Biology and therapy of primary mediastinal B-cell lymphoma: current status and future directions

Abstract

Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T-cell mediated destruction via strategies that include loss of tumour cell antigenicity, T-cell exhaustion and activation of suppressive T-regulatory cells. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA-EPOCH-R (dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first-line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment-resistant disease, targeting aberrant cellular signalling and immune evasion.

Keywords: haematological oncology; malignant lymphomas; non-Hodgkin lymphoma; tumour biology; tumour immunotherapy.

Figure 1

Dysregulated immune response in the primary mediastinal B‐cell lymphoma (PMBCL) tumour microenvironment. Activating (red) genetic lesions/copy number gains and inactivating (blue) gene mutations in components of the JAK‐STAT signalling pathway diminish tumour immunogenicity via upregulation of programmed death ligands (PDLs) and C‐C motif chemokine ligand 17 (CCL17). Microdeletions in CD58 and mutations/structural rearrangements in class II major histocompatibility complex transactivator (CIITA) impair tumour antigenicity via downregulation of conjugate formation and major histocompatibility complex (MHC) class II, respectively. These immune escape strategies lead to T‐cell exhaustion, activation of suppressive T‐regulatory cells (Treg) and crippled immune surveillance. The impact of genetic aberrations in components of the nuclear factor kappa B (NF‐ĸB) signalling pathway on the PMBCL tumour microenvironment is not known.

Figure 2

Potential therapeutic options in PMBCL. Prospective studies to establish optimal first and subsequent line treatment and monitoring strategies are currently ongoing. This schema outlines a range of options that are either currently available or under evaluation (such as ctDNA). ASCT, autologous stem cell transplant; CR, complete response; ctDNA, circulating tumour DNA; DA‐EPOCH‐R, dose‐adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab; EOT, end of treatment; PD‐1, programmed cell death 1 (also termed PDCD1); PET, positron emission tomography; PMBCL, primary mediastinal B‐cell lymphoma; R‐CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone; RT, radiotherapy.