Pediatric Hodgkin lymphoma: biomarkers, drugs, and clinical trials for translational science and medicine

Abstract

Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

Keywords: Hodgkin lymphoma; adolescent; biomarker; pediatric; tumor microenvironment.

Figure 1. Potential molecular biomarkers in pediatric Hodgkin lymphoma

Interplay of biomarkers in different molecular networks in the tumor microenvironment of Hodgkin lymphoma presenting with infiltration, evasion, and metastasis. Bcl-2, B-cell lymphoma 2; HA, Hyaluronic acid; ICAM-1, Intercellular Adhesion Molecule 1; IκB, Inhibitor of κB; IKK, IκB kinase; LFA-1, Lymphocyte Function Antigen-1; LMP-1, latent membrane protein 1; Th, T helper; VEGEF, Vascular Growth Endothelial Factor.

Figure 2. Molecular targets and agents affecting specific targets in pediatric Hodgkin lymphoma

Multiple pathways are implicated in Hodgkin lymphoma and thus present potential targets for therapy. The various targets and agents illustrate the need for future clinical trials to focus on synergistic action of inhibitors to kill tumor cells. The drugs are listed in blue boxes adjacent to the corresponding target. HDAC, histone deacetylase; MMAE, monomethyl auristatin E; PD1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.