Immune Checkpoint Inhibitors in Primary Mediastinal B-Cell Lymphoma: A Monocentric Real-Life Experience and Future Potential
Authors: Zinzani Pier Luigi , Argnani Lisa , Cantelli Martina , Gugliotta Gabriele , Casadei Beatrice , Gentilini Marianna , Stefoni Vittorio , Pellegrini Cinzia , Morigi Alice , Fabbri Nicole , Gabrielli Giulia , Mazzoni Camilla , Maglio Pierluca , Bagnato Gianmarco , Broccoli Alessandro 
Published: December 2024

Patients with relapsed or refractory primary mediastinal B cell lymphoma (R/R PMBCL) have a poor prognosis, with an overall response rate (ORR) to salvage chemotherapy of 25% and a 2-year overall survival (OS) rate after diagnosis of R/R PMBCL of 15%. PMBCL cells overexpress programmed cell death 1 ligand (PDL1), enabling evasion of immune surveillance. Immune checkpoint inhibitors (ICIs) restore the T-lymphocyte mediated anti-tumor effect and have received FDA approval for the therapy of classical Hodgkin lymphoma and PMBCL. Here we presented our monocentric experience with ICIs in the context of R/R PMBCL.

Forty-six patients were treated with pembrolizumab (n=31) or with the combination of nivolumab and brentuximab vedotin (nivoBV, n=15) after a median number of previous therapies of 2 (range 1-6), 72% were female. No statistical significant difference occurred in the main characteristics in the two cohorts.

After a median number of 3 cycles (range 1-20) for pembrolizumab and 2 for nivoBV (range 1-52), best ORR was for pembrolizumab 54.1% (with 16 complete response [CR]) and 72.7% for nivoBV (with 6 CR). Best response was reached at a median of 3 (range 1-7) cycles for pembrolizumab and of 2 (range 1-4) for nivoBV. Final global ORR was 48.6% with 40.5% of CR rate. Nine patients underwent ICI as bridging therapy (BT) for CAR T-cell obtaining 6 CR, while other 3 patients initially candidates to use ICI as BT to CAR T were re-scheduled to continue ICI that became to all effects a further line of therapy (all obtained a CR after 35-36 cycles and are still in continuous CR).

Seventy-two adverse events (AE) occurred in 34 patients, 17 ones were of grade ≥3 and 10 were classified as immune-related AE. In the nivoBV cohort more extra-hematological AEs occurred, both overall (p = 0.006) and considering only those of grade 3-4 (p = 0.0301). Three patients in the nivoBV cohort had an early ICI discontinuation due to an extra-hematological AE. Hematological toxicity was represented only by 9 neutropenia in 9 patients all of grade ≥3 and judged related to therapy.

Nineteen patients underwent further therapy after ICI. At a median follow up for the whole study population of five years, median OS was not reached, progression-free survival (PFS) was 47.1% at 8 years with a plateau reached after ten months, disease free survival (DFS) was 100%, and no statistical difference occurred between the two subgroups. At the latest follow up, 28 patients were still alive, 25 in CR and 3 in PR on initial treatment. Among patients in CR, 16 are maintaining continuous CR without any kind of consolidation, 8 achieved CR after CAR T-cell and 1 patient in CR received consolidation therapy with autologous stem cell transplantation.

In conclusion our results demonstrate that ICI therapy for R/R PMBCL is associated with high response rate and durable outcomes. The study is still ongoing to expand the sample size due to the rarity of the disease to further investigate the potential of ICIs as BT to CAR T-cell or transplantation and to identify the specific subset of patients who can be cured only with ICIs.