Next-Generation Therapies in Mantle Cell Lymphoma (MCL): The Evolving Landscape in Treatment of Relapse/Refractory After CAR-T Cells

Mantle cell lymphoma (MCL) is a biological and clinical heterogeneous disease, ranging from more indolent subtypes to highly aggressive ones with a dismal prognosis. Bruton’s tyrosine kinase inhibitors (BTKis), such as ibrutinib, ameliorated the outcome of relapse/refractory (R/R) patients, but responses are usually quite short, requiring further treatments. In this setting, immunotherapy was demonstrated to have a key role, first with chimeric antigen receptor (CAR)-T cells, which completely changed the prognosis of these patients, showing a high rate of and long-lasting responses. However, many cases do not yet respond or relapse after CAR-T cells, and a subset of patients are not eligible for CAR-T cells in the first place. In this particular setting of MCL patients, next-generation therapies are emerging, such as new non-covalent BTKi molecules and novel monoclonal antibodies (MABs), which represent a heterogeneous group of agents, including Antibody-drug conjugate (ADC) and T-cell-engaging (TCE) products. The impact of these agents is expected to be meaningful firstly on relapse/refractory disease and subsequently also in early treatment lines. The aim of this review is to explore the main therapeutic strategies emerging in the context of MCL patients who failed or are not eligible for CAR-T-cells treatment, focusing on the most relevant therapeutic drugs, especially on the different monoclonal antibodies.