Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.
Identifieur interne : 002290 ( PubMed/Curation ); précédent : 002289; suivant : 002291Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.
Auteurs : Michael W. Deininger [États-Unis] ; J Graeme Hodgson [États-Unis] ; Neil P. Shah [États-Unis] ; Jorge E. Cortes [États-Unis] ; Dong-Wook Kim [Corée du Sud] ; Franck E. Nicolini [France] ; Moshe Talpaz [États-Unis] ; Michele Baccarani [Italie] ; Martin C. Müller [Allemagne] ; Jin Li [États-Unis] ; Wendy T. Parker ; Stephanie Lustgarten [États-Unis] ; Tim Clackson [États-Unis] ; Frank G. Haluska [États-Unis] ; Francois Guilhot [France] ; Hagop M. Kantarjian [États-Unis] ; Simona Soverini [Italie] ; Andreas Hochhaus [Allemagne] ; Timothy P. Hughes ; Victor M. Rivera [États-Unis] ; Susan Branford [Australie]Source :
- Blood [ 1528-0020 ] ; 2016.
Descripteurs français
- KwdFr :
- Analyse de mutations d'ADN (), Humains, Imidazoles (usage thérapeutique), Inhibiteurs de protéines kinases (usage thérapeutique), Leucémie myéloïde en phase chronique (génétique), Leucémie myéloïde en phase chronique (traitement médicamenteux), Mutation (physiologie), Protéines de fusion bcr-abl (génétique), Pyridazines (usage thérapeutique), Résistance aux médicaments antinéoplasiques (génétique), Substitution d'acide aminé, Séquençage nucléotidique à haut débit, Traitement médicamenteux adjuvant, Traitement néoadjuvant.
- MESH :
- génétique : Leucémie myéloïde en phase chronique, Protéines de fusion bcr-abl, Résistance aux médicaments antinéoplasiques.
- physiologie : Mutation.
- traitement médicamenteux : Leucémie myéloïde en phase chronique.
- usage thérapeutique : Imidazoles, Inhibiteurs de protéines kinases, Pyridazines.
- Analyse de mutations d'ADN, Humains, Substitution d'acide aminé, Séquençage nucléotidique à haut débit, Traitement médicamenteux adjuvant, Traitement néoadjuvant.
English descriptors
- KwdEn :
- Amino Acid Substitution, Chemotherapy, Adjuvant, DNA Mutational Analysis (methods), Drug Resistance, Neoplasm (genetics), Fusion Proteins, bcr-abl (genetics), High-Throughput Nucleotide Sequencing, Humans, Imidazoles (therapeutic use), Leukemia, Myeloid, Chronic-Phase (drug therapy), Leukemia, Myeloid, Chronic-Phase (genetics), Mutation (physiology), Neoadjuvant Therapy, Protein Kinase Inhibitors (therapeutic use), Pyridazines (therapeutic use).
- MESH :
- chemical , genetics : Fusion Proteins, bcr-abl.
- drug therapy : Leukemia, Myeloid, Chronic-Phase.
- genetics : Drug Resistance, Neoplasm, Leukemia, Myeloid, Chronic-Phase.
- methods : DNA Mutational Analysis.
- physiology : Mutation.
- chemical , therapeutic use : Imidazoles, Protein Kinase Inhibitors, Pyridazines.
- Amino Acid Substitution, Chemotherapy, Adjuvant, High-Throughput Nucleotide Sequencing, Humans, Neoadjuvant Therapy.
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.
DOI: 10.1182/blood-2015-08-660977
PubMed: 26603839
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Wendy T. Parker<affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation><affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation>Le document en format XML
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Seragnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy;</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Hematology-Oncology "L. and A. Seragnoli," S. Orsola-Malpighi University Hospital, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Muller, Martin C" sort="Muller, Martin C" uniqKey="Muller M" first="Martin C" last="Müller">Martin C. Müller</name><affiliation wicri:level="1"><nlm:affiliation>III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jin" sort="Li, Jin" uniqKey="Li J" first="Jin" last="Li">Jin Li</name><affiliation wicri:level="2"><nlm:affiliation>MolecularMD, Portland, OR;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Oregon</region></placeName><wicri:cityArea>MolecularMD, Portland</wicri:cityArea></affiliation></author><author><name sortKey="Parker, Wendy T" sort="Parker, Wendy T" uniqKey="Parker W" first="Wendy T" last="Parker">Wendy T. Parker</name><affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation></author><author><name sortKey="Lustgarten, Stephanie" sort="Lustgarten, Stephanie" uniqKey="Lustgarten S" first="Stephanie" last="Lustgarten">Stephanie Lustgarten</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Clackson, Tim" sort="Clackson, Tim" uniqKey="Clackson T" first="Tim" last="Clackson">Tim Clackson</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Haluska, Frank G" sort="Haluska, Frank G" uniqKey="Haluska F" first="Frank G" last="Haluska">Frank G. Haluska</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Guilhot, Francois" sort="Guilhot, Francois" uniqKey="Guilhot F" first="Francois" last="Guilhot">Francois Guilhot</name><affiliation wicri:level="1"><nlm:affiliation>INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers, France;</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers</wicri:regionArea></affiliation></author><author><name sortKey="Kantarjian, Hagop M" sort="Kantarjian, Hagop M" uniqKey="Kantarjian H" first="Hagop M" last="Kantarjian">Hagop M. Kantarjian</name><affiliation wicri:level="2"><nlm:affiliation>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston</wicri:cityArea></affiliation></author><author><name sortKey="Soverini, Simona" sort="Soverini, Simona" uniqKey="Soverini S" first="Simona" last="Soverini">Simona Soverini</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy;</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Hochhaus, Andreas" sort="Hochhaus, Andreas" uniqKey="Hochhaus A" first="Andreas" last="Hochhaus">Andreas Hochhaus</name><affiliation wicri:level="1"><nlm:affiliation>Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, Timothy P" sort="Hughes, Timothy P" uniqKey="Hughes T" first="Timothy P" last="Hughes">Timothy P. Hughes</name><affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation></author><author><name sortKey="Rivera, Victor M" sort="Rivera, Victor M" uniqKey="Rivera V" first="Victor M" last="Rivera">Victor M. Rivera</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Branford, Susan" sort="Branford, Susan" uniqKey="Branford S" first="Susan" last="Branford">Susan Branford</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2016">2016</date><idno type="RBID">pubmed:26603839</idno><idno type="pmid">26603839</idno><idno type="doi">10.1182/blood-2015-08-660977</idno><idno type="wicri:Area/PubMed/Corpus">002316</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002316</idno><idno type="wicri:Area/PubMed/Curation">002290</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002290</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.</title><author><name sortKey="Deininger, Michael W" sort="Deininger, Michael W" uniqKey="Deininger M" first="Michael W" last="Deininger">Michael W. Deininger</name><affiliation wicri:level="2"><nlm:affiliation>Huntsman Cancer Institute University of Utah, Salt Lake City, UT;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Utah</region></placeName><wicri:cityArea>Huntsman Cancer Institute University of Utah, Salt Lake City</wicri:cityArea></affiliation></author><author><name sortKey="Hodgson, J Graeme" sort="Hodgson, J Graeme" uniqKey="Hodgson J" first="J Graeme" last="Hodgson">J Graeme Hodgson</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P" last="Shah">Neil P. Shah</name><affiliation wicri:level="2"><nlm:affiliation>University of California San Francisco, San Francisco, CA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>University of California San Francisco, San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Cortes, Jorge E" sort="Cortes, Jorge E" uniqKey="Cortes J" first="Jorge E" last="Cortes">Jorge E. Cortes</name><affiliation wicri:level="2"><nlm:affiliation>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston</wicri:cityArea></affiliation></author><author><name sortKey="Kim, Dong Wook" sort="Kim, Dong Wook" uniqKey="Kim D" first="Dong-Wook" last="Kim">Dong-Wook Kim</name><affiliation wicri:level="1"><nlm:affiliation>Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea;</nlm:affiliation><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul</wicri:regionArea></affiliation></author><author><name sortKey="Nicolini, Franck E" sort="Nicolini, Franck E" uniqKey="Nicolini F" first="Franck E" last="Nicolini">Franck E. Nicolini</name><affiliation wicri:level="1"><nlm:affiliation>Centre Hospitalier Lyon Sud, Pierre Benite, & INSERM U1052, Lyon, France;</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Centre Hospitalier Lyon Sud, Pierre Benite, & INSERM U1052, Lyon</wicri:regionArea></affiliation></author><author><name sortKey="Talpaz, Moshe" sort="Talpaz, Moshe" uniqKey="Talpaz M" first="Moshe" last="Talpaz">Moshe Talpaz</name><affiliation wicri:level="2"><nlm:affiliation>Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Michigan</region></placeName><wicri:cityArea>Comprehensive Cancer Center, University of Michigan, Ann Arbor</wicri:cityArea></affiliation></author><author><name sortKey="Baccarani, Michele" sort="Baccarani, Michele" uniqKey="Baccarani M" first="Michele" last="Baccarani">Michele Baccarani</name><affiliation wicri:level="1"><nlm:affiliation>Department of Hematology-Oncology "L. and A. Seragnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy;</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Hematology-Oncology "L. and A. Seragnoli," S. Orsola-Malpighi University Hospital, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Muller, Martin C" sort="Muller, Martin C" uniqKey="Muller M" first="Martin C" last="Müller">Martin C. Müller</name><affiliation wicri:level="1"><nlm:affiliation>III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jin" sort="Li, Jin" uniqKey="Li J" first="Jin" last="Li">Jin Li</name><affiliation wicri:level="2"><nlm:affiliation>MolecularMD, Portland, OR;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Oregon</region></placeName><wicri:cityArea>MolecularMD, Portland</wicri:cityArea></affiliation></author><author><name sortKey="Parker, Wendy T" sort="Parker, Wendy T" uniqKey="Parker W" first="Wendy T" last="Parker">Wendy T. Parker</name><affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation></author><author><name sortKey="Lustgarten, Stephanie" sort="Lustgarten, Stephanie" uniqKey="Lustgarten S" first="Stephanie" last="Lustgarten">Stephanie Lustgarten</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Clackson, Tim" sort="Clackson, Tim" uniqKey="Clackson T" first="Tim" last="Clackson">Tim Clackson</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Haluska, Frank G" sort="Haluska, Frank G" uniqKey="Haluska F" first="Frank G" last="Haluska">Frank G. Haluska</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Guilhot, Francois" sort="Guilhot, Francois" uniqKey="Guilhot F" first="Francois" last="Guilhot">Francois Guilhot</name><affiliation wicri:level="1"><nlm:affiliation>INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers, France;</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers</wicri:regionArea></affiliation></author><author><name sortKey="Kantarjian, Hagop M" sort="Kantarjian, Hagop M" uniqKey="Kantarjian H" first="Hagop M" last="Kantarjian">Hagop M. Kantarjian</name><affiliation wicri:level="2"><nlm:affiliation>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston</wicri:cityArea></affiliation></author><author><name sortKey="Soverini, Simona" sort="Soverini, Simona" uniqKey="Soverini S" first="Simona" last="Soverini">Simona Soverini</name><affiliation wicri:level="1"><nlm:affiliation>Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy;</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Hochhaus, Andreas" sort="Hochhaus, Andreas" uniqKey="Hochhaus A" first="Andreas" last="Hochhaus">Andreas Hochhaus</name><affiliation wicri:level="1"><nlm:affiliation>Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany;</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, Timothy P" sort="Hughes, Timothy P" uniqKey="Hughes T" first="Timothy P" last="Hughes">Timothy P. Hughes</name><affiliation><nlm: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.