Biologic Classification of Hodgkin Lymphoma: A New Era for an Old Disease?

For over 50 years, the management of Hodgkin lymphoma (HL) has been based on stage at presentation and more recently by initial treatment response on interim PET scan; unlike with other lymphomas, histomorphology has not guided therapy, except for nodular lymphocyte-predominant HL. Investigators report a retrospective analysis of circulating plasma tumor DNA sequencing, gene expression profiling, and tumor microenvironment (TME) profiling in blood and tissue samples from patients enrolled in trials for previously untreated advanced-stage HL (German Hodgkin Study Group HL21) and early-stage unfavorable HL (NIVAHL). Samples and patient outcomes from a frontline pediatric HL trial (EuroNet-PHL-C2) served as the validation cohort. Minimal residual disease (MRD) was assessed after two cycles of combination chemotherapy for patients in the HL21 trial.

Three biologic HL subtypes were identified and confirmed in the external validation cohort:

• Inflammatory immune escape HL — frequent chromosomal copy number variations, including 9p24.1 amplification containing PD-L1
• Virally-driven HL — enrichment of HL-associated Epstein-Barr virus and/or human herpesvirus 6
• Oncogene-driven HL — mutations in NFkB and interferon signaling, MHC-1-Ag presentation, and cell cycle regulation.

TME characterization also showed three distinct gene expression profiles that correlated with the biologic subtypes, as did TME immune cell composition.

Three-year progression-free survival was improved after two treatment cycles in MRD-negative versus MRD-positive patients with inflammatory immune escape HL (91.5% vs. 55.5%) and virally driven HL (95.1% vs. 72.5%), whereas outcomes were similar between MRD-negative and MRD-positive patients with oncogene-driven HL (3-year PFS >90%).