Gene expression profiling (GEP) to identify subtypes of diffuse large B-cell lymphoma (DLBL) for stratified randomisation to R-CHOP +/- bortezomib. A trial in progress in the UK NCRI and SAKK lymphoma groups.
Authors: Davies, A., Immins, T. et al.
Volume: 31 Supplement 1
Introduction: DLBL subtypes are identified by patterns of gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells.
The outcomes of treatment with standard R-CHOP therapy are inferior for the ABC type in retrospective series, and this study investigates whether adding bortezomib can reverse this deficit. The trial uses GEP to stratify cases at entry, with adaptive statistical design to analyse the outcome by subtype at predefined timepoints.
Methods: Patients (pts) newly diagnosed with DLBL undergo staging and commence R-CHOP. During the first cycle, formalin-fixed paraffin-embedded (FFPE) tissue undergoes extraction of messenger RNA (Ambion RecoverAll™ Total Nucleic Acid Isolation Kit for FFPE) for GEP of 24 000 probe sets using Illumina cDNA-mediated Annealing, Selection, extension, and Ligation (DASLW) assay at the central laboratory. Cases are allocated to GCB, ABC or unclassified (U) type before the 2nd cycle, using an established algorithm based upon 20 genes. Pts with successful GEP are randomized to continue R-CHOP +/ bortezomib 1.3 mg/m,2 days 1+8 of cycles 2–6. The study will randomize a minimum 260 ABC type cases, to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with two-sided significance 5% and 90% power. The design allows closure of randomisation for GCB cases if 6 month PFS is <80% after 55 receive R-CHOPB.
Futility analysis in GCB is planned after 73 treated with R-CHOP-B are followed for one year: if PFS is <85%, further exploration of bortezomib in this group is not warranted.
Results: During the first 14 months of recruitment, 242 samples have been analysed.
58 (24%) biopsies had inadequate material for GEP, but the remaining 184 were classified as 58 (32%) ABC, 104 (56%) GCB and 22 (12%) U. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 11 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the pts of different subtypes are shown in the table: Conclusions: This study demonstrates the feasibility of GEP at diagnosis in a large trial, with some indication that baseline prognostic features may be adverse in ABC type DLBL. Recruitment to the study continues at a rate of approximately 25 per month in 100 centres.
133 A RANDOMIZED, MULTICENTRE, TWO-ARM PHASE III COMPARATIVE STUDY ASSESSING THE ROLE OF MEDIASTINAL RADIOTHERAPY AFTER RITUXIMAB-CONTAINING CHEMOTHERAPY REGIMENS TO PATIENTS WITH NEWLY DIAGNOSED PRIMARY MEDIASTINAL LARGE B-CELL LYMPHOMA (PMLBCL): THE IELSG-37 STUDY M. Martelli,1 E. Zucca,2 M. Gospodarowicz,3 P. W. Johnson,4 U. Ricardi,5 N. Azinwi,6 U.
Metser,7 S. Barrington,8 A. Biggi,9 L. Ceriani,10 A. Versari,11 B. Malkowski,12 L.
Kostakoglu,13 G. Ciccone,14 S. Chauvie,15 F. Cavalli,16 A. J. Davies,17 1Hematology Institute, Sapienza University of Rome, Rome, Italy,2Lymphoma Unit,Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, 3Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Canada,4UK NCRI Lymphoma Group, Southampton General Hospital, Southampton, UK, 5Deptment of Radiation Oncology, Ospedale S. Giovanni Battista, Turin, Italy,6Department of Radio-Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland, 7Department of Medical Imaging, University of Toronto, Toronto, Canada,8PET Imaging Center, King’s College London - St Thomas’, London, UK,9Nuclear Medicine, Santa Croce e Carle Hospital, Cuneo, Italy,10Medicina Nucleare e Centro PET-CT, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland,11Medicina Nucleare, S. Maria Nuova Hospital, Reggio Emilia, Italy, 12Department of Nuclear Medicine, Regional Oncology Hospital, Bydgoszcz, Poland,13Department of Nuclear Medicine, Mount Sinai Hospital, New York, USA,14SCDO Epidemiologia dei Tumori, AO Citta’ della Salute e della Scienza di Torino, Turin, Italy,15Medical Physics Unit, Santa Croce e Carle Hospital, Cuneo, Italy,16Division of Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland,17Cancer Research UK, Southampton General Hospital, Southampton, UK Abstract 132 Table 1.
ABC GCB U Age: median 68 62 65 Age: range 23–86 27–82 32–81 % performance status 0–1 87 87 81 % at least one extranodal site 53 46 59 % bone marrow positive 11 25 47 % raised LDH 23 16 24 % IPI score >3 41 34 35