A RANDOMIZED TRIAL OF OBSERVATION VERSUS RADIOTHERAPY IN PRIMARY MEDIASTINAL B‐CELL LYMPHOMA PATIENTS WITH COMPLETE METABOLIC RESPONSE AFTER STANDARD IMMUNOCHEMOTHERAPY

Introduction: Primary mediastinal B-cell lymphoma (PMBCL) has a poor prognosis if remission is not rapidly achieved, or the disease recurs. Mediastinal radiotherapy (RT) may consolidate responses to dose-intensive immunochemotherapy; however, it increases the risk of second malignancies and coronary or valvular heart disease. The IELSG37 (NCT01599559) randomized trial was planned with a non-inferiority design to test whether RT can be omitted in PMBCL patients who achieve a complete metabolic response (CMR) after immunochemotherapy. Methods: Patients with newly diagnosed PMBCL were eligible. The initial rituximab and anthracyclines-based immunochemotherapy regimen was chosen according to local practice. Based on the Lugano classification, CMR was defined as Deauville score 1–3, upon central review of positron emission computed tomography (PET/CT) scans. Responding patients were randomized to observation (OBS) or consolidation RT (30 Gy). Randomization was stratified on gender, chemotherapy regimen, country, and PET/CT score. The primary endpoint was progression-free survival (PFS) after randomization. The sample size (540 patients to enroll, and 376 to randomize) was calculated assuming a 30-month PFS probability of 0.85 in both arms, with alpha at 0.05, 80% power, and a hazard ratio (HR) of 1.77 as a non-inferiority margin. Results: Although the number of observed events at a median follow-up of 30 months was considerably lower than expected, the Independent Data Monitoring Committee (IDMC) recommended completing the planned total accrual without increasing the study size or duration. According to the IDMC recommendation, the primary endpoint analysis was performed with ≥80% of patients having a minimum follow-up of 30 months. 545 patients (209 men, 336 women) were enrolled. Induction immunochemotherapy was completed and response assessed in 530 patients, 268 of them (50.6%) achieved a CMR and were randomly allocated to OBS (N = 132) or RT (N = 136). At a median follow-up of 5 years, the 30-month PFS was 98.5% (95% CI, 94.3–99.6) in the RT arm and 96.2% (95% CI, 91.1–98.4) in the OBS arm (p = 0.278). The estimated relative effect of radiotherapy versus observation in terms of hazard ratio (HR) was 0.47 (0.12–1.88) without adjustments and 0.68 (0.16–2.91) after stratification for the variables used for randomization. At 30 months the absolute risk reduction from RT was 2.3% (−1.5 to 6.2) unadjusted, and 1.2% (−3.2 to 7.0) with stratified HR. The number needed to treat is high (43 patients, unadjusted, and 126 after stratification). Overall survival at 5 years was 99% in both arms. Longer follow-up is needed to evaluate late toxicity. Conclusions: This is the largest prospective trial of PMBCL ever conducted. Although the event rate did not reach the anticipated level, the study evidence strongly supports the omission of RT in patients with CMR after immunochemotherapy. The research was funded in part by grants from the Swiss National Science Foundation (SNSF) – Project 32003B_146931, Krebsforschung Schweiz – Project KFS-2852-08-2011 and Cancer Research UK (C30423/A16247) The enrolment of Swiss patients was supported by the Swiss Group for Clinical Cancer Research (SAKK). Keywords: aggressive B-cell non-Hodgkin lymphoma, PET-CT, radiation therapy Conflicts of interests pertinent to the abstract A. J. Davies Consultant or