Prompt Assessment of Tumor Load and Treatment Response in Patients with Lymphoma By a Blood-Based Multi-Omics Approach

Abstract

Introduction Lymphoma is a class of highly heterogeneous hematological malignancy derived from malignant clonal proliferation of lymphocytes. Periodic imaging examinations are the current standard for clinical assessment of lymphoma treatment response. Liquid biopsy is an emerging, non-invasive method for quantitative assessment of cancer treatment response. In this prospective study, we applied a noninvasive multi-omics assay named SeekInClarity to assess lymphoma treatment response and predict patient outcomes. Methods 149 patients meeting the WHO diagnosis criteria of lymphoid neoplasm were prospectively recruited from two clinical sites. The study is in progress, and 114 patients were included in the current interim analysis. 8.8% of patients who were lost to follow-up or quickly died were excluded. SeekInClarity assay integrates the analysis of genomic feature and common plasma tumor protein markers (PTMs, including AFP, CEA, CA153, CA125, CA199, CYFRA21-1 and CA724). Genomic features including copy number aberration (CNA) and the fragment size (FS) that are pan-cancer hallmarks were analyzed by shallow whole genome sequencing. Patients received SeekInClarity test before and after 1, 2, 4 and 6 cycles of treatment to generate the molecular tumor burden score (MTB). MTB positive/negative suggests that molecular signal of tumor is detectable/undetectable. Results The value of each dimension (protein marker, CNA and FS) in the prior-treatment (baseline) lymphoma samples were significantly higher than that in healthy control samples (Mann-Whitney test: P<0.001). 72.8% base line samples were MTB positive. After 2 cycles of treatment, the samples from patients who experienced disease progression showed higher MTB positivity rate than that from those without disease progression (85.7% vs. 26.7). MTB- patients showed a significantly longer progression free survival (PFS) time than MTB+ patients [HR: 12.6, 95% CI:4.1-38.6, P<0.0001] regardless of tumor stage and lymphoma subtype. Patients with reduced sample MTB values compared to baseline sample MTB values after two cycles of treatment had significantly better disease-free survival than patients with increased sample MTB values after treatment [HR: 5.0, 95% CI:0.48-52.5; P<0.0001]. We further divided the patients into two groups according to the degree of reduction in MTB values in the pre- and post-treatment samples (>50% & <50%), and we found that patients with higher MTB decrease (>50%) showed a better PFS than those with lower MTB decrease (<50%, P < 0.001). Conclusions This prospective study demonstrated that SeekInClarity, a non-invasive, multidimensional blood-based assay, can promptly evaluate the treatment response of lymphoma patients, and the MTB status showed an excellent correlation with clinical outcome. The dynamic change of MTB exhibited a good prognostic power of lymphoma. It challenged the status quo of employing imaging as a sole standard for evaluating early treatment response.