title: High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma.
abstract: We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC, ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI-adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222.
authors.affiliation: Department of Biological Hematology and Immunology, Assistance Publique Hôpitaux de Paris (AP-HP), Groupe Hospitalier Mondor, Créteil, France; Institut Mondor de Recherche Biomédicale-INSERM U955, Equipe 9, Henri Mondor Hospital, Créteil, France; Université Paris-Est, Créteil, France;
authors.forename: Marie-Hélène
authors.identifier: http://orcid.org/0000-0002-8010-2343
authors.initials: MH
authors.lastname: Delfau-Larue
authors.affiliation: Departments of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, Germany;
authors.forename: Wolfram
authors.initials: W
authors.lastname: Klapper
authors.affiliation: Department of Pathology, Hospices Civils de Lyon, Lyon-1 University, Pierre Benite, France;
authors.forename: Françoise
authors.initials: F
authors.lastname: Berger
authors.affiliation: INSERM U918, Institute for Research and Innovation in Biomedicine, Centre Henri Becquerel, Rouen, France;
authors.forename: Fabrice
authors.initials: F
authors.lastname: Jardin
authors.affiliation: Department of Pathology, Hôpital Saint-Louis, AP-HP, Paris, France;
authors.forename: Josette
authors.initials: J
authors.lastname: Briere
authors.affiliation: Hospices Civils de Lyon, Lyon-1 University, Centre National de la Recherche Scientifique (CNRS), Unite Mixte de Recherche (UMR) 5239, Pierre Benite, France;
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: CHU de Dijon, Dijon, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Casasnovas
authors.affiliation: Centre Hospitalo-Universitaire Brabois, Nancy, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Feugier
authors.affiliation: Université Paris-Est, Créteil, France; Lymphoid Malignancies Unit, GH Mondor, AP-HP, Creteil, France;
authors.forename: Corinne
authors.initials: C
authors.lastname: Haioun
authors.affiliation: Institut de Cancérologie Gustave Roussy, Villejuif, France;
authors.forename: Vincent
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Department of Clinical Hematology, Hôpital Saint-Louis, AP-HP, Paris, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Thieblemont
authors.affiliation: Department of Internal Medicine III, University Hospital Munich, Munich, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Unterhalt
authors.affiliation: Department of Internal Medicine III, University Hospital Munich, Munich, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.affiliation: Biological Hematology, Necker Hospital, Paris Descartes, AP-HP, INSERM 1151, Institut Necker Enfants Malades, Paris, France;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: Second Medical Department, University Hospital Schleswig-Holstein, Kiel, Germany;
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.affiliation: Department of Clinical Hematology, University Paris Descartes, CNRS, UMR 8147, Necker Hospital, Paris, France; and.
authors.forename: Olivier
authors.initials: O
authors.lastname: Hermine
authors.affiliation: Department of Internal Medicine III, University Hospital Munich, Munich, Germany; Department of Medical Informatics, Biometry, and Epidemiology, University of Munich, Munich, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Hoster
mesh_terms: D000328:Adult; D000368:Aged; D024221:Antineoplastic Protocols; D064592:Autografts; D003561:Cytarabine / Q000008:administration & dosage*; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D019942:Genes, p16; D016158:Genes, p53; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011379:Prognosis
chemical_list: D019394:Ki-67 Antigen; D003561:Cytarabine