FRONTLINE INTENSIFIED ABVD DEMONSTRATES SUPERIOR EFFICACY THAN PET‐ADAPTED ABVD IN ADVANCED HODGKIN LYMPHOMA: THE FIL‐ROUGE PHASE 3 TRIAL BY THE FONDAZIONE ITALIANA LINFOMI

Introduction: PET-adapted ABVD with deferred intensification is the favored therapy for most patients advanced Hodgkin Lymphoma (HL), while upfront (‘first hit’) escBEACOPP remains an option in high-risk disease. These strategies are challenged by brentuximab vedotin (BV)-based AVD regimen due to superior outcomes versus ABVD. The FIL-Rouge trial (NCT03159897) was designed implement ‘first-hit’ principle into platform demonstrating superiority of a dose-dense/dose-intense (ABVDDD-DI; Russo et al. 2014, Figure 1A), without BV and PET-adaptation, PET2-adapted program. Methods: This open-label, phase 3 trial, blinded centralized PET assessment, accrued untreated pts aged 18–60 advanced-stage HL (IIB extranodal and/or bulky, III, IV) at 46 FIL Centers. Pts were randomized 1:1 stratified stage (IIB/III, IV), age (<45/≥45), bulky (Yes/No), IPS (0–2/≥3). In comparator arm, received two (d1, d14; q28 days); PET2−ve (DS 1–3) continued four ABVD, those PET2+ve 4–5) diverted or ASCT. experimental cycles ABVDDD-DI d11; q21 days; doxorubicin 70 mg/m2/cycle) followed ABVDDD (Figure 1B). ISRT (30 Gy) planned PET−ve 3) rests (≥2.5 cm) PET+ve 4−5). given had receive RT sites if CR 1−3). primary endpoint minimum expected absolute improvement 10% 3-y PFS. Results: From July 2017 March 2021, 503 enrolled (males 54%; median 33.6 [IQR 26.2–43.0] IIB (20%), III (33%), IV (47%) score 0–2 (58%), (25%) 4–7 (17%). Nodal (≥10 mediastinal (MT > 0.35) present 13% 24% pts, respectively. At interim PET, CRs ≤ 85.5% 80.5% (p = 0.15). FU 35 mo.s, 97 PFS event (ABVDDD-DI n 32; 65). per ITT 86.7% (95% CI: 81.7–90.4) 73.2% 66.9–78.5) (Δ: 13.46%; p 0.0001) [HR 0.44 CI 0.28–0.67; 0.0002)] 3C). A also achieved 87.0% vs. 71.9%) disease 86.4% 70%) 3D, E). delivered 32% Nine died (ABVDDD-DI: PD, 1 COVID; ABVD: 4 H1N1). Neutropenia ≥G3 (40.8% 30.4%; 0.016) mucositis (3.2% 0%; 0.005) occurred more frequently No excess cardiotoxicity (G2: 0.8%, G3: 0.8%) nor respiratory events 6%, 2.4%, G4: 0.4%) recorded (cardiac, G2: 0.4%, 0.4%; respiratory, 4.4%, 1.2%, 0.4%). Conclusions: study met its objective. improved 3-year >10%, reduced need RT, no alarming acute safety signals. It active bulk research funded by: Bando AIFA (Agenzia Italiana del Farmaco)-2016-02364973. Keywords: chemotherapy, lymphoma conflicts interests pertinent abstract.