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In these two short reports, the authors approach the issue of whether hydroxyurea (HU) use in young males has major irreversible effects on sperm production. Joseph et al analyzed and compared sperm parameters in male patients with sickle cell disease (SCD) who were exposed or not exposed to HU before puberty. They report semen abnormalities in all patients but no differences between groups. Independently, Gille et al provide evidence for the lack of in vivo HU-related decreases in the spermatogonial pool in biopsy specimens from young males with SCD but evidence for a negative effect of SCD itself. Together, these reports suggest that the use of HU in young males does not adversely affect fertility.

We report here the 3-year stenosis outcome in 60 stroke-free children with sickle cell anaemia (SCA) and an abnormal transcranial Doppler history, enrolled in the DREPAGREFFE trial, which compared stem cell transplantation (SCT) with standard-care (chronic transfusion for 1-year minimum). Twenty-eight patients with matched sibling donors were transplanted, while 32 remained on standard-care. Stenosis scores were calculated after performing cerebral/cervical 3D time-of-flight magnetic resonance angiography. Fourteen patients had stenosis at enrollment, but only five SCT versus 10 standard-care patients still had stenosis at 3 years. Stenosis scores remained stable on standard-care, but significantly improved after SCT (P = 0·006). No patient developed stenosis after SCT, while two on standard-care did, indicating better stenosis prevention and improved outcome after SCT.

Focussing on sickle cell disease (SCD), the objective of this study was to assess adolescents' sexual heath experience in the context of their chronic illness.We included teenagers from 14 to 19 years old followed for SCD in a hospital located in Créteil (France) from March 2017 to February 2018. Their sexual health experience was assessed by a self-questionnaire with three key themes: contraceptive experience, awareness of sexuality with chronic disease and level of information on the genetic transmission of the disease.99 questionnaires were analysed. Only six SCD adolescents (one girl and five boys) reported being sexually active. Despite a very regular follow-up of their illness, only 13% of the boys and girls had received information on contraception at the hospital. Most adolescents (85% of boys and 81% of girls) did not think that the disease would interfere with sexual intercourse. The genetic pattern was well known (85% of boys and 87% of girls).Young people with SCD need more information on contraception. Clinicians caring for them should be aware of the need for sexual health information in order to propose prevention actions adapted to these young people with chronic disease.

Introduction: Early detection of Acute chest syndrome (ACS) can improve the prognosis of sickle cell disease (SSD. Recommendations for screening remain based on chest X-ray imaging and young patients with SCD are repeatedly exposed to diagnostic radiation. Lung ultrasound (LUS) can detect early lung lesions suggestive of ACS during a vaso-occlusive crisis (VOC). The objective of our study was to define the accuracy of LUS in detecting early lung lesions suggestive of ACS in patients hospitalized for VOC. Methods: This was a prospective multicentre study conducted on 4 paediatric departments in patients with SCD hospitalized with VOC and aged 1-18 years. The inclusion criteria were children presenting VOE with normal chest x-ray at admission. Clinicians with expertise in point of care LUS performed LUS on admission and on 3 consecutive days and compared it with chest radiographs taken on admission, on the last day or before if the patient had clinical signs suggestive of ACS. Accuracy, sensitivity, specificity, likelihood ratios, and positive and negative predictive value were calculated for the performance characteristics of LUS compared to chest X-ray. Results: LUS was performed on 121 SCD patients hospitalized for VOC. The prevalence of ACS was 12%, all patients with ACS had consolidations on their LUS and 93% of them on admission or Day 1. The sensitivity of LUS in our cohort was 100% and the specificity 40% compared to chest radiography. Conclusion: LUS appears to be a useful and feasible tool for the early detection of ACS during hospitalization of SCD patients presenting with a VOCs, compared with chest radiography.

Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.

Introduction The preservation of fertility is an integral part of care of children requiring gonadotoxic treatments for cancer or non-malignant diseases. In France, the cryopreservation of ovarian tissue has been considered and has been offered as a clinical treatment since its inception. The aim of this study is to review 20 years of activity in fertility preservation by ovarian tissue cryopreservation (OTC) for children and the feasibility of oocyte isolation and cryopreservation from the ovarian tissue at a single center. Material and methods Retrospective study including patients aged 15 years or younger who underwent OTC, combined for some with oocyte cryopreservation of isolated oocytes, before a highly gonadotoxic treatment for malignant or non-malignant disease was initiated. We describe the evolution of activities in our program for fertility preservation and patient characteristics at the time of OTC and follow up. Results From April 1998 to December 2018, 418 girls and adolescents younger than 15 years of age underwent OTC, representing 40.5% of all females who have had ovarian tissue cryopreserved at our center. In all, 313 patients had malignant diseases and 105 had benign conditions. Between November 2009 and July 2013, oocytes were isolated and also cryopreserved in 50 cases. The mean age of patients was 6.9 years (range 0.3-15). The most frequent diagnoses in this cohort included neuroblastoma, acute leukemia and hemoglobinopathies; neuroblastoma being the most common diagnosis in very young patients. During follow up, three patients requested the use of their cryopreserved ovarian tissue. All had undergone ovarian tissue transplantation, one for puberty induction and the two others for restoring fertility. So far, no pregnancies have been achieved. Eighty-four patients who had OTC died. Conclusions Ovarian tissue cryopreservation is the only available technique for preserving fertility of girls. To our knowledge this is the largest series of girls and adolescents younger than 15 years so far reported on procedures of OTC before highly gonadotoxic treatment in a single center.

Resume Le depistage neonatal de la drepanocytose a permis de reduire considerablement la mortalite de cette pathologie a l’âge pediatrique, actuellement inferieure a 1,1 % a 5 ans et 3 % a 18 ans, grâce a la prevention et au traitement precoce des infections et a la transfusion sanguine lors des episodes d’anemie aigue. Le risque de developper un infarctus arteriel cerebral a egalement diminue de 10 % a moins de 1,1 % a 5 ans grâce au depistage precoce et a la prise en charge par transfusions regulieres. Neanmoins, la drepanocytose reste une maladie invalidante, avec a 5 ans une probabilite d’hospitalisation pour crise vaso-occlusive (CVO) douloureuse de 63 %, pour syndrome thoracique aigu (STA) de 45 %, et pour anemie aigue de 30 %. La prise en charge de la CVO repose sur l’hydratation et le traitement antalgique. La transfusion est proposee en cas de crise prolongee ou d’anemie aigue. Bien qu’aucun essai n’ait ete realise pour demontrer l’interet de la transfusion precoce dans le traitement du STA, du fait de l’evolution rapidement progressive possible, elle est recommandee des le diagnostic de STA, et a ete largement utilisee. La ventilation non invasive se developpe, comme alternative a la transfusion par crainte des accidents hemolytiques post-transfusionnels, sa place restant a valider. Il est indispensable de savoir reconnaitre precocement ces accidents, et de les prevenir. L’intensification therapeutique qui regroupe un traitement medicamenteux, l’hydroxycarbamide, les programmes transfusionnels et la greffe de cellules souches hematopoietiques, reste proposee en France majoritairement apres la recurrence des complications. De nombreux arguments incitent a la proposer plus precocement, pour prevenir la survenue des complications.

