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.

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2025
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