{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:09:22Z","timestamp":1791324562759,"version":"4.3.1"},"reference-count":167,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The R-CHOP immunochemotherapy protocol has been the first-line (1L) standard of care (SOC) for diffuse large B-cell lymphoma (DLBCL) patients for decades and is curative in approximately two-thirds of patients. Numerous randomized phase III trials, most of them in an \u201cR-CHOP \u00b1 X\u201d design, failed to further improve outcomes. This was mainly due to increased toxicity, the large proportion of patients not in need of more than R-CHOP, and the extensive molecular heterogeneity of the disease, raising the bar for \u201cone-size-fits-all\u201d concepts. Recently, an R-CHP regimen extended by the anti-CD79b antibody\u2013drug conjugate (ADC) Polatuzumab Vedotin proved superior to R-CHOP in terms of progression-free survival (PFS) in the POLARIX phase III trial. Moreover, a number of targeted agents, especially the Bruton\u2019s tyrosine kinase (BTK) inhibitor Ibrutinib, seem to have activity in certain patient subsets in 1L and are currently being tested in front-line regimens. Chimeric antigen receptor (CAR) T-cells, achieving remarkable results in \u22653L scenarios, are being exploited in earlier lines of therapy, while T-cell-engaging bispecific antibodies emerge as conceptual competitors of CAR T-cells. Hence, we present here the findings and lessons learnt from phase III 1L trials and piloting phase II studies in relapsed\/refractory (R\/R) and 1L settings, and survey chemotherapy-free regimens with respect to their efficacy and future potential in 1L. Novel agents and their mode of action will be discussed in light of the molecular landscape of DLBCL and personalized 1L perspectives for the challenging patient population not cured by the SOC.<\/jats:p>","DOI":"10.3390\/cancers14061453","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T12:58:36Z","timestamp":1647003516000},"page":"1453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["DLBCL 1L\u2014What to Expect beyond R-CHOP?"],"prefix":"10.3390","volume":"14","author":[{"given":"Maike","family":"Stegemann","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Kepler University Hospital, Johannes Kepler University, Krankenhausstra\u00dfe 9, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophy","family":"Denker","sequence":"additional","affiliation":[{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Berlin Institute of Health at Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens A.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Kepler University Hospital, Johannes Kepler University, Krankenhausstra\u00dfe 9, 4020 Linz, Austria"},{"name":"Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Medical Department, Division of Hematology, Oncology and Tumor Immunology, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine, Helmholtz Association, Robert-R\u00f6ssle-Stra\u00dfe 10, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2040","DOI":"10.1182\/blood-2010-03-276246","article-title":"Long-Term Outcome of Patients in the LNH-98.5 Trial, the First Randomized Study Comparing Rituximab-CHOP to Standard CHOP Chemotherapy in DLBCL Patients: A Study by the Groupe d\u2019Etudes Des Lymphomes de l\u2019Adulte","volume":"116","author":"Coiffier","year":"2010","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S1470-2045(06)70664-7","article-title":"CHOP-like Chemotherapy plus Rituximab versus CHOP-like Chemotherapy Alone in Young Patients with Good-Prognosis Diffuse Large-B-Cell Lymphoma: A Randomised Controlled Trial by the MabThera International Trial (MInT) Group","volume":"7","author":"Pfreundschuh","year":"2006","journal-title":"Lancet Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S1470-2045(08)70002-0","article-title":"Six versus Eight Cycles of Bi-Weekly CHOP-14 with or without Rituximab in Elderly Patients with Aggressive CD20+ B-Cell Lymphomas: A Randomised Controlled Trial (RICOVER-60)","volume":"9","author":"Pfreundschuh","year":"2008","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41408-020-00403-1","article-title":"Incidence of Relapsed\/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Including CNS Relapse in a Population-Based Cohort of 4243 Patients in Sweden","volume":"11","author":"Harrysson","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJM199309303291402","article-title":"A Predictive Model for Aggressive Non-Hodgkin\u2019s Lymphoma. 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