Overexpression of the OCT-1 Gene Is a Biomarker Associated with Poor Outcomes in Diffuse Large B-Cell Lymphoma (DLBCL) - Data from a Retrospective Cohort from Latin America: Defining a Very High-Risk Clinical-Molecular Subgroup

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy, representing 30-40% of all non-Hodgkin's lymphomas (NHLs). They comprise a group of aggressive and heterogeneous neoplasms in terms of clinical presentation, response to therapy and prognosis. The OCT-1 gene is a member of the homodomain-POU family of transcriptional regulators of B-lymphoid differentiation. OCT-1 acts by controlling the expression of specific B-cell genes, such as BCL-2, a potent inhibitor of apoptosis that is essential for the differentiation of B-cells in the germinal center. These genes can be expressed in DLBCL, but the role of BCL-2 in its prognosis has been contradictory and the prognostic impact of the OCT-1 gene has not yet been tested in this lymphoma.

Methods: In this observational, retrospective, single-center study, we investigated the prognostic impact of BCL-2 and OCT-1 gene expression in Brazilian patients with DLCBL treated with immunopolychemotherapy R-CHOP in a real-world context. The BCL-2 and OCT-1 genes were assessed in 78.5% (77/98) DLBCL patients, and the RNA for quantitative real-time PCR (qRT-PCR) was isolated from formalin-fixed and paraffin-embedded (FFPE) samples. The values obtained for gene expression were transformed into categorical variables according to their medians (6.27 for BCL-2 and 24.5 for OCT-1). The association between clinical and laboratory variables and results of gene expression was verified by the Fischer test. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate analysis was performed using Cox's bivariate regression method and multivariate analysis using Cox multiple regression methodology.

Results: The median age of the cohort was 54.5 years (15-84), 50% (49/98) were male, 49.4% (38/77) and 51.4% (40/77) showed expression of OCT-1 and BCL- 2 ≥ median, respectively. The clinical characteristics of the 98 Brazilian patients with DLBCL that comprised our cohort are summarized in Table 1. The overall response rate (ORR) in all patients was 68.4% (67/98), 65.3% (64/98) showed a complete response (CR), and 3.1% (3/98) showed partial response (PR), while 6.1% (6/98) were primary refractory. With a median follow-up of 3.77 years (95% CI: 3.2-4.1), the median overall survival (OS) was 5.43 years (95% CI: 2.2-NR) and the median progression-free survival (PFS) was 5.15 years (95% CI: 2.9-NR). The 5-year OS and PFS was 54.2% (42.2% -64.8%) and 52.0% (40.1-62.6%), respectively. In the univariate analysis OCT-1 ≥ median was associated with shortened OS (HR: 2.45, 95% CI: 1.21-4.96, p = 0.013) and PFS (HR: 2.27, 95% CI: 1.14-4.51, p = 0.019). Overexpression of BCL-2 was associated with worse PFS (HR: 2.00, 95% CI: 1.02-3.95, p = 0.043). Subgroup analysis showed that OCT-1 overexpression predominated in elderly individuals (≥ 60 years) in a statistically significant mode (29/38 cases - 76.3%, p = 0.029). It was also observed that overexpression of OCT-1 was associated with worse OS in the high-risk adjusted International Prognostic Index (aIPI) subgroup (p = 0.048) - Figure 1, and worse PFS in patients ≥ 60 years old (p = 0.025) - Figure 2. In the multivariate analysis, overexpression of OCT-1 was associated with poor PFS (HR: 2.22, 95% CI: 1.06-4.76, p = 0.035).

Conclusion: In this study, we demonstrated that overexpression of the OCT-1 gene was an independent prognostic factor associated with adverse outcomes in Brazilian patients with DLCBL. We also show that in patients with unfavorable risk, such as the elderly and those with intermediate-high and high-risk IPI, overexpression of OCT-1 contributed to the identification of a very high-risk clinical-molecular subgroup, where the results with standard R-CHOP therapy are unsatisfactory, and they may benefit from intensified therapeutic strategies. Our results are preliminary and need to be validated in subsequent studies of prospective nature and with an expanded sample.