</nlm:affiliation><wicri:noCountry code="subField">Australia; and</wicri:noCountry></affiliation></author><author><name sortKey="Rivera, Victor M" sort="Rivera, Victor M" uniqKey="Rivera V" first="Victor M" last="Rivera">Victor M. Rivera</name><affiliation wicri:level="2"><nlm:affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>ARIAD Pharmaceuticals, Inc., Cambridge</wicri:cityArea></affiliation></author><author><name sortKey="Branford, Susan" sort="Branford, Susan" uniqKey="Branford S" first="Susan" last="Branford">Susan Branford</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>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</wicri:regionArea></affiliation></author></analytic><series><title level="j">Blood</title><idno type="eISSN">1528-0020</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Substitution</term><term>Chemotherapy, Adjuvant</term><term>DNA Mutational Analysis (methods)</term><term>Drug Resistance, Neoplasm (genetics)</term><term>Fusion Proteins, bcr-abl (genetics)</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Imidazoles (therapeutic use)</term><term>Leukemia, Myeloid, Chronic-Phase (drug therapy)</term><term>Leukemia, Myeloid, Chronic-Phase (genetics)</term><term>Mutation (physiology)</term><term>Neoadjuvant Therapy</term><term>Protein Kinase Inhibitors (therapeutic use)</term><term>Pyridazines (therapeutic use)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de mutations d'ADN ()</term><term>Humains</term><term>Imidazoles (usage thérapeutique)</term><term>Inhibiteurs de protéines kinases (usage thérapeutique)</term><term>Leucémie myéloïde en phase chronique (génétique)</term><term>Leucémie myéloïde en phase chronique (traitement médicamenteux)</term><term>Mutation (physiologie)</term><term>Protéines de fusion bcr-abl (génétique)</term><term>Pyridazines (usage thérapeutique)</term><term>Résistance aux médicaments antinéoplasiques (génétique)</term><term>Substitution d'acide aminé</term><term>Séquençage nucléotidique à haut débit</term><term>Traitement médicamenteux adjuvant</term><term>Traitement néoadjuvant</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Fusion Proteins, bcr-abl</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Leukemia, Myeloid, Chronic-Phase</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Drug Resistance, Neoplasm</term><term>Leukemia, Myeloid, Chronic-Phase</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Leucémie myéloïde en phase chronique</term><term>Protéines de fusion bcr-abl</term><term>Résistance aux médicaments antinéoplasiques</term></keywords><keywords scheme="MESH" qualifier="methods" xml:lang="en"><term>DNA Mutational Analysis</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Mutation</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Imidazoles</term><term>Protein Kinase Inhibitors</term><term>Pyridazines</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Leucémie myéloïde en phase chronique</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Imidazoles</term><term>Inhibiteurs de protéines kinases</term><term>Pyridazines</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Substitution</term><term>Chemotherapy, Adjuvant</term><term>High-Throughput Nucleotide Sequencing</term><term>Humans</term><term>Neoadjuvant Therapy</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de mutations d'ADN</term><term>Humains</term><term>Substitution d'acide aminé</term><term>Séquençage nucléotidique à haut débit</term><term>Traitement médicamenteux adjuvant</term><term>Traitement néoadjuvant</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26603839</PMID><DateCreated><Year>2016</Year><Month>02</Month><Day>12</Day></DateCreated><DateCompleted><Year>2016</Year><Month>06</Month><Day>29</Day></DateCompleted><DateRevised><Year>2017</Year><Month>04</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1528-0020</ISSN><JournalIssue CitedMedium="Internet"><Volume>127</Volume><Issue>6</Issue><PubDate><Year>2016</Year><Month>Feb</Month><Day>11</Day></PubDate></JournalIssue><Title>Blood</Title><ISOAbbreviation>Blood</ISOAbbreviation></Journal><ArticleTitle>Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.</ArticleTitle><Pagination><MedlinePgn>703-12</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1182/blood-2015-08-660977</ELocationID><Abstract><AbstractText>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.</AbstractText><CopyrightInformation>© 2016 by The American Society of Hematology.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Deininger</LastName><ForeName>Michael W</ForeName><Initials>MW</Initials><AffiliationInfo><Affiliation>Huntsman Cancer Institute University of Utah, Salt Lake City, UT;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hodgson</LastName><ForeName>J Graeme</ForeName><Initials>JG</Initials><AffiliationInfo><Affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shah</LastName><ForeName>Neil P</ForeName><Initials>NP</Initials><AffiliationInfo><Affiliation>University of California San Francisco, San Francisco, CA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cortes</LastName><ForeName>Jorge E</ForeName><Initials>JE</Initials><AffiliationInfo><Affiliation>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kim</LastName><ForeName>Dong-Wook</ForeName><Initials>DW</Initials><AffiliationInfo><Affiliation>Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nicolini</LastName><ForeName>Franck E</ForeName><Initials>FE</Initials><AffiliationInfo><Affiliation>Centre Hospitalier Lyon Sud, Pierre Benite, & INSERM U1052, Lyon, France;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Talpaz</LastName><ForeName>Moshe</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Baccarani</LastName><ForeName>Michele</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Department of Hematology-Oncology "L. and A. Seragnoli," S. Orsola-Malpighi University Hospital, Bologna, Italy;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Müller</LastName><ForeName>Martin C</ForeName><Initials>MC</Initials><AffiliationInfo><Affiliation>III. Med. Klinik, Universitätsmedizin Mannheim, Mannheim, Germany;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Li</LastName><ForeName>Jin</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>MolecularMD, Portland, OR;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Parker</LastName><ForeName>Wendy T</ForeName><Initials>WT</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lustgarten</LastName><ForeName>Stephanie</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Clackson</LastName><ForeName>Tim</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Haluska</LastName><ForeName>Frank G</ForeName><Initials>FG</Initials><AffiliationInfo><Affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Guilhot</LastName><ForeName>Francois</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>INSERM Clinical Investigation Center 1402, Centre Hospitalier et Universitaire de Poitiers, France;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kantarjian</LastName><ForeName>Hagop M</ForeName><Initials>HM</Initials><AffiliationInfo><Affiliation>Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Soverini</LastName><ForeName>Simona</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hochhaus</LastName><ForeName>Andreas</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hughes</LastName><ForeName>Timothy P</ForeName><Initials>TP</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rivera</LastName><ForeName>Victor M</ForeName><Initials>VM</Initials><AffiliationInfo><Affiliation>ARIAD Pharmaceuticals, Inc., Cambridge, MA;</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Branford</LastName><ForeName>Susan</ForeName><Initials>S</Initials><AffiliationInfo><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.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>P30 CA016672</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 CA178397</GrantID><Acronym>CA</Acronym><Agency>NCI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D017427">Clinical Trial, Phase II</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>11</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Blood</MedlineTA><NlmUniqueID>7603509</NlmUniqueID><ISSNLinking>0006-4971</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007093">Imidazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D047428">Protein Kinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011724">Pyridazines</NameOfSubstance></Chemical><Chemical><RegistryNumber>4340891KFS</RegistryNumber><NameOfSubstance UI="C545373">ponatinib</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.10.2</RegistryNumber><NameOfSubstance UI="D016044">Fusion Proteins, bcr-abl</NameOfSubstance></Chemical></ChemicalList><CitationSubset>AIM</CitationSubset><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="Cites"><RefSource>N Engl J Med. 2013 Nov 7;369(19):1783-96</RefSource><PMID Version="1">24180494</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>J Clin Oncol. 2014 Feb 10;32(5):415-23</RefSource><PMID Version="1">24297946</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Eur J Cancer. 2014 Mar;50(4):793-800</RefSource><PMID Version="1">24365090</PMID></CommentsCorrections><CommentsCorrections RefType="Cites"><RefSource>Blood. 2014 Jul 3;124(1):153-5</RefSource><PMID 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MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019008" MajorTopicYN="N">Drug Resistance, Neoplasm</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016044" MajorTopicYN="N">Fusion Proteins, bcr-abl</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D059014" MajorTopicYN="N">High-Throughput Nucleotide Sequencing</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007093" MajorTopicYN="N">Imidazoles</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015466" MajorTopicYN="N">Leukemia, Myeloid, Chronic-Phase</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug 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