{"doi":"10.1002/hon.70096_477","title":"477 | LONGITUDINAL MULTI‐OMICS INVESTIGATION IN IBRUTINIB‐BORTEZOMIB‐R‐CHOP‐TREATED DLBCL PATIENTS","abstract":"Introduction: Enormous efforts have been made to improve first-line treatment in highly heterogeneous diffuse large B-cell lymphoma (DLBCL), with positive trials largely relying on initial molecular profiling to mark benefitting patients. In order to overcome this, we designed an explorative trial with targeted treatment additions, and extensive biosampling of fresh frozen tumor and blood-based liquid biopsies before treatment, acutely during cycle 1, and, in case of a residual tumor manifestation at interim staging, prior to cycle 3. This approach is unique and was not implemented in previous clinical studies. Methods: The prospective, phase I/II, investigator-initiated trial (IIT) “ImbruVeRCHOP”, treated 38 DLBCL patients with IPI ≥ 2 and 61–80 years of age, in first-line with six 21d-cycles of R-CHOP as well as ibrutinib (420 mg/d orally daily C1–6) and bortezomib (1.3 mg/m2 subcutaneously at C1–6, d1 + 8) followed by two cycles of rituximab only (ClinicalTrials.gov identifier NCT03129828, EudraCT number 2015-003429-32). Results: With a follow-up phase of 30 months by the end of 2024, the study met its primary endpoint, a superior 2-year progression-free-survival of 76% (exceeding the per-protocol comparator of 67%). Patients achieved high treatment adherence of 91% for the R-CHOP backbone, which was enabled by quadruple prophylaxis (G-CSF, ciprofloxacine, acyclovir, cotrimoxazole). Overall response rate was 86%. 36 of 38 patients were included for molecular analyses with whole-exome sequencing, bulk- and small-RNA sequencing, 10x Xenium-based spatial single-cell transcriptomics and the most current version of the EuroClonality-NGS DNA capture panel for minimal residual disease. Conclusions: Our interim report at ICML 2023 indicated that the ibrutinib + bortezomib extension of R-CHOP is feasible and effective in this elderly higher-risk all-comer first-line population. The now updated report will present the final clinical trial data and locate them within the current landscape of molecular classifications and other clinical studies. Most importantly, we present liquid biopsy results paired with multi-layered omics information including spatial single-cell omics to dissect acute molecular response dynamics and to distinguish treatment responders from non-responders to an BCR/NF-κB double-targeting treatment extension of the R-CHOP backbone. Research funding declaration: This study is supported by Janssen-Cilag, and further by grants to C.A.S. from the BMBF, the Deutsche Forschungsgemeinschaft, the Berliner Krebsgesellschaft, the Förderverein Hämatologie und internistische Onkologie, and from the Deutsche Krebshilfe. S.D., A.B., M.F., and J.K.: (Digital) Clincian Scientist Program by Berlin Institute of Health. Keywords: aggressive B-cell non-Hodgkin lymphoma; molecular targeted therapies Potential sources of conflict of interest: U. Keller Other remuneration: U.Ke. reports personal fees from Janssen Cilag, outside the submitted work (Advisory board fees, speakers honorary, and travel support). R. Marks Consultant or advisory role: participated in an Advisory board with Janssen-Cilag C. A. Schmitt Other remuneration: C.A.S. receives honoraria for medical advice from Roche and Janssen-Cilag, and coordinates clinical research (namely the ImbruVeRCHOP trial) partly funded by Janssen-Cilag.","journal":"Hematological Oncology","year":2025,"id":568505,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1472767,"name":"Aitomi Bittner","orcid":"0000-0001-6434-0950","position":1,"is_corresponding":false},{"id":1473330,"name":"Mareike Frick","orcid":null,"position":2,"is_corresponding":false},{"id":1473331,"name":"J. 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Hoffmann","orcid":null,"position":4,"is_corresponding":false},{"id":1472768,"name":"Corinna Trenker","orcid":"0000-0002-4573-7802","position":5,"is_corresponding":false},{"id":1130863,"name":"Ulrich Keller","orcid":"0000-0002-8485-1958","position":6,"is_corresponding":false},{"id":1473333,"name":"Christian Bogner","orcid":null,"position":7,"is_corresponding":false},{"id":1194689,"name":"Andreas Hüttmann","orcid":"0000-0003-2230-3873","position":8,"is_corresponding":false},{"id":1472769,"name":"Jan Dürig","orcid":"0000-0002-7672-3905","position":9,"is_corresponding":false},{"id":1034644,"name":"Martin Janz","orcid":"0000-0002-1127-0044","position":10,"is_corresponding":false},{"id":1034661,"name":"Stephan Mathas","orcid":"0000-0001-9626-1413","position":11,"is_corresponding":false},{"id":1472770,"name":"Reinhard Marks","orcid":"0000-0001-9513-7971","position":12,"is_corresponding":false},{"id":1472771,"name":"Tim Strüßmann","orcid":"0000-0002-4975-1599","position":13,"is_corresponding":false},{"id":1473334,"name":"I. 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