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

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 TP53<sup>mut</sup>-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.

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Journal
Leukemia
Published
2025-11-03
DOI
https://doi.org/10.1038/s41375-025-02787-0
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Christa Homburg, Jeanette K. Doorduijn, Simone Ferrero, Vincent H. J. van der Velden et al.
Leukemia
Lymphoma Diagnosis and Treatment
article

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

Christa Homburg, Jeanette K. Doorduijn, Simone Ferrero, Vincent H. J. van der Velden, María Gomes da Silva, Anna Laqua, Eva Hoster, Paula Gameiro, Claudia Dorothea Baldus, Alejandro Medina, Carlo Visco, Martin H. Dreyling, Beatrice Alessandria, Linmiao Jiang, Mouhamad Khouja, Eva Giné, Elisa Genuardi, Guranda Chitadze, Ramón García‐Sánz, O. J. H. M. Verhagen, Peter Stewart, Monika Brüggemann, Marco Ladetto, Nikos Darzentas, Karol Pál, Christian Schmidt, David González de Castro, Christiane Pott
article en

Abstract

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 TP53<sup>mut</sup>-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.

LeukemiaVol. 40(1)
University of Verona (IT), Queen's University Belfast (GB), Central European Institute of Technology (CZ), Universidad de Salamanca (ES), Masaryk University (CZ), Erasmus MC (NL), Sanquin (NL), Christian-Albrechts-Universität zu Kiel (DE), Central European Institute of Technology – Masaryk University (CZ), Zimmer Biomet (Germany) (DE), IPO Porto (PT), University Hospital Schleswig-Holstein (DE), Hospital Clínic de Barcelona (ES), Instituto de Investigación Biomédica de Salamanca (ES), Instituto Português de Oncologia de Coimbra Francisco Gentil (PT), Erasmus MC Cancer Institute (NL), Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo (IT), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Turin (IT), Ludwig-Maximilians-Universität München (DE), University of Lübeck (DE)
Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, Gilead Sciences, Celgene, BeiGene, Incyte, Astellas Pharma, Servier, Swedish Orphan Biovitrum, MorphoSys
Openalex Percentile: Top 55%
Lymphoma Diagnosis and Treatment
DOIOpen Access PDFOpenAlex
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