Targeted Treatment Additions Ibrutinib + Bortezomib + R-CHOP for Higher-Risk DLBCL: Efficacy, Feasibility and Molecular Signatures for Future Treatment Decisions

Introduction

Targeted treatment additions to R-CHOP for patients with diffuse large B-cell lymphoma (DLBCL) did fail to improve outcome in recent phase III trials. However, there are molecular subgroups that benefit, in retrospect. We have conducted an explorative single-arm open-label phase I/II study from 2017-2024, investigating ibrutinib + bortezomib + R-CHOP as proximal and distal BCR/NF-κB double-targeting strategy for higher-risk DLBCL patients with no molecular pre-selection and collected repeated lymphoma biopsies for multi-omics profiling in the course of therapy to identify molecular signatures indicative of lasting responsiveness.

Methods

Within the investigator-initiated trial (IIT) ImbruVeRCHOP, 38 newly diagnosed DLBCL patients with IPI ≥ 2 and 61-80 years of age were treated with six 21d-cycles of R-CHOP plus ibrutinib (420 mg/d p.o.) and bortezomib (1.3 mg/m² s.c. d1 + 8) followed by two subsequent applications of single-agent rituximab (ClinicalTrials.gov identifier NCT03129828, EudraCT number 2015-003429-32). Lymphoma and liquid biopsies were obstained pre treatment, once during cycle 1 and, in case of a residual and reasonably accessible tumor manifestation, once again at interim CT imaging prior to cycle 3.

Results

The follow-up phase of the study ends in 2024. Some multi-omics results such as WES and RNA seq are already available; liquid biopsy for detection of minimal residual disease as well as spatial transcriptomics and spatial proteomics are currently being processed. The study cohort with patients from Germany and Austria has a median age of 71 and reached a high R-CHOP dose adherence of 91% (compared to 73% in patients over 60 years in the PHOENIX trial, RCHOP + ibrutinib) under strongly recommended quadruple prophylaxis (G-CSF, ciprofloxacine, acyclovir, cotrimoxazole). The median follow-up is currently 18 months and the CT-based overall response rate is 73%. The primary endpoint is 2-year progression-free-survival. The toxicity profile is moderate with mostly grade 1-3 adverse events, 53% of the patients had grade 4 toxicities. 6 fatal events were observed during follow-up due to infections, secondary malignancy and lymphoma relapse.

Conclusions

The targeted treatment addition of R-CHOP with ibrutinib + bortezomib for elderly high-risk patients with DLBCL is effective and feasible. Our study will give an updated analysis of treatment outcome and insights into candidate molecular response signatures identifying patients benefiting from this therapy optimization.

Na:Octapharma: Research Funding; Novartis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: travel grants; AstraZeneca: Other. Savic:Berliner Krebsgesellschaft e.V.: Research Funding; Deutsche Forschungsgesellschaft (DFG): Research Funding; Guerbet: Honoraria, Research Funding. Bullinger:Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Hexal: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Menarini: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Bayer: Research Funding. Schmitt:Janssen Cilag: Research Funding.