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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.

Efforts to implement family cord blood banking have been developed in the past decades for siblings requiring stem cell transplantation for conditions such as sickle cell disease. However, public banks are faced with challenging decisions about the units to be stored, discarded, or used for other endeavors. We report here 20 years of experience in family cord blood banking for sickle cell disease in two dedicated public banks. Participants were pregnant women who had a previous child diagnosed with homozygous sickle cell disease. Participation was voluntary and free of charge. All mothers underwent mandatory serological screening. Cord blood units were collected in different hospitals, but processed and stored in two public banks. A total of 338 units were stored for 302 families. Median recipient age was six years (11 months-15 years). Median collected volume and total nucleated cell count were 91 mL (range 23–230) and 8.6×108 (range 0.7–75×108), respectively. Microbial contamination was observed in 3.5% (n=12), positive hepatitis B serology in 25% (n=84), and homozygous sickle cell disease in 11% (n=37) of the collections. Forty-four units were HLA-identical to the intended recipient, and 28 units were released for transplantation either alone (n=23) or in combination with the bone marrow from the same donor (n=5), reflecting a utilization rate of 8%. Engraftment rate was 96% with 100% survival. Family cord blood banking yields good quality units for sibling transplantation. More comprehensive banking based on close collaboration among banks, clinical and transplant teams is recommended to optimize the use of these units.

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.

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.

Background Coexistent auto-immune and inflammatory diseases (AIID) and sickle cell disease (SCD) have been recently described in adults and children, however its frequency and physiopathology remain unclear (1–6). Objectives The aim of this study is the analysis of clinical and biological characteristics at AIID diagnosis and the evolution under treatment in children with SCD Methods Between May 1991 and March 2018, 35 of 3,800 SCD children diagnosed with AID in seven hospitals in Paris and suburb were analyzed in a retrospective survey. Results Thirty-five patients reported 44 AIID: auto-immune liver disease (AILD, n=13), inflammatory bowel disease (IBD, n=7), juvenile idiopathic arthritis (JIA, n=6), systemic lupus erythematosus (n=5), autoimmune hemolytic anemia (n=3), Sjogren’s syndrome (n=2), histiocytic necrotizing lymphadenitis (n=2), vasculitis (n=2), myasthenia gravis (n=2), sarcoidosis (n=2), inflammatory uveitis (n=1), sclerodermia/juvenile dermatomyositis (n=1). Median age at diagnosis was 10 [2 – 18] years. The mean delay between first symptom and diagnosis was 15.5 (± 29) months. The time of diagnostic was significantly longer for patients with JIA compared to other AID (63 versus 10 days, p=0.004). Sixteen patients (45.7%) had hypergammaglobulinemia > 20 g/L at diagnosis. AILD had a hypergammaglobulinemia at the time of diagnosis (30.0g/L), with a statically significant decrease at the end of follow-up (18.2g/L, p=0,0048). Among 21 patients (60%) treated with systemic steroids, it triggered vaso-occlusive crisis in 14 (66.7%), one acute chest syndrome, one transient ischemic attack. Thirteen of 35 patients (37.1%) were managed with biotherapy for AIID, well tolerated. Three patients (8.6%) underwent stem cell transplantation, one died of a cortico-resistant and multipolar graft versus host reaction, two were cured of both AIID and SCD. Nine severe infections were reported, four under steroids, five under biotherapy. Conclusion Diagnosis and therapeutic care of coexistent auto-immune and inflammatory diseases are difficult and challenging in children with SCD. Annual monitoring of inflammatory markers could be recommended to detect AIID earlier and prevent diagnostic delay in case of high ascension in SCD patients. References [1] Li-Thiao-Te V, Uettwiller F, Quartier P, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 17 janv 2018;16(1):5. [2] Cherner M, Isenberg D. The overlap of systemic lupus erythematosus and sickle cell disease: report of two cases and a review of the literature. Lupus. juin 2010;19(7):875–83. [3] Adelowo O, Edunjobi AS. Juvenile idiopathic arthritis coexisting with sickle cell disease: two case reports. BMJ Case Rep. 1 dec 2011;2011. [4] Michel M, Habibi A, Godeau B, Bachir D, Lahary A, Galacteros F, et al. Characteristics and outcome of connective tissue diseases in patients with sickle-cell disease: report of 30 cases. Semin Arthritis Rheum. dec 2008;38(3):228–40. [5] Galmiche S, Amiot X, Georgin-Lavialle S, et al. Maladies inflammatoires chroniques de l’intestin chez des patients atteints de syndrome drepanocytaire majeur: a propos de 6 cas. Disponible sur: http://www.em-premium.com.frodon.univ-paris5.fr/article/1122766/resultatrecherche/34 [6] Jitraruch S, Fitzpatrick E, Deheragoda M, et al. Autoimmune Liver Disease in Children with Sickle Cell Disease. J Pediatr. oct 2017;189:79-85.e2. Disclosure of Interests Caroline Vinit: None declared, Corinne Guitton: None declared, Patricia Benhaim: None declared, Florence Missud: None declared, Mariane De Montalembert: None declared, Lahoueri Amor: None declared, Cecile Arnaud: None declared, Oussama Charara: None declared, Vincent Gajdos: None declared, Veronique Hentgen Consultant for: SOBI, Novartis, Abbvie, Speakers bureau: Novartis, Annie Kamdem: None declared, Sylvie Nathanson: None declared, Brigitte Bader-Meunier: None declared, isabelle melki: None declared, Isabelle Kone-Paut Grant/research support from: SOBI has supported drug product (anakinra) for the presented study, Consultant for: SOBI, Novartis, Pfizer, Abbvie, UCB, CHUGAI, ROCHE, Pierre Quartier Consultant for: AbbVie, Chugai-Roche, lilly, Novartis, Novimmune, Sanofi, and SOBI, Consultant for: AbbVie, Chugai-Roche, Lilly, Novartis, Novimmune, Sanofi, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Speakers bureau: AbbVie, BMS, Chugai-Roche, Novartis, Pfizer, and SOBI, Loic De Pontual: None declared, Luu-Ly Pham: None declared

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

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 (

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.

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.

Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

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.

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.

