Decoding the molecular heterogeneity of pediatric monomorphic post–solid organ transplant lymphoproliferative disorders

Abstract

Post-transplant lymphoproliferative disorders (PTLD) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr Virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLD) has not been elucidated and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCL), mostly classified as activated B-cell, and seven Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing and copy-number (CN) arrays. Overall, PTLD-BL carried mutations in MYC,ID3, DDX3X, ARID1A or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL and less CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with worse outcome. All seven PTLD-BL were alive after treatment with pediatric B-cell Non-Hodgkin Lymphoma protocols, whereas 54% of DLBCL patients were cured with immunosuppression reduction, rituximab and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low intensity treatment and the shared pathogenesis between PTLD-BL and EBV+ IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

Management of paediatric monomorphic post‐transplant lymphoproliferative disorders with low‐intensity treatment: A multicentre international experience

“…Recent molecular characterisation of paediatric BL mPTLD has shown mutational profiles of BL mPTLD consistent with sporadic BL, suggesting the need of intensive therapy, as delivered to paediatric B-NHL. 17 In keeping with that study, our series of BL patients showed a longer time from transplant to mPTLD diagnosis in MYC-rearranged cases. It is notable that five of 10 cases requiring second-line therapy in our study had either BL morphology or MYC-rearrangement, with PFS approaching significance in this subgroup, but escalation of therapy intensity in these cases was associated with outcomes comparable to the patients not needing therapy escalation.…”