title: Variations of the ataxia telangiectasia mutated gene in patients with chronic lymphocytic leukemia lack substantial impact on progression-free survival and overall survival: a Cancer and Leukemia Group B study.
abstract: The impact of mutation of the ATM (ataxia telangiectasia mutated) gene in chronic lymphocytic leukemia (CLL) treatment outcome has not been examined. We studied ATM mutations in 73 patients treated with fludarabine and rituximab. ATM gene mutation analysis was performed using temperature gradient capillary electrophoresis. The impact of detected variants on overall survival (OS) and progression-free survival (PFS) was tested with proportional hazards models. None of the 73 patients demonstrated truncating ATM mutations; 17 (23%, 95% confidence interval 14-35%) had non-silent variants (ATM-NSVs), including 13 known ATM polymorphisms and four missense variants. ATM-NSVs were not significantly associated with any baseline characteristics including immunoglobulin heavy chain variable gene (IGVH) status. In multivariable models, no significant differences in complete response (p =0.70), PFS (p =0.59) or OS (p =0.13) were observed. Our data indicate that truncating ATM mutations are rare in patients with CLL. Furthermore, in this dataset, these non-silent variants had limited impact on PFS and OS.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Lozanski
authors.forename: Amy S
authors.initials: AS
authors.lastname: Ruppert
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Arletta
authors.initials: A
authors.lastname: Lozanski
authors.forename: David M
authors.initials: DM
authors.lastname: Lucas
authors.forename: Amber
authors.initials: A
authors.lastname: Gordon
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Vicki A
authors.initials: VA
authors.lastname: Morrison
authors.forename: Kanti M
authors.initials: KM
authors.lastname: Rai
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D017063:Outcome Assessment, Health Care / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000069283:Rituximab; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D025521:Tumor Suppressor Proteins; D000069283:Rituximab; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D014740:Vidarabine; C024352:fludarabine