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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

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34

The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hematology centers across France recruited 198 incident (ie, newly diagnosed) cases of ITP between April 2008 and June 2011. These cases were compared with 878 age- and sex-matched controls without ITP recruited in general practice. Information on vaccination was obtained from patients' standardized telephone interviews. Sixty-six of 198 cases (33.3%) and 303 of 878 controls (34.5%) received at least 1 vaccine within the 12 months before the index date. We found no evidence of an increase in ITP after vaccination in the previous 6 or 12 months (adjusted odds ratio [OR] for the previous 12 months = 1.0; 95% confidence interval, 0.7-1.4). When the 2-month time window was used, higher ORs were observed for all vaccines (OR = 1.3). This increase was mainly attributable to the vaccination against diphtheria-tetanus-pertussis-poliomyelitis (OR = 1.5) and was not statistically significant. The results of the present study show that in an adult population, the exposure to common vaccines is on average not associated with an observable risk of developing ITP.

Introduction Adults with ITP usually respond to corticosteroids but typically relapse after discontinuation. Rituximab is thought to be an effective off-label second-line treatment but only few prospective data exist about its long-term efficacy and its long-term safety is a matter of concern. The tolerance and particularly the risk of severe infection is a crucial factor for assessing the risk/benefit ratio of this treatment in ITP. Three years ago, we opened a non-interventional prospective registry in France to investigate the safety (primary outcome) and the efficacy of rituximab in off-trials adults with ITP (ClinicalTrials.Gov: NC1101295). Two hundred and fifty two patients were included on a two-year period. A follow-up duration of five-year is planned. We report here the first results after one year of follow-up. Methods The ITP-Ritux registry was set up by the French reference center of adult’s immune cytopenias. Thirty one centers participated to the study. Consecutive patients diagnosed with primary ITP according to the international guidelines (Rodeghiero et al, Blood 2009) who were treated with rituximab were included. Patients with a secondary ITP and those who were previously treated with rituximab were excluded. Response to treatment was assessed according to international guidelines: complete response (CR) was defined by platelet count ³100x109/L and response (R) by a platelet count between 30 and 100x109/L with at least a doubling of the pre-treatment count. The prospective and sequential monitoring of rituximab efficacy and safety was made by using of a standardized electronic case report form. Study nurses visited each center regularly to update the clinical and biological data on the enrolled patients. Results Between July 2010 and July 2012, 252 patients (64% of females) with a mean age of 51±21 (16-97) years were enrolled. The median duration of ITP was 1.3 (0-56) years with 44 patients (17%) with a newly diagnosed ITP, 61 (24%) with persistent ITP and 147 (58%) with chronic ITP at time of rituximab treatment. The median platelet counts at time of ITP diagnosis and rituximab first infusion were respectively 18x109/L (1-100) and 17x109/L (1-186). Patients received a median of 2 treatment lines (range 0-7) before rituximab and 25 (10%) were splenectomized. The standard regimen of 375 mg/m2 weekly rituximab infusions for 4 weeks was administered to 179 patients whereas 73 patients (29%) received a fixed dose of 1000 mg on day 1 and day 15. At time of the present analysis, the median follow-up was 18 months and the one-year response was available in 209 patients. A one-year overall response was observed in 90/209 (43%) patients including a CR in 28% and a R in 15%. Nineteen patients who failed to respond to rituximab were splenectomized during the year following rituximab infusions. Sixty eight adverse events occurred in 47 patients (19%). Rituximab infusions have to be stopped in only 3 patients for severe hypotension, dyspnoea with laryngeal discomfort and reversible serum sickness respectively. Three other patients developed severe adverse event related to rituximab requiring admission in hospital including 1 episode of profound neutropenia while 6 episodes of infections occurred in 2 patients. Seven patients (2.7%) have died during follow-up, 52 to 385 days after rituximab infusions. All patients who died but one aged of 18 were 68 to 98-year old. Only one death could be potentially related to rituximab (enterococcus faecium pulmonary infection), 2 deaths were of unknown origin, other causes were: suicide (n=1), multiple myeloma (n=1) and fatal haemorrhage related to ITP (n=2). We did not observe any episode of progressive multifocal encephalopathy or any other case of opportunistic infection. Discussion and conclusion Our preliminary results based on the first large non-interventional prospective registry of ITP-adults treated with rituximab in the “real life” confirm that this treatment leads overall to 40% of response after one year of follow-up. Safety of rituximab at 1 year appears to be good since severe infections were uncommon and no opportunistic infections were observed. The ongoing monitoring and upcoming analysis with a planned follow-up up to 5-years will provide more data on long-term safety. Disclosures: No relevant conflicts of interest to declare.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.