Early Assessment of Lymphoma Therapeutic Efficacy Via a Blood-Based Multi-Omics Test

Introduction: Lymphoma is a heterogeneous group of hematological malignancies originating from the clonal proliferation of lymphocytes. Periodic functional imaging examinations are the current standard for clinical assessment of treatment response. In this prospective study, we applied a blood-based multi-omics test, SeekInClarity, to assess treatment response and predict patient outcomes in the major types of lymphoma. Methods : We prospectively recruited 116 patients with various lymphoma subtypes from two clinical centers, The First Affiliated Hospital of Zhengzhou University and Sun Yat-sen University Cancer Center. Blood samples were collected at pre-treatment (baseline) and after two cycles of treatment (landmark) for the analysis. Molecular tumor burden (MTB) score was determined by SeekInClarity, which integrated genomic hallmarks such as copy number aberrations (CNA) and fragment size (FS) from shallow whole-genome sequencing (sWGS, 3x coverage) of cfDNA with seven protein markers. MTB status at landmark and the dynamic change in MTB between baseline and landmark were used to assess which patients would benefit from various first-line regimens. Results: At 95.0% specificity, cancer signals were detected in 74.1% (86/116) of patients at baseline. Advanced tumor stages correlated with higher MTB scores, with MTB+ ratios of 31.8%, 63.6%, 84.6%, and 91.2% for stage I, II, III, and IV, respectively. After two cycles of treatment, MTB+ patients had significantly worse progression-free survival (PFS) compared to the MTB- patients (HR: 0.13, 95% CI, 0.05-0.33, P < 0.001). Overall survival (OS) was significantly worse in the MTB+ group (HR: 0.24, 95% CI, 0.06-0.97, P < 0.05) as well. These findings were consistent across stages, subtypes, and regimens. There was no OS difference between the patients grouped by high or low expression of the traditional biomarker lactate dehydrogenase (LDH) or β2-microglobulin (B2M). The disease progression (PD) rate was 5.2 times higher in the MTB+ group compared to the MTB- group (41.5% vs 8.0%, P < 0.001), demonstrating superior effectiveness compared to LDH (1.1 times, 20.7% vs 18.1%, P = 0.15) and B2M (3.1 times, 43.8% vs 14.0%, P = 0.02). All 116 patients, except four with stable disease, were classified as partial or complete response at landmark based on imaging. However, 13 patients progressed within six months after treatment, with six patients (46.2%) detected in advance through MTB reduction at landmark. Meanwhile, higher MTB reduction at landmark were associated with better OS (P < 0.05). Multivariate Cox regression analysis confirmed that MTB reduction at landmark was an independent prognostic indicator for PFS, showing a significant increase in disease progression when MTB reduction was low (HR: 0.11, 95% CI: 0.03-0.42, P < 0.001), while the other clinical parameters were not significant Conclusions: This study demonstrates the clinical effectiveness of the blood-based multi-omics SeekInClarity test in assessing lymphoma treatment response. On-treatment reduction of MTB correlates with patient survival and predicts efficacy in advance. Additionally, MTB status after two cycles of treatment serves as an independent prognostic factor for both PFS and OS.