advisory role: Abbvie,Celgene/BMS, GenMab, Incyte, Kite, a Gilead company, Roche Honoraria: Acerta Pharma/AstraZeneca, Celgene/BMS, Janssen, Kite, a Gilead company, Roche Research funding: Acerta Pharma/AstraZeneca, Celgene/BMS, GSK, Janssen, Kite, a Gilead company, Roche Educational grants: Roche, Celgene/BMS E. Zucca Consultant or advisory role: BeiGene, Celgene/BMS, Curis, Eli/Lilly, Incyte, Ipsen, Janssen, Merck, Miltenyi Biomedicine, Roche Research funding: AstraZeneca, Celgene/BMS, Celltion Healthcare, Incyte, Janssen, Merck and Roche Educational grants: Abbvie, BeiGene, Janssen, Kyte (a Gilead Company), and Roche I. Kryachok Consultant or advisory role: Takeda, Abbvie, Roche Research funding: Bayer, Merck, Labcorp, Dr Reddis Educational grants: Sandoz Other remuneration: Takeda, Abbvie, Roche (expert testimony); Takeda, Abbvie, Roshe, Astra Zeneca, Sandoz, Jansenn (speakers’ bureau) B. Botto Consultant or advisory role: Takeda, Novartis M. Balzarotti Consultant or advisory role: Gilead, Roche, Takeda, Janssen, AstraZeneca, Incyte Honoraria: Gilead, Novartis, Incyte, Roche, Kiowa Research funding: Roche Other remuneration: Roche, Incyte, Gilead (speakers’ bureau) A. Tucci Consultant or advisory role: Janssen, Gentili, Sanofi, Takeda, Kiowa Kyrin, MSD, Incyte L. Arcaini Consultant or advisory role: Roche, Janssen-Cilag, Verastem, Incyte, EUSA Pharma, Celgene/Bristol Myers Squibb, Kite/Gilead, ADC Therapeutics Research funding: Gilead Sciences Other remuneration: Speakers’ Bureau: EUSA Pharma, Novartis A. Dabrowska-Iwanicka Consultant or advisory role: Abbvie Honoraria: Janssen Educational grants: Abbvie A. J. M. Ferreri Consultant or advisory role: Gilead, Novartis, Roche, PletixaPharm Incyte Research funding: BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amben, Genmab, ADC Therapeutics, Gilead, Novartis, Roche, Pfizer Other remuneration: Patents & Royalties: Ospedale San Raffaele srl; Speakers Bureau: Adienne F. Zaja Consultant or advisory role: Novartis, Amgen, Riche, Abbvie, Janssen Cilag, Takeda, BMS, Grifols, Argenx, Sobi, Begene Research funding: Novartis, Amgen, Abvvie, Janssen Other remuneration: Fundings for educational projects: Janssen Cilag Abbvie, Kyowa Kirin, Takeda, Beigene, Astra Zeneca A. Fossa Consultant or advisory role: Roche, BMS, Novartis, Kite-Gilead, Takeda, Kyowa-Kirin Honoraria: Roche, BMS, Novartis, Kite-Gilead, Takeda, Kyowa-Kirin Other remuneration: Speakers' Bureau: Janssen M. Jerkeman Consultant or advisory role: Janssen Honoraria: Roche, Janssen, Gilead, Abbvie, AstraZeneca, Autolus, Pierre Fabre Research funding: Roche, Janssen, Gilead, Abbvie, AstraZeneca Other remuneration: Novartis (expert testimony) A. Janikova Consultant or advisory role: Roche, Gilead, Takeda Educational grants: Roche M. Gomes Da Silva Consultant or advisory role: Janssen, Gilead Sciences, MSD, Celgene Roche, Takeda, Novartis, ADC Therapeutics Research funding: Gilead Genesis and AstraZeneca Other remuneration: Speakers Bureau: Janssen; Travel support: Abbvie, Roche, Janssen U. Metser Consultant or advisory role: POINT Biopharma Inc U. Ricardi Honoraria: AstraZeneca Research funding: BrainLab Other remuneration: AstraZeneca (speakers’ bureau) M. Martelli Consultant or advisory role: Gilead, Roche, Novartis, Incyte, Beigene, Eusapharma Honoraria: Gilead, Roche, Novartis, Incyte, Beigene, Eusapharma, BMS Educational grants: Roche Other remuneration: Gilead, Roche, Novartis, Incyte, Beigene, Eusapharma (speakers’ bureau)

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