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<p>Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome <i>TP53</i><sup><i>mut</i></sup><i>-</i>mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.</p>

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Noninvasive genotyping and early disease dynamics demonstrate the efficacy of ibrutinib in combination with immunochemotherapy in patients with mantle cell lymphoma treated in the TRIANGLE trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月3日

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  • Mouhamad Khouja,
  • Elisa Genuardi,
  • Simone Ferrero,
  • Anna Laqua,
  • Beatrice Alessandria,
  • Onno J. H. M. Verhagen,
  • Christa H. E. Homburg,
  • Ramón García Sanz,
  • Alejandro Medina Herrera,
  • Vincent H. J. van der Velden,
  • Maria Gomes da Silva,
  • Paula Gameiro,
  • Jeanette Doorduijn,
  • Eva Giné,
  • Carlo Visco,
  • Monika Brüggemann,
  • Claudia D. Baldus,
  • Marco Ladetto,
  • Christian Schmidt,
  • Martin Dreyling,
  • Linmiao Jiang,
  • Eva Hoster,
  • Nikos Darzentas,
  • Karol Pal,
  • Guranda Chitadze,
  • James Peter Stewart,
  • David Gonzalez,
  • Christiane Pott,
  • Maria Gomes da Silva

摘要

Adding ibrutinib to first-line immunochemotherapy (Ibru-R-chemo) showed superiority in younger mantle cell lymphoma (MCL) patients in the TRIANGLE trial (NCT02858258). To investigate response mechanisms and kinetics across treatment arms, we genotyped 57 patients from cell-free (cf)DNA using targeted-capture sequencing and investigated measurable residual disease (MRD) in cfDNA and peripheral blood by targeted-sequencing and qPCR. Pre-treatment cfDNA and circulating tumor (ct)DNA levels predicted outcomes, and precisely genotyped all patients. Circulating tumor cell (CTC)-clearance was more frequent and rapid than ctDNA-clearance across arms. At interim staging (IS), 55% of patients were ctDNA-positive while 35% and 41% were CTC-positive by qPCR and immunoglobulin gene (IG)-NGS. At end of induction, 43% were ctDNA-positive, while 15% (qPCR) and 25% (IG-NGS) were CTC-positive. MRD by qPCR was most predictive for outcomes. Ibru-R-chemo seemed to overcome TP53mut-mediated risk (hazard ratio 1.9 vs. 10) and induce early MRD response, represented by enhanced CTC (71% vs. 57%) and ctDNA clearance (59% vs. 24%) at IS. Flow-cytometry-based immunomonitoring showed ibrutinib’s influence on inhibitory T-cell phenotypes, showing ≥25% reduction in PD1+ and PD1+ KLRG1+ CD4+-T-cells in four patients. Taken together, besides direct anti-B-cell efficacy, ibrutinib improves chemotherapy efficiency by reconstituting an effective immune system and enhancing immune cell control.