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Blood. 2014 Jul 17;124(3):420-5. doi: 10.1182/blood-2013-12-538975. Epub 2014 Jun 10.

PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia.

Author information

1
Roche Pharma Research and Early Development, Penzberg, Germany;
2
Biostatistics, Genentech Inc., South San Francisco, CA;
3
F. Hoffman-La Roche Ltd., Basel, Switzerland;
4
Molecular Diagnostics and Cancer Cell Biology, Genentech Inc., South San Francisco, CA;
5
Laboratory for Leukemia Diagnostics, Ludwig Maximilians University, Munich, Germany;
6
Department of Haematology, Medical University, Lodz, Poland;
7
Hematology Department, Saint Petersburg Pavlov State Medical University, Saint Petersburg, Russia;
8
Haematooncology and Bone Marrow Transplantation Department, Medical University, Lublin, Poland;
9
Department of Hematology, Institut de Cancérologie de l'Ouest, Nantes, France;
10
Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland;
11
Department of Hematology, Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain;
12
Dorevitch Pathology Laboratory, Frankston Hospital, Frankston, Australia;
13
Division of Clinical Hematology, Walter C. Mackenzie Health Sciences Centre, Edmonton, AB, Canada;
14
Haematology Department, Samara Region Clinical Hospital, Samara, Russia;
15
Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada;
16
Department of Hematology, Rigshospitalet, Copenhagen, Denmark;
17
Department of Haematology & Oncology, Division of Haematology, Ospedale Niguarda Ca' Granda, Milan, Italy;
18
Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany;
19
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
20
Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany;
21
Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany;
22
BioOncology, Genentech Inc., South San Francisco, CA; and.
23
Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

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).

PMID:
24916506
DOI:
10.1182/blood-2013-12-538975
[Indexed for MEDLINE]
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