Biomarkers and novel therapeutic approaches for diffuse large B-cell lymphoma in the era of precision medicine

Abstract

Despite the great efforts for better treatment options for diffuse large B-cell lymphoma (DLBCL) (most common form of non-Hodgkin lymphoma, NHL) to treat and prevent relapse, it continues to be a challenge. Here, we present an overview of DLBCL and address the diagnostic assays and molecular techniques used in its diagnosis, role of biomarkers in detection, treatment of early and advanced stage DLBCL, and novel drug regimens. We discuss the significant biomarkers that have emerged as essential tools for stratifying patients according to risk factors and for providing insights into the use of more targeted and individualized therapeutics. We discuss techniques such as gene expression studies, including next-generation sequencing, which have enabled a more understanding of the complex pathogenesis of DLBCL and have helped determine molecular targets for novel therapeutic agents. We examine current treatment approaches, outline the findings of completed clinical trials, and provide updates for ongoing clinical trials. We highlight clinical trials relevant to the significant fraction of DLBCL patients who present with complex cases marked by high relapse rates. Supported by an increased understanding of targetable pathways in DLBCL, clinical trials involving specialized combination therapies are bringing us within reach the promise of an effective cure to DLBCL using precision medicine. Optimization of therapy remains a crucial objective, with the end goal being a balance between high survival rates through targeted and personalized treatment while reducing adverse effects in DLBCL patients of all subsets.

Keywords: DLBCL; R-CHOP; diagnosis; precision medicine; prognosis.

Figure 1. Key oncogenetic pathways and major molecular subtypes of DLBCL.

DLBCL may arise from multiple oncogenetic alterations in B-cells. The main oncogenic pathways involve the translocation of genetic material, gene amplification, and somatic hypermutations (SMH). The two major molecular subtypes of DLBCL, the germinal center, and the activated type, are listed.

Figure 2. Novel drug targets and pharmacological therapies under investigation for the treatment of DLBCL.

Abbreviations: RTK: Receptor tyrosine kinases; IL-2: Interleukin 2; ILR: Interleukin receptor; TCR: T-cell receptor; HLA: Human leukocyte antigen; APC: Antigen-presenting cells; TNF-α: Tumor necrosis factor-α; VEGF: Vascular endothelial growth factor; Ac: Acetyl group. HDACs: Histone deacetylase; DNAMTs: DNA methyltransferases; RAR: Retinoic acid receptor.

Figure 3. Illustration of chimeric antigen receptor T-cell (CAR-T) immunotherapy approach.

CAR-T immunotherapy approach allows the use of the patient’s T-cells to attack cancer cells. CAR-T immunotherapy requires collecting patient’s immune cells and modifying them to express specific CARs that recognize specific cancer antigens by transfecting T- cells with viral vectors. Once T cells are successfully engineered to express the antigen-specific CAR, they are expanded and then re-administered into the patient to recognize and kill cancer cells.