Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial.
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Pulsoni Alessandro, Ferrero Simone, Tosti Maria Elena, Luminari Stefano, Dondi Alessandra, Cavallo Federica, Merli Francesco, Liberati Anna Marina, Cenfra Natalia, Renzi Daniela, Zanni Manuela, Boccomini Carola, Ferreri Andrés J M, Rattotti Sara, Zilioli Vittorio Ruggero, Bolis Silvia Anna, Bernuzzi Patrizia, Musuraca Gerardo, Gaidano Gianluca, Perrone Tommasina, Stelitano Caterina, Tucci Alessandra, Corradini Paolo, Bigliardi Sara, Re Francesca, Cencini Emanuele, Mannarella Clara, Mannina Donato, Celli Melania, Tani Monica, Annechini Giorgia, Assanto Giovanni Manfredi, Grapulin Lavinia, Guarini Anna, Cavalli Marzia, De Novi Lucia Anna, Bomben Riccardo, Ciabatti Elena, Genuardi Elisa, Drandi Daniela, Della Starza Irene, Arcaini Luca, Ricardi Umberto, Gattei Valter, Galimberti Sara, Ladetto Marco, Foà Robin, Del Giudice Ilaria
Аннотация
METHODS: This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11.
FINDINGS: Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients.
INTERPRETATION: Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested.
FUNDING: AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.