A bioclinical prognostic model using MYC and BCL2 predicts outcome in relapsed/refractory diffuse large B-cell lymphoma

Abstract

The objective of this study was to create a bioclinical model, based on clinical and molecular predictors of event-free and overall survival for relapsed/refractory diffuse large B-cell lymphoma patients treated on the Canadian Cancer Trials Group (CCTG) LY12 prospective study. In 91 cases, sufficient histologic material was available to create tissue microarrays and perform immunohistochemistry staining for CD10, BCL6, MUM1/IRF4, FOXP1, LMO2, BCL2, MYC, P53 and phosphoSTAT3 (pySTAT3) expression. Sixty-seven cases had material sufficient for fluorescent in situ hybridization (FISH) for MYC and BCL2 In addition, 97 formalin-fixed, paraffin-embedded tissue samples underwent digital gene expression profiling (GEP) to evaluate BCL2, MYC, P53, and STAT3 expression, and to determine cell-of-origin (COO) using the Lymph2Cx assay. No method of determining COO predicted event-free survival (EFS) or overall survival (OS). Factors independently associated with survival outcomes in multivariate analysis included primary refractory disease, elevated serum lactate dehydrogenase (LDH) at relapse, and MYC or BCL2 protein or gene expression. A bioclinical score using these four factors predicted outcome with 3-year EFS for cases with 0-1 vs 2-4 factors of 55% vs 16% (P<0.0001), respectively, assessing MYC and BCL2 by immunohistochemistry, 46% vs. 5% (P<0.0001) assessing MYC and BCL2 messenger ribonucleic acid (mRNA) by digital gene expression, and 42% vs 21% (P=0.079) assessing MYC and BCL2 by FISH. This proposed bioclinical model should be further studied and validated in other datasets, but may discriminate relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients who could benefit from conventional salvage therapy from others who require novel approaches. The LY12 study; clinicaltrials.gov Identifier: 00078949.

Trial registration: ClinicalTrials.gov NCT00078949.

Figure 1.

Relationship between IHC, digital GEP and FISH testing, and results for overlapping cases. FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; GEP: gene expression profiling.

Figure 2.

Hazard ratios by different thresholds of MYC and BCL2 GEP for EFS and OS. Vertical dash line indicates pre-specified 1.5× median threshold used in the analysis. EFS: event-free survival; OS: overall survival; mRNA: messenger ribonucleic acid.

Figure 3.

Outcome of rrDLBCL according to bioclinical model score comparing 0–1 factors (low-risk) vs. 2–4 factors (high-risk), where factors include: primary refractory disease, elevated LDH, MYC expression, and BCL2 expression. Bioclinical model assessing MYC and BCL2 by IHC (Figure 3A EFS, Figure 3B OS) or by GEP (Figure 3C EFS, Figure 3D OS). EFS: event-free survival; OS: overall survival; GEP: gene expression profiling; IHC: immunohistochemistry.