Primary Mediastinal B Cell Lymphoma (PMBCL): A Multicentric Observational Study of Spanish Lymphoma Group Geltamo
Authors: Cabero Martínez Almudena , García Bacelar Ana , Mendibil Esquisabel Begoña , Nuñez Cespedes Javier , Jiménez Ubieto Ana , Gainza Gonzalez Eukene , Perez Ceballos Elena , De La Cruz Beatriz , Garcia Noblejas Ana , Fernández-Caldas Paula , Gutierrez Norma C. , Sánchez-González Blanca , Figueroa Mora Rocío , Lopez Garcia Alberto , García Belmonte Daniel , Sanchez de Castro Maria , Cerezo Velasco Estefania , Martin Martitegui Xabier , Luzardo Henríquez Hugo Daniel , Rovira Jordina , Lopez Gomez Luis Antonio , Solano Jackeline , Torres Tienza Ana , Infante Maria Stefania , Santiago Alonso Raquel , Del Campo Raquel , De Miguel Llorente Dunia , Roldán-Pérez Alicia , Pardal Emilia , Gonzalez Mena Beatriz , Rodríguez Gil Miguel Ángel , Domínguez Velasco Nazaret , Blanco Juan Albert , Blum Dominguez Maria Alejandra , López Marin Javier , Peñarrubia-Ponce María , Bastos-Oreiro Mariana , Martín García-Sancho Alejandro 
Published: December 2024

Introduction
PMBL accounts for 2-4% of non Hodgkin lymphomas (NHL), predominantly affects young women and presents with a bulky mediastinal mass, often with pleural and pericardial effusions. There is no consensus on upfront treatment for PMBL, although some retrospective studies suggest that more intensive regimens than R-CHOP-21 could improve efficacy results. Thereby, dose adjusted (DA)-EPOCH-R regimen has been adopted as frontline treatment for many centers. Refractory/relapsed (R/R) PMBL has traditionally had a dismal prognosis, but nowadays new therapeutic alternatives are available that could be curative, such as CART therapy.
Methods and objectives
We conducted a retrospective multicenter study within GELTAMO group. Each participating center included patients histologically diagnosed with PMBL from 2007 to 2023. The aim of this study was to analyze clinical and biological characteristics of these patients and the efficacy of frontline and subsequent treatments.
Results
A total of 236 patients from 36 Spanish centers were included. Median age was 35 years (14-69) and there was a female predominance (64%). 65% of patients had bulky mediastinal mass, 39% presented with B symptoms and 69% had high LDH. Most of them had localized disease (stage I-II, 64%), good performance status (ECOG 0-1, 86%), and low risk IPI score (0-1, 62%). Regarding histological findings, the median Ki67 index was 75% (range 15-100%) and most patients were positive for CD30, MUM1, BCL2 and BCL6 (70%, 60%, 62% and 70%, respectively).
All patients received chemoimmunotherapy as first-line, often combined with consolidative radiotherapy (RT). 156 patients (66%) were treated with Da-EPOCH-R, 63 patients (27%) with R-CHOP-21 and 15 patients (6%) received other chemoimmunotherapy regimens. A significantly higher rate of patients treated with R-CHOP-21 versus DA-EPOCH-R received consolidative RT (55.6% vs 21.8%, p&lt;0.01).
The overall response rate (ORR) after first-line was 85.6% (79.2% complete response, CR). Among patients treated with DA-EPOCH-R +/- RT, 83% achieved CR versus 76% of patients treated with R-CHOP-21 +/- RT (p=0.19). In the multivariate analysis, patients with high LDH, B symptoms or superior vena cava syndrome (SVCS) at diagnosis had lower probability of reaching CR.
With a median follow-up in alive patients of 52 months (range 4-214), progression free survival (PFS) and overall survival (OS) at 4 years were 76.8% and 90.5%, respectively. Patients treated with DA-EPOCH-R vs R-CHOP-21 showed a trend toward better PFS (83.1% vs 68.5% at 4 years, p=0.07). In the multivariate analysis, the only factors with independent influence on PFS were high LDH (HR 2.4, 95% CI 1.1 - 5.3, p=0.04) and ECOG≥2 at diagnosis (HR 2.1, 95% CI 1.1-4.1, p=0.03), whereas SVCS (HR 3.6, 95% CI 1.4-9.4, p=0.01) and pleural or pericardial effusion at diagnosis (HR 3.5, 95% CI 1.2-10.4, p=0.03) significantly influence OS.
A total of 52 patients (22%) had R/R disease (54.7% refractory disease) after a median of 7 months (range 1-26), with a higher relapse rate in patients treated with R-CHOP-21 vs DA-EPOCH-R (30.2% vs 18.8%, p=0.05). With a median follow-up of 42 months (range 3-181), PFS2 and OS2 at 36 months were 38% and 70.9%, respectively.
At first relapse, 20 patients (39.2%) received autologous stem cell transplantation (ASCT) as consolidation therapy after second line chemoimmunotherapy. Of them, 16 patients maintain prolonged CR and 4 patients progressed or relapsed after ASCT (3 of them with progression or stable disease before ASCT).
Nine patients received CAR-T cell therapy in third or subsequent treatment lines. Of them, 6 patients achieved CR, 1 PR, 1 patient progressed and 1 patient died early due to CAR-T cell toxicity. All patients who achieved CR maintain that response after a median follow-up of 14 months after CAR-T therapy.
Conclusions
Our results suggest that DA-EPOCH-R could have higher efficacy than R-CHOP-21 with significantly less use of RT. The prognosis is good for most patients, although those with high LDH, ECOG≥2, SVCS or pleural-pericardial effusions had worse survival outcomes. R/R patients seem to have better prognosis than reported in historical series. In this sense, ASCT and CAR-T cell therapy demonstrated very promising results with durable remissions, although these findings should be confirmed in larger series.