Circulating tumor DNA determinants of response and outcome in relapsed/refractory mantle cell lymphoma

Clinical tools to guide treatment decisions in relapsed/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 patients with R/R MCL 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 polymerase chain reaction assay. Features of clonal hematopoiesis (CH) at baseline were associated with hematologic 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 cell-free DNA. 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.