Asthma in children with sickle cell anemia (SCA) is associated with increased morbidity and mortality. However, the definition of asthma in SCA is based on a physician's impression. In a retrospective cohort of children with SCA, relationships between a physician diagnosis of asthma and total and allergen-specific immunoglobulin E levels were evaluated. In children with SCA, elevated total and specific immunoglobulin E levels were significantly associated with a diagnosis of asthma (P0.05), further supporting the concept that asthma is a separate comorbid condition of SCA.

Introduction: Patients with sickle cell disease (SCD) may develop a persistent mixed chimerism (MC) after hematopoietic stem cell transplantation (HSCT) associated with clinical control of the disease. In order to further investigate this condition we analyzed the chimerism in sorted myeloid and lymphoid subpopulations, and erythroid progenitors.Methods: Between 1990 and 2013, 112 sickle cell disease (SCD) patients underwent allogeneic HSCT after myeloablative conditioning. Among the 107 patients with available chimerism at 2 years, 55.1% had a MC, i.e. 9590nana6AA9111.893.83.13.10191223311337.5577AS15513.556.5412.60583471na4975604AS13210.65433.3nana5344444658323717AS1311.547.841.23.21.48575na9273837618A/Dpubjab8012.647.90nana887795959494.59912A/b0Thal579.69503291689698999910011AA5413.49703088781001009998985AA3410.978.38nana444641na5058432AS468.42468.1nana21709.45.43112.5na8AS1339.734.7632.401631121013089AS1539.552.145.920183026161117153AA3310.189.553.22.330631718231317

Background Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. Procedure Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. Results In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years’ treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1–7.9) and 4.0% (95% CI: 1.8–7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. Conclusions Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.

Introduction:Regular supportive transfusion therapy from an early age is common practice in young children with β thalassemia major (βTM), sickle-cell disease (SCD) and Diamond-Blackfan anemia (DBA). Patients consequently accumulate iron that can affect organ function and delay growth/development. As such, iron chelation therapy is often necessary from an early age, with lifelong requirements for patients who cannot be cured with hematopoietic stem cell transplantation. Deferasirox, a once-daily oral iron chelator, has demonstrated efficacy and safety in adult and pediatric patients with chronic iron overload. Long-term evaluation of deferasirox in young pediatric patients with transfusional hemosiderosis is valuable, as conducted in the 5-yr multinational, observational ENTRUST study. Here, we report safety and efficacy outcomes in pediatric patients with transfusional hemosiderosis receiving up to 5 yrs of continuous deferasirox treatment in clinical practice. Methods :Patients aged 2- Results:267 patients (mean age 3.2 yrs: 61.4% 5% of patients) because of loss to follow-up (n=19, 7.1%) and AEs (n=18, 6.7%; most commonly increased alanine or aspartate aminotransferase [ALT/AST], n=7 each). The number of patients discontinuing treatment because of AEs declined year on year; n=10 in Yr 1, n=4 in Yr 2, n=2 in Yr 3, and n=1 in Yrs 4 and 5, respectively. From Yr 3 onwards, there were no discontinuations due to an increase in ALT or AST. Change from baseline in serum ferritin by duration of deferasirox exposure (FAS) is summarized (Table). In the 130 patients exposed to deferasirox for 5 yrs, median serum ferritin levels decreased from 1777 (range 509-5804) ng/mL at baseline to 1414 (range 166-7030) ng/mL, a median change from baseline of -425 (range -4131-5576) ng/mL (Table). 145 patients completed 5 yrs of follow-up and had data on AEs collected during this entire period. The most frequently occurring AEs with suspected relationship to study drug (occurring in ≥4 patients) were increased ALT (n=29, 20.0%), increased AST (n=12, 8.3%), vomiting (n=9, 6.2%), rash (n=6, 4.1%) and increased blood creatinine (n=6, 4.1%). Overall, there was a gradual decrease in the number of patients experiencing drug-related AEs in the safety set with each year of deferasirox exposure (Figure). Conclusions:This long-term, observational study of deferasirox in pediatric patients supports previous findings indicating favorable safety and efficacy. Approximately half the patients completed the 5-yr study, with many patients discontinuing for reasons unrelated to study drug, indicating good acceptance of treatment. Patients remaining on deferasirox benefited from sustained improvements in iron load, though this was not immediate, likely because of delayed increases in dose based on weight gain and ongoing iron intake. Among patients who continued on deferasirox tolerance was increasing over time as indicated by yearly decreasing numbers of AEs. In patients followed for up to 5 yrs, AEs were consistent with the known deferasirox safety profile, with no progressive increases in the incidence of renal-related AEs. These data therefore support the long-term use of deferasirox in young iron overloaded patients in everyday clinical practice. Disclosures Vichinsky: Novartis, ApoPharma Inc. and ARUP Laboratories: Research Funding; Novartis: Consultancy. El-Beshlawy:Novartis, ApoPharma Inc: Research Funding. Bruederle:Novartis Pharmaceuticals Corporation: Employment. Han:Novartis: Employment.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ0), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 109/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Stroke is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). This study aimed at defining predictive factors for abnormally high velocities (≥ 2 m/sec) based on the Créteil pediatric sickle cell anemia (SCA) cohort composed of 373 stroke-free SCA children. α genes and β-globin haplotypes were determined. Biologic parameters were obtained at baseline. α-thalassemia was present in 155 of 325 and G6PD deficiency in 36 of 325 evaluated patients. TCD was abnormal in 62 of 373 patients. Multivariate logistic regression analysis showed that G6PD deficiency (odds ratio [OR] = 3.36, 95% confidence interval [CI] 1.10-10.33; P = .034), absence of alpha-thalassemia (OR = 6.45, 95% CI 2.21-18.87; P = .001), hemoglobin (OR per g/dL = 0.63, 95% CI 0.41-0.97; P = .038), and lactate dehydrogenase (LDH) levels (OR per IU/L = 1.001, 95% CI 1.000-1.002; P = .047) were independent risk factors for abnormally high velocities. This study confirms the protective effect of alpha-thalassemia and shows for the first time that G6PD deficiency and hemolysis independently increase the risk of cerebral vasculopathy.

Background: "Drepagreffe" is a French national prospective trial involving 67 sickle cell anemia (SCA)-children with a history of abnormal cerebral arterial velocities by TCD, and comparing for the first time the outcome of cerebral vasculopathy following transfusion program (TP) or transplantation (HSCT). Inclusion criteria at enrollment were children with SCA (SS/Sb0), younger than 15 years, with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec) and placed on long-term TP, with at least one non-SCA sibling, and with parents accepting HLA-typing and HSCT if a genoidentical donor was available. The 2 arms (TP/HSCT) were defined by the random-availability of a genoidentical donor. Seven of the 67 patients had a history of stroke. Transplanted patients (n=32) received a conditioning regimen of Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin, with CSA and a short course of MTX or MMF for GvHD prophylaxis. In the TP arm (n=35), HbS% was maintained at < 30%, with an Hb at 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, and cerebral MRI/MRA were performed along with cognitive performance testing, the latter being done in parallel in the non-SCA siblings. Preliminary findings on cerebral velocities as the primary endpoint were reported at the last ASH meeting (abstract 67237), and demonstrated that all patients were alive at one year and that the 32 transplanted patients had no chronic GVHD and the same hemoglobin profile as their donor. Velocities were significantly lower post-HSCT than under TP (p Patients and Methods: We report here the cerebral imaging (MRI/MRA) and cognitive performance data performed at enrollment and after 12 months. The scoring applied for MRI was: 3 = territorial, 2 = borderzone (cortical and subcortical), 1 = white matter or basal ganglia infarcts, 0 to 3 = atrophia, and for MRA: 1 = mild stenosis (25-49%), 2 = moderate stenosis (50-74%), 3 = severe stenosis (75-99%), 4 = occlusion for each artery and 0 to 2 for Moya presence. Cognitive testing using the WPPSI-3 (3-6 yr), WISC-4 (7-16 yr) or WAIS-3 (>16 yr) scales, depending on the age, was performed in patients and in siblings when possible. Results: MRI/MRA data were available in 66/67 patients. At enrollment (M0), ischemic lesions and stenoses were present in 25 and 35/66 patients, respectively. Cognitive testing was obtained in 64 patients and 56 siblings. Paired analysis with siblings (Table 1) showed significant differences in Verbal Comprehension Index (VCI) with a mean difference of 7.6±14.5(p =0.0004), Processing Speed Index (PSI) 6.3±20.5 (p =0.04), and Full Scale IQ (FSIQ) 7.3±15.0 (p =0.01). After exclusion of the 7 patients with stroke history, significant differences were still observed in VCI (p =0.013) and FSIQ (p =0.019). Patient cognitive performance indexes were correlated negatively and significantly with the MRI and MRA scores (Table 2). At post-enrollment (M12),ischemic lesions and stenoses were present in 26/66 patients. The mean variation in MRI and MRA scores between M12 and M0 was not significantly different between the 2 arms (Table 3). The cognitive tests were performed at M12 in 60 patients (Table 4) and the performance indexes were improved in the TP compared to the HSCT arm, but only significantly for FSIQ. Conclusion This first prospective trial initially showed that HSCT reduces more significantly the cerebral velocities at M12 and in a higher proportion of patients than TP. Here, we show that patients with a history of abnormal cerebral velocities had significantly lower cognitive performances than their siblings, even in the absence of stroke history; however, there was no significant difference between the 2 arms for the outcomes of ischemic lesions and stenosis at M0 and M12. The fact that cognitive performances were improved in the TP compared to the HSCT arm might be explained by the stress of the HSCT procedure and the lack of schooling during this period. Despite the higher ability of HSCT to decrease velocities at M12 compared to TP, a longer follow-up will be required to demonstrate its effect on stenosis and cognitive performances; therefore, patients will be reassessed at 3 years post-HSCT. Disclosures Bernaudin: Novartis: Research Funding.

Background : Evidence-based practices have shown that transfusion program (TP) is beneficial to SCA-patients with abnormally high velocities by Doppler; however, TP cannot be stopped safely, except following HSCT. No prospective trial has to date compared the extent of cerebral vasculopathy following TP or HSCT. The premise of the French National Trial “Drepagreffe” is that cerebral velocities will be reduced to a greater extent after HSCT than under TP. Patients and Methods : We present here preliminary results from this prospective trial with 2 arms (TP/HSCT), defined by the random-availability of a genoidentical donor. Inclusion criteria were SCA (SS/Sb0) children younger than 15 years with a history of abnormal cerebral arterial velocities (TAMMX ≥ 200 cm/sec), placed on long-term transfusion programs, with at least one non-SCA sibling and parents accepting HLA-typing and HSCT if a genoidentical donor was available. Transplanted patients received as conditioning regimen Busilvex-CY 200 mg/kg and 20 mg/kg rabbit Thymoglobulin with CSA and short MTX or MMF for GVHD prophylaxis. In the TP arm, HbS% was maintained at < 30% with Hb 9-11g/dL. At enrollment and 12 months post-enrollment, blood screening, Doppler, cerebral MRI/MRA were performed along with cognitive performance testing, the latter done in parallel in the control sibling. Primary endpoint was the significantly greater reduction of velocities in the HSCT than in the TP arm. Among the various secondary endpoints, Doppler normalization defined by velocities < 170 cm/s in all arteries was to occur more often after HSCT than on TP. Results: SCA-children (n=67; 36F-31M) from 10 French SCA-centers were enrolled between 12/2010 and 6/2013 at the mean (SD) age of 7.6 (3.1) years. History of stroke was present in 6 patients (4 in HSCT and 2 in TP) and 1 TIA in HSCT arm. At TP initiation, velocities≥200/cm/sec were found in middle (n=50), anterior (n=11) and internal carotid arteries (n=30) as abnormal velocities were observed in more than one artery in several patients. Mean (SD) maximum velocities were 219 (26) cm/s (range: 200-333). At enrollment all patients were on TP and paired analysis showed that mean(SD) maximum velocities had significantly decreased (p Conclusions: This prospective national trial comparing TP vs. HSCT in SCA-patients with a history of abnormal velocities shows for the first time that HSCT repeatedly and significantly results in a greater decrease in velocities than TP, and has very little toxicity. These preliminary results are encouraging and suggest that suppression of host SCA-erythropoiesis by HSCT is the treatment of choice for SCA-children with abnormal-TCD and genoidentical donor. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Bernaudin: Novartis: Research Funding.

