https://orcid.org/0000-0002-6378-5381
Key Points
Multiple dimensions of ctDNA expose heterogeneity in relapsed/refractory mantle cell lymphoma to predict response and outcome
Dynamic ctDNA assessment by duplex sequencing complements radiological evaluation and response measurement by circulating tumor cells
Clinical tools to guide treatment decisions in relapsed and refractory mantle cell lymphoma (R/R MCL) are limited. Moreover, the translational potential of circulating tumor DNA (ctDNA) remains largely unproven. We designed and applied panel-based duplex sequencing of ctDNA to study molecular determinants of response and outcome in 58 R/R MCL patients treated with venetoclax, lenalidomide, and rituximab. Genetic analysis revealed molecular predictors of response that were independent of clinical prognostic factors, with SMARCA4-mutated R/R MCLs responding to therapy, whereas TP53 mutations conferred resistance. Pretreatment ctDNA captured spatial heterogeneity, and its concentration was associated with multiple clinicopathological disease features and survival, independently of molecular predictors. Dynamic ctDNA assessment for minimal residual disease complemented clinical response evaluation and uncovered refractoriness in patients with molecular remission according to contemporary real-time quantitative PCR assay. Features of clonal hematopoiesis (CH) at baseline were associated with hematological toxicity during treatment and poor outcomes on follow-up. Positive selection of TP53-related CH during treatment did not compromise the specificity of ctDNA response analysis, and fragmentation signatures allowed distinction between MCL ctDNA and CH-bearing cfDNA. Taken together, we report novel features in MCL ctDNA that reveal new minimally invasive tools that could potentially transform clinical decision-making in R/R MCL.
