In younger patients with mantle cell lymphoma (MCL) outcomes remain heterogeneous: while standard induction with cytarabine-intensified immunochemotherapy and autologous stem cell transplantation (ASCT) can deliver durable remissions, high-risk features (such as blastoid morphology, high Ki-67, TP53 alterations, elevated MIPI) still portend adverse results. The large three-arm phase III TRIANGLE trial (NCT02858258) from the European MCL Network previously established that adding the Bruton’s Tyrosine Kinase inhibitor (BTKi) Ibrutinib to induction immunochemotherapy (and maintenance) significantly improves failure-free survival over immunochemotherapy + ASCT alone.
This new study builds on this by using circulating cell-free DNA (cfDNA) and circulating tumour DNA (ctDNA) to characterise early disease kinetics, assess measurable residual disease (MRD) dynamics and explore how ibrutinib might influence tumour cell clearance, immune reconstitution and risk stratification beyond conventional bone-marrow (BM) or peripheral-blood (PB) genomic DNA MRD assays.
In a subset of 57 advanced-stage MCL patients from the TRIANGLE trial (PB infiltration ≥10 %, available plasma and MRD data), we performed deep IGH rearrangement analysis (EuroClonality IG-NGS) and targeted-capture sequencing on both tumour cell (gDNA) and plasma/ctDNA compartments. We found that ctDNA was highly informative: the IGH::CCND1 fusion was detected in 56/57 patients via ctDNA, and somatic variants (e.g., ATM, TP53, KMT2D, CCND1, SAMHD1) were found in cfDNA in 95 % of cases, sometimes exclusively in ctDNA and not in tumour cells. Baseline cfDNA/ctDNA levels correlated with MIPI risk groups and independently predicted inferior overall survival in multivariable analysis (for example ctDNA > 3.72 log10 MMPM carried HR ~4.33).
Furthermore, MRD analyses revealed that ctDNA detection at interim-staging (IS) and end-of-induction (EoI) was more frequent than PB tumour-cell (CTC) qPCR positivity. Importantly, patients receiving ibrutinib (arms A + I or I) demonstrated faster and deeper clearance of both CTC and ctDNA: at EoI they achieved ~87 % CTC negativity vs ~74 % in the immunochemotherapy-only arm, and ctDNA negativity ~70 % vs ~43 %, respectively. The authors interpret this as evidence that ibrutinib not only enhances induction response kinetics but may mobilise tumour cells from sanctuary sites (lymph nodes) into the circulation, thus enhancing chemosensitivity.
Another notable finding: TP53 mutation detected in ctDNA (11/57 patients) predicted markedly inferior 3-year FFS (45 % vs 93 %) and OS (45 % vs 98 %) in the immunochemotherapy-only arm, but not in the ibrutinib-containing arms (3-year FFS ~83 % vs 93 %). This suggests that BTKi incorporation may partially abrogate the poor prognostic impact of TP53 alterations in first-line MCL.
Finally, a small flow-cytometry immunophenotyping cohort hinted at immune-modulatory effects of ibrutinib: reductions in PD-1^+ and KLRG1^+/PD-1^+ CD4 T-cells during induction in the ibrutinib-treated patients suggest improved T-cell fitness and potential contribution to long-term immune control beyond direct tumour cytotoxicity.
In summary, this study underlines the utility of liquid‐biopsy (cfDNA/ctDNA) in MCL for baseline profiling, early response kinetics and MRD monitoring, and provides mechanistic insight into how ibrutinib improves outcomes. In younger, transplant-eligible patients it supports the paradigm shift towards BTKi-containing induction/maintenance strategies (with or without ASCT) and highlights MRD dynamics and TP53 status as important stratifiers for future risk-adapted approaches. Further work will need to validate ctDNA thresholds, optimise MRD time-points, and determine how best to integrate MRD-guided therapeutic decisions in MCL.