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Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα signaling via NF-κB" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (

Introduction Les inhibiteurs de Janus kinases (anti-JAK) sont des therapies ciblees qui bloquent la signalisation intracellulaire de plusieurs cytokines. Ils sont utilises dans le traitement de pathologies auto-inflammatoires et dysimmunitaires. Leur principal interet reside dans leur voie d’administration : orale et topique. Avec l’augmentation des indications ainsi que le developpement de nouvelles molecules, la securite d’utilisation de ces therapies ciblees est un element crucial. L’objectif de cette etude etait d’evaluer la securite des 3 premiers anti-JAK commercialises a partir des declarations de pharmacovigilance internationale. Materiels et methodes Dans cette etude observationnelle retrospective, les donnees de pharmacovigilance provenaient de la base de donnees de l’Organisation Mondiale de la Sante de declaration des evenements indesirables (VigiBase, 24 millions de declarations). Toutes les declarations comportant les medicaments suspects suivants ont ete incluses : ruxolitinib, tofacitinib et baricitinib. Chaque declaration comporte un/plusieurs evenements indesirables, classes selon la terminologie du Dictionnaire medical des affaires reglementaires MedDRA. Des analyses de disproportionnalite ont ete realisees afin d’estimer l’information component (IC). Un evenement indesirable est considere comme un signal de securite si la borne inferieure de l’intervalle de credibilite a 95 % (IC025) est positive. Resultats Nous avons identifie 126 815 declarations d’evenements indesirables impliquant un anti-JAK. Les traitements par ruxolitinib, tofacitinib et baricitinib etaient significativement associes avec la survenue d’infections (IC025 1,7 au niveau de la classe therapeutique, et plus precisement pour les infections virales [herpes et influenza], fongiques et mycobacteriennes) ; d’affections musculosquelettiques et du tissu conjonctif (IC025 1,1) ; d’embolies et de thromboses (IC025 0,4) ; de tumeurs malignes et benignes (IC025 0,8, et plus precisement les tumeurs malignes cutanees). Le tofacitinib etait associe avec la survenue de perforations gastro-intestinales (IC025 1,5). Nous n’avons pas identifie de signal concernant les evenements cardiovasculaires indesirables majeurs. Discussion La sous-declaration des evenements indesirables et l’absence de detail quant aux examens cliniques, biologiques ou d’imagerie ayant permis le diagnostic de l’evenement indesirable constituent les principales limites de cette etude. Un suivi plus long et de nouvelles etudes observationnelles pourront contribuer a l’amelioration de la connaissance des risques associes au traitement par anti-JAK au sein de differentes populations de patients selon la pathologie sous-jacente et les comorbidites. Conclusion Nous avons identifie des signaux de securite significatifs a partir des donnees de declaration internationale des evenements indesirables en lien avec les 3 premiers anti-JAK commercialises : evenements infectieux, embolies et thromboses, perforations gastro-intestinales et tumeurs malignes cutanees.

