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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 (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Refractory immune thrombocytopenia (ITP) was previously defined as lack of a minimum response to splenectomy and the requirement for long-term treatment to reduce the risk of significant bleeding events. In this multicenter study, we included 37 patients with multirefractory ITP, defined as no response to splenectomy, rituximab, romiplostim, and eltrombopag. As compared with a historical cohort of 183 ITP patients, matched on the calendar year of ITP diagnosis with a 5:1 ratio, patients with multirefractory ITP were more likely to have secondary ITP (odds ratio [OR], 4.84; 95% confidence interval [CI], 1.31-17.86; P = .018) and monoclonal gammopathy of undetermined significance (OR, 5.94; 95% CI, 1.08-32.48; P = .04). The median duration of ITP before being recognized as multirefractory was 78 months (range, 6-450). The patients showed failure of a median of 10.5 prior treatment lines for ITP (range, 6-15). At the end of follow-up (median, 84 months; range, 12-455), only 1/14 patients achieved response with immunosuppressant therapy alone. By contrast, 7/10 patients achieved response with a combination of immunosuppressant therapy and thrombopoietin-receptor agonists that lasted for a median of 15 months (range, 6-32). Throughout the course of ITP, 5/37 patients died, 3 with ITP (bleeding, n = 2; sepsis n = 1); 15 (40%) had at least 1 bacterial infection and 9 (24%) at least 1 episode of thrombosis. In conclusion, multirefractory ITP was associated with high morbidity and mortality. Combining an immunosuppressant therapy with thrombopoietin-receptor agonists may be a good strategy for management for these patients with severe disease.

We conducted a prospective multicenter registry of 248 adult patients with immune thrombocytopenia (ITP) treated with rituximab to assess safety. We also assessed response and predictive factors of sustained response. In total, 173 patients received 4 infusions of 375 mg/m2 and 72 received 2 fixed 1-g infusions 2 weeks apart. The choice of the rituximab regimen was based on the physician’s preference and not patient characteristics. Overall, 38 patients showed minor intolerance to rituximab infusions; infusions had to be stopped for only 3 patients. Seven showed infection (n = 11 cases), with an incidence of 2.3 infections/100 patient-years. Three patients died of infection 12 to 14 months after rituximab infusions, but the role of rituximab was questionable. In total, 152 patients (61%) showed an overall initial response (platelet count ≥30 × 109/L and ≥2 baseline value). At a median follow-up of 24 months, 96 patients (39%) showed a lasting response. On multivariate analysis, the probability of sustained response at 1 year was significantly associated with ITP duration <1 year (P = .02) and previous transient complete response to corticosteroids (P = .05). The pattern of response was similar with the 2 rituximab regimens. With its benefit/risk ratio, rituximab used off-label may remain a valid option for treating persistent or chronic ITP in adults. This trial was registered at www.clinicaltrials.gov as #NC1101295.

RésuméLa famille malgache des Anisacanthidae se subdivise en trois groupes: Anisacanthinae, Leiophasmatinae n. subfam.et Xerantherinae n. subfam.Les Anisacanthinae comprennent AnisacanthaRedtenbacher 1906, Paranisacanthan. gen., ParectatosomaWood-Mason 1879, Somacanthan. gen.Les Leiophasmatinae comprennent LeiophasmaUvarov 1940 et probablement Amphiphasman. gen.Les Xerantherinae incluent Archantherixn. gen., Cenantherixn. gen., ParorobiaChopard 1952 et XerantherixBrancsik 1893. PseudoleosthenesRedtenbacher 1906 est considéré comme un membre de la famille des Damasippoididae.

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 (<1 year) or chronic). Cases and controls were followed up for 15 months and platelets counts, hemorrhagic complications and treatment initiation or intensification for ITP were recorded. We defined ITP worsening by a combined score including the occurrence of bleeding and/or occurrence of severe thrombocytopenia (i.e. < 30 G/L) and/or changes in ITP disease status. Results:ITP worsening was significantly increased in pregnant women with ITP when compared to matched controls, affecting respectively 52.7% versus 38.2% (p= 0.05) of patients (figure 1). It occurred mainly during the second and third trimesters. However, the frequency of severe thrombocytopenia (28.2% vs 25.2%, p= 0.69) and incidence of bleeding (22.9% vs 15.3%, p= 0.15) were similar in both groups, even when considering severe bleeding only (Khellaf’s bleeding score >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.

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.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.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.No relevant conflicts of interest to declare.

In a fully molecular HLA-matched setting, the outcome of allogeneic stem-cell transplantation (allo-SCT) can be affected by mismatches in minor histocompatibility antigens (mHAs) that might impact on the risk of graft-versus-host (GvH) and graft-versus-leukemia (GvL) effects. The association between mHA disparities and outcome was investigated in 96 consecutive patients who underwent myeloablative HLA-matched allo-SCT (from 69 HLA-identical siblings and 27 HLA-matched unrelated donors, all typed and matched at both allelic levels for HLA-A, -B, -Cw, -DRB1, and -DQB1 loci) for standard-risk hematological malignancy (AML n = 41; ALL n = 29; MDS n = 12; CML n = 8; others n = 6). All patients but 9 received bone marrow graft. Allelic mHAg typing was performed by PCR with sequence-specific primers for 9 autosomally encoded mHA and H-Y (PCR-SSP; Spierings et al. PLoS ONE. 2006 Dec 20; 1:e42). The distribution of autosomal mHAs among donor and recipients conformed to the expected frequencies for this population. As expected, the prevalence of mHAg mismatches was higher in unrelated compared to related recipient/donor pairs (p < .003). In univariate analysis, patients who received a graft with more than 2 mHAg mismatches developed more often grade II-IV acute GvH disease (p = .01; HR=2.92 [1.28–6.64]). In multivariate analysis, HA2 mismatch emerged as an independent determinant of acute GvH disease (p = .05; HR = .42). When only mismatches in the GvL/GvH direction were considered, mismatch for HA-1, that is expressed mainly by the hematopoietic system, tended to influence the incidence of both acute and chronic GvH disease (p = .06; HR=1.47 [0.97–2.21] and p = .049; HR = 1.45 [1.00–2.10], respectively) but also to confer a reduced risk of relapse (p = .07; HR = .58 [0.32–1.05]). Mismatch for HA-8, that has a broad tissue distribution, emerged as an independent risk factor of grade II-IV acute GvH disease (p = .02; HR = 1.77 [1.08–2.89]). This study confirms the impact of mHAg mismatches on patients’ outcome after fully HLA-matched allo-SCT and highlights both the cumulative effect of mHAg disparities on outcome and the distinctive contribution of individual mHAs on GvH versus GvL effects of allo-SCT.

The curative potential of allo-SCT for malignancies derives from the progressive reconstitution of the immune system and the development of effective anti-tumor immunity, but GVHD and disease relapse remain considerable obstacles to improvement in overall outcomes. Because in recipients target antigens are persisting, donor-derived T-cell responses may be expected to lead to the accumulation of a sizable proportion of differentiated T-cells, as happens following infection with persisting pathogens. A few cross-sectional studies have pointed to the preponderance of certain memory T-cell subsets associated with chronic GVHD (cGVHD), but the subset identified differed between studies. Inasmuch as qualitative T-cell recovery takes months to years to complete and there is substantial variability in time to development of GVHD or relapse, serial analysis might be more suitable to unveil early changes in T-cell subset composition attributable to transplantation-related events. From October 2003 on, 55 pts who underwent an allo-SCT after myeloablative conditioning were monitored prospectively in terms of clinical post-graft complications, including graft rejection, infections, GVHD and relapse. Blood samples were obtained on days 30±2, 60±3, 90±5, 180±10 and 365±15 post-transplant. Naive (CD45RA+CCR7+), central memory (TCM, CD45RAnegCCR7+), effector memory (TEM, CD45RAnegCCR7neg), and terminally differentiated effector (TTD, CD45RA+CCR7neg) were enumerated within the CD4+ and CD8+ pools, and the percentage of cells coexpressing CD28 was calculated within each eight subsets. The degree of donor-derived T-cell chimerism was assessed by real time PCR (sensitivity ≤ 1%). Median follow-up was 733 d (404–1251). Dynamics of CD4+ and CD8+ naive, TCM, TEM, and TTD were similar between the pts who developed cGVHD (n=15) and those who did not and between pts who relapsed and those who did not. However, costaining to detect CD28 demonstrated contrasting differences between cGVHD and relapse. At day 30, pts who subsequently relapsed (n=17) had elevated percentages of cells keeping CD28 expression within CD8+ T-cell subsets (TCM, p=.001; TCM, p=.021; and TTD, p=.007). Conversely, pts who subsequently developed cGVHD (n=15; only one relapsed) had diminished percentages of CD28+ cells within the two CD8+CCR7+ subsets at day 30 (p=.002 and p=.034, respectively). Loss of CD28 expression is known to be a hallmark of CMV infection but multivariate analysis ruled out, however, a confounding effect of CMV. Adjusted hazard ratios were 0.10 (95% CI, 0.01-0.76; p=.026) and 5.56 (95% CI, 1.16-25.00; p=.032) with CD28neg cells 16.7% of all CD8+ TCM at day 30 for relapse and cGVHD, respectively. Furthermore, pts with relapse had more often mixed chimerism at day 30 while those with cGVHD had more often full-donor chimerism (p=.042 and p=.023, respectively). CONCLUSION: This prospective study is the first to associate an early contrasting change in CD8+CD28neg T-cells with the risk of relapse and cGVHD after a myeloablative conditioning. Determination at day 30 of the proportions of CD8+ T-cell subsets expressing CD28 and of the level of T-cell chimerism could assist in predicting risk of relapse and cGVHD and help build an algorithm for the management of immunosuppressive treatment.