KEY TAKEAWAYS
- The IELSG37 trial assessed whether omitting RT for PMBCL pts who achieve CMR after immunochemotherapy is a viable treatment strategy.
- The primary endpoint was PFS following randomization.
- The trial results suggested that for PMBCL pts achieving CMR after immunochemotherapy, omitting radiotherapy may be a valid treatment approach with favorable short-term outcomes.
Primary mediastinal B-cell lymphoma (PMBCL) is associated with a favorable prognosis when patients achieve remission promptly through intensive immunochemotherapy. However, using mediastinal radiotherapy (RT) in these cases, while potentially consolidating responses, increases the risk of second malignancies and coronary or valvular heart disease.
The IELSG37 trial was designed with a non-inferiority approach to investigate whether radiotherapy (RT) can be excluded for patients (pts) who attain complete metabolic response (CMR) following immunochemotherapy.
The study enrolled pts with newly diagnosed primary mediastinal B-cell lymphoma (PMBCL). The initial treatment regimen, consisting of rituximab and anthracycline-based therapy, was chosen based on local practice. CMR was determined through a central review of positron emission computed tomography (PET/CT) scans, categorized as Deauville scores 1 to 3 following the Lugano classification. Responding pts were randomly assigned to either observation (OBS) or consolidation RT (30 Gy). The randomization process was stratified by gender, chemotherapy regimen, country, and PET/CT score.
The primary objective was progression-free survival (PFS) following randomization. A sample size of 540 pts was planned for enrollment, with 376 patients to be randomized. This calculation assumed a 30-month PFS probability of 0.85 in both arms, with alpha at 0.05, 80% power, and a non-inferiority margin set at a hazard ratio (HR) of 1.77.
An interim analysis, performed at a median follow-up of 30 months, revealed a significantly lower number of observed events than anticipated. Consequently, the Independent Data Monitoring Committee (IDMC) recommended proceeding with the originally planned accrual without extending the study’s size or duration. In line with the IDMC’s guidance, the primary endpoint analysis was performed with at least 80% of patients having a minimum 30-month follow-up period. A total of 545 pts (209 men, 336 women) were enrolled, induction immunochemotherapy was completed, and response was assessed in 530 pts. Among them, 268 pts (50.6%) achieved CMR and were randomly assigned to either OBS (n=132) or RT (n=136).
The median follow-up duration for randomized pts was 59 months (interquartile range, 42-64). At 30 months from randomization, PFS 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 accounting for the variables used for randomization. The absolute risk reduction from RT at 30 months was 2.3% (unadjusted, -1.5 to 6.2) and 1.2% (after adjustment, -3.2 to 7.0). The number needed to treat was high (43 patients, unadjusted, and 126 after stratification). Both arms showed a 5-year overall survival of 99%. To date, three grade 3-4 cardiac events and 3 second cancers were reported, occurring in pts randomized to receive radiation.
This study was the largest prospective investigation of PMBCL to date. Despite the lower-than-expected event rate, it provided substantial evidence supporting the omission of RT for patients achieving CMR after immunochemotherapy. Longer follow-up is necessary to assess late toxicities comprehensively.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT01599559
Martelli, M., Ceriani, L., Zucca, E., Kryachok, I., Ciccone, G., Ricardi, U., Botto, B., Balzarotti, M., Tucci, A., Veronica Usai, S., Pennese, E., Arcaini, L., Dabrowska-Iwanicka, A., José María Ferreri, A., Marli, F., Zhao, W., Hodgson, D., Ionescu, C., Rigacci, L., Cellini, C., Stelitano, C., Zaja, F., Guarini, A., Spina, M., Fossa, A., Cwynarski, K., Mikhaeel, N.G., Jerkeman, M., Janíková, A., Huettmann, A., Gomes Da Silva, M., Stevens, D., Petrucci, L., Barrington, S., Malkowski, B., Metser, U., Versari, A., Bagni, O., Chauvie, S., Cozens, K., Perticone, S., Lelmini, N., Cavalli, F., Gosodarowicz, M., Johnson, P.W., Davies, A. OMISSION OF RADIOTHERAPY IN PRIMARY MEDIASTINAL B-CELL LYMPHOMA PATIENTS FOLLOWING COMPLETE METABOLIC RESPONSE TO STANDARD IMMUNOCHEMOTHERAPY: RESULTS OF THE IELSG37 RANDOMISED TRIAL (NCT01599559). EHA Library. Martelli M. 06/08/2023; 387801; S101