Contexte La drepanocytose SC represente 30 % des syndromes drepanocytaires majeurs. Peu de cohortes neonatales s’interessent au devenir clinique de ces patients. Nous decrivons dans une cohorte neonatale l’incidence des complications aigues et chroniques des drepanocytaires SC. Methode Etaient inclus tous les patients SC depistes neonataux suivis au centre hospitalier de Creteil, en excluant ceux dont le suivi avait ete effectue dans un autre centre avant l’âge de 6 mois. Le suivi prospectif recueillait l’apparition des complications aigues necessitant une hospitalisation et les evenements apparus au cours du suivi lors des bilans systematiques. Les donnees ont ete censurees a la date de la derniere visite. Resultats Quatre-vingt patients ont ete suivis pendant une duree mediane de 7,99 ans soit 708 patients annees entre 1986 et 2013. Soixante patients (75 %) ont presente au moins une complication aigue. Le risque cumule de syndrome thoracique aigu et de sequestration splenique aigue a 10 ans est de 51 % et 15 % respectivement soit une incidence de 7,2 et 1,4 pour 100 patients annees (PA) respectivement. Le taux de crises vaso-occlusives est de 30,01 pour 100 PA. Il n’y a pas eu de complication infectieuse ni d’accident vasculaire cerebral ni de deces. La retinopathie est la complication chronique la plus frequente avec une incidence de 1,34 pour 100 PA, IC 95 % (0,69–2,67) soit un risque cumule de 23,8 % a 15 ans. Discussion Le suivi de cette cohorte met en avant le poids de la maladie avec un nombre important de complications. Le depistage neonatal permet de prevenir les complications infectieuses graves grâce notamment a l’education parentale. Le suivi chronique de ces patients est indispensable pour depister precocement les complications. Aujourd’hui aucune therapeutique n’est validee dans la drepanocytose SC, l’utilisation d’un programme de saignees comme chez l’adulte pourrait etre une alternative pour diminuer l’incidence de ces complications.

Asthma and sickle cell disease are two common chronic diseases that may exist as co-morbid conditions. Our group has recently demonstrated that asthma, the most common chronic disease among children, is a distinct co-morbid condition among children with sickle cell anemia (SCA)[1][1] and has a

Introduction Sickle cell anemia (SCA) is a monogenic disease with multigenic expressivity. The ability to identify high-risk SCA-children would permit accurate prognostication and better genetic counselling, and facilitate the planning of clinical trials. Miller et al. (CSSCD) reported in 2000 that early dactylitis, baseline Hb level Patients and Methods This study revisits this issue using the Créteil Newborn Cohort (1986-2011). The dates and nature of the 1st SCA-related manifestations and further clinical events were prospectively recorded: vaso-occlusive crises (VOC) including dactylitis, acute chest syndromes (ACS), strokes, splenic sequestrations and acute anemia < 6g/dl. Alpha-genes, beta-globin haplotypes, G6PD activity, CD36 platelet expression were determined and baseline biological parameters (WBC, PMN, platelets, Hb, Hct, MCV, reticulocytes, HbF%, LDH) were recorded between 1-2 years of age, a minimum of 3 months away from a transfusion, one month from a painful episode and before any intensive therapy. The criteria of severity retained for this study were death or events requiring intensive therapy, defined as hydroxycarbamide (HC) prescribed for patients having experienced at least 3 VOC/year or 2 ACS or with baseline Hb Results This newborn cohort consists of 363 patients (55 SC,28 Sb+,262 SS,15 Sb0,3 SDPunjab). Median age at last visit was 6.4 years, providing 2827 patient-years of follow-up. As no SC or Sb+ patient died or experienced events requiring intensive therapy, analysis of severity criteria was only performed on SS, Sb0, SDPunjab, referred as SCA-patients (n=280). Alpha-thalassemia was present in 41.6%, Bantou/Bantou beta haplotype in 43.4% (vs 5.9% in the CSSCD cohort), Benin/Benin in 22.9%, Senegal/Senegal in 10.2%, “other” in 23.4%. G6PD deficiency was observed in 11.4% and CD36 non-expression in 7%. Kaplan-Meier estimates of survival by age 5 and 18 were 97.6% (95%CI:95.6-99.6%). One-hundred-fifty-one/280 SCA-patients (54%) required intensive therapy at the median age of 3.8yr (0.1-20): 69 HC, 136 TP, and 41 HSCT (patients may have successively received HC, TP and HSCT). Cumulative risk of severity criteria was 45% by age 5 and 70% by age 10. Univariate Cox analysis showed that Bantou presence (52.6%), CD36 non-expression, early SCA-1st manifestation (400x109/L) (HR=2.82,95%CI:1.70-4.69,p Conclusion This study confirms Miller’s report, showing that the risk level can be estimated by age 2 in SCA-patients, a result potentially useful for prospective trials (HC/HSCT). Moreover, we show for the first time that the presence of a single Bantou haplotype has predictive value for severity in this cohort where its frequency is much higher than in the CSSCD cohort. Disclosures: Bernaudin: Novartis: Research Funding.

