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Abstract
BackgroundHigh risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.Methods and materialsBioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses.ResultsTo identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFβ1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients.ConclusionThe results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing).
Highlights
High risk, unfavorable classical Hodgkin lymphoma includes those patients with primary refractory or early relapse, and progressive disease
Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues
Retrospective clinical samples of peripheral blood leukocytes (PBL) collected from 25 NS-classical Hodgkin lymphoma (cHL) patients were categorized into three groups mainly on the basis of their response to frontline therapy: 1) good outcome pre-therapy: chemo-na ïve relapse free/progression-free survival > 4 years (GO, n=12); 2) poor outcome pre-therapy: chemo-naïve primary refractory or early relapsing (PO(CN), n=6; 3) poor outcome post-therapy: chemo-exposed, multiple relapse within 4 years (PO(CE), n=7)
Summary
Unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. The International Prognostic Score was introduced to improve the risk stratification of patients [3], its applicability is limited for predicting high risk cHL patients, regardless of clinical stage While patients in this group may benefit from analysis of the tumorassociated macrophage marker CD68, which can be used to predict adverse outcomes of cHL [4], the prediction is controversial [5]. Brentuximab vedotin therapy improved clinical outcomes for relapsing and refractory classical HL (RR-cHL) patients by producing survival times that were 6 months longer than for patients on the conventional treatment arm [6]. This increased survival could perhaps be due to increased chemoresistance that can result from heavy pretreatment. The availability of biomarkers that identify patients who will have a poor outcome to conventional frontline therapy will permit more aggressive treatment of these patients, improving their prognosis
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