Standard therapies versus novel therapies in Hodgkin lymphoma

The prognostic models in Hodgkin lymphoma (HL) such as the International Prognostic Score (IPS), retrospectively constructed in the last twenty years from different cohorts of patients treated with ABVD or ABVD-equivalent regimens have been shown a limited predictive value on treatment outcome when applied to a prospective cohort of patients. In the turn of millennium a new class of prognostic factors has emerged, aimed to test the chemosensitivity to treatment in a single patient-basis, such as the minimal residual disease (MRD) assessment with molecular biology, or interim PET/CT performed early during treatment. The main challenge in the management of both early and advanced-stage HL is to achieve a durable remission or cure while minimizing therapy toxicity. An adaptive therapy strategy based on interim PET results could distinguish high from low-risk patients: the former with a potential benefit from an intensify regimen, the latter in whom treatment could be de-escalated or abbreviated for minimizing long-term adverse effects. Conversely, chemosensitivity evaluation in early-stage HL has been the underpinning of de-escalation trials aimed at assessing the safety and the efficacy of omitting radiotherapy in interim PET-negative patients. Brentuximab Vedotin (BV) is a novel antibody-drug conjugate targeting CD30 linked to a potent synthetic antitubulin chemotherapeutic agent, monomethyl auristatin E (MME). BV showed an impressive activity against refractory/relapsed HL and now is being incorporated in a modified ABVD schedule in first-line treatment of HL, with promising efficacy and a low toxicity profile. This novel therapeutic strategy will tell us if traditional ABVD or BEACOPP chemotherapy could be abandoned for the brand-new targeted therapy. Despite the brilliant results of HL treatment, which proved able to achieve a long-term disease control in 80-90% of the patients, the search of new prognostic has continued over the last two decades and the progress of the knowledge of the pathobiology of HL has led to a discovery of a series of markers related to microenvironment of HL tissue and molecular mechanisms to escape host immune reaction against the tumor. The strong association between the locus A of the human leukocyte antigen (HLA-A) system and EBV-positive HL suggests that both an abnormal antigen presentation and some specific EBV antigen per se could play a pivotal role in the pathogenesis of cHL. In EBV+HL patients, the susceptibility or the resistance to develop HL depends on the HLA allele A-*01 or A-*02, respectively. Tumor escape mechanism to block the immune response of the host against the neoplastic tissue is one of the property of a recently discovered subset of myeloid-derived suppressor cells (MDSC) that induce tumor vasculogenesis and escape from immunity via T cell suppression. Initially, these myeloid cells were identified as granulocytes or monocytes; however, MDSC derive from multipotent progenitor cells that can differentiate in the tissue as monocyte-derived MDSC (Mo-MDSC) with a phenotype CD14+/dull and granulocyte-derived MDSC (G-MDSC) expressing CD15 on cell surface. The latter were shown to produce arginase. Recent investigations suggest that MDSC present in the bone marrow in patients with several solid and hematological cancers in response to chemokine release in the tumor site are correlated with tumor-associated macrophages (TAM). Both TAM and MDSC have been strongly associated with a significantly worse prognosis in HL. As a consequence, several efforts are ongoing to standardize the methods to assess TAM and MDSC and prospective studies are being planned to validate their prognostic role.