Background: Thrombopoietin receptor agonists(TPO-RAs) have been thought to play only a supporting role in ITP management. Several retrospective studies and a recent prospective study have reported unexpected cases of durable remission after TPO-RAs discontinuation in adult ITP in up to 30%. However, newly diagnosed ITP cases for which spontaneous remission may occur have been included in most of these studies. Thus, the main purpose of this study was to determine the proportion of patients with either persistent or chronic phase and no recent exposure to any potentially curative therapy (i.e., splenectomy or rituximab) achieving long-term remission off-treatment at 24 and 52 months after at least 3 months of TPO-RAs exposure with a complete response (CR). Patients/methods: We conducted a nationwide prospective multicenter interventional study (NCT03119974). Inclusion criteria were: 1) Patients aged > 18 years, with persistent or chronic primary ITP, 2) A stable CR defined by a platelet count > 100 x 10 9/L for more than 2 months on TPO-RA therapy, 3) Treatment with TPO-RA for at least 3 months. Main exclusion criteria were: 1) Anticoagulation or anti-platelet treatment, 2) Previous failure of TPO-RA discontinuation, 3) Concomitant treatment with corticosteroids ± intravenous immunoglobulin 4) Rituximab or splenectomy within the 2 months preceding or after TPO-RA initiation. After inclusion, the decrease and wean of either eltrombopag or romiplostim was initiated according to a standardized protocol (respectively tapering of 25 mg every 2 weeks or tapering of 1 ug/kg every week). In any case TPO-RAs had to be stopped at week 10. In case of relapse after TPO-RA discontinuation, the decision to start a new therapy was left at every investigator discretion. The primary endpoint was the proportion of patients achieving an overall response (CR + R) at week 24 (6 months) after TPO-RAs discontinuation. Secondary outcomes were overall response rate over the study period (W52), bleeding events, and to identify predictive factors, for overall prolonged response (W24 and W52). Results: Forty-nine patients (30 females, 61%), with persistent (n=2) or chronic (n=47, 96%) chronic ITP, with a median age of 58.5 years IQR (41 to 73) fulfilling the eligibility criteria were included over 2 year-period in 22 centers from the French reference network for adult' ITP. Forty patients received eltrombopag and 9 romiplostim at the time of inclusion. One patient was excluded since she was diagnosed pregnant one day after inclusion. In intention to treat 27/48 (56.2%; 95% CI, 29.5 to 58.8) patients achieved the primary-endpoint and maintained an overall response at week 24 after TPO-RAS discontinuation with a complete response for 15/27 (55%). During the full follow-up period of 52 weeks after TPO-RAs discontinuation, overall response was observed in 25/48 (52.1%; 95% CI, 37.2 to 66.2) patients (Figure 1). Bleeding events occurred in 13/21 (61.9%) and 15/23 (65.2%) patients relapsing respectively at 24 and 52 months with a median platelet count of 31´10 9/L(26 to 39) and 31 ´10 9/L(23 to 39). No severe bleeding episode (French bleeding score > 8) occurred. Median time of relapse after tapering initiation was 8 weeks. Among 21 patients with a relapse ( Conclusion: These results showed an unexpectedly high rate of sustained off-treatment remission after TPO-RAs discontinuation in chronic ITP among patients who initially achieve a stable CR. When they occur, relapses are mainly observed within the first weeks after discontinuation, very rarely afterwards and with no severe bleeding. While no predictive factor of lasting remission has been yet identified, our study strongly supports a progressive tapering of the dose of TPO-RAs in patients achieving a stable CR on treatment. Figure 1: Relapse at 52 weeks after TPO-RAs discontinuation Figure 1 Figure 1. Disclosures Mahevas: GSK: Research Funding; Amgen: Honoraria. Viallard: Novartis: Consultancy; Grifols: Consultancy; LFB: Consultancy; Amgen: Consultancy. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Michel: Novartis: Consultancy; Amgen: Consultancy; UCB: Honoraria; Argenx: Honoraria; Rigel: Honoraria; Alexion: Honoraria. Godeau: Sobi: Consultancy; Novartis: Consultancy; Amgen: Consultancy; Grifols: Consultancy.

Background : Neonatal immune thrombocytopenia (NITP) is a well described complication in newborns of women with ITP. It is reported to occur in about 15% to 30% of neonates. Previous pregnancies with NITP or ITP refractory to splenectomy have been described as associated with NITP mostly in retrospective studies. Methods: We conducted a nationwide prospective multicenter observational case-control study (ClinicalTrials.gov NCT02892630). Thirty-three centers including in the network of ITP experts in France participated in the study. Over a two years period, we enrolled 180 pregnant women with a history of ITP diagnosed before pregnancy and 171 of them were followed up until the delivery. Neonatal platelet counts were available for 136 newborns. Risk factor for developing NITP were evaluated as well as NITP treatment and complications. Results: NITP defined as a platelet count < 100 x 109/L was observed in 37 newborns (27.2%). More severe NITP with platelet counts < 50 x 109/L and < 30 x 109/L, were reported in 19 (14%) and 13 (9.6%) newborns respectively. Intravenous immune globulins were given to 18 newborns. Their median platelet count was 25.5 x 109/L (6; 56). Platelet transfusion was used for 8 newborns with a median platelet count of 13.5 x 109/L (6; 50). NITP was complicated by a hemorrhagic event in only 2 newborns, with a fatal bleeding in 1. Decline in disease ITP status in the mother during pregnancy and previous history of NITP were identified as predictors of NITP < 50 x 109/L by a univariate analysis while only previous history of NITP was confirmed in multivariate analysis (adjusted odds ratio (OR) 4.55; 95% confidence interval (CI) 1.48-13.92; p= 0.008). Decline in ITP disease status in the mother during pregnancy was the sole predictive factor for severe NITP defined as platelet < 30 x 109/L in multivariate analysis (adjusted OR 3.99; 95% CI 1.04-15.36; p = 0.044). Conclusion: Our study confirms that for ITP women with several pregnancies, a previous history of NITP is a risk factor for NITP. We also identify for the first time worsening of disease status during pregnancy to be a novel risk factor of severe NITP. In contrast, we did not confirm that a history of splenectomy was associated with an increased risk of NITP as suggested in retrospective studies (Loustau et al, Br J Haematol 2014; 166 929-35). Our results support that pregnancy in women with ITP is associated with an acceptable risk of severe bleeding in the newborn with NITP which is low but yet existing. Hence, close monitoring of pregnancy and delivery of mothers with ITP and their newborns is required, mainly in women who have a previous history of NITP or experienced a worsening of ITP during the pregnancy. Disclosures Haioun: Takeda: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Roche: Honoraria; Servier: Honoraria; Miltenyi: Honoraria. Mahevas:GSK: Research Funding. Michel:Rigel: Consultancy; Bioverativ: Consultancy; Alexion Pharmaceuticals: Consultancy. Godeau:Novartis: Honoraria; Amgen: Honoraria; Amgen: Research Funding; LFB: Honoraria.

