Predictors of first line treatment failure in classic Hodgkin lymphoma: A comprehensive review

Classic Hodgkin lymphoma is a highly curable B-cell malignancy; however, 10-30 % of patients experience primary refractory disease or early relapse. While PET/CT is a cornerstone in response-adapted therapy, it has notable limitations, including variable sensitivity, and inability to capture molecular heterogeneity or predict minimal residual disease. Emerging non-invasive techniques such as circulating tumour DNA (ctDNA) analysis, extracellular vesicle-associated biomarkers, and cytokine profiling offer new avenues for dynamic, real-time disease monitoring. Liquid biopsy through ctDNA analysis enables early relapse detection, characterization of clonal evolution, and personalized risk stratification. Additionally, tumour-associated macrophages, tumour-derived exosomes, and immune checkpoint markers such as PD-L1 and IL1β+ monocytes/macrophages have been identified as potential indicators of non-response. Advanced molecular profiling of Hodgkin Reed-Sternberg cells further reveals key genetic mutations (e.g., SOCS1, TNFAIP3, PTPN1) contributing to immune evasion, particularly in non-responders. Despite these advancements, a critical gap remains in the integration of these novel biomarkers into clinical practice. Current studies often lack stratification of high-risk subsets, limiting the development of targeted therapies. Bridging this gap through advanced molecular profiling, immune landscape assessments, and the incorporation of novel, non-invasive techniques alongside PET/CT will be crucial for refining risk models and optimizing outcomes for patients with refractory or relapsed disease.