Excellent Outcomes with Brentuximab-Nivolumab for Relapsed/ Refractory Primary Mediastinal B-Cell Lymphoma in the Real-World Setting

Primary mediastinal B-cell lymphoma (PMBL) is a rare but aggressive subtype of non-Hodgkin lymphoma that predominantly occurs in adolescents and young adults. Most patients (>95%) are cured after first line treatment and those with relapsed refractory (R/R) disease have poor outcomes, with 2-year overall survival as low as 15%. Current standard of care particularly underserves this high-risk population. PMBL is characterised by high expression of programmed death-1 ligand and variable expression of CD30. Nivolumab, an anti-programmed death-1 immune checkpoint inhibitor and brentuximab vedotin (BV), an anti-CD30 antibody- drug conjugate have been demonstrated to have synergistic activity in R/R PMBL, with overall response rates (ORR) of 70% (CHECKMATE 436).

The aim of this study was to describe real world outcomes of R/R PMBL patients treated with BV nivolumab and compare outcomes with R/R patients who received standard of care. A retrospective analysis was performed on patients with R/R PMBL treated at two UK centres from 2003-2024. Medical records were reviewed for patient demographics, treatments received and related toxicities. ORR and overall survival (OS) data were collected. Survival curves were generated using ggsurvplot function from the ‘survminer’ package (0.4.9) in R (v4.3.1)

Fourteen patients were included in the analysis, with a median follow up of 2.3 years (range 0.8-16). The median age at diagnosis was 28 years (range 17-53), 57% of patients were female. The median lines of therapy received in this cohort was 4 (range 2-7). Six patients were treated with BV nivolumab, with a median of 3 lines of prior therapy (range 1-5). Two patients had received CAR-T cell therapy and one patient had received bispecific antibody therapy prior to BV nivolumab. This group of patients had highly refractory disease, with only one patient achieving a complete metabolic response (CMR) to any therapy prior to BV nivolumab. The ORR in patients who received BV nivolumab was 83%, with 66% achieving CMR, with a median follow up of 12.3 months (range 0.5-25) from first dosing of BV nivolumab. The median time to CMR from initiation of therapy was 34 days (range 22-76). One patient had consolidation with autologous stem cell transplantation, and two with allogeneic stem cell transplantation. None of these patients had post-transplant BV nivolumab. Two patients achieving response to BV nivolumab were not consolidated with transplant. One patient received 14 cycles BV nivolumab and the other patient received 10 cycles BV nivolumab. BV was discontinued in both cases due to worsening peripheral neuropathy. Both patients continue nivolumab monotherapy and remain in complete remission. Treatment related adverse events were reported in all patients receiving BV nivolumab. Five patients (83%) had grade 3-4 treatment related adverse events; the most common were neutropenia (n=3) and infection (n=2). Other grade 1-2 treatment related adverse events included rash (n=3), peripheral neuropathy (n=4) and neutropenia (n=2). For R/R PMBL patients who received standard of care (n=8), the OS was 38% vs 83% in the BV nivolumab treated group (p=0.66).

These real-world data demonstrate that BV nivolumab is highly efficacious in R/R PMBL patients, including those progressing after CAR-T cell and bispecific antibody therapy, with an ORR of 83%. The OS for the BV nivolumab treated group was higher than in those receiving standard of care. The toxicity profile of BV nivolumab is acceptable, with treatment related adverse events similar to those reported in Phase II clinical trials (CHECKMATE 436). BV nivolumab should be considered for PMBL patients with primary refractory disease or at first relapse, serving as a potential bridge to other consolidative therapies of curative intent.