Prognostic factors, therapeutic approaches, and distinct immunobiologic features in patients with primary mediastinal large B-cell lymphoma on long-term follow-up

Abstract

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL) without prognostic factors or a single standard of treatment clearly defined. In this study we performed retrospective analysis for clinical outcomes of 166 patients with PMBCL. In overall PMBCL, higher International Prognostic Index, stage, Ki-67 proliferation index, and positron emission tomography (PET) maximum standardized uptake values (SUVmax) at diagnosis were significantly associated with poorer survival, whereas MUM1 expression and higher peripheral blood lymphocyte/monocyte ratios were significantly associated with better survival. Patients who received R-HCVAD or R-EPOCH had better clinical outcome than did those who received the standard treatment R-CHOP. Treatment response and end-of-treatment PET SUVmax had remarkable correlations with survival outcome. In patients with refractory or relapsed PMBCL, stem cell transplant significantly improved overall survival. PMBCL had distinct gene expression signatures compared with overall DLBCL-NOS but not with DLBCL with PD-L1/PD-L2 amplification. PMBCL also showed higher PD-L2 expression in B-cells, lower PD-1 expression in T-cells, and higher CTLA-4 expression in T-cells and distinct miRNA signatures compared with DLBCL-NOS. The prognostic factors, effectiveness of treatment, transcriptional and epigenetic signatures, and immunologic features revealed by this study enrich our understanding of PMBCL biology and support future treatment strategy.

Fig. 1. Prognostic factors at diagnosis in PMBCL.

a IPI > 1 was associated with poorer overall and progression-free survival; advanced stage was associated with poorer progression-free survival. b Ki-67 ≥ 70% was associated with poorer overall and progression-free survival; PET SUV_max > 11.6 (≥12.8 in this cohort) was associated with poorer overall survival. c MUM1 positivity and higher lymphocyte:monocyte ratio were associated with better overall and progression-free survival, respectively. PMBCL primary mediastinal large B-cell lymphoma, IPI International Prognostic Index, PET positron emission tomography, SUV_max maximum standardized uptake value.

Fig. 2. Prognostic factors after treatment in PMBCL.

Treatment response (a) and end-of treatment PET SUV_max (b) were associated with overall and progression-free survival. PMBCL primary mediastinal large B-cell lymphoma, CR complete response, PR partial response, SD stable disease, PD progressive disease, PET positron emission tomography, SUV_max maximum standardized uptake value.

Fig. 3. Treatment options and prognosis in PMBCL.

a R-HCVAD and R-EPOCH appeared to be more effective than R-CHOP. b Stem cell transplant (autologous in most cases) improved overall survival in patients with relapsed/refractory PMBCL. c Among relapsed/refractory cases, relapsed patients who had partial-response to frontline therapy and refractory patients with progressive disease benefited the most from stem cell transplant. c Relapsed/refractory PMBCL patients with and without stem cell transplant had simiarly poor progression-free survival. PMBCL primary mediastinal large B-cell lymphoma, R-HCVAD rituximab, cyclophosphamide, mesna, doxorubicin, vincristine, dexamethasone, methotrexate, and cytarabine, R-EPOCH rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, R-CHOP rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, CR complete response, PR partial response, PD progressive disease.

Fig. 4. Immune checkpoint expression in PMBCL versus DLBCL.

a Compared with de novo DLBCL, PMBCL expressed significantly higher levels of PD-L2 in B-cells. b Compared with de novo DLBCL, PMBCL expressed significantly lower levels of PD-1 in T-cells but higher levels of CTLA-4 in T-cells. c Prognostic significance of PD-1 expression in T-cells, CTLA-4 expression in T-cells, and PD-L2 in B-cells in PMBCL. PMBCL primary mediastinal large B-cell lymphoma, DLBCL diffuse large B-cell lymphoma.

Fig. 5. miRNA profiles in PMBCL versus DLBCL.

a Heatmap for top 20 upregulated and 15 downregulated miRNAs in PMBCL compared with de novo DLBCL. b Scatter plots for top 20 upregulated and downregulated miRNAs in PMBCL patients with PFS events (blue bars) compared with those without events (brown bars). PMBCL primary mediastinal large B-cell lymphoma, DLBCL diffuse large B-cell lymphoma.