Abstract 88 Background. Strokes are a well-known complication of sickle-cell anemia (SCA), and are largely due to intracranial arteriopathy, detected by routine transcranial Doppler (TCD). Adams et al. showed in the STOP I trial (N Engl J Med, 1998) the efficiency of transfusion programs for primary stroke prevention in patients identified by TCD as being at risk of stroke. We recently reported in the CHIC newborn cohort (Bernaudin et al., Blood, 2011) that early TCD imaging (TCDI) screening significantly reduces the risk of stroke by age 18 from the previously reported 11% to only 1.9%, but has not allowed adequate prevention of silent infarcts, with a risk of 37.1% by age 14, suggesting that TCDI does not distinguish all SCA-patients at risk of silent infarcts. Extracranial internal carotid artery (eICA) vasculopathy is considered rare and has not been routinely assessed; however, several recent cases of stroke with extracranial arteriopathy prompted the inclusion of eICA evaluation in routine screening. The aim of the study was to establish the ranges of eICA velocities in SCA-patients, to determine the cut-off limits of velocities predictive of eICA stenoses by extracranial MRA, to evaluate the prevalence of abnormal eICA velocities and to determine their association with intracranial stenoses and/or silent infarcts by MRI. Methods. Since June-2011, all stroke-free SCA patients from the CHIC and Debre cohorts who had routine yearly TCDI for intracranial arteries were also systematically assessed for eICA using submandibular windows (Gorman et al., Neurology 2009) and the same 2Mhz TCDI transducer probe. Time-averaged mean of maximum velocities (TAMMV) were obtained for intra and extracranial cerebral arteries. By color Doppler mapping, the course of eICA was considered as straight, or as tortuous if the artery changed direction with an angle > 120° between adjacent segments. Extracranial cervical MRA was added to routine intracranial MRI/MRA, performed every 2 years or as soon as abnormal velocities were found. Results. Between June 2011 and January 2012, 435 consecutive SCA-children from the two cohorts (202M, 233F) were assessed by Doppler at the median age of 8.5 years (range: 1.3–18.7). MRI/intra and extracranial MRA was performed in 104 patients. At time of Doppler assessment, mean±SD hemoglobin was 9.1±1.6 g/dl. eICA velocities were significantly correlated with middle cerebral arteries (MCA) velocities (r=0.234, p Conclusion. This study shows for the first time that in cohorts previously assessed early by TCDI for intracranial arteries, about 10% stroke-free patients have eICA vasculopathy. Moreover, we show that intra and/or extracranial stenoses are significant risk factors for silent infarcts. These data may explain why silent infarcts still occurred in patients early assessed by TCDI exploring only intracranial arteries. Thus, extracranial Doppler assessment should be routinely done with TCD to evaluate the full extent of cerebral vasculopathy in SCA. Disclosures: No relevant conflicts of interest to declare.

Abstract 1067 Background: Elevation of tricuspid regurgitant jet velocity (TRJV) predicts high systolic pulmonary artery pressure and early mortality in adults with sickle cell anemia (SCA). To date, few studies have reported the concomitant analysis of lung alterations and high TRJV in SCA-children. Objective: To evaluate the relationship between lung function, TRJV and hematologic parameters in SCA-children. Patients and Methods: SCA-children of the Creteil-CHIC cohort were assessed at steady state on the same day by cardiac echocardiography, pulmonary function tests (PFT), clinical and biological parameters. All data were recorded in the CHIC database. Forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), total lung capacity (TLC) and diffusing capacity for carbon monoxide (DLCO) were measured with the single-breath technique. DLCO was adjusted to hemoglobin and to the alveolar volume (KCOc). Univariate and multivariate linear regression analyses were performed to evaluate factors correlating with TRJV and KCOc and logistic regression was applied to evaluate the risk factors associated with elevated TRJV (≥ 2.5 m/s). Results: A total of 228 check-ups with cardiac and lung assessment, performed in 163 SCA-patients (160 SS, 3 SB0) was analyzed. Check-ups were performed at the median age of 13.2 years (range: 5.7–19.9). Among the 228 check-ups, 151 were performed after intensification (59 on hydroxyurea, 57 on transfusion program and 38 after hematopoietic stem cell transplantation (HSCT). TRJV (median value: 2.2 m/s, range 1.4–3.1) was significantly positively correlated with age (r=0.164, p=0.013), was not correlated with TLC but was significantly and negatively correlated with FVC before b2 (r=−0.145, p=0.03) and after b2 (r=−0.184, p=0.008), FEV1 before b2 (r=−0.213, p=0.001) and after b2 (r=−0.178, p=0.012), FEV1/FVC before b2 (r=23?0.165, p=0.013) and positively correlated with KCOc (r=0.379, p Conclusion: In this study, we confirm that SCA-children have an elevated gas transfer per unit lung volume (KCOc) correlated to hemolysis and HbS%. We show for the first time that an increase in KCOc significantly raises the risk for TRJV ≥ 2.5 m/s, even after adjustment for reticulocytes. Only HSCT, which resulted in significantly lower reticulocytes and KCOc, is significantly associated with lower TRJV. These data are encouraging and suggest that HSCT could be recommended to patients with elevated TRJV Disclosures: No relevant conflicts of interest to declare.

Abstract 513 Background: The accelerated hemolysis in SCA increases bilirubin excretion and the susceptibility to pigment gallstone formation. Uridine diphosphate-glucuronosyltransferase (UGT1A1) gene polymorphism and alpha-thalassemia are factors known to modify this risk. However, their relative influence and other factors such as SCA disease severity and the use of ceftriaxone for acute febrile episodes remain to be explored in a newborn cohort. The goal of this study was to define the cumulative incidence and risk factors for the occurrence of gallstones in a SCA-newborn-cohort. Patients and Methods: Alpha-genes, beta-globin haplotypes, UGT1AI genotype, G6PD-enzymatic activity were recorded; baseline biological parameters were determined during the second year of life, away from crises and transfusions as previously described (Blood 2011,117, 4). Annual check-ups including abdominal sonography were performed as soon as the age of 1 year. Cholecystectomy was systematically performed in the 6 months following the discovery and confirmation of presence of gallstones. All hospitalizations and their causes were prospectively recorded. Patients were censored on the date of gallstone occurrence or last abdominal sonography; event rates/year (pain crises, ACS, febrile episodes) were calculated, and KM-estimated cumulative risk for gallstones and Cox regression were used to assess the predictive factors for gallstones. Results: SCA-patients (364: 353 SS, 8 Sb0, 3 SDPunjab; 182 F,182 M) born before February 2010 and followed until the age of 18–20 years were included in this study. Alpha-thalassemia was present in 46% patients (available in 323; 2 genes: n=33; 3 genes: n=116; 4 genes: n=172; 5 genes: n=2); beta-haplotypes (available in 291) were Car/Car in 42.6%, Ben/Ben in 19.9%, Sen/Sen in 9.6%, and others in 27.8%. G6PD activity (available in 309) was deficient in 11.6%. UGTA1 polymorphism (available in 175) showed Gilbert genotype in 19.8%, i.e., 7/7 in 13.4% and 7/8 in 6.4%. The frequency of the other genotypes was: 5/6: 6.4%; 5/7:7%; 5/8:0.6%; 6/6:23.3%, 6/7:34.3%; and 6/8:8.1%. Unconjugated bilirubin values at baseline were significantly correlated with the total number of UGTA1A1 repeats (r=0.415, p Conclusion: This prospective SCA newborn-cohort study shows that gallstones may begin as soon as 2.5 years of age and that the cumulative risk reaches a high 35.6% by age 15. The deletion of 2 alpha genes, the presence of at least one UGT1A1 (TA8) allele and high baseline reticulocyte count are independent and significant predictive factors showing that the risks are multifacturial and highly and primarily dependent on hemolysis Disclosures: No relevant conflicts of interest to declare.

