Epstein-Barr virus-associated lymphomas decoded.

Epstein-Barr virus (EBV)-associated lymphomas cover a range of histological B- and T-cell non-Hodgkin and Hodgkin lymphoma subtypes. The role of EBV on B-cell malignant pathogenesis and its impact on the tumour microenvironment are intriguing but incompletely understood. Both the International Consensus Classification (ICC) and 5th Edition of the World Health Organization (WHO-HAEM5) proposals give prominence to the distinct clinical, prognostic, genetic and tumour microenvironmental features of EBV in lymphoproliferative disorders. There have been major advances in our biological understanding, in how to harness features of EBV and its host immune response for targeted therapy, and in using EBV as a method to monitor disease response. In this article, we showcase the latest developments and how they may be integrated to stimulate new and innovative approaches for further lines of investigation and therapy.

Intra-tumoral and peripheral blood TIGIT and PD-1 as immune biomarkers in nodular lymphocyte predominant Hodgkin lymphoma.

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.

Diagnosis and management of primary central nervous system lymphoma: a consensus practice statement from the Australasian Lymphoma Alliance.

Primary central nervous system lymphoma is a clinicopathological disease entity that accounts for 1% of all non-Hodgkin lymphoma (NHL). Advanced patient age, adverse disease biology and complexities of diagnosis and treatment render outcomes markedly inferior to systemic NHL. Despite this, an increasing evidence base, including limited randomised controlled clinical trial data, is informing optimal therapeutic strategies with methotrexate-based induction chemotherapy schedules and intensified consolidation in selected patients. This practice statement represents an evidence-based review of the literature and has been devised to assist healthcare professionals in the diagnosis and management of this disease.

ALK-Positive Histiocytosis with Peripheral Blood Histiocytes: A Case Report.

Histiocytoses are a diverse group of rare, clinically heterogeneous disorders characterised by tissue infiltration of histiocytes, which may result in organ dysfunction and failure. Over 100 different subtypes of histiocytoses have been recognised, including rare cases of ALK-positive histiocytosis. We report a case of histiocytosis in a neonate who presented with refractory thrombocytopenia, anaemia, and intermittent neutropenia. Histiocytes were present in both peripheral blood smears and bone marrow; ALK positivity was demonstrated by immunohistochemistry. Given the scarce reports of this condition, the variable organ involvement, and the different approaches to management in the cases described, we seek to expand the literature by providing a report of our patient whose condition improved without chemotherapy. The presence of histiocytes in peripheral blood smears of patients with this condition has not previously been reported, and it underscores the importance of routine careful evaluation of blood smears.

How I approach new onset thrombocytopenia.

Thrombocytopenia is a common reason for referral to hematologists in community and hospital practice. A broad differential diagnosis, combined with the potentially life-threatening nature of some presentations necessitates a rapid evaluation of the situation and potential need for emergency intervention; followed by further comprehensive investigation to confirm the diagnosis and institution of longer term management. This review offers an approach to the initial assessment, diagnosis, and referral. We then highlight aspects of the clinical history, examination and laboratory investigations which may provide critical insights into the most likely diagnosis. ITP is the commonest cause of severe isolated thrombocytopenia in the general community and is the most common cause of thrombocytopenia in patients referred to our hematology service. It remains a diagnosis of exclusion and a high degree of vigilance for alternative diagnoses should be maintained, particularly if presentations are atypical or expected response to treatment is not seen. Adult presentation of hereditary thrombocytopenia syndromes can mimic new onset thrombocytopenia, however, improving access to genetic testing will facilitate accurate diagnosis and avoid unnecessary treatment.

Transfusion-related acute lung injury (TRALI): a retrospective review of reported cases in Queensland, Australia over 20 years.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare but potentially fatal transfusion reaction. An effective haemovigilance programme is important in implementing successful and targeted risk reduction strategies. We aim to provide a summary of TRALI cases referred for investigation in Queensland (QLD) Australia from 1999 to 2019, describing the epidemiological and laboratory features of local TRALI cases. MATERIALS AND METHODS: A retrospective audit evaluated all cases reported to the QLD Australian Red Cross Lifeblood over the 20-year study period. Cases were categorised according to the 2004 Canadian consensus criteria. RESULTS: Of the 91 cases referred for investigation, expert review confirmed 30 of TRALI and 18 of possible TRALI. A total of 238 donors and 110 blood products were assessed in confirmed cases. TRALI affected patients of all ages. Most patients had underlying haematological malignancies (25%), surgery (15%) or liver disease (13%). TRALI incidence was measured at 1 in 130,000 per issued product in QLD. Red cells were transfused in 32 cases, platelets in 18 and plasma products in 21, with 16 cases involving multiple products. Following laboratory assessment, 23% of cases had findings supportive of antibody mediated TRALI and 21% as likely non-antibody mediated. Possible TRALI was identified in 37.5% of cases of which 25% were antibody mediated and 12.5% non-antibody mediated. Nine (18.5%) cases were uncategorised due to insufficient immunologic investigations. DISCUSSION: Rates of TRALI incidence measured are lower than those seen in many international studies. A reduction in confirmed cases has been noted over recent years, supporting the implementation of risk-reduction strategies. We report a relatively higher proportion of non-antibody mediated TRALI and possible TRALI cases in more recent years, suggesting the need to further understand the role of product age and biological risk modifiers.