Survival Patterns of Non-Randomized Patients in the IELSG37 Study: Deauville Score 4 Is Not Necessarily Associated with Poor Outcome in Primary Mediastinal Lymphoma

Background: Primary mediastinal B-cell lymphoma (PMBCL) is clinically and biologically distinct from other types of aggressive lymphoma, it is characterized by a bulky mediastinal mass and most commonly occurs in women between 30 and 40 years of age. Although consolidation radiotherapy (RT) has yielded extremely positive outcomes in PMBCL, it carries a higher risk of long-term complications. Consequently, there has been an ongoing debate regarding the necessity of RT in patients responding to frontline immunochemotherapy.

Methods: In the IELSG37 study, PMBCL 530 patients were treated with rituximab- and doxorubicin-containing regimens; 98% had stage I-II. Their response was assessed by positron emission computed tomography (PET/CT); 268 achieved a complete metabolic remission (CMR) defined as Deauville score (DS) 1 to 3 according to the Lugano classification and were randomly allocated to observation or mediastinal RT. The primary analysis [Zucca et al. J Clin Oncol 2023; 41 (suppl 17): abs. LBA7505] has shown that patients in CMR can safely forgo RT. The 3-year overall survival (OS) rate was 99% irrespective of irradiation. RT provided only minimal benefit on progression-free survival (PFS), which was over 96% at 3 years in both arms. Here we present the outcome of the 262 patients who were not randomized and were managed according to the preference of their treating physician.

Results: Median follow-up was 64 months (interquartile range [IQR], 49-69). Besides 230 patients failing frontline treatment (174 DS4 and 56 DS5), the non-randomized cohort also included 1 patient with DS2 (who refused randomization and received RT) and 31 patients with DS3 who were initially considered as partial responders before a protocol amendment that changed the definition of CMR from DS 1-2 to DS 1-3. Among these non-randomized patients with DS3, 27 had RT consolidation, 1 was only observed, 2 had salvage chemotherapy ± RT, and 1 had missing data due to consent withdrawal; their 3-year PFS was very close to the one of the randomized patients with DS3 (90 vs 92%, p=0.99).

In the DS4 group, 12 patients were observed, 149 had only RT, and 13 had second-line chemotherapy, with (12) or without (1) autologous stem cell rescue, 8 of 13 also had RT. Among the patients with DS5, only 2 were observed, 32 had only RT, and 22 had second-line chemotherapy, with (15) or without (7) autologous stem cell rescue; 12 of them also had RT. The outcome of patients with DS4 was overlapping the one of the patients achieving a CMR, with 3-year PFS of 97.1% (95%CI 93-99) and 97.4% (95%CI 95-99), respectively, while patients with DS5 had a significantly poorer 3-year PFS (62.4%, 95%CI 48-74) [Figure1A]. The 3-year OS showed a similar trend (98% in patients with DS4, 99% in those randomized, and 78% in the DS5 group). Notably, compared to patients receiving consolidation RT alone or only observed, the residual lesions on post-immunochemotherapy PET/CT scans of patients with DS4 and DS5 who were treated more aggressively (with salvage chemotherapy ± autologous transplant and/or RT) displayed significantly higher tracer maximum standardized uptake value (SUVmax, median: 8.2, IQR 4.6-16.5 vs. 3.8, IQR 3.1-4.9; p<0.0001) and larger residual metabolic tumor volume (MTV, median: 18 ml, IQR 3-95 vs. 3.6, ml, IQR 1-10; p<0.0001). These patients had significantly worse outcomes compared to those who received consolidation RT or were observed only [Figure 1B].

Conclusions: Patients with DS4 had outcomes similar to those of patients achieving a CMR, indicating that this group may either include a significant number of "false-positive" cases with inflammatory uptake or that their residual disease is limited and can potentially be cured with consolidation RT. Patients with DS5 had a significantly poorer outcome, although nearly half of them did well with RT alone. It seems plausible that clinical condition of the patient and/or imaging features of the residual disease have influenced treatment choices in patients without CMR after frontline immunochemotherapy. Further studies are needed to investigate whether PET metrics and/or liquid biopsies can aid in personalizing treatment and identifying patients who could potentially avoid irradiation.