Autologous Stem Cell Transplantation for Primary Mediastinal B Cell Lymphoma in the Rituximab Era: A Retrospective Study By the EBMT Lymphoma Working Party

Introduction: The addition of rituximab to induction therapy had improved the outcome of patients with primary mediastinal B cell lymphoma (PMBCL). For those patients who are primary refractory or relapse after having achieved a remission, high-dose therapy and autologous stem cell transplantation (ASCT) is considered as standard treatment. Only scanty information, however, is available regarding the role of ASCT in patients with relapsed / refractory PMBCL in the rituximab era. Moreover, the impact of pre- and post-transplant irradiation remains uncertain. The objective of the current study was to investigate the results of ASCT for PMBCL in the rituximab era, identify variables predictive for outcome, and assess the role of adjuvant radiotherapy.

Patients and methods: For this retrospective study, all EBMT registered patients with PMBCL aged between 18 and 70 years who were treated with a first ASCT between 2000 and 2012 were eligible. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers with potentially eligible patients were contacted to provide additional treatment and follow-up information including a written histopathology report. Statistical analysis used log rank test to assess the impact of baseline characteristics on survival endpoints. In multivariate analysis, the relevance of prognostic factors was estimated using Cox regression models. Curves of cumulative incidence of relapse (IR) were compared by Gray's test. Multivariate analysis of IR used Fine and Gray models.

Results: 86 patients with confirmed PMBCL were eligible and had the full data set required for this analysis. 51% were female, median age was 34 years (range 20-69). Median time from diagnosis to ASCT was 12 months (12-299). 63.5% of the patients presented with a bulky mediastinal mass, larger than 10cm at diagnosis, 30.5% had stage IV disease, and 44% had B symptoms. 92% had received at least 2 lines of therapies, 85% had rituximab and 30% had received radiotherapy prior to transplantation. At ASCT, 11% still had a mass greater than 10 cm, and 19% a mass of 5-10cm. Remission status at ASCT was CR/PR1 in 21% of the patients, CR/PR>1 in 51%, and refractory disease in 28%. 31 patients (41%) received irradiation post-transplant. Thirteen patients of 24 patients (54%) transplanted in PR attained CR at day +100 post ASCT. With a median follow-up of 39 months (24-73), 3-year non-relapse mortality, IR, event-free survival (EFS) and overall survival (OS) for the whole series were 9%, 33%, 58% and 71%, respectively. By univariate analysis, refractory disease at ASCT and residual mass > 5cm at ASCT were significant adverse predictors for IR, EFS, and OS. 3-year EFS was 35% in refractory subjects vs 66% in chemosensitive patients (p=0.001), and 100% in those autografted in CR/PR1 vs 60% in those transplanted in more advanced response p=0.018. Notably, patients transplanted with refractory disease with a history of irradiation prior to ASCT had a superior outcome compared with non-irradiated refractory patients.Multivariate analysis suggested post-transplant irradiation to be associated with a significantly reduced IR (HR=0.24; p=0.028) and improved EFS (HR=0.24; p=0.018) and OS (HR=0.21; p=0.032).

Discussion: In conclusion, this analysis gives first specific evidence that ASCT can provide durable remissions in patients with relapsed / refractory PMBCL in the rituximab era. Pre or post-transplant irradiation appears to be important, though deserves further studies.