Precision Medicine in Non-Hodgkin Lymphoma: Advances in BTK Inhibition, CD30-Directed Antibody-Drug Conjugates, and HDAC-Mediated Epigenetic Therapy with Pirtobrutinib, Brentuximab Vedotin, and Belinostat.

Non-Hodgkin lymphoma (NHL) encompasses a biologically diverse group of malignancies for which the integration of precision medicine has markedly reshaped therapeutic strategies. Recent advances in molecular profiling, target identification, and drug development have led to the introduction of highly selective agents capable of overcoming resistance mechanisms and improving outcomes in relapsed or refractory disease. This review highlights three targeted therapies-pirtobrutinib, brentuximab vedotin, and belinostat-and their evolving roles in modern NHL management. Pirtobrutinib, a next-generation, non-covalent Bruton tyrosine kinase (BTK) inhibitor, demonstrates preserved activity in patients previously treated with covalent BTK inhibitors (BTKi), addressing a critical unmet need in B-cell lymphomas. Brentuximab vedotin, an antibody-drug conjugate targeting CD30, has significantly improved therapeutic precision by delivering cytotoxic agents directly to lymphoma cells and has become a central component of treatment for CD30-expressing NHL subtypes. Belinostat, a broad-spectrum histone deacetylase (HDAC) inhibitor, offers a mechanistically distinct epigenetic approach, particularly in peripheral T-cell lymphomas (PTCL), where conventional chemotherapy has limited efficacy. Together, these agents exemplify three complementary paradigms of precision oncology in NHL: kinase signaling inhibition, antigen-directed cytotoxic delivery, and epigenetic modulation. This review synthesizes current evidence, clinical trial data, and future perspectives regarding the integration of pirtobrutinib, brentuximab vedotin, and belinostat into evolving treatment paradigms. Cumulatively, these therapies illustrate both the progress and the ongoing challenges of biomarker-driven treatment in NHL, including resistance mechanisms, toxicity management, optimal therapeutic sequencing, and variability in evidence maturity across targeted strategies. While pirtobrutinib and brentuximab vedotin are supported by increasingly robust clinical evidence in selected lymphoma subtypes, the role of belinostat remains constrained by modest response rates and limited randomized data, underscoring the continued need for biomarker refinement and more precisely individualized therapeutic approaches in NHL precision medicine.