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Cerebral vasculopathy in children with sickle cell anemia is responsible for strokes and silent cerebral infarcts and is the most debilitating complication providing motor sequelae and cognitive deficiency. However, the most important advance in pediatric management is the detection of children at a risk of stroke using transcranial Doppler with chronic transfusion applied in children detected at risk, which reduces the stroke risk from 11% to less than 2%. In this chapter, we will describe the place of Doppler, magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) with neck assessment and the place of different treatments, i.e., chronic transfusion, hydroxyurea, new drugs, and stem cell transplantation.

International audience; Sickle cell anemia (SCA) is a disease characterized by abnormal red blood cell rheology. Because of their effects on HbS polymerization and red blood cell deformability, alpha-thalassemia and the residual HbF level are known genetic modifiers of the disease. The aim of our study was to determine if the number of HbF quantitative trait loci (QTL) would also favor a specific sub-phenotype of SCA as it is the case for alpha-thalassemia. Our results confirmed that alpha-thalassemia protected from cerebral vasculopathy but increased the risk for frequent painful vaso-occlusive crises. We also showed that more HbF-QTL may provide an additional and specific protection against cerebral vasculopathy but only for children with alpha-thalassemia (-α/αα or -α/-α genotypes).

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.

Cerebral vasculopathy is the most severe complication affecting children with sickle cell anemia. Significant progress has been made in the management of sickle cell anemia cerebral vasculopathy, including early transcranial Doppler screening, chronic transfusion, and hydroxyurea. Nevertheless, for patients with a potential matched-sibling donor (MSD), stem cell transplantation (SCT) is now the treatment offering the best cerebral vasculopathy outcome. In the absence of MSD, alternative SCT should be recommended only in those with worsening cerebral vasculopathy despite standard treatments, and should be limited to related haplo-identical SCT undertaken in controlled studies.

Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.

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.

As a live attenuated vaccine, yellow fever vaccine (YFV) is not routinely performed after allogeneic hematopoietic stem cell transplant (HSCT) despite it being the only efficient preventive therapy. We retrospectively identified 21 HSCT recipients immunized with YFV at a median of 39 months after HSCT and a median of 33 months after withdrawal of immunosuppression without any side effects. Eighteen evaluable patients had protective immunity after YFV. We also observed that a third of the recipients vaccinated with YFV before HSCT had persistent protective immunity after HSCT.

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.

BackgroundDonors other than matched siblings and low-intensity conditioning regimens are increasingly used in haematopoietic stem cell transplantation. We aimed to compare the relative risk of donor type and conditioning regimen intensity on the transplantation outcomes of in patients with sickle cell disease.MethodsFor this retrospective cohort study, we collected data from 90 US centres reported to the Center for International Blood and Marrow Transplant Research. Eligible patients were younger than 50 years, had genetically confirmed sickle cell disease (Hb SS) or sickle beta thalassemia (Hb Sβ), and underwent allogeneic haematopoietic cell transplantation between Jan 15, 2008, and Dec 28, 2017. We considered transplants from donor-recipient pairs matched at the allele-level (HLA-A, HLA-B, HLA-C, and HLA-DRB1), including HLA-matched sibling donors, haploidentical related donors, matched unrelated donors, or mismatched unