title: PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia.
abstract: Addition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) messenger RNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted R-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. These trials were registered at www.clinicaltrials.gov as #NCT00090051 (REACH) and #NCT00281918 (CLL8).
authors.affiliation: Roche Pharma Research and Early Development, Penzberg, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Weisser
authors.affiliation: Biostatistics, Genentech Inc., South San Francisco, CA;
authors.forename: Ru-Fang
authors.initials: RF
authors.lastname: Yeh
authors.affiliation: F. Hoffman-La Roche Ltd., Basel, Switzerland;
authors.forename: Guillemette
authors.initials: G
authors.lastname: Duchateau-Nguyen
authors.affiliation: F. Hoffman-La Roche Ltd., Basel, Switzerland;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palermo
authors.affiliation: F. Hoffman-La Roche Ltd., Basel, Switzerland;
authors.forename: Tri Quang
authors.identifier: http://orcid.org/0000-0002-6769-8664
authors.initials: TQ
authors.lastname: Nguyen
authors.affiliation: Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA;
authors.forename: Susanna Y
authors.initials: SY
authors.lastname: Stinson
authors.affiliation: Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA;
authors.forename: Nancy
authors.initials: N
authors.lastname: Yu
authors.affiliation: Laboratory for Leukemia Diagnostics, Ludwig Maximilians University, Munich, Germany;
authors.forename: Annika
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Department of Haematology, Medical University, Lodz, Poland;
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.affiliation: Hematology Department, Saint Petersburg Pavlov State Medical University, Saint Petersburg, Russia;
authors.forename: Galina N
authors.initials: GN
authors.lastname: Salogub
authors.affiliation: Haematooncology and Bone Marrow Transplantation Department, Medical University, Lublin, Poland;
authors.forename: Anna
authors.initials: A
authors.lastname: Dmoszynska
authors.affiliation: Department of Hematology, Institut de Cancérologie de l'Ouest, Nantes, France;
authors.forename: Philippe
authors.initials: P
authors.lastname: Solal-Celigny
authors.affiliation: Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Warzocha
authors.affiliation: Department of Hematology, Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain;
authors.forename: Javier
authors.initials: J
authors.lastname: Loscertales
authors.affiliation: Dorevitch Pathology Laboratory, Frankston Hospital, Frankston, Australia;
authors.forename: John
authors.initials: J
authors.lastname: Catalano
authors.affiliation: Division of Clinical Hematology, Walter C. Mackenzie Health Sciences Centre, Edmonton, AB, Canada;
authors.forename: Loree
authors.initials: L
authors.lastname: Larratt
authors.affiliation: Haematology Department, Samara Region Clinical Hospital, Samara, Russia;
authors.forename: Viktor A
authors.initials: VA
authors.lastname: Rossiev
authors.affiliation: Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bence-Bruckler
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark;
authors.forename: Christian H
authors.initials: CH
authors.lastname: Geisler
authors.affiliation: Department of Haematology & Oncology, Division of Haematology, Ospedale Niguarda Ca' Granda, Milan, Italy;
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.affiliation: Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany;
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.affiliation: Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany;
authors.forename: Anna-Maria
authors.initials: AM
authors.lastname: Fink
authors.affiliation: Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Bloehdorn
authors.affiliation: Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany;
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: BioOncology, Genentech Inc., South San Francisco, CA; and.
authors.forename: Nancy
authors.initials: N
authors.lastname: Valente
authors.affiliation: Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Wenger
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA;
authors.forename: David
authors.initials: D
authors.lastname: Dornan
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D051417:Focal Adhesion Kinase 1 / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000235:genetics* / Q000628:therapy*; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000069283:Rituximab; D003520:Cyclophosphamide; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D014740:Vidarabine; C024352:fludarabine