International audience

The effect of a standardized musical intervention for adolescents with sickle cell disease was studied. Two groups were evaluated using the visual analog scale of pain and the anxiety-state inventory before and after a standardized musical intervention or breathing intervention. A significant decrease in scores was observed, most notably for the group benefiting from the standardized musical intervention. This intervention could be integrated into the overall management of adolescents with sickle cell disease.

The effect of a standardized musical intervention for adolescents with sickle cell disease was studied. Two groups were evaluated using the visual analog scale of pain and the anxiety-state inventory before and after a standardized musical intervention or breathing intervention. A significant decrease in scores was observed, most notably for the group benefiting from the standardized musical intervention. This intervention could be integrated into the overall management of adolescents with sickle cell disease.

BackgroundCurrent data suggest that COVID-19 is less frequent in children, with a milder course. However, over the past weeks, an increase in the number of children presenting to hospitals in the greater Paris region with a phenotype resembling Kawasaki disease (KD) has led to an alert by the French national health authorities.MethodsMulticentre compilation of patients with KD in Paris region since April 2020, associated with the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (‘Kawa-COVID-19’). A historical cohort of ‘classical’ KD served as a comparator.ResultsSixteen patients were included (sex ratio=1, median age 10 years IQR (4·7 to 12.5)). SARS-CoV-2 was detected in 12 cases (69%), while a further three cases had documented recent contact with a quantitative PCR-positive individual (19%). Cardiac involvement included myocarditis in 44% (n=7). Factors prognostic for the development of severe disease (ie, requiring intensive care, n=7) were age over 5 years and ferritinaemia >1400 µg/L. Only five patients (31%) were successfully treated with a single intravenous immunoglobulin (IVIg) infusion, while 10 patients (62%) required a second line of treatment. The Kawa-COVID-19 cohort differed from a comparator group of ‘classical’ KD by older age at onset 10 vs 2 years (pConclusionKawa-COVID-19 likely represents a new systemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children. Further prospective international studies are necessary to confirm these findings and better understand the pathophysiology of Kawa-COVID-19.Trial registration numberNCT02377245

Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells 15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs. 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells

International audience; Sickle cell disease is associated with severe complications and early mortality in adults. In children, hematopoietic stem cell transplant from HLA-identical sibling can stop the progression of the disease and leads to more than 95% long-term free survival without sickle cell disease. The aim of this workshop was to define indications and modalities of allogeneic hematopoietic stem cell transplant in children and adults with sickle cell disease. Patient and sibling HLA typing should be proposed, early in the course of the disease, when intensification therapies are required. Indications of transplant from HLA-identical sibling in children and adults are, cerebral vasculopathy, occurrence of vaso-occlusive events despite hydroxycarbamide, renal and hepatic diseases related to SCD, chronic anemia

Introduction Allogeneic hematopoïetic stem cell transplantation (HSCT) is the only established curative therapy for patients (pts) with sickle cell disease (SCD). It is mostly performed in children 1, due to higher risk of graft-versus-host disease (GVHD) and transplant related mortality in adults. Different approaches have been developped to improve tolerance of transplant in adults: use of reduced intensity conditioning (RIC) regimens 2 and intensive immunosuppression to avoid GVHD. Here, we have studied the impact of such approaches on immune reconstitution in adolescents and adults transplanted for SCD. Patients and methods We report 39 transplants in adolescents and adults, performed in Saint Louis hospital from 2008 to 2020: 25 were matched related transplants (MRT) and 14 haplo-identical related transplant (HRT). In MRT, conditioning was myeloablative (MAC) in 15 pts (busulfan, cyclophosphamide, rabbit anti-thymoglobulin (ATG) 20 mg/kg) and non myeloablative (NMA) in 10 pts (alemtuzumab 1 mg/kg, 3 Gy total body irradiation (TBI)). In MAC transplants, stem cell source was bone marrow and post-transplant immunosuppression was methotrexate and cyclosporine. In NMA transplants, stem cell source was peripheral blood cells with post-transplant immunosuppression by sirolimus. In the 14 HRT, the conditioning was reduced (cyclophosphamide, thiotepa, fludarabine, 2 Gy TBI, ATG 4.5 mg/kg), stem cell source was bone marrow and GVHD prophylaxis was ensured by post-transplant cyclophosphamide (100 mg/kg), sirolimus and mycophenolate mofetil. Results Median age at transplant was 17 years (y) old (range (r) 14-39). With a median follow-up of 3.6 y, the 2-y overall survival and survival without SCD were 97% (IC95%: 0.92-1) and 92% (IC95%: 0.83-1) respectively: no event after MRT, 1 death of GVHD and 2 graft rejections after HRT. The acute GVHD grade II-IV rate was 33%: 21% after HRT, 13% after MAC MRT and 0% after NMA MRT. Chronic GVHD occured in 3 pts (8%): severe in 1 HRT and mild in 2 MAC MRT. At 6 months, the blood chimerism evaluated in the 36 patients alive without rejection, was more often mixed (5 to 95% of donor) after NMA MRT (100%) versus MAC MRT (40%, p = 0.003) and HRT (18%, p < 0.001). Total lymphocytes (TL) counts increased rapidly in HRT and MAC MRT with a normalization from 3 months post-transplant. In contrast, NMA MRT experienced a slower recovery: at 6 months, median count was 1039/mm3 (r 463-1767) compared to 2071/mm3 (r 882-5985, p = 0.002) after MAC MRT and 2382/mm3 (r 676-3978, p = 0.005) after HRT. After NMA MRT, TL counts remained lower than normal values up to 12 months with a median of 1195/mm3 (r 870-3210) (Figure 1A). HRT displayed a rapid normalization of CD4 counts with a 3-month median count of 645/mm3 (r 350-1076) higher than reported after MRT (p < 0.001). Evolution of CD4 counts was similar after NMA and MAC MRT. They were lower than normal values during the first 12 months: median 364/mm3 and 388/mm3 respectively at 12 months (p = 0.25) (Figure 1B). From 3 months post-transplant, CD8 counts reached normal values after MAC MRT (314/mm3, r 108-2175) and were superior to normal after HRT (1335/mm3, r 66-4529), with a significant difference between HRT and MRT (p = 0.003). After NMA MRT, there was a trend for lower 3-month CD8 counts compared to MAC MRT: median of 107/mm3 (r 18-631, p = 0.08). CD8 counts remained under normal values after NMA MRT up to 12 months post-transplant (Figure 1C). From 3 to 6 months, CD4 and CD8 were mostly memory, with only 3.2% (r 0.1%-20.6%) and 6.2% (r 2.1%-11.2%) of CD45RA+ CCR7+ naïve CD8+ and CD4+ respectively. In the 3 groups NK cell counts reached normal values after 3 months. B lymphocytes counts normalized in the first months post-transplant except for patients who received rituximab for EBV reactivation. From 3 to 6 months, B lymphocytes were mostly naive: 98% of CD27- (r 92%-99%). Gammaglobuline levels were normal from 3 months in the 3 groups. Twelve (31%) pts were treated for a CMV and 6 (15%) for an EBV reactivation. No patient had CMV or adenovirus disease, or post-transplant lymphoproliferative disorder. Infections according to transplant types are detailed in figure 1D. Conclusion NMA MRT were associated with a delayed CD4 and CD8 recovery probably due to alemtuzumab. As previously reported 3, HRT displayed a rapid immune reconstitution. Despite use of serotherapy in the three modalities of transplant, the rate of viral infections remained acceptable without severe episode. Figure 1 Figure 1. Disclosures Pondarré: ADDMEDICA: Honoraria. Peffault De Latour: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Amgen: Consultancy, Other, Research Funding; Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Boissel: CELGENE: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria.

