TY - JOUR
T1 - Circulating Tumor DNA Determinants of Response and Outcome in Relapsed/Refractory Mantle Cell Lymphoma
AU - Meriranta, Leo
AU - Rask Kragh Jørgensen, Rasmus
AU - Pasanen, Annika
AU - Kolstad, Arne
AU - Hutchings, Martin
AU - Niemann, Carsten Utoft
AU - El Galaly, Tarec Christoffer
AU - Riise, Jon
AU - Christensen, Jacob Haaber
AU - Sonnevi, Kristina
AU - Pedersen, Lone Bredo
AU - Wader, Karin Fahl
AU - Glimelius, Ingrid
AU - Leppä, Sirpa
AU - Jerkeman, Mats
N1 - Copyright © 2025 American Society of Hematology.
PY - 2025/5/22
Y1 - 2025/5/22
N2 - 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.
AB - 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.
U2 - 10.1182/bloodadvances.2025015791
DO - 10.1182/bloodadvances.2025015791
M3 - Journal article
C2 - 40402132
SN - 2473-9529
JO - Blood advances
JF - Blood advances
ER -