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.

2nd Medical Department University Hospital Schleswig Holstein Kiel Germany

CEITEC MU Central European Institute of Technology Masaryk University Brno Czech Republic

CIBERONC Hospital Universitario de Salamanca IBSAL Universidad de Salamanca Salamanca Spain

Clinical Research Unit CATCH ALL Christian Albrechts University of Kiel Kiel Germany

Department of Engineering for Innovative Medicine University of Verona Verona Italy

Department of Hematology Erasmus MC Cancer Institute University Medical Center Rotterdam Rotterdam Netherlands

Department of Immunocytology Sanquin Diagnostic Services Amsterdam The Netherlands

Department of Medicine 3 University Hospital Ludwig Maximilian University Munich Germany

Department of Molecular Biotechnologies and Health Sciences Hematology Division Università di Torino Torino Italy

Haematology Unit Instituto Português de Oncologia de Lisboa Francisco Gentil Lisbon Portugal

Hematology Department Hospital Clínic de Barcelona IDIBAPS Barcelona Spain

Institute for Medical Information Processing Biometry and Epidemiology LMU University Munich Munich Germany

Laboratory Medical Immunology Department of Immunology Erasmus MC University Medical Center Rotterdam Rotterdam The Netherlands

Precision Medicine Centre Patrick G Johnston Centre for Cancer Research Queen's University Belfast Belfast United Kingdom

SC Ematologia Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo Alessandria Italy

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