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD) allowing a SCD-free survival over 95% among children with matched HLA-identical donor (Gluckman E. Blood, 2017; Bernaudin F. Haematologica, 2020). In adults, myeloablative HSCT is associated with more graft-versus host disease (GVHD) and higher toxicity (Cappelli B. Haematologica, 2019). More recent approaches using non myeloablative (NMA) conditioning regimen (3 gray (Gy) total body irradiation (TBI) plus alemtuzumab) followed by HLA-identical peripheral blood stem cells (PBSC) and post-transplant sirolimus appear safe in adults (Hsieh MM. JAMA, 2014), but incidence of graft failure might be higher than the one reported after myeloablative conditioning (MAC) (Alzahrani M. Br J Haematol, 2021). Here, we compare outcomes after MAC or NMA conditioning regimens in patients over 15 years old transplanted from a matched related donor (MRD). Patients and methods All consecutive patients transplanted for SCD from a MRD from January 2015 to October 2020 were eligible if they were over 15 years old and received a busulfan-based MAC conditioning regimen or a NMA conditioning regimen. Chimerism was studied by analyzing various polymorphisms after polymerase chain reaction (PCR) amplification of DNA obtained from whole blood cells. Rejection was defined as donor chimerism Results Thirty-four patients were included: 20 in the MAC and 14 in the NMA groups. Median age at transplant was 17 years (range 15-46) without difference between groups. Forty four percent of patients had a history of cerebral vasculopathy, 79% of recurrent vaso-occlusive crises and 76% of acute chest syndrome. ABO major incompatibility was present in 15% of patients. There was no difference in patient characteristics according to the conditioning regimen group except for pre-transplant cerebral vasculopathy, more frequently reported in the MAC group: 70% versus 6% in the NMA group (p In the MAC group, conditioning regimen associated busulfan (12.8 mg/kg IV), cyclophosphamide (N=17) or fludarabine (N= 3) and anti-thymoglobulin (ATG, mostly 20mg/kg). Stem cell source was bone marrow and post-transplant immunosuppression combined cyclosporine and mycophenolate or methotrexate. In the NMA group, conditioning regimen associated 3Gy TBI and alemtuzumab (1mg/kg), followed by PBSC and post-transplant sirolimus. All patients engrafted and no secondary graft failure was observed. One MAC group patient died from GVHD. The 2-year overall and EFS were 95% (CI 95%: 85.9-100) in the MAC group (median follow-up of 39 months (range 8-63)) and 100% (CI 95%: 100-100) in the NMA group (median follow-up of 17 months (range 9-39)). Incidence of grade II-IV acute GVHD was 0% in the NMA group versus 20% in the MAC group (p=0.12). Incidence of chronic GVHD was 0% in the NMA group versus 25% in the MAC group (p=0.06). From the 27 patients with follow-up>12 months, 17/17 discontinued immunosuppressive therapy in the MAC group versus 8/10 in the NMA group. Hematopoietic recovery was faster in the NMA group with less platelet and red blood cell units transfused (Table). Throughout the follow-up, median donor chimerism was higher after MAC transplantation than after NMA transplantation: 98% (range 69-100) and 86 % (range 50-97) respectively at 1 year (p=0.017). Donor chimerism remained above 50% throughout the follow-up in all patients except 1 of the NMA group who displayed stable chimerism between 40 and 50%. All patients achieved HbS level close to the one of their donors. There was no difference between the 2 groups regarding occurrence of infections. MAC transplant was more often associated with hypertension, neurological complications, severe mucositis and need of enteral or parenteral nutrition. Moreover, duration of hospitalization was longer in MAC group: 54 days (range 39-192) versus 35 days in the NMA group (range 21-52) (p Conclusion In this series of adolescents and adults transplanted for SCD, the survival without SCD was excellent with a faster hematological recovery and a lower toxicity after NMA HSCT. Longer follow-up is required to confirm stable mixed donor chimerism and the cure of SCD after NMA approach. Figure 1 Figure 1. Disclosures Joseph: bluebird bio: Consultancy. Boissel: Servier: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; CELGENE: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Pondarré: ADDMEDICA: Honoraria.

Background Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization. Objectives To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France. Methods Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barre syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations. Results With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results. Conclusion Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.

Perceived exertion is an important self-limiting factor influencing functional capacity in patients with sickle cell anemia (SCA). Exercise-related hemoglobin desaturation (EHD) may occur during a six-minute walking test (6MWT) and could influence the perceived rate of exertion. The aims of this study were (1) to compare the 6MWT responses (heart rate, perceived rate of exertion, and distance covered) between SCA children with and without EHD, and (2) to test the associations between EHD and several biological/physiological parameters. Nine of 51 SCA children (18%) at steady state (mean age 11.9 &plusmn, 3.8 years) exhibited EHD at the end of the 6MWT. The rate of perceived exertion increased with exercise in the two groups, but reached higher values in the EHD group. Heart rate and performance during the 6MWT did not differ between the two groups. The magnitude of change in SpO2 during the 6MWT was independently associated with the red blood cell (RBC) deformability and RBC aggregates strength. This study demonstrates that SCA children with EHD during a 6MWT have a higher rate of perceived exertion than non-EHD children despite a similar physiological demand, and that abnormal RBC rheology determinants appear to be significant contributors.

