# 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

## TL;DR

The TRIANGLE trial shows that adding ibrutinib to standard treatment improves outcomes in mantle cell lymphoma patients by enhancing immune response and reducing cancer markers.

## Contribution

This study demonstrates how ibrutinib improves chemotherapy outcomes by reconstituting immune function and reducing tumor markers in mantle cell lymphoma.

## Key findings

- Pre-treatment ctDNA levels predicted patient outcomes and allowed precise genotyping.
- Ibru-R-chemo showed enhanced CTC and ctDNA clearance compared to standard treatment.
- Ibru-R-chemo reduced inhibitory T-cell markers like PD1+ and PD1+ KLRG1+ CD4+-T-cells.

## 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.