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. 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 rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of 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. 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 status was evaluable, 32 (30%) had a detectable 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. 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. AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.

中文翻译：

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早期滤泡性淋巴瘤患者的局部放疗和可测量残留疾病驱动的免疫治疗 (FIL MIRO)：前瞻性、多中心、2 期试验的最终结果


早期滤泡性淋巴瘤的主要治疗方法是局部放疗，抗 CD20 单克隆抗体 (mAb) 可能发挥作用。我们的目的是使用可测量残留病（MRD）驱动的方法来评估这些治疗的效果。这项前瞻性、多中心、2 期试验在意大利 Fondazione Italiana Linfomi (FIL) 的 27 个中心进行。符合资格的参与者是新诊断、经组织学证实的滤泡性淋巴瘤（I 期或 II 期；I-IIIa 级）的成年人（≥18 岁）。患者最初接受了 12 天的 24 Gy 受累野放射治疗；放疗后或随访期间 MRD 呈阳性的患者接受 8 剂静脉注射（每剂 1000 毫克；每周一剂）抗 CD20 mAb ofatumumab。主要终点是受累野放射治疗后 MRD 阳性且奥法木单抗治疗后 MRD 阴性的患者比例。如果患者在入组时外周血或骨髓样本重排呈阳性，则将其纳入主要终点分析人群。 MRD 阳性定义为外周血或骨髓中重排的持续存在，由 FIL MRD 网络实验室进行集中评估。该试验已在 EudraCT 注册，注册号为 2012-001676-11。 2015年5月2日至2018年6月1日期间，我们招募了110名参与者，其中106名（96%）符合资格并接受了受累野放射治疗。其中，105 人（99%）为白人，1 人（1%）为黑人，50 人（47%）为男性，56 人（53%）为女性。在 105 名可评估状态的参与者中，32 名 (30%) 在基线时有可检测到的重排。放疗后，30 名患者中有 12 名 (40%) 达到 MRD 阴性状态，其中 3 名 (25%) 患者的这种状态持续时间较长（至少 36 或 42 个月）。 在放疗后 MRD 阳性的患者中，奥法木单抗在 25 名可评估患者中的 23 名（92%；95% CI 74-99）中诱导 MRD 阴性。经过中位随访 46·1 个月 (IQR 42·8–50·8)，这 23 名患者中有 14 名 (61%) 保持完全缓解且 MRD 阴性。最常见的 3-4 级不良事件是输液相关反应，在 4 名患者中观察到。局部放疗通常与滤泡性淋巴瘤的根除无关。 MRD 驱动的抗 CD20 单克隆抗体巩固使几乎所有患者都能达到分子缓解，并且随着时间的推移可降低复发率。因此建议 MRD 驱动的整合具有临床优势。意大利 AIRC 癌症研究基金会、诺华国际和葛兰素史克。