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Cr&eacute, teil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (&plusmn, 2.3) vs. 3.3 (&plusmn, 1.8) days, p &lt, 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion (p &lt, 0.0001). The multivariate model retained pain score (&ge, 9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (&ge, 260 &times, 109/L) and neutrophil (&gt, 10 &times, 109/L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74&ndash, 0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS.

This study&rsquo, s objective was to assess, on a national scale, residual risks of death, major disease-related events, and quality of care during the first five years in children diagnosed at birth with sickle cell disease (SCD). Data were retrospectively collected from medical files of all children with SCD born between 2006&ndash, 2010 in France. Out of 1792 eligible subjects, 1620 patients (71.8% SS or S/beta&deg, thalassemia -SB&deg, ) had available follow-up data, across 69 centers. Overall probability of survival by five years was 98.9%, with 12/18 deaths related to SCD. Probability of overt stroke by five years in SS/SB&deg, patients was 1.1%, while transcranial Doppler (TCD) was performed in 81% before three years of age. A total of 26 patients had meningitis/septicemia (pneumococcal in eight cases). Prophylactic penicillin was started at a median age of 2.2 months and 87% of children had received appropriate conjugate pneumococcal vaccination at one year. By five years, the probability of survival without SCD-related events was 10.7% for SS/SB&deg, patients. In contrast, hydroxyurea was prescribed in 13.7% and bone marrow transplant performed in nine patients only. In this study, residual risks of severe complications were low, probably resulting from a good national TCD, vaccination, and healthcare system coverage. Nonetheless, burden of disease remained high, stressing the need for disease-modifying or curative therapy.

Over the past 3 decades, the pediatric department of the university Intercommunal Cr&eacute, teil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbS&beta, 0 thalassemia) and 157 with milder genotypes (HbSC and HbS&beta, + thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.

Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism 10 g/dL) and three with AS donors (hemoglobin

Background: Several controlled studies had established hydroxycarbamide as a gold standard for treatment of children affected with sickle cell disease. The European Sickle Cell Disease Cohort - Hydroxyurea (ESCORT-HU) is a cohort study designed to monitor in a large number of patients over a long period of time the use of hydroxycarbamide in current practice. Here we present the results on the paediatric cohort. Methods: Children were enrolled between January 2009 and June 2017. Patients were followed-up according to usual clinical monitoring. Efficacy was studied in a subpopulation naive for the treatment at enrolment, by comparing changes in Hb and HbF% levels, and in clinical outcomes after 12 months of treatment. Safety was assessed from the occurrence of adverse events in the total cohort. Findings: Eight hundred and twelve children (10.1 ± 2.3 years) have been enrolled; of these 141 were naive to the treatment. Median duration of follow-up for the whole cohort was 29 months (0-108). Seventy-four % of the patients were treated within the licensed indication (painful crisis and acute chest syndrome); 26% of children were treated for off-label indications, mostly severe anaemia and brain protection. Mean dosages ranged from 16.6 ± 3.1 mg/kg/d at initiation to 22.0 ± 4.4 mg/kg/d after 4 years. No attempt was made in most cases to reach the maximal tolerated dose. Mean increases of Hb at 6 and 12 months (g/dl), and HbF at 6 months (%) were + 0.68, +1.0, and + 6.1% respectively. Hydroxycarbamide also reduced the number of painful crises (p

IMPORTANCE: In children with sickle cell anemia (SCA), high transcranial Doppler (TCD) velocities are associated with stroke risk, which is reduced by chronic transfusion. Whether matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) can reduce velocities in patients with SCA is unknown. OBJECTIVE: To determine the association of MSD-HSCT with TCD velocities as a surrogate for the occurrence of ischemic stroke in children with SCA. DESIGN, SETTING, AND PARTICIPANTS: Nonrandomized controlled intervention study conducted at 9 French centers. Patients with SCA were enrolled between December 2010 and June 2013, with 3-year follow-up ending in January 2017. Children with SCA were eligible if younger than 15 years, required chronic transfusions for persistently elevated TCD velocities, and had at least 1 sibling without SCA from the same 2 parents. Families agreed to HLA antigen typing and transplantation if a matched sibling donor was identified or to standard care in the absence of a matched sibling donor. EXPOSURES: MSD-HSCT (n = 32), compared with standard care (n = 35) (transfusions for ≥1 year with potential switch to hydroxyurea thereafter), using propensity score matching. MAIN OUTCOMES AND MEASURES: The primary outcome was the highest time-averaged mean of maximum velocities in 8 cerebral arteries, measured by TCD (TCD velocity) at 1 year. Twenty-five of 29 secondary outcomes were analyzed, including the highest TCD velocity at 3 years and normalization of velocities (

Objectif Determiner les facteurs cliniques et biologiques associes au developpement du syndrome thoracique aigu (STA) pendant une crise vaso-occlusive (CVO) chez les enfants atteints de drepanocytose. Methodes Etude observationnelle monocentrique prospective realisee dans le service pediatrique de l’hopital universitaire intercommunal Creteil. Tous les enfants atteints de drepanocytose (tous les genotypes de drepanocytose) admis consecutivement de novembre 2013 a decembre 2016, pour des CVO douloureuse et aucun signe de STA ont ete inclus. Les parametres cliniques et les donnees biologiques recueillis a l’admission et dans les 48 heures suivant l’admission ont ete compares entre ceux qui ont developpe un STA et ceux qui ne l’ont pas developpe. Les variables statistiquement significatives par analyse univariee ou considerees comme pertinentes sur le plan clinique ont ete prises en compte pour une analyse multivariee afin de determiner les facteurs de risque associes au developpement d’un STA chez les enfants presentant une CVO. Les variables retenues dans le modele multivarie ont ete utilisees pour construire un score predictif de STA. Resultats Parmi les 191 hospitalisations pour CVO douloureuse, chez 176 enfants atteints, 35 ont developpe un STA pendant l’hospitalisation. En comparant le STA aux CVO, la duree moyenne de sejour a l’hopital etait plus longue (7,6 ± 2,3 ± 2,3 vs 3,3 ± 1,8 jours [p 10 × 109/L) a l’admission est associe au developpement d’un STA. Le score predictif de STA ainsi obtenu avait une aire sous la courbe du RDC de 0,82[IC95 % : 0,74–0,89] et une valeur predictive negative de 97,7 %. Conclusion Les mesures cliniques et biologiques a l’admission peuvent servir de parametres simples pour identifier les enfants presentant un risque accru de developpement de SCA pendant l’exposition aux COV et pour faciliter le diagnostic precoce de cette complication respiratoire. De plus, l’elevation persistante de la numeration leucocytaire au jour 2 peut etre consideree comme un signe d’un SCA en evolution.

