Abstract

Introduction: DLBCL subtypes may be classified by gene expression corresponding to germinal centre (GCB) or activated peripheral blood (ABC) B-cells. Treatment outcomes with R-CHOP therapy were inferior for ABCs in retrospective series, and this study investigated whether adding bortezomib could reverse the adverse prognosis. The trial used gene expression profiling (GEP) to stratify cases, with adaptive design to analyse the outcome by subtypes at predefined timepoints.

Methods: Newly diagnosed patients with DLBCL underwent staging and commenced standard R-CHOP. During cycle 1, formalin-fixed paraffin-embedded (FFPE) tissue was used to extract messenger RNA for GEP using the Illumina DASL array platform. Cases were allocated to GCB, ABC or Unclassifiable (Unc) type before starting cycle 2, using an established algorithm based upon 20 genes. Patients with successful GEP were randomised 1:1 to receive R-CHOP +/- bortezomib 1.6 mg/m2 s/c on days 1+8 in cycles 2-6. The study was powered to detect a difference in progression-free survival (PFS) of 10% with bortezomib, with a 2-sided significance, 5% and 90% power. The adaptive design allowed for closure of randomization for GCB cases if 1-year PFS was <70% after 55 received RB-CHOP (interim safety analysis) or if 1-year PFS was <85% after 73 received RB-CHOP and followed for 1 year (futility analysis).

Results: Between 6/2011 and 5/2015 1132 patients were enrolled from 109 sites, with 1078 samples analysed. Of these, 157 (15%) biopsies had inadequate material for GEP, but the remaining 921 were classified as 246 (27%) ABC, 476 (52%) GCB and 199 (22%) Unc. Successful classification was possible from both surgical and needle core biopsies. Median laboratory turnaround time was 12 working days and all results were available prior to the scheduled administration of cycle 2. Characteristics of the patients of different subtypes are shown in the table. Following both interim analyses the DMEC recommended continued recruitment of patients with a GCB phenotype.

Table.
ABCGCBUnc
Age (years): median 67 63 63 
Age (years) : range 23 to 86 20 to 82 20 to 85 
% performance status 0-1 88 88 90 
% at least one extranodal site 53 54 62 
% bone marrow involved 15 14 23 
% LDH>ULN 69 76 79 
% IPI score 0/1 29 27 26 
% IPI score 2/3 57 55 55 
% IPI score 4/5 15 19 19 
% B symptoms 46 43 49 
% Bulk>10cm 17 26 21 
ABCGCBUnc
Age (years): median 67 63 63 
Age (years) : range 23 to 86 20 to 82 20 to 85 
% performance status 0-1 88 88 90 
% at least one extranodal site 53 54 62 
% bone marrow involved 15 14 23 
% LDH>ULN 69 76 79 
% IPI score 0/1 29 27 26 
% IPI score 2/3 57 55 55 
% IPI score 4/5 15 19 19 
% B symptoms 46 43 49 
% Bulk>10cm 17 26 21 

Conclusions: This study has demonstrated the feasibility of GEP at diagnosis to subsequently guide therapy in a large multicentre trial. Although patients with ABC type lymphoma were in general slightly older, they did not appear to have other adverse prognostic features at diagnosis vs GCB. All patients will have completed therapy by the time of the meeting, allowing the initial response and toxicity data to be available for presentation.

Disclosures

Davies:GIlead: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; CTI: Honoraria; Takeda: Honoraria, Research Funding; Bayer: Research Funding; GSK: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Pfizer: Honoraria; Celgene: Honoraria, Research Funding. Off Label Use: The addition of bortezomib to R-CHOP chemotherapy in diffuse large B-cell lymphoma. Pocock:Janssen: Honoraria. Jack:Jannsen: Research Funding. Johnson:Takeda: Honoraria; Pfizer: Honoraria; Janssen: Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.