Overview of T-cell Lymphomas

T-cell lymphomas are a mixed bag of diseases with a similar origin but diverse in biology and behavior. This review aims to highlight the key changes to the WHO classification and summarize the therapeutic paradigm as of the time of writing in November 2018

Peripheral T-Cell Lymphoma: Review and Updates of Current Management Strategies

The classification of T-cell and natural-killer- (NK-) cell lymphomas has been updated in the 4th edition of the World Health Organization (WHO) classification of tumors of the haematopoietic and lymphoid tissue published in 2008. Based on recent epidemiological studies, NK-cell lymphomas occur almost exclusively in Asia and South America, although T-cell lymphomas appear to occur in the East as commonly as in the West. Due to the low prevalence of this disease, diagnosis and optimal treatment of patients have not been studied prospectively in large randomized trials. Nevertheless, there has been development in the understanding of T-cell lymphomas and how they should be managed; FDG-PET emerges as an increasingly important tool in diagnosis, gene-expression signatures may aid with prognostication in the future, and novel therapies are currently being studied to improve outcomes in T-cell lymphomas. More work, however, needs to be done, and international collaboration will be pertinent to deriving meaningful results from future clinical studies

Counterproductive effects of anti-CD38 and checkpoint inhibitor for the treatment of NK/T cell lymphoma

IntroductionNatural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy.MethodsWe conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses.Results and DiscussionOur analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies

DDX3X loss is an adverse prognostic marker in diffuse large B-cell lymphoma and is associated with chemoresistance in aggressive non-Hodgkin lymphoma subtypes.

Funder: addenbrooke's charitable trust, cambridge university hospital

Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes

The molecular biology of primary nodal T- and NK-cell lymphoma and its relationship with extranodal NK/T-cell lymphoma, nasal type is poorly understood. In this study, we assessed the relationship between nodal and extranodal Epstein-Barr virus-positive T/NK-cell lymphomas using gene expression profiling and copy number aberration analyses. We performed gene expression profiling and copy number aberration analysis on 66 cases of Epstein-Barr virus-associated T/NK-cell lymphoma from nodal and extranodal sites, and correlated the molecular signatures with clinicopathological features. Three distinct molecular clusters were identified with one enriched for nodal presentation and loss of 14q11.2 (TCRA loci). T/NK-cell lymphomas with a nodal presentation (nodal-group) were significantly associated with older age, lack of nasal involvement, and T-cell lineage compared to those with an extranodal presentation (extranodal-group). On multivariate analysis, nodal presentation was an independent factor associated with short survival. Comparing the molecular signatures of the nodal and extranodal groups it was seen that the former was characterized by upregulation of PD-L1 and T-cell-related genes, including CD2 and CD8, and downregulation of CD56, consistent with the CD8+/CD56-immunophenotype. PD-L1 and CD2 protein expression levels were validated using multiplexed immunofluorescence. Interestingly, nodal group lymphomas were associated with 14q11.2 loss which correlated with loss of TCR loci and T-cell origin. Overall, our results suggest that T/NK-cell lymphoma with nodal presentation is distinct and deserves to be classified separately from T/NK-cell lymphoma with extranodal presentation. Upregulation of PD-L1 indicates that it may be possible to use anti-PD1 immunotherapy in this distinctive entity. In addition, loss of 14q11.2 may be a potentially useful diagnostic marker of T-cell lineage

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance

Pathogenesis and biomarkers of natural killer T cell lymphoma (NKTL)

Abstract Natural killer T cell lymphoma (NKTL) is an aggressive disease with very poor treatment outcomes in the advanced stages. With chemotherapy, initial response rates to treatment are high but responses are short lived. A better understanding of the complex molecular pathogenesis of this disease is essential in order to design and develop better therapeutics with improved efficacy. This review aims to summarise the key pathogenic mechanisms in NKTL which may have significant prognostic and therapeutic implications

Relevance of the International Prognostic Index in the Rituximab era

Letter to the edito