Introduction L’echographie thoracique prend une part de plus importante dans le diagnostic et le suivi des pathologies pulmonaires de l’enfant. L’objectif de ce travail est de decrire les lesions pulmonaires observees a l’echographie pulmonaire (LUS) chez des enfants suivis pour drepanocytose et presentant des signes cliniques de syndrome thoracique aigue. Methodes Nous avons realise une etude observationnelle retrospective portant sur 35 enfants suivis pour drepanocytose, âges entre 4 et 18 ans, qui ont presente des signes cliniques de syndrome thoracique aigu au centre hospitalier intercommunal de Creteil (CHIC) entre mai 2017 et mars 2019. Tous ont eu au moins une radiographie thoracique de face (CXR) et une LUS pendant leur sejour. Le STA a ete defini par l’association de signes cliniques et de signes radiographiques (groupe CXR ACS) ou echographiques. Le groupe LUS ACS a ete defini comme l’association de signes cliniques et echographiques de STA avec une CXR negative. Les signes cliniques comprenaient de la fievre, des douleurs thoraciques, une hypoxemie, une tachypnee, des sibilants, une toux ou une detresse respiratoire aigue. Resultats Trente-sept patients ont ete inclus. Deux exclus a posteriori pour absence de radiographie de thorax. La radiographie thoracique n’a detecte que 43 % des cas de STA, tandis que l’echographie pulmonaire 100 % des cas. Les signes cliniques de STA etaient plus severes dans le groupe CXR ACS. Les signes echographiques de STA etaient homogenes entre les differents patients, incluant consolidations avec bronchogrammes et lignes B. Soixante et onze pour cent des epanchements pleuraux ont ete detectes uniquement par l’echographie pulmonaire. Quatre-vingt pour cent des enfants du groupe ACS LUS ont ete transfuses ou echanges malgre l’absence de signes radiographiques de STA. Conclusion L’echographie pulmonaire pourrait etre une solution plus informative et moins invasive que la radiographie thoracique pour le diagnostic du syndrome thoracique aigu. La transfusion ou l’echange precoces bases sur des signes cliniques et echographiques pourraient eviter l’aggravation clinique dans la majorite des cas. De futures etudes prospectives randomisees sont necessaires pour valider nos observations.

International audience; BACKGROUND : Sickle cell disease (SCD) patients undergo multiple red blood cell (RBC) transfusions and are regularly exposed to low‐prevalence (LP) antigens specific to individuals of African descent. This study evaluated the prevalence of antibodies against LP antigens in SCD patients and the need to identify these antibodies in everyday practice.STUDY DESIGN AND METHODS : Plasma from 211 SCD patients was tested with RBCs expressing the following LP antigens: RH10 (V), RH20 (VS), RH23 (DW), RH30 (Goa), KEL6 (Jsa), and MNS6 (He).RESULTS : Nine LP antibodies were found in eight patients (3.8%): five anti‐RH23, two anti‐RH30, and two anti‐MNS6. The exposure risk, calculated for each LP antigen, was below 3% per RBC unit, for all antigens tested. Thus, in this cohort of transfused SCD patients, the prevalence of LP antibodies was similar to that of antibodies against antigens of the FY, JK, and MNS blood group systems. These findings also reveal the occurrence of anti‐RH23 in SCD patients. No anti‐RH20 or anti‐KEL6 were found, despite the high frequency of mismatch situations.CONCLUSION : These results highlight the immunogenicity of these LP antigens, and the evanescence of antibodies against LP antigens. They also highlight the importance of appropriate pretransfusion testing for patients frequently transfused, who are likely to be exposed to multiple types of blood group antigens.

International audience; BACKGROUND Donor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent beta-thalassemia. After previously establishing that lentiviral transfer of a marked beta-globin (beta(A-T87Q)) gene could substitute for long-term red-cell transfusions in a patient with beta-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent beta-thalassemia. METHODS In two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent beta-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA(T87Q)). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbA(T87Q), transfusion requirements, and average vector copy number. RESULTS At a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-beta(0)/beta(0) genotype had stopped receiving red-cell transfusions; the levels of HbA(T87Q) ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a beta(0)/beta(0) genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed. CONCLUSIONS Gene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe beta-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials. gov numbers, NCT01745120 and NCT02151526.)

International audience; In this retrospective study, we evaluate long-term complications in nearly all β-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs. 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient’s age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.

Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Creteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study. Homozygous β-haplotype patients represented 74% of cases (37.4% CAR/CAR, 24.3% BEN/BEN, and 12.1% SEN/SEN). HU was given to 168 cohort SCA children. Hematological parameters were recorded when HbF was maximal, and changes (ΔHU-T0) were calculated. At baseline, CAR-haplotype and α-gene numbers were independently and negatively correlated with Hb and positively correlated with lactate dehydrogenase. HbF was negatively correlated with CAR-haplotype numbers and positively with BEN- and SEN-haplotype numbers. The BCL11A/rs1427407 "T" allele, which is favorable for HbF expression, was positively correlated with BEN- and negatively correlated with CAR-haplotype numbers. With HU treatment, Δ and HbF values were positively correlated with the BEN-haplotype number. BEN/BEN patients had higher HbF and Hb levels than CAR/CAR and SEN/SEN patients. In conclusion, we show that BEN/BEN patients have the best response on HU and suggest that this could be related to the higher prevalence of the favorable BCL11A/rs1427407/T/allele for HbF expression in these patients.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure single gene disorders such as thalassemia and sickle cell anemia (SCA). These non-malignant diseases have in common severe hemolytic anemia and high proliferative bone marrow, requiring frequent transfusions. The risk of rejection is high and graft-vs-host disease is not desirable. Important progress has been made in the management of these diseases, including leukocyte depletion of blood products, and chelation therapy, for both diseases, and erythrocytapheresis and hydroxycarbamide for SCA. However, morbidity and quality of life are still of concern. Results have also significantly improved for HSCT, with the reduction of rejection by using anti-thymocyte globulin (ATG), which also decreases the risk of chronic graft-vs-host disease. Current data show a more than 90% chance of cure with myeloablative conditioning in children with hemoglobinopathy and a geno-identical donor. Results are similar whether the cell source is cord blood or bone marrow. Because of the risk of conditioning-related infertility, ovarian and/or testis cryopreservation should be discussed. Non-myeloablative conditioning regimens have also been successfully developed in adults with SCA and organ dysfunction, making cure possible. These encouraging results should incite to perform HLA typing early in families with hemoglobinopathies, and to systematically propose sibling cord blood cryopreservation for those without geno-identical donor.