Background: Adult immune thrombocytopenia (ITP) is a rare autoimmune disease that can affect women of childbearing age. The effect of pregnancy on women with a pregestational diagnosis of ITP is still unclear and has never been prospectively studied. Objective: Investigate the effect of pregnancy on the course of ITP. Methods: We conducted a nationwide prospective multicenter observational case-control study (ClinicalTrials.gov NCT02892630). Thirty-three centers from the French ITP reference center network participated in the study. Over a two years period, we enrolled 131 pregnant women with a pregestational diagnosis of ITP and 131 non pregnant women of childbearing age with ITP who served as controls. Matching criteria included: history of splenectomy, disease status (defined as non-responder, responder or complete responder depending on platelet count and the need of treatment modification in the last 2 months) and ITP duration (i.e; persistent (7) (16% vs 9.2%, p= 0.11).In contrast, initiation and intensification of therapy were significantly increased in pregnant women compared to matched controls, respectively 32.1% versus 20.6% (p = 0.01) of patients. Importantly, this increased need for therapy did not lead to an increase in maternal and obstetrical complications. In particular, we found no increase of complications that could have been exacerbated by corticosteroid and intravenous immunoglobulins use such as gestational diabetes or high blood pressure. Also compared to pre-gestational period, at 6 months post-partum, only 16.8% of pregnant women showed disease worsening. This frequency was comparable in the control group after 15 months follow-up (16.8%, p = 0.57). Conclusion: The current guidelines on therapy for pregnant women with pregestational ITP are mostly based on expert opinions and retrospective studies that mainly recommend treatment for pregnant women with a platelet count < 30 x 109/L. This prospective observational study investigating ITP progression during pregnancy shows that women with ITP were more intensively treated during pregnancy compared with matched controls. Paradoxically, this does not coincide with an increased of clinical or biological worsening in pregnant womenwhich raises questions of the relevance of this therapeutic conduct although we cannot exclude that these therapies may have prevented disease progression during pregnancy. Finally in late post-partum period, disease worsening was low and seems to be link to the natural course of the disease. Disclosures Haioun: Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Roche: Honoraria; Servier: Honoraria; Amgen: Honoraria; Miltenyi: Honoraria. Mahevas:GSK: Research Funding. Michel:Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy; Bioverativ: Consultancy. Godeau:Novartis: Honoraria; LFB: Honoraria; Amgen: Honoraria; Amgen: Research Funding.

The benefit of belatacept on antibody-mediated rejection (ABMR) incidence after kidney transplant with preformed donor-specific antibodies (DSAs) has never been assessed. Between 2014 and 2016, we conducted a multicenter prospective clinical trial with 49 patients to determine kidney allograft outcome in recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000) treated with belatacept (BELACOR trial). Immunosuppressive strategy included antithymocyte globulin, belatacept, mycophenolate mofetil, and steroids. An ancillary control group was designed retrospectively, including patients fulfilling the same inclusion criteria treated with calcineurin inhibitors. In BELACOR group, no patient exhibited acute ABMR, patient and allograft survival at 1 year was 100% and 95.4%, respectively, and the estimated glomerular filtration rate was 53.2 mL/min/1.73 m2 . However, the 12-month incidence of acute T cell-mediated rejection was 25.4% (14.5% to 42.4%). Comparison with the control group showed significantly higher T cell-mediated rejection incidence only in the BELACOR group (P = .003). Considering the DSAs, the outcome was similar in the 2 groups except a significantly higher number of patients displayed a complete disappearance of class II DSAs in the BELACOR group (P = .001). Belatacept was not associated with an acute ABMR increased risk and may be considered as immunosuppressive strategy in transplant recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000). Prospective randomized trials are needed to confirm these results.

International audience; Accurate estimation of the dose of ionizing radiation to which individuals have been exposed is critical for therapeutic treatment. We investigated whether gene expression profiles could be used to evaluate the dose received, thereby serving as a biological dosimeter. We used cDNA microarrays to monitor changes in gene expression profiles induced by ionizing radiation in mouse total blood. The subsets of genes best characterizing each dose were identified by resampling the original data set and calculating the intersection of the dose signatures. This analytical strategy minimizes the impact of potential genetic/epigenetic variation between mice and overcomes the bias in gene selection inherent to microarray technology. The significance of the identified signatures was evaluated by monitoring the type I error rate by in silico negative control simulation. Based on the distribution of the mean ratios of the selected probes, we were able to identify transcription profiles giving 83% to 100% correct estimation of the dose received by test mice, demonstrating that the selected probes could be used to determine the dose of radiation to which the animals had been exposed. This method could potentially be generalized to determine the level of exposure to other toxins and could be used to develop new related clinical applications.