Ibrutinib plus R-CHOP followed by maintenance in untreated ABC-DLBCL patients with IPI ≥2: A first analysis of phase II Study FIL_RI-CHOP
Year: 2025
Type: conference-abstract
Abstract: Background: Patients with activated (ABC) subtype diffuse large B-cell lymphoma (DLBCL) exhibit inferior outcomes following R-CHOP treatment. Current evidence indicates that covalent irreversible Bruton tyrosine kinase inhibitors (BTKi) have shown higher responses in non-germinal center (non-GCB) DLBCLs compared to GCB. In untreated non-GCB DLBCLs, phase 3 PHOENIX study (Younes et al. J Clin Oncol. 2019; 37:1285-95) showed that adding ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve outcomes in the intent-to-treat population. However, patients aged < 60y treated with R-CHOP-I experienced significantly improved progression-free survival (PFS) and overall survival (OS) compared with those receiving R-CHOP alone. The FIL_RI-CHOP trial aims to assess whether combining R-CHOP-I, followed by ibrutinib maintenance, is safe and improves PFS in young, untreated patients with high-risk ABC DLBCL. Methods: This is a prospective, multicenter, single-arm, phase II trial enrolling patients aged ≥18 and <65 years with newly diagnosed ABC-DLBCL at poor prognosis (IPI ≥2). An initial R-CHOP cycle (cycle 1) was permitted as standard-of-care (step 1), to allow timely treatment initiation while a central pathology review and Cell of Origin (COO) assessment were performed. COO subtyping was determined using the NanoString’s Lymphoma Subtyping (LST) gene expression signature. Patients with confirmed ABC-DLBCL (step 2) received the experimental treatment (R-CHOP + Ibrutinib 560 mg/day continuously) from cycle 2 to cycle 6, followed by two additional cycles of rituximab plus ibrutinib (cycles 7 and 8), and 18 months of ibrutinib maintenance for those achieving at least partial response post-induction. The primary endpoint is 2-year PFS. Secondary endpoints include overall response rate (ORR), complete (CRR), event-free survival (EFS), OS and safety. This preliminary analysis evaluates safety and response rate at the end of induction (EOI). Results: From July 2019 to August 2024, 279 patients were registered across 39 Fondazione Italiana linfomi (FIL) sites; 215 (76%) fulfilled eligibility criteria, were enrolled in step1, and received R-CHOP while awaiting the COO results. COO was classified as GCB in 139 of 215 patients (65%) and as ABC in 75 of 215 patients (35%), with 28/75 (37%) being double expressors. Among ABC-DLBCL cases, concordance with the Hans algorithm was 95% (71/75). All 75 ABC-DLBCLs proceeded to Step 2, and received experimental treatment. Median age was 57 years (IQR 50–60); 58.7% were male. Advanced Ann Arbor stage (III–IV) was observed in 72 of 75 patients (96%), elevated LDH levels in 58 (77.3%), involvement of ≥2 extranodal sites in 33 (44%) and IPI > 2 in 34 (46%). After 4 cycles, interim total-body CT scan showed an ORR of 90.7%, with 21.3% (16/ 75) complete responses (CR) and 69.3% (52/75) partial responses. At the EOI, assessed by PET-CT, ORR was 85.33% with a metabolic CR of 72%. A total of 64 patients initiated ibrutinib maintenance. Eleven patients (14.6%) discontinued treatment during the induction phase, prior to initiating maintenance therapy. Reasons for discontinuations were: disease progressions in 5 (6.6%), consent withdrawal in 2 (2.6%), and adverse events (AEs) in 4 (5.3%) – including 1 sudden death, 1 covid infection, 1 prolonged cytopenia and 1 gastrointestinal disorders. Neutropenia was the most common hematological toxicity (grade 3–4 per cycle: 6%; per patient: 13%), whereas febrile neutropenia was rare (≤2%). Extra-hematological AEs were primarily low-grade gastrointestinal and neurological disorders. Three cardiac events (grade 1-2) were reported; infections occurred in 24% of patients. Conclusions: These findings demonstrate that central pathology review and NanoString’s LST COO assessment are feasible without delaying treatment initiation. The addition of ibrutinib to R-CHOP appears feasible and effective, achieving >70% metabolic CR with a manageable safety profile in young, high-risk ABC-DLBCL patients. R-CHOP plus ibrutinib may represent a safe, effective, and potentially cost-effective treatment strategy in this population. Final results including the impact of ibrutinib maintenance will be presented at the meeting.
Source: Blood
Authors: Alice Di Rocco, Annalisa Chiappella, Andrea Evangelista, Valentina Tabanelli, Emanuele Ravano, Chiara Pagani, Federica Cavallo, Elisa Lucchini, Mattia Novo, Attilio Guarini, Anna Merli, Annalisa Arcari, Michele Cimminiello, Francesco Merli, Elsa Pennese, Manuela Zanni, Donato Mannina, Ausilia Gorgone, Guido Gini, Anna Mele, Jacopo Olivieri, Michele Spina, Monica Tani, Andrés José María Ferreri, Chiara Ghiggi, Stefan Hohaus, Marta Coscia, Sara Galimberti, Arcangelo Liso, Mariella Lo Schirico, Benedetta Puccini, Sara Usai, Claudia Peracchio, Alessandra Dondi, Umberto Vitolo, Maurizio Martelli
Institutions: Policlinico Umberto I, Sapienza University of Rome, Fondazione IRCCS Istituto Nazionale dei Tumori, University of Turin, European Institute of Oncology, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Ospedale Maggiore, Azienda sanitaria universitaria Giuliano Isontina, Istituto Tumori Bari, Ospedale Infermi di Rimini, Guglielmo da Saliceto Hospital, Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Azienda Ospedaliera Ospedali Riuniti Papardo Piemonte, Azienda Ospedaliero-Universitaria delle Marche, Pia Fondazione di Culto e Religione Azienda Ospedaliera "Card. G. Panico", Azienda sanitaria universitaria Friuli Centrale, Centro di Riferimento Oncologico, Ospedale "Santa Maria delle Croci" di Ravenna, University of Milan, IRCCS Ospedale San Raffaele, Ospedale Policlinico San Martino, Agostino Gemelli University Polyclinic, Istituti di Ricovero e Cura a Carattere Scientifico, University of Insubria, Aziende Socio Sanitarie Territoriale dei Sette Laghi, University of Pisa, University of Perugia, Istituto Oncologico Veneto, Azienda Ospedaliero-Universitaria Careggi, Fondazione Intergruppo Italiano Linfomi Onlus, Candiolo Cancer Institute
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417001704
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