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.

Background: The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach.
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.
Competing Interests: Declaration of interests AP reports support for the study from Novartis and AIRC 5 × 1000; payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, and BeiGene; payment for expert testimony from Takeda Pharmaceuticals and Roche; support for attending meetings and/or travel from Takeda Pharmaceuticals, Roche, Janssen Pharmaceuticals, BeiGene, Pfizer, and AbbVie; and participation on a data safety monitoring board or advisory board for Takeda Pharmaceuticals, Roche, and Janssen Pharmaceuticals. SL reports payment or honoraria for lectures or presentations from Roche, BeiGene, Regeneron Pharmaceuticals, and Kite Pharma; support for attending meetings and/or travel from Roche and BeiGene; and participation on a data safety monitoring board or advisory board from Roche, Regeneron Pharmaceuticals, Miltenyi Biomedicine, Takeda Pharmaceuticals, Sobi, and Incyte. GG reports consulting fees from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, and Johnson & Johnson and payment or honoraria for lectures or presentations from AbbVie, AstraZeneca, BeiGene, Incyte, Lilly, Johnson & Johnson, and Hikma Pharmaceuticals. PC received consulting fees from AbbVie, ADC Therapeutics, Amgen, BeiGene, Celgene, Daiichi Sankyo, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals and payment for lectures from AbbVie, Amgen, Celgene, Gilead/Kite, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Novartis, Roche, Sanofi, Sobi, and Takeda Pharmaceuticals. LA received consulting fees from Roche, Janssen-Cilag, Verastem Oncology, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics, and Novartis and payment or honoraria for lectures or presentations from EUSA Pharma and Novartis. ML received grants or contracts from Roche, BeiGene, ADC Therapeutics, and Janssen Pharmaceuticals and consulting fees and/or payment or honoraria from AbbVie, Amgen, ADC Therapeutics, Sobi, BeiGene, Bristol Myers Squibb, EUSA Pharma, Gilead/Kite, Novartis, Incyte, Janssen Pharmaceuticals, Jazz Pharma, Lilly, Regeneron Pharmaceuticals, Roche, Ellipses Pharma, GSK, and Istituto Gentili. IDG received payment or honoraria for lectures or presentations from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; support for attending meetings and/or travel from Takeda Pharmaceuticals, Janssen Pharmaceuticals, Roche, and AstraZeneca; and support for participation on a data safety monitoring board or advisory board from Takeda Pharmaceuticals and Roche. All other authors declare no competing interests.
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