The TNF receptor (TNFR) family plays a central role in the development of the immune response. Here we describe the reciprocal regulation of the recently identified TNFR superfamily member herpes virus entry mediator (HVEM) (TR2) and its ligand LIGHT (TL4) on T cells following activation and the mechanism of this process. T cell activation resulted in down-regulation of HVEM and up-regulation of LIGHT, which were both more pronounced in CD8+ than CD4+ T lymphocytes. The analysis of HVEM and LIGHT mRNA showed an increase in the steady state level of both mRNAs following stimulation. LIGHT, which was present in cytoplasm of resting T cells, was induced both in cytoplasm and at the cell surface. For HVEM, activation resulted in cellular redistribution, with its disappearance from cell surface. HVEM down-regulation did not rely on de novo protein synthesis, in contrast to the partial dependence of LIGHT induction. Matrix metalloproteinase inhibitors did not modify HVEM expression, but did enhance LIGHT accumulation at the cell surface. However, HVEM down-regulation was partially blocked by a neutralizing mAb to LIGHT or an HVEM-Fc fusion protein during activation. As a model, we propose that following stimulation, membrane or secreted LIGHT binds to HVEM and induces receptor down-regulation. Degradation or release of LIGHT by matrix metalloproteinases then contributes to the return to baseline levels for both LIGHT and HVEM. These results reveal a self-regulating ligand/receptor system that contributes to T cell activation through the interaction of T cells with each other and probably with other cells of the immune system.

This survey demonstrates that AEs occurring in the setting of DMSO-reduced HPC grafts are directly related to the amount of granulocytes and thus emphasizes the need for high-quality apheresis products so as to improve the safety of HPC infusion.

The online version of this article has a Supplementary Appendix. BackgroundHigh-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin's lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin's lymphoma. Design and MethodsWe report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatmentrefractory Hodgkin's lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. ResultsFive-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57-10.73 ConclusionsIn patients with relapsed/refractory Hodgkin's lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.Key words: Hodgkin's lymphoma, PET, outcome, relapsed refractory, ASCT.Citation: Devillier R, Coso D, Castagna L, Brenot Rossi I, Anastasia A, Chiti A, Ivanov V, Schiano JM, Santoro A, Chabannon C, Balzarotti M, Blaise D, and Bouabdallah R. Positron ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

Anti-PD-1 monoclonal antibodies (anti PD-1 mAbs) such as nivolumab and pembrolizumab are associated with high response rates in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (HL). To date, no prognostic factor for overall survival (OS) has been established with these agents in HL. We examined whether the first early response assessment evaluated using 18F-Fluorodeoxyglucose PET/CT (ePET 1), may be associated with OS in this setting. Methods: This retrospective study included 45 patients from 34 institutions. In a blinded, centralized review, three independent radiologists classified ePET 1 obtained at a median of 2.0 months (interquartile range: 1.7-3.7 months) after nivolumab initiation using existing criteria (i.e., Lugano 2014, LYRIC 2016). Patients were classified at ePET 1 according to 4 possible response categories: complete metabolic response (CMR), partial metabolic response (PMR), no metabolic response (NMR), or progressive metabolic disease (PMD). As the OS of patients with NMR and PMR were similar, they were grouped together. OS was estimated using the Kaplan-Meier method and compared between groups using log-rank testing. Results: Eleven patients (24%) died after a median follow-up of 21.2 months. The classification at ePET 1 was identical between Lugano and LYRIC since all 16 progression events at ePET 1 classified as indeterminate response per LYRIC were confirmed on subsequent evaluations. Both Lugano and LYRIC 2016 classified patients as CMR in 13 pts (29%), PMD in 16 pts (36%), NMR in 4 pts (9%) and PMR in 12 pts (27%). The 2-year OS [95CI] probability was significantly different in patients with

Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLAmatched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N 5 74) or MMUD (N 5 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P 5 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P 5 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P 5 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P 5 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P 5 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P 5 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P 5 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.

Lenalidomide is an oral non-chemotherapy immunomodulatory agent with an acceptable toxicity profile and manageable side-effects. Efficacy has widely been demonstrated, especially in MCL, FL and non-Germinal Center DLBCL patients. Further studies are now warranted to better define the strategy for the use of lenalidomide in B-NHL patients, and clarify which subgroup of patients will really benefit of lenalidomide as part of first-line treatment or in a relapsed/refractory setting.

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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The RELEVANCE trial (ClinicalTrials.gov identifier: NCT01650701 ) showed that lenalidomide plus rituximab (R2) provided similar efficacy to rituximab plus chemotherapy (R-chemo) in patients with advanced-stage, previously untreated follicular lymphoma (FL). We report the second interim analysis of the RELEVANCE trial after 6 years of follow-up. Patients with previously untreated grade 1-3a FL were assigned 1:1 to R2 or R-chemo, followed by rituximab maintenance. Coprimary end points were complete response (confirmed/unconfirmed) at week 120 and progression-free survival (PFS). At median follow-up of 72 months, 6-year PFS was 60% and 59% for R2 and R-chemo, respectively (hazard ratio = 1.03 [95% CI, 0.84 to 1.27]). Six-year overall survival was estimated to be 89% in both groups. Median PFS and overall survival were not reached in either group. Overall response after progression was 61% and 59%, and 5-year estimated survival rate after progression was 69% and 74% in the R2 and R-chemo groups, respectively. The transformation rate per year in the R2 and R-chemo groups was 0.68% and 0.45%, and secondary primary malignancies occurred in 11% and 13% ( P = .34), respectively. No new safety signals were observed. R2 continues to demonstrate comparable, durable efficacy and safety versus R-chemo in previously untreated patients with FL and provides an acceptable chemo-free alternative.