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

Khouja, Mouhamad ; Genuardi, Elisa; Ferrero, Simone ; Laqua, Anna; Alessandria, Beatrice; Verhagen, Onno J. H. M.; Homburg, Christa H. E.; Sanz, Ramón García ; Medina Herrera, Alejandro; Velden, Vincent H. J. van der ; da Silva, Maria Gomes ; Gameiro, Paula ; Doorduijn, Jeanette ; Giné, Eva; Visco, Carlo ; Brüggemann, Monika ; Baldus, Claudia D. ; Ladetto, Marco; Schmidt, Christian; Dreyling, Martin ; Jiang, Linmiao ; Hoster, Eva ; Darzentas, Nikos; Pal, Karol ; Chitadze, Guranda; Stewart, James Peter; Gonzalez, David ; Pott, Christiane und da Silva, Maria Gomes (2026): 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. In: Leukemia, Bd. 40, Nr. 1: S. 95-105

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 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie ; Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik III (Onkologie)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0887-6924
• Sprache: Englisch