title: Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL.
abstract: Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ≥ 2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ≥ 2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiple-hit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome.
authors: Service d'Hématologie Clinique Adulte et de Thérapie Cellulaire, Centre Hospitalier Universitaire (CHU) de Clermont-Ferrand, Clermont-Ferrand, France; Equipe d'accueil (EA) 7283-Cancer Resistance Exploring and Targeting (CREAT), Centre d'Investigation Clinique (CIC) 501, Université d'Auvergne, Clermont-Ferrand, France;
authors: Romain
authors: R
authors: Guièze
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Pauline
authors: P
authors: Robbe
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Ruth
authors: R
authors: Clifford
authors: Service d'Hématologie Clinique, CHU de Rennes, Rennes, France;
authors: Sophie
authors: S
authors: de Guibert
authors: Departement de Biostatistiques, CHU de Clermont-Ferrand, Clermont-Ferrand, France;
authors: Bruno
authors: B
authors: Pereira
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Adele
authors: A
authors: Timbs
authors: Service d'Hématologie Clinique et Thérapie Cellulaire, CHU de Bordeaux, Bordeaux, France;
authors: Marie-Sarah
authors: MS
authors: Dilhuydy
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Maite
authors: M
authors: Cabes
authors: Service d'Hématologie, CHU de Toulouse, Toulouse, France;
authors: Loïc
authors: L
authors: Ysebaert
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Adam
authors: A
authors: Burns
authors: Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (APHP) La Pitié-Salpétrière, Paris, France;
authors: Florence
authors: F
authors: Nguyen-Khac
authors: Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (APHP) La Pitié-Salpétrière, Paris, France;
authors: Frédéric
authors: F
authors: Davi
authors: Laboratoire de Cytogénétique, CHU de Clermont-Ferrand, Clermont-Ferrand, France; EA4677-Equipe de Recherche sur les Traitements Individualisés des Cancers en Auvergne (ERTICA), Université d'Auvergne, Clermont-Ferrand, France;
authors: Lauren
authors: L
authors: Véronèse
authors: Laboratoire de Cytogénétique, CHU de Clermont-Ferrand, Clermont-Ferrand, France; EA4677-Equipe de Recherche sur les Traitements Individualisés des Cancers en Auvergne (ERTICA), Université d'Auvergne, Clermont-Ferrand, France;
authors: Patricia
authors: P
authors: Combes
authors: Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (APHP) La Pitié-Salpétrière, Paris, France;
authors: Magali
authors: M
authors: Le Garff-Tavernier
authors: Service d'Hématologie Clinique, APHP La Pitié-Salpétrière, Paris, France;
authors: Véronique
authors: V
authors: Leblond
authors: Service d'Hématologie Biologique, Assistance Publique des Hôpitaux de Paris (APHP) La Pitié-Salpétrière, Paris, France;
authors: Hélène
authors: H
authors: Merle-Béral
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Reem
authors: R
authors: Alsolami
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Angela
authors: A
authors: Hamblin
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Joanne
authors: J
authors: Mason
authors: Royal Liverpool and Broadgreen University Hospitals National Health Service Trust, Liverpool, United Kingdom;
authors: Andrew
authors: A
authors: Pettitt
authors: Department of Hematology/Oncology, St-James University Hospital, Leeds, United Kingdom; and.
authors: Peter
authors: P
authors: Hillmen
authors: Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Jenny
authors: J
authors: Taylor
authors: Oxford National Institute for Health Research (NIHR) Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors: Samantha J L
authors: SJ
authors: Knight
authors: Service d'Hématologie Clinique Adulte et de Thérapie Cellulaire, Centre Hospitalier Universitaire (CHU) de Clermont-Ferrand, Clermont-Ferrand, France; Equipe d'accueil (EA) 7283-Cancer Resistance Exploring and Targeting (CREAT), Centre d'Investigation Clinique (CIC) 501, Université d'Auvergne, Clermont-Ferrand, France;
authors: Olivier
authors: O
authors: Tournilhac
authors: Oxford Molecular Diagnostics Centre, University of Oxford, Oxford, United Kingdom;
authors: Anna
authors: A
authors: Schuh
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy*; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D016879:Salvage Therapy / Q000379:methods*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D016159:Tumor Suppressor Protein p53; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins