Multicentre retrospective study of intravascular large B‐cell lymphoma treated at academic institutions within the United States

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149677/1/bjh15923.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149677/2/bjh15923_am.pd

PHASED VARIANTS IMPROVE DLBCL MINIMAL RESIDUAL DISEASE DETECTION AT THE END OF THERAPY

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CARMA1- and MyD88-dependent activation of Jun/ATF-type AP-1 complexes is a hallmark of ABC diffuse large B-cell lymphomas.

A hallmark of the diffuse large B-cell lymphoma (DLBCL) of the activated B-cell (ABC) type, a molecular subtype characterized by adverse outcome, is constitutive activation of the transcription factor nuclear factor-κB (NF-κB), which controls expression of genes promoting cellular survival and proliferation. Much less, however, is known about the role of the transcription factor activator protein-1 (AP-1) in ABC DLBCL. Here, we show that AP-1, like NF-κB, was controlled by constitutive activation of the B-cell receptor signaling component caspase recruitment domain-containing membrane-associated guanylate kinase 1 (CARMA1) and/or the Toll-like receptor signaling component myeloid differentiation primary response gene 88 (MyD88) in ABC DLBCL cell lines. In contrast to germinal center (GC) B-cell (GCB) DLBCL, ABC DLBCL cell lines expressed high levels of the AP-1 family members c-Jun, JunB, and JunD, which formed heterodimeric complexes with the AP-1 family members activating transcription factor (ATF) 2, ATF3, and ATF7. Inhibition of these complexes by a dominant-negative approach led to impaired growth of a majority of ABC DLBCL cell lines. Individual silencing of c-Jun, ATF2, or ATF3 decreased cellular survival and revealed c-Jun/ATF2-dependent control of ATF3 expression. As a consequence, ATF3 expression was much higher in ABC vs GCB DLBCL cell lines. Samples derived from DLBCL patients showed a clear trend toward high and nuclear ATF3 expression in nodal DLBCL of the non-GC or ABC subtype. These findings identify the activation of AP-1 complexes of the Jun/ATF-type as an important element controlling the growth of ABC DLBCL

Treatment cost and life expectancy of diffuse large B-cell lymphoma (DLBCL) : a discrete event simulation model on a UK population-based observational cohort

Background Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma. Previous studies examining the cost of treating DLBCL have generally focused on specific first-line therapy alone; meaning that their findings can neither be extrapolated to the general patient population nor to other points along the treatment pathway. Based on empirical data from a representative population-based patient cohort, the objective of this study was to develop a simulation model that could predict costs and life expectancy of treating DLBCL. Methods All patients newly diagnosed with DLBCL in the UK’s population-based Haematological Malignancy Research Network (www.hmrn.org) in 2007 were followed until 2013 (n=271). Mapped treatment pathways, alongside cost information derived from the National Tariff 2013/14, were incorporated into a patient level simulation model in order to reflect the heterogeneities of patient characteristics and treatment options. The NHS and social services perspective was adopted, and all outcomes were discounted at 3.5% per annum. Results Overall, the expected total medical costs were £22,122 for those treated with curative intent, and £2,930 for those managed palliatively. For curative chemotherapy, the predicted medical costs were £14,966, £23,449 and £7,376 for first, second, and third line treatments, respectively. The estimated annual cost for treating DLBCL across the UK was around £88-92 million. Conclusions This is the first cost modelling study using empirical data to provide ‘real world’ evidence throughout the DLBCL treatment pathway. Future application of the model could include evaluation of new technologies/treatments to support healthcare decision makers, especially in the era of personalised medicine