cancer Institute , Buffalo , NY , USA ;
authors.forename: Meir
authors.initials: M
authors.lastname: Wetzler
authors.affiliation: d The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Steven
authors.initials: S
authors.lastname: Devine
authors.affiliation: e City of Hope Comprehensive Cancer Center , Duarte , CA , USA ;
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: f Dana-Farber Cancer Institute, Harvard Medical School , Boston , MA , USA ;
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: a Department of Medicine , University of Chicago Medical Center , Chicago , IL , USA ;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: d The Ohio State University Comprehensive Cancer Center , Columbus , OH , USA ;
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: g Health Informatics Institute, University of South Florida , Tampa , FL , USA ;
authors.forename: Susan
authors.initials: S
authors.lastname: Geyer
authors.affiliation: h St. Jude Children's Research Hospital , Memphis , TN , USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: a Department of Medicine , University of Chicago Medical Center , Chicago , IL , USA ;
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl
keywords: Drug resistance; lymphoid leukemia; prognostication; transcription factor changes