S101: omission of radiotherapy in primary mediastinal b-cell lymphoma patients following complete metabolic response to standard immunochemotherapy: results of the ielsg37 randomised trial (nct01599559)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Primary mediastinal B-cell lymphoma (PMBCL) has a good prognosis if remission is rapidly achieved with dose-intensive immunochemotherapy. In these patients, mediastinal radiotherapy (RT) may consolidate responses; however, it increases the risk of second malignancies and coronary or valvular heart disease. Aims: The IELSG37 (NCT01599559) trial was planned with a non-inferiority design to test whether RT can be omitted in patients who achieve a complete metabolic response (CMR) after immunochemotherapy. Methods: Patients with newly diagnosed PMBCL were eligible. Initial rituximab and anthracycline-based regimen was chosen according to local practice. CMR was defined, upon central review of positron emission computed tomography (PET/CT) scans, as Deauville score 1 to 3, according to the Lugano classification. Responding patients were randomised to observation (OBS) or consolidation RT (30 Gy). Randomisation was stratified on gender, chemotherapy regimen, country, and PET/CT score. The primary endpoint was the progression-free survival (PFS) after randomisation. The sample size (540 patients to enrol, and 376 to randomise) 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 non-inferiority margin. Results: An interim analysis at median follow-up of 30 months showed a much lower number of observed events than expected, hence, the Independent Data Monitoring Committee (IDMC) of the trial recommended to complete the planned total accrual without increasing the study size or duration. The primary endpoint analysis was performed, according to the IDMC recommendation, 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). The median follow-up time of randomised patients was 59 months (interquartile range, 42-64). PFS at 30 months from randomisation was 98.5% (95%CI, 94.2-99.6) in the RT arm and 96.2% (95%CI, 91.1-98.4) in the OBS arm (Log-rank P=0.274). The estimated relative effect of radiotherapy vs 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 randomisation. 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) after adjustment. The number needed to treat is high (43 patients, unadjusted, and 126 after stratification). The 5-year overall survival was 99% in both arms. To date, 3 grade 3-4 cardiac events and 3 second cancers were recorded, all in patients randomised to radiation. Summary/Conclusion: This is the largest prospective study of PMBCL ever carried out. Although the event rate did not reach the expected level, and longer follow-up is required to properly evaluate late toxicities, our findings provide solid evidence to support the omission of RT in patients achieving a CMR after immunochemotherapy.Keywords: Extranodal lymphoma, Diffuse large B cell lymphoma, Radiotherapy, Positron emission tomography (PET)