Abstract 263 Early occurrence of dactylitis, severe anemia and leukocytosis have been identified as risk factors for adverse outcome in children with SCA (Miller NEJM 2000), but the impact of acute splenic sequestrations (ASS) on disease severity has not yet been reported. The goal of this study was to define the predictive factors of ASS and to evaluate if this complication was a risk factor for disease severity. Methods. SS patients of the newborn cohort, seen at our SCA Center in Créteil before 3 months of age and older than 2 years at the last visit (n=197), were included in this study. Alpha and beta genotypes, and G6PD activity were determined. Blood parameters were recorded at steady state during the second year of life. ASS was defined as an Hb-decrease of ≥20% associated with a spleen-increase ≥2cm. Vaso-occlusive crises (VOC) requiring hospitalizations and acute chest syndromes (ACS) were recorded. The yearly rates of VOC and ACS were calculated for the entire follow-up and for the period before any intensification (transfusion program, hydroxyurea or SCT). Results. Median follow-up was 7.9 yr (range 2–24), providing 1820 patient-years. Alpha-Thal was present in 70/162 (43.2%); beta-haplotypes, available in 140 patients, were Car/Car in 62 (44.3%), Ben/Ben in 35 (25%), Sen/Sen in 7 (5%), and others in 34 (25.7%). G6PD deficiency was present in 24/171 (14%). At baseline, mean (SD) blood parameters were: Hb: 8g1/dL (1.2); Ht: 24.6% (3.9); MCV: 79.2 fL(8.3); HbF: 15.7% (8.2); LDH: 919 UI/L (369) and reticulocytes: 296 (114); WBC: 14.3 (5.2), neutrophils 5.8 (3.1) × 109/L. Among the 197 SS-patients, 64 (32%) experienced their first ASS at the median age of 2.0 yr (range 0.1–12.9) and 36/64 recurred. ASS occurred before 1 yr of age in 10 (5%) and before 2 yr in 33/197 (17%). Splenectomy was performed in 24 of them at the median age of 5.1 yr (range 2.7–12.9). The KM-estimated cumulative risk of ASS occurrence at age 7 was 32% (95%CI: 25–39%). The Cox-regression analysis showed that gender, G6PD deficiency, beta haplotypes were not risk factors whereas alpha-Thal significantly increased the risk of ASS occurrence (HR: 1.9, 95% CI:1.1-3.3, p=0.021). Among blood parameters, multivariate Cox analysis retained low platelet (HR: 1.4 per 1×107/L decrease; 95%CI:1.1-1.8, p=0.014) and high reticulocyte counts (HR=2.0 per 1×107/L increase; 95%CI:1.6-2.6) as independent significant predictive factors for ASS. Comparison of patients with or without ASS history showed no significant difference in the rate of ACS but significantly higher rates of VOC during the entire follow-up (0.68±0.58 vs 0.47±0.55; p=0.014) and in the number of hospitalizations (1.64±0.83 vs 1.29±0.92; p=0.01) in patients with ASS history. Rates of VOC before intensification were 1.1±0.7 and even 2.2±2.0 in those having experienced ASS before age 1 vs 0.6±0.7 (p=0.001) in those with no ASS history. Conclusion. Results from this study in a newborn cohort show that ASS are more frequent in patients with alpha-Thal and are associated with a higher rate of VOC. Splenectomy is usually recommended in case or recurrent ASS; however, our previous results show that geno-identical SCT can cure 95%SCA children and partly restore splenic function. We suggest that this procedure be proposed to those with available donor before considering total splenectomy. Disclosures: No relevant conflicts of interest to declare.

Abstract 1536 Poster Board I-559 Background Pulmonary hypertension (PHT) is a widely recognized complication of sickle cell disease (SCD). It affects 32% of adults with SCD and is associated with an increased risk for early mortality. Screening of children with SCD by Doppler echocardiography has been recommended, using tricuspid regurgitant jet velocity (TRJV) to estimate pulmonary artery systolic pressure. However, the prevalence and risk factors of elevated TRJV in children with SCD at steady state have not been extensively defined. Methods SCD patients of the CHIC-cohort were prospectively assessed : alpha and beta genotype, G6PD, platelet-CD36 expression were determined; baseline blood parameters between 1 and 3 years of age were recorded and re-assessed every year at steady state with clinical data, TCD screening, abdominal sonography and every two years by Doppler echocardiography, evaluation of lung function and cerebral MRI/MRA. Pulmonary hypertension was defined as a TRJV ≥2.5 m/s. Univariate and multivariate logistic regression analyses were performed to evaluate risk factors for elevated TRJV. Results A total of 662 echocardiograms with available measure of TRJV were performed away from vaso-occlusive crises (VOC) and acute chest syndromes (ACS) in 320 SCD-patients (268 SS, 1 SDPunjab, 7 Sb0; 14 Sb+, 30 SC) between 12/98 and 07/09 and were included in the analyzes: 127/662 were performed in patients on hydroxurea (HU) therapy, 121 on transfusion program (TP) and 63 after stem cell transplantation (SCT). In SS/Sb0 patients, TRJV did not correlate with fractional shortening, ejection fraction, TCD velocities, systemic and diastolic blood pressure, cumulative number of VOC and ACS, LDH and SpO2, but correlated with age (r=0.258,p Conclusion In this pediatric cohort, early assessed by TCD and transfused in case of abnormal occurrence, no association was found between cerebral vasculopathy and elevated TRJV, which could be the result of early initiation of transfusion programs as soon as TCD became abnormal. The data also confirm the link between pulmonary hypertension, low oxygen saturation and hemolysis, previously reported by others. In addition, we show for the first time that CD36 deficiency is a risk factor for elevated TRJV in SCD patients. CD36 deficiency has been shown to be a common occurrence in subjects of African descent. The CD36 scavenger receptor is a multifunctional receptor, which is expressed on the surface of various cell types, and is involved in immunity, metabolism and angiogenesis. Previous studies suggested that CD36 deficiency did not modify the clinical course of SCD patients but echocardiograms had not been analyzed. Recent studies showed that hypoxia increases CD36 expression via its HIF-1 responsive promoter element and activation of the PI3K pathway, suggesting that CD36 deficient SCD patients could have an abnormal response to hypoxia. Additional studies will be needed to understand the relationship between PHT and CD36 deficiency and the role of hypoxia in these patients. Disclosures No relevant conflicts of interest to declare.