Background Children with sickle cell anemia (SCA) have an 11% risk of stroke by the age of 18. Chronic transfusion applied in patients detected to be at risk by transcranial Doppler allows a significant reduction of stroke risk. However, chronic transfusion exposes to several adverse events, including alloimmunization and iron overload, and is not curative. Hematopoietic stem cell transplantation allows termination of the transfusion program, but its benefit has not been demonstrated. Design DREPAGREFFE ( NCT01340404 ) is a multicenter, prospective trial enrolling SCA children younger than 15 years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥ 200 cm/s). Only those with at least one non-SCA sibling and parents accepting HLA-typing and transplantation with a genoidentical donor were eligible. Chronic transfusion was pursued in patients with no available donor, whereas others were transplanted. Comparison between the 2 arms (transfusion vs transplantation) was analyzed using both genetic randomization and propensity-score matching as a sensitivity analysis. The primary end-point was the velocity measure at 1 year. Secondary endpoints were the incidence of stroke, silent cerebral infarcts and stenoses, cognitive performance in comparison with siblings, allo-immunization, iron-overload, phosphatidyl-serine, angiogenesis/hypoxia, brain injury-related factor expression, quality of life and cost. Objectives To show that genoidentical transplantation decreases velocities significantly more than chronic transfusion in SCA children at risk of stroke. Discussion DREPAGREFFE is the first prospective study to evaluate transplantation in SCA children. It compares the outcome of cerebral vasculopathy following genoidentical transplantation versus chronic transfusion using genetic randomization and causal inference methods.

Neonatal alloimmune thrombocytopenia (NAIT) is a common but significant challenge for neonatologists and a potentially devastating disease that may lead to intracranial bleeding. The underlying mechanism of thrombocytopenia is expected to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We report severe recurrent NAIT related to human platelet antigen (HPA)-15 systems in 2 consecutive siblings. The first child presented with intracranial hemorrhage at birth and subsequently died. The diagnosis of NAIT, although initially suspected, was ruled out after negative investigation of only HPA-1, HPA-3, and HPA-5 systems. The second child experienced a clinically milder presentation but a profound thrombocytopenia. In both siblings, NAIT was unexpectedly associated with amegakaryocytosis, suggesting that alloimmunization could extend at the megakaryocyte level. In addition, both siblings presented with drastic abnormalities in the B-cell compartment, which led to broad investigations for an immune-deficiency syndrome and provided a novel pathophysiologic hypothesis. Both placental examinations revealed major lymphoid infiltration involving the villous placenta, which is consistent with the diagnosis of villitis of unknown etiology. Severe thrombocytopenia in an otherwise healthy newborn should raise high the suspicion of NAIT. The diagnosis of NAIT should not be ruled out until extensive human platelet antigen systems have been investigated to screen for fetal-maternal antigen incompatibility. This is crucial not only for the newborn to allow optimal lifesaving treatments but also for effective management of future pregnancies. Interestingly, antibodies to HPA-15 have previously been reported with severe NAIT-related thrombocytopenia, but we are the first to report associated in vivo amegakaryocytosis.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure single gene disorders such as thalassemia and sickle cell anemia (SCA). These non-malignant diseases have in common severe hemolytic anemia and high proliferative bone marrow, requiring frequent transfusions. The risk of rejection is high and graft-vs-host disease is not desirable. Important progress has been made in the management of these diseases, including leukocyte depletion of blood products, and chelation therapy, for both diseases, and erythrocytapheresis and hydroxycarbamide for SCA. However, morbidity and quality of life are still of concern. Results have also significantly improved for HSCT, with the reduction of rejection by using anti-thymocyte globulin (ATG), which also decreases the risk of chronic graft-vs-host disease. Current data show a more than 90% chance of cure with myeloablative conditioning in children with hemoglobinopathy and a geno-identical donor. Results are similar whether the cell source is cord blood or bone marrow. Because of the risk of conditioning-related infertility, ovarian and/or testis cryopreservation should be discussed. Non-myeloablative conditioning regimens have also been successfully developed in adults with SCA and organ dysfunction, making cure possible. These encouraging results should incite to perform HLA typing early in families with hemoglobinopathies, and to systematically propose sibling cord blood cryopreservation for those without geno-identical donor.

The presence of cerebral macrovasculopathy as detected by transcranial Doppler (TCD) exposes children with sickle cell anemia (SCA) to a high risk of stroke, preventable by chronic transfusion or stem cell transplantation (SCT). However, long-term outcomes of stenosis have not been well described. The Drepagreffe trial (NCT01340404) was a prospective trial comparing cerebral vasculopathy outcome after SCT vs standard-care in children with abnormal TCD with or without stroke history. Results from the whole population have recently been reported (Bernaudin et al, JAMA 2019). The decrease in velocities was significantly higher after SCT than standard-care (p Sixty-seven SCA-children on chronic transfusion for abnormal-TCD history were enrolled (Dec-2010/June-2013) in this prospective trial with two treatment groups defined by the random-availability of having a matched-sibling donor (MSD). Thirty-two with MSD were transplanted while 35 without MSD were maintained on chronic transfusion for at least one-year and eventually switched to hydroxyurea thereafter if no stenosis and normalized velocities. Cerebral and cervical magnetic-resonance angiography (MRA) was systematically performed at enrollment, and 1- and 3-year post-enrollment. Stenosis was defined as a narrowing ≥25%. The MRA stenosis-score, was calculated as the weighted sum of the scores in the 8 assessed cerebral arteries (right and left middle cerebral (MCA), anterior (ACA), internal carotid (ICA) and extracranial internal carotid arteries (eICA)), with 0 = stenosis, 1 = mild stenosis (25-49%), 2 = moderate stenosis (50-74%), 3 = severe stenosis (75-99%), and 4 = occlusion. All 67 patients were alive at 3-year, and the 32 transplanted patients successfully engrafted. No stroke or recurrence occurred during the follow-up. No chronic-GVHD was observed. Among the 7 patients with stroke-history, all had stenosis at enrollment and the stenosis score increased in the 4 transplanted patients, but always in the arteries with previous stenosis and those feeding ischemic territories, while stenosis score remained mostly stable in the 3 patients maintained on chronic transfusion,. However, the difference between treatment groups was not significant (p=0.057). Among the 60 stroke-free patients at enrollment, 28 with MSD were transplanted while 32 without MSD were maintained on chronic transfusion. At enrollment, 28 patients (14 patients in each treatment group) had stenosis. At 1-year, 9 patients in the SCT group had stenosis, whereas in the transfusion/standard-care group, 10 had stenosis. At 3-year, 5 patients in the SCT group had stenosis, while 10 still had stenosis in the standard-care group. Moreover, 2 patients, who had no stenosis at enrollment, developed one stenosis between 1 and 3-year, despite chronic transfusion in one case and after switch to hydroxyurea in the other. In another patient, stenosis had disappeared on chronic transfusion at 1-year, although it reappeared at 3-year after a switch to hydroxyurea. In the SCT group, no worsening of stenosis was observed, and stenosis improved in 13/14 and was stable in one; in contrast, worsening of stenosis score was observed in the standard-care group in 6 patients on chronic transfusion (p=0.035), The stenosis-score between enrollment and 3-year improved more significantly in the SCT group (mean (SD): -1.39 (2.47)) than in the standard care group (-0.06 (1.18)); (p=0.012). Conclusions: This prospective trial reporting the outcome of stenosis in stroke and stroke-free SCA-patients with a history of abnormal-TCD shows a trend to worsening of the stenosis-score after SCT in stroke-patients, but no stroke recurrence; in contrast, in stroke-free patients, stenosis outcome was significantly better after SCT and with better prevention of stenosis occurrence than on standard care. These results support early recommendation of SCT in children with a history of abnormal-TCD and an MSD. Figure Disclosures Verlhac: Addmedica, Paris: Other: Financial Support; Bluebird Bio: Consultancy. Brousse:bluebird bio: Consultancy; Add medica: Consultancy. De Montalembert:Addmedica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Bernaudin:GBT: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Other: Help for travel to meeting; BlueBirdBio: Consultancy.

