title: Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.
abstract: BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ~20% of total alleles (referred to as "low-level mutations"), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.
authors.affiliation: Huntsman Cancer Institute University of Utah, Salt Lake City, UT;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA;
authors.forename: J Graeme
authors.initials: JG
authors.lastname: Hodgson
authors.affiliation: University of California San Francisco, San Francisco, CA;
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea;
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Centre Hospitalier Lyon Sud, Pierre Benite, & INSERM U1052, Lyon, France;
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.affiliation: Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI;
authors.forename: Moshe
authors.initials: M
authors.lastname: Talpaz
authors.affiliation: Department of Hematology-Oncology "L. and A. Seragnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy;
authors.forename: Michele
authors.initials: M
authors.lastname: Baccarani
authors.affiliation: III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim, Germany;
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.affiliation: MolecularMD, Portland, OR;
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics and Molecular Pathology, SA Pathology, Centre for Cancer Biology, School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and.
authors.forename: Wendy T
authors.initials: WT
authors.lastname: Parker
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lustgarten
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA;
authors.forename: Tim
authors.initials: T
authors.lastname: Clackson
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA;
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
authors.affiliation: INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers, France;
authors.forename: Francois
authors.initials: F
authors.lastname: Guilhot
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy;
authors.forename: Simona
authors.initials: S
authors.lastname: Soverini
authors.affiliation: Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany;
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: SA Pathology and South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Genetics and Molecular Pathology, SA Pathology, Centre for Cancer Biology, School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA;
authors.forename: Victor M
authors.initials: VM
authors.lastname: Rivera
authors.affiliation: Department of Genetics and Molecular Pathology, SA Pathology, Centre for Cancer Biology, School of Medicine and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia.
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
mesh_terms: D019943:Amino Acid Substitution; D017024:Chemotherapy, Adjuvant; D004252:DNA Mutational Analysis / Q000379:methods; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D020360:Neoadjuvant Therapy; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl