title: Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy.
abstract: Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1, SF3B1, ATM, TP53, BIRC3, POT1, XPO1, and KRAS Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum β-2-microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment.
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Carmen Diana
authors.initials: CD
authors.lastname: Herling
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Marion
authors.initials: M
authors.lastname: Klaumünzer
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Cristiano Krings
authors.initials: CK
authors.lastname: Rocha
authors.affiliation: Cologne Center for Genomics, and.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics, and.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Bahlo
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kluth
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Giuliano
authors.initials: G
authors.lastname: Crispatzu
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Joanna
authors.initials: J
authors.lastname: Schiller
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Anja
authors.initials: A
authors.lastname: Engelke
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany; and.
authors.forename: Eugen
authors.initials: E
authors.lastname: Tausch
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany; and.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Valentin
authors.initials: V
authors.lastname: Goede
authors.affiliation: Cologne Center for Genomics, and Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Reinhardt
authors.affiliation: Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany; and.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn, Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases, University of Cologne, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Internal Medicine I, Center of Integrated Oncology Cologne-Bonn.
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
mesh_terms: D059786:Abnormal Karyotype; D000368:Aged; D000369:Aged, 80 and over; D002699:Chlorambucil / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000069283:Rituximab / Q000008:administration & dosage*; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; C440849:POT1 protein, human; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D002699:Chlorambucil; D000069283:Rituximab; D016283:Proto-Oncogene Proteins p21(ras)