Distinct molecular determinants of treatment‐failure in elderly Hodgkin lymphoma identified by cell‐free DNA profiling: A LYSA Study

Introduction: While nearly all younger patients (pts) with Hodgkin's lymphoma (HL) are cured with conventional chemotherapy, outcomes are significantly worse in those over age 60. Intriguingly, among older HL pts, those with EBV+ disease have even poorer outcomes (Keegan et al., JCO 2005), yet the biological basis for this phenomenon is not understood. The paucity of malignant cells in HL tumors has hampered genomic studies. Circulating tumor DNA (ctDNA) profiling can overcome these limitations, allowing noninvasive genotyping and risk stratification in HL (Spina et al., Blood 2018; Alig et al., ASH 2022). Here, we use a fully non-invasive approach for genomic profiling of elderly HL pts, focusing on the impact of ctDNA and EBV status on clinical outcomes. Methods: We profiled 57 pts (64%) from NCT02414568, a prospective, multicenter phase II LYSA-PVAB study of newly diagnosed classical HL >60 years (Ghesquières et al., ASH2019). All pts received 6 cycles of PVAB (prednisone, vinblastine, doxorubicin, and bendamustine). Plasma cfDNA was genotyped using Cancer Personalized Profiling by Deep Sequencing (CAPP-Seq); MRD was monitored using Phased variant Enrichment and Detection Sequencing (PhasED-Seq). Pts were classified into high and low pretreatment ctDNA levels using a threshold of 2.5 log hGE/mL (Alig et al., ASH2022). We defined EBV status either by LMP1 staining of FFPE tumor tissue or by VirCAPP-Seq targeting 180 viral species, where a predefined threshold of 32 genomes/ml was previously validated as 94% accurate (Garofalo et al., ASH 2022). Results: Pretreatment ctDNA was detected in 94% of pts with a median concentration of 2.2% (MAF), which was significantly correlated with disease burden measured by TMTV (p = 0.034). Pts with high pre-treatment ctDNA levels (39%) had significantly worse PFS (HR = 2.3, p = 0.039). EBV+ pts also had inferior PFS (HR = 2.2, p = 0.04) and OS (HR = 3.1, p = 0.028) (Figures A-B). In multivariate analysis, both indices remained independently associated with worse outcomes (HR = 2.5, p = 0.01 for pre-treatment ctDNA and HR = 2.7, p = 0.01 for EBV status). Interestingly, pre-treatment ctDNA levels did not differ between EBV+ and EBV- tumors (p = 0.92), while specific genetic aberrations were significantly associated with respective EBV status (Figure C). Among evaluable pts for MRD monitoring, detection of ctDNA after four cycles of chemotherapy was highly associated with risk of death (Figure D). The research was funded by: NIH/NCI R01 R01CA257655 Keywords: Diagnostic and Prognostic Biomarkers, Genomics, Epigenomics, and Other -Omics, Hodgkin lymphoma Conflicts of interests pertinent to the abstract. C. Rossi Consultant or advisory role: Genmab, Janssen, Incyte Educational grants: Kyte, Abbvie S. K. Alig Consultant or advisory role: Takeda Pharmaceuticals D. M. Kurtz Consultant or advisory role: Adaptive Biotechnologies, Roche, Foresight O. Casasnovas Consultant or advisory role: Roche, Takeda Educational grants: Roche, Takeda, BMS, Janssen A. A. Alizadeh Consultant or advisory role: Adaptive Biotechnologies, Foresight Diagnostics, Roche, BMS, Gilead, Genentech, Karyopharm