Background: The goals of newborn screening programs (NBS) for sickle cell disease (SCD) are to reduce early mortality and morbidity, by introducing preventive measures like penicillin prophylaxis, pneumococcal vaccines and Transcranial Doppler (TCD) screening. The main objective of this study (NCT 03119922) was to assess on a national scale and during the first 5 years residual risks of death, overt stroke and bacterial meningitis/septicemia resulting from current TCD and pneumococcal prophylactic utilization in SCD children diagnosed at birth. An additional objective was to determine the frequency of other main SCD-related events and the use of disease-modifying or curative therapy. Methods: Using the national NBS database between 2006-2010, data was collected in 2014/2015 from the patients' medical files up to the age of 5 years, and included age at first prescription of penicillin, occurrence of death/overt stroke/bacterial meningitis and septicemia, age at first transfusion (TF), use of pneumococcal vaccines/chronic transfusion program/hydroxyurea (HU)/hematopoietic stem cell transplantation (HSCT) and TCD results. Results: Out of 1792 eligible subjects, 152 (8%) were lost to follow-up. A total of 1620 patients with available follow-up data across 69 centers constituted the EVADREP cohort. Of them, 71.8% had SS or S beta°-thalassemia (SB°) while 20.3% had SC /S Beta+-thalassemia (SB+) disease, and 59.6% resided in Paris area. Overall mortality rate for all patients was 0.23/100 person-years during the 5 first years of life and probability of survival at 5 years was 98.9% (95%CI: 98.2-99.3), with 18 deaths during the study period, 12 related to SCD (11 patients SS or SB°). The probability of overt stroke at 5 years was 1.1% all in SS/SB° patients. DTC was performed in 56% and 81% of patients before 2 and 3 years of age, respectively. The probability of abnormal TCD at 5 years was 10.4%. A total of 26 patients had a severe infection (meningitis or septicemia), lethal in 8 cases and caused by a pneumococcal strain in 8 cases. More than 99% of patients were prescribed prophylactic penicillin, started at a median age of 2.2 months of life. Full pneumococcal vaccination (at least 4 PCV and one P23) was performed in only 47.4% before 3 years but the probability of receiving P23 was 90% at 5 years. At 3 years, 42.9% of the EVADREP cohort had experienced a first VOE and the probability of survival without VOE was 62.4% [60.0-64.8] at 5 years. When pooling all SCD-related events (death, stroke, severe infection, VOE, acute anemia, as well as abnormal DTC, pneumonia and/or ACS and transfusion), 58.6% of children had experienced at least one event at 3 years. The probability of survival without SCD-related events at 5 years was 10.7% [0.9-12.6] for SS/SB° patients and 46.3% (41.5-51) for SC/SB+. In sharp contrast, HU was prescribed in 13.7% and HSCT performed in 9 patients only. Vaccination and DTC coverage, use of TF program and HU were significantly higher in larger centers. Summary/Conclusion: Current residual risks of severe complications and mortality rates on a national scale are similar to those observed in SCD expert center cohorts, presumably as a result of good TCD and vaccination coverage and an easy access to health care in France. Further improvement could be achieved with better referral to centers of expertise. The burden of disease is still high and increased use of disease modifying or curative therapy should benefit more children in the future. Disclosures Brousse: Add medica: Consultancy; bluebird bio: Consultancy. Bernaudin:BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Sperm parameters alteration is documented in untreated men with sickle cell disease (SCD). An aggravating effect of hydroxyurea (HU) on sperm parameters is also well established: HU, at current doses, causes significant, rapid, and unpredictable impairment of spermatogenesis. Reversal of its effect when treatment is stopped has also been documented, albeit in patients given very low doses of treatment (10 mg/kg/d). In France, sperm banking is free of charge and recommended whenever possible before initiation of HU treatment. While recent guidelines have broadened the indication of HU for asymptomatic infantssuch banking is impossible in younger boys before puberty. In addition, little is known on the effect of HU on sperm parameters when given at this specific period. Objectives and Methods: The main objective of this study was to compare sperm parameters after treatment resolution in young males treated by HU prior to puberty with sperm parameters of untreated males. Secondary objective was to analyze longitudinally sperm parameters during HU washout in those treated prior to puberty.Data regarding indication of HU, dosage, date of initiation and stop, clinical profile including vaso occlusive events (VOE) transfusion episodes and date of puberty was collected. Alternative treatment before or during semen analysis was also documented. A period of 3 months of HU wash out was required prior to semen analysis in treated patients. Results: A total of 26 patients (43 semen samples) were studied, with 16 patients treated with HU prior to puberty (HU-PP) and 10 untreated (HU-naive). Characteristics of patients are presented in Table 1. Indication of HU was cerebral vasculopathy (n=3), VOE (n=5), severe anemia (n=1) or combined (n= 7). The median stopping of the HU before CECOS is 4.5 years [0.5-11.0]. An alternative treatment based on a transfusion program was initiated in 14 patients (87.5%) at the time of sperm analysis in the HU-PP group versus 5 patients (50%) in the HU-naive group. Duration of transfusion program was 126 months [3-188] in HU-PP versus 13 [7-100] in the HU naive group. We compared the fraction of abnormal values in semen samples in both groups (25 samples in the HU-PP group and 18 in the HU-naive). No significant difference was observed regarding volume of ejaculate, spermatozoid concentration, total sperm count, spermatozoid motility, morphology and vitality, and sexual abstinence before sampling in both groups (Table 1). In the HU-PP group, there was a trend in improvement of sperm parameters with the duration of transfusion program. In addition, a kinetic analysis of sperm parameters during the period of HU wash out was performed in 3 patients exposed to HU prior to puberty, demonstrating reversibility of HU toxicity in all. All 26 patients were offered semen cryopreservation. For 22 of them, semen parameters after thawing indicated a possible use for assisted reproductive technologies, mostly in vitro fertilization with intracytoplasmic sperm injection. In the remaining 4 (3 in HU-PP group and 1 in HU naïve), there was serious concern about the possible use because of a very low initial sperm concentration and the absence of motile spermatozoids after thawing. Discussion/Conclusion: Toxicity of HU upon spermatogenesis has been well documented in animal studies and in adult males. In many settings, such issues may be a drawback for parents and/or caregivers to treat young boys before semen banking can be performed, given the lack of robust information on reversibility after treatment resolution. Abnormalities of sperm count are also common in non-treated males so that demonstrating the specific effect of HU may be complex. Oseggbe et al. and Berthaud et al. showed that 91% of untreated SCD males have at least one abnormal sperm parameter. Here, we show that after treatment resolution, there are no differences in sperm parameters in patients exposed to HU before puberty compared to untreated males. Because a majority of patients benefitted from transfusion therapy at the time of analysis, we were however unable to demonstrate whether reversal of toxicity occurs spontaneously or requires transfusion. Notwithstanding possible limitations due to small sample size, this study shows that in boys with severe disease requiring HU treatment before puberty, toxicity of HU on sperm parameters should not be a major drawback. Disclosures Bernaudin: AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Consultancy. De Montalembert:Novartis: Consultancy, Honoraria; Addmedica: Consultancy, Honoraria; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees. Brousse:bluebird bio: Consultancy; Add medica: Consultancy.