Background Silent infarcts are associated with impaired cognitive functioning and have been shown to be predictors of stroke (Miller ST J Pediatr 2001). Until now, reported risk factors for silent infarcts were low pain event rate, history of seizures, high leukocyte count and Sen bS haplotype (Kinney TR Pediatrics 1999). Here, we seek to define the prevalence and risk factors of silent infarcts in the Créteil SCA pediatric cohort comprising patients assessed at least yearly by transcranial doppler (TCD) since 1992, and by MRI/MRA. Methods This study retrospectively analyzed data from the Créteil cohort stroke-free SS/Sb0 children (280; 134 F, 146 M), according to institutional review board. Time-averaged mean of maximum velocities higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program (TP). A switch to hydroxyurea was proposed to patients with normalized velocities (< 170 cm/sec) and normal MRA on TP, although TP was re-initiated in case of abnormal velocities recurrence. Patients with “conditional” velocities (170–199 cm/sec) were assessed by TCD 4 times yearly. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF, LDH levels; MCV; SpO2) were obtained a minimum of 3 months away from a transfusion, one month from a painful episode, after 12 months of age, before the first TCD, and always before therapy intensification. Results. Patients were followed for a total of 2139 patient-years. Alpha-Thal was present in 114/254 patients (45%) and 27/241 (11.2%) had G6PD deficiency. Beta genotype, available in 240 patients, was BaBa in 102 (42.5%), BeBe in 54 (22.5%), SeSe in 19 (7.9%) and “other” in 65 (27.1%); TCD was abnormal in 52 of 280 patients (18.6%). MRA showed stenoses in 30 of 226 evaluated patients (13.3%) while MRI demonstrated presence of silent infarcts in 81/280 patients (28.9%). Abnormal TCD (p Conclusion We recently showed that G6PD deficiency, absence of alpha-Thal, and hemolysis are independent significant risk factors for abnormal TCD in stroke-free SCA patients (Bernaudin et al, Blood, 2008, in press). Here, we report that an abnormal TCD is the most significant risk factor for stenoses and, expanding previous studies, we demonstrate that stenoses, low Hb and gender are significant independent risk factors for silent infarcts.

Introduction In this study, we sought to validate the previous findings that asthma increases the incidence of acute chest syndrome (ACS) and pain in children with sickle cell anemia (SCA). Methods A retrospective cohort was comprised of children with SCA evaluated for at least six months from a single medical center. Asthma was defined as being present when the first wheezing episode was heard by a physician after the age of 2 years or after 3 episodes of bronchiolitis before the age of 2 years. ACS was defined as a recent abnormal X-ray of the lungs associated with fever, respiratory signs or thoracic pain. A painful episode was defined as pain that resulted in hospitalization. Therapeutic intervention (hydroxyurea, blood transfusion therapy or transplant) was uniformly applied to all children with three or more episodes of pain that required hospitalization within a 12 month period. Patient years were accumulated from birth until death, lost to follow up, last visit to the center or a therapeutic intervention, whichever came first. Results A total of 297 children with SCA were evaluable for a doctor diagnosis of asthma for a total of 1,805 patient-years. The mean length of follow-up was 6.1 patient-years. A doctor diagnosis of asthma was present in 8.4% (25 of 297). Among the children with asthma 75% (19 of 25) were consistently prescribed a beta 2 agonist or inhaled corticosteroids. After adjustment for the effect of age, asthma was significantly associated with ACS event (p = 0.03) but pain was not (>0.05). Conclusion Among children with SCA, asthma is associated with an increased incidence of ACS, but not pain that required hositalization. The absence of an association between asthma and pain may be related to uniform therapeutic intervention for children with repetitive painful episodes that require hospitalizations coupled with active treatment for asthma in most of the children.

Background Predicting the severity of sickle cell anemia (SCA) is important for providing better informed genetic counseling and for better targeting of intensive therapies. Stroke is the most severe complication in children with SCA and is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). We attempted to define the risk factors associated with high velocities. Methods This study concerned the Créteil pediatric SCA cohort, composed of newborn patients, screened and followed at our Center since birth, and of patients secondarily referred to the Center because of the severity of their disease. Time-averaged mean of maximum velocities (TAMMX) higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program initiated. Cerebral MRI/MRA was done after the age of 5 years or earlier in case of abnormal TCD. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF, LDH levels; MCV; SpO2) were obtained a minimum of 3 months away from a transfusion, one month from a painful episode, after 18 months of age and, before intensive therapy. Results SS children (390; 189 F, 201 M) were annually explored by TCD (n=2286) since 1992, and followed for a total of 1962 patient-years. The follow-up before initiation of intensive therapy was 1032 patient-years. Nineteen patients experienced an overt stroke. TCD was abnormal in 65 of 390 patients (17%). MRI (n=850) was performed in 268 patients, was abnormal in 86 cases and showed silent infarcts in 67 of 249 patients (27%). Silent infarcts were seen in 33% of patients with abnormal TCD. Alpha genes study, available in 336 patients, demonstrated alpha-thalassemia in 158 patients (47%): 31 had a deletion of 2 genes (7.9%) and 127 of 1 gene (32.6%). G6PD deficiency was present in 26 of 228 evaluated patients (11%). Beta-globin haplotypes studied in 316 patients were Car/Car in 125 (40%), Ben/Ben in 76 (24%), Sen/Sen in 30 (9%) and, “other” in 85 (27%). Univariate analysis showed that the risk of abnormally high velocities was not related to sex, beta-globin haplotypes, pain and acute chest syndrom rates, WBC, PMN, platelets counts, HbF level and SpO2 but was significantly associated with the absence of alpha-thalassemia (p< 0.001), G6PD deficiency (p=0.012), low Hb and Ht levels (p< 0.001), high reticulocyte count (p=0.008), high MCV (p=0.004) and high LDH level (p 1200 UI/L [OR=4.5, 95% CI (1.5–13.5)], (p=0.007) were independent risk factors of abnormally high velocities. Conclusion This study confirms that the risk of high velocities in patients with SCA is significantly decreased by the presence of alpha-thalassemia. It shows for the first time that hemolysis is a more significant risk factor than the degree of anemia and that absence of alpha-thalassemia, G6PD deficiency and hemolysis are significant independent risk factors of cerebral vasculopathy in patients with SCA.

