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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\n                    <jats:italic>TP53<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>mut<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>-<\/jats:italic>\n                    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\u2019s influence on inhibitory T-cell phenotypes, showing \u226525% 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.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02787-0","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T06:43:01Z","timestamp":1762152181000},"page":"95-105","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["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"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9892-9461","authenticated-orcid":false,"given":"Mouhamad","family":"Khouja","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Genuardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9711-1502","authenticated-orcid":false,"given":"Simone","family":"Ferrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laqua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice","family":"Alessandria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onno J. 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VHJV: BD biosciences: Other: laboratory services agreement; Agilent: Other: laboratory services agreement; Cytognos: Other: laboratory services agreement; Euroflow: Patents & Royalties. M.B. Amgen: Honoraria, Research Funding, Travel Support. Incyte: Honoraria. Janssen: Honoraria. Pfizer: Honoraria. Cytognos: Other: laboratory services agreement; Euroflow: Patents & Royalties. RGS: Janssen: Honoraria, Other: Travel support, Research Funding; BeiGene: Honoraria, Other: Travel Support; Gilead: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria, Research Funding; GSK: Honoraria, Other: Travel Support; Astra Zeneca: Honoraria; In Vivo Scribe: Patents & Royalties: Indirect perception, Euroclonality primers; Novartis: Honoraria, Research Funding. EG: Janssen: Honoraria, Research Funding; Lilly: Honoraria, Research Funding; Roche: Honoraria; Gilead: Honoraria; Astra Zeneca: Honoraria. CV: J and J: Honoraria, Research Funding; Lilly: Honoraria; Roche: Honoraria; Gilead: Honoraria; Astra Zeneca: Honoraria; Incyte: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Kyowa Kirin: Honoraria; BeiGene: Honoraria; Sobi: Honoraria. MD: Astra Zeneca, Beigene, BMS\/Celgene, Gilead\/Kite, Janssen, Lilly\/Loxo, Novartis, Roche: Consultancy; Abbvie, Bayer, BMS\/Celgene, Gilead\/Kite, Janssen, Roche: Research Funding; Amgen, Astra Zeneca, Gilead\/Kite, Janssen, Lilly, Novartis, Roche: Honoraria. DG: AstraZeneca, Roche, Amgen, Eli Lilly, Novartis, Menarini, Janssen, Illumina, Incyte: Consultancy and Honoraria; AstraZeneca, Roche: Research Funding; Univ8 Genomics Ltd.: Other: Founder and Director of Univ8 Genomics Ltd.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The trial was led according to the Declaration of Helsinki. All patients gave their written informed consent after have been informed about the purpose and investigational nature of the trial. Prior to initiation, the clinical trial including molecular analysis received approval by the ethics committee of the medical faculty of Ludwig-Maximilian-University of Munich with the reference number 659-15 fed.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}