Advances in First-Line Treatment of Classical Hodgkin Lymphoma in the Era of Novel Agents

Classical Hodgkin lymphoma (cHL) remains one of the most curable hematologic malignancies, with long-term survival exceeding 80–90% in most contemporary series. However, a subset of patients experience primary refractory disease, relapse, treatment-related toxicity, or late complications associated with conventional chemotherapy and radiotherapy. Over the last decade, major advances in frontline treatment have transformed the therapeutic landscape of cHL through the incorporation of targeted therapy and immune checkpoint inhibition into first-line regimens. Brentuximab vedotin (BV), an anti-CD30 antibody–drug conjugate, and programmed death-1 (PD-1) inhibitors such as nivolumab and pembrolizumab have significantly improved outcomes in advanced-stage disease and are increasingly being explored in limited-stage settings. The ECHELON-1 trial established BV-AVD as superior to ABVD in advanced-stage disease with improved progression-free survival and overall survival, while the SWOG S1826 study demonstrated superior progression-free survival and reduced toxicity with nivolumab-AVD compared with BV-AVD. Based on the SWOG S1826 data, nivolumab-AVD is emerging as the preferred frontline standard for most fit patients with advanced-stage cHL, though this remains an area of evolving practice. PET-adapted strategies remain a critical backbone of treatment optimization even in the era of novel agents, enabling individualized de-escalation or escalation based on early metabolic response. These advances have shifted frontline treatment paradigms toward chemotherapy de-escalation, PET-adapted strategies, and immune-based treatment approaches. In parallel, the role of radiotherapy continues to evolve with efforts aimed at minimizing long-term toxicity without compromising cure rates, particularly in PET-negative patients with limited-stage disease. This review summarizes the biological rationale, pivotal clinical trials, evolving treatment strategies, current guideline recommendations, and future directions in first-line treatment of cHL, with emphasis on evidence-based incorporation of novel agents and practical implications for modern clinical practice.