About 11% of SS patients will have a first stroke by age 18–20 years. Abnormal high velocities are associated with a high risk of stroke, which can be significantly reduced by a long-term transfusion program. The stroke rate in Californian SCD children has declined since the advent of transcranial doppler (TCD), but there are no reports on the outcome of patients screened from birth by TCD. Since 1992, TCD has been systematically performed from the age of 12–18 months in the Creteil cohort. MRI/MRA was performed annually after the age of 5 years, or earlier in case of abnormal TCD. Patients with abn. high velocities (TAMMX >= 200 cm/s) were offered transfusion regimens for stroke prevention, but hydroxyurea was proposed secondarily to patients who had normal MRA findings and whose velocities normalized (< 170 cm/s). TCD was performed every three months in these patients, and a transfusion program was resumed if the findings were again abnormal. We report the cerebrovascular outcome of patients born after 1988 who were regularly followed in our center and screened by TCD. This cohort consisted of 242 SCD patients (178 SS, 9 Sb0, 41 SC, and 14 Sb+). Mean follow-up was 6.2 y (range 0.1–17.8), representing 1498 patient-years overall and 1139 patient-years in the SS/Sb0 population. Alpha gene deletion was present in 41% of patients (71/175). The beta genotype was available in 165 patients, and was homozygous Bantou (n=56, 34%), Senegal (n=9, 5.5%), Benin (n=35, 21.2%), or "other" (n=65, 39.4%). Four deaths occurred, all involving SS patients, at 1.2 y (enteritis in 1995), 1.8 y (trip to Africa in 2003), 1.9 y (pneumo. meningitis in 1997) and 3.7 y (ACS and curare allergy in 1998). The mortality rate was 0.27 per 100 patient-years overall and 0.35 in SS/Sb0 patients. The Kaplan-Meier (KM) estimate of the risk of abn. velocities (> 200 cm/s) was 15.7% at 5 y and 22.7% at 10 y of age in SS/Sb0 patients. No SC/Sb+ patients had abn. velocities. Strokes occurred in only two SS patients: the first patient had abn. high velocities detected at the age of 1.5 years and had a stroke at the age of 1.6 years, just before the TCD control and initiation of the transfusion program. The second patient had normal left-sided velocities but no available temporal window on the right side after the age of 1.4 y; this patient had a stroke at age 4.4 y. These observations prompted us to begin TP after the first abn. TCD and to perform MRI/MRA when no window was available. The rates of stroke were 0.13 per 100 patient-years overall, and and 0.18 per 100 patients-years in SS/Sb0 patients. The KM estimate of the risk of stroke was 1.02% at 5 y and 18 y of age in SS/Sb0 patients. KM estimates of the risk of ischemic lesions at 5 and 10 y were respectively 6.4% and 17.7% in SS/Sb0 patients with normal TCD and 20.9% and 43.5% in patients with a history of abn. TCD (Log Rank test 0.0035). This single-center study shows that a strategy based on early and regular TCD can efficiently prevent stroke in a newborn screened cohort: the rate of stroke and the KM risk of stroke were far lower than recently reported (Quinn CT Blood 2004). However, the risk of ischemic lesions remained high particularly in patients with a history of abn. velocities. Abn. TCD velocities identify a high-risk group who may qualify for matched related donor stem cell transplantation.

Frequent vaso-occlusive crisis (VOC) and acute chest syndromes (ACS) cause high morbidity and early death and justify intensification of treatment. We report the comparative effects of Hydroxyurea (HU), Transfusion program (TP) or Stem Cell Transplant (SCT) on VOC and/or ACS occurrence in 76 SS/Sb0 patients. Patients and Methods: This study only concerned the patients always followed and hospitalized in our pediatric center in Creteil, from 1979 to June 2004: among this cohort of 256 SS/Sb0 patients, 76 received a treatment intensification justified by a high frequency of hospitalizations (3 3 VOC/y or 2 ACS/y). For this indication, HU was proposed since 1992 in 53 patients older than 3 years of age without abnormal cerebral velocities on Trans-cranial Doppler (TCD), TP in 42 patients younger than 3 years of age or having abnormal TCD (> 200 cm/sec) or HU failure in VOC/ACS frequency reducing, and SCT was performed in 15 patients with an available HLA identical sibling donor (14/15 successful). Several patients successively received different treatments: HU-TP (n=19), HU-TP-SCT (n=5), TP-SCT (n=6) and one patient who rejected the graft was treated with HU. We compared (student t-test) the causes, the frequency and duration of hospitalizations occurred during the year preceding the treatment intensification with those observed after the intensification program. For transplanted patients, we distinguishly considered the events having occurred during the first year post-transplant and those having occurred after. Results: Mean (± SD) follow-up before intensification was 8.1 years (± 4.5) with 2.3 hospitalizations/year (± 2.2) occured since birth. During the year preceding the treatment intensification, an higher number of hospitalizations (3.9 ± 2.1) occurred with 24.3 days of hosp (± 19.1) and the mean number of VOC was 2.3 (± 2) and ACS was 0.5 (± 0.8). After intensification, number of hospitalizations and VOC and ACS, duration of hosp significantly (p Conclusion: Intensive treatments were significantly efficient to decrease the number and the duration of hospitalizations and the number of VOC and ACS. TP maintening HbS level < 40% was significantly more efficient than HU to prevent VOC (p