Patients with sickle cell anemia (SCA) have increased susceptibility to infections partially explained by functional splenic and alternative complement pathway defects. Cord blood transplants (CBT) and high doses anti-thymoglobulin (ATG) are suspected to be responsible for viral complications and EBV lymphoma but most of the reports concerned unrelated SCT. The aim of the present study was to compare the immune reconstitution after CBT vs BMT from HLA-identical sibling, in patients prepared with the same myeloablative conditioning regimen (MAC). This retrospective analysis concerns SCA-children all followed in the same CHI-Créteil referral center and transplanted from a HLA-identical sibling with MAC consisting of busulfan, cyclophosphamide and rabbit ATG (Genzyme at 20mg/kg). Pre- and post-transplant clinical and biological data were prospectively recorded in the local database. Lymphocyte subpopulations (CD3+, CD4+, CD8+), IgG, IgA, IgM were recorded each month during the first year post-transplant. Jolly bodies (classified as 0=absent, 1=rare, 2=a few, 3=numerous) and HBs, DTPolio vaccinal serologies were assessed at transplant time (T0), 1 (T1) and 2 years (T2) post-transplant. Revaccination with DTPolio was performed at 1y post-transplant One-hundred-seven SCA-patients (41F,56M) with severe disease were transplanted (1992-2012) with BM (n=83), CB (n=21), CB+BM (=3) at median (range) age: 9.7y (3.4-22.2) for BMT and 6.1y (3.2-12.9) for CBT (p=0.002). Four patients had splenectomy and 5 others partial splenectomy. Rate of rejection was higher after CBT (p=0.002) with 2 non-engraftments and no late rejection whatever the source. TRM was not different despite the occurrence of 3 deaths only after BMT (obliterant bronchiolitis at 1.1year, hemorrhagic stroke at day36, adenoviral encephalitis at month5). Acute GVHD ≥II was observed in 18 patients (16 BMT, 2 CBT) and mild and extensive chronic-GVHD in 5 and 2 patients respectively after BMT and 1 mild after CB+BMT. At 5-year DFS was 95.3% (CI:91.3-99.3%). No significant difference in GVHD and DFS rates was observed according to the source. Neutrophils reached 500/mm3 at mean day32 vs day21 (p Paired analysis comparing results at T0 vs T1 and T2 showed a significant decrease of the mean (SD) Jolly bodies score from 1.38 (0.85) at T0 to 0.50 (0.81) at T1 and 0.28 at T2 (p We confirm the improvement of splenic function after SCT and conclude that contrary to unrelated CBT and SCT using high dose ATG, CBT from HLA-identical sibling do not expose significantly to more frequent viral infections or reactivations and have satisfactory vaccinal response Figure Disclosures Bernaudin: BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy.

Erythrocytapheresis procedures, increasingly used in the management of patients with severe complications of sickle cell disease, are limited by adequate venous access. We have successfully used short-term femoral catheter insertion, during a 6.5-year period for a total of 443 procedures, to perform long-term erythrocytapheresis in 18 consecutive children with sickle cell disease.

Although hematopoietic stem cell transplantation (HSCT) offers curative potential for beta-thalassemia major (beta-TM), it is associated with a variable but significant incidence of graft rejection. We studied the French national experience for improvement over time and the potential benefit of antithymocyte globulin (ATG). Between December 1985 and December 2007, 108 patients with beta-TM underwent HSCT in 21 different French transplantation centers. The majority of patients received a matched sibling transplant (n = 96) and a busulfan- and cyclophosphamide-based conditioning regimen (n = 95), also with ATG in 57 cases. Ninety-five of the 108 patients survived, with a median follow-up of 12 years. Probabilities of 15-year survival and thalassemia-free survival after first HSCT were 86.8% and 69.4%, respectively. Graft failure occurred in 24 patients, 11 of whom underwent a second HSCT. The use of ATG was associated with a decrease in rejection rate from 35% to 10%. Thalassemia-free survival improved significantly with time, reaching 83% in the 54 patients undergoing HSCT after 1994 (median time of HSCT). In view of the increased risk of graft rejection after matched sibling HSCT, current French national guidelines recommend, for all children at risk for beta-TM, the systematic addition of ATG to the myeloablative conditioning regimen and special attention to optimize transfusion and chelation therapy in the pretransplantation period.