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.

Identification of Very Low-Risk Subgroups of Patients with Primary Mediastinal Large B-Cell Lymphoma Treated with R-CHOP

“…In addition, baseline PET may not be feasible for logistic reasons in many patients with PMLBCL presenting with acute complications requiring urgent treatment, especially if not available on‐site, whereas evaluation of biological prognostic factors may not be possible in many cases because of the small size of the biopsies. For these reasons, clinical prognostic models are expected to remain particularly useful in the specific setting of PMLBCL and may be enhanced by functional imaging and biologic markers [66].…”

PD-1 and LAG-3 Checkpoint Blockade: Potential Avenues for Therapy in B-Cell Lymphoma

“…These genomic alterations occur at significantly higher frequency in PMBCL than other B-NHL subtypes. Accordingly, this correlates with increased PD-1 ligand expression on tumor cells [ 58 , 101 , 102 ]. Translocations of the 9p locus are highly specific for PMBCL often involving PDCDLG2 (gene encoding PD-L2) and lead to expression of PD-L2 at higher levels than PD-L1, a phenomenon not seen in other B-LPDs, including cHL [ 56 , 100 , 101 , 103 ].…”

“…Accordingly, this correlates with increased PD-1 ligand expression on tumor cells [ 58 , 101 , 102 ]. Translocations of the 9p locus are highly specific for PMBCL often involving PDCDLG2 (gene encoding PD-L2) and lead to expression of PD-L2 at higher levels than PD-L1, a phenomenon not seen in other B-LPDs, including cHL [ 56 , 100 , 101 , 103 ]. MHC class II transactivator (CIITA), is a recurrent gene fusion partner for 9p.24 translocations in PMBCL which further reduced tumor immunogenicity through decreased antigen presentation and these translocations are associated with poorer outcomes [ 102 ].…”

Primary mediastinal large B cell lymphoma

“…34 High-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) and immune checkpoint blockade therapy are effective treatments for relapsed or refractory PMBCL. 35 The total effective rate of HDT/ASCT was 77.2% (complete remission, 63.6%). The median follow-up time was 53.5 months.…”

“…33 MUM1 expression and higher peripheral blood lymphocyte/ monocyte ratio are significantly correlated with a better survival rate. 35 In conclusion, PMBCL is a rare subtype of aggressive Bcell lymphoma, which is more common in adolescents and young adults, mainly women. Treatment should consider maximum efficacy and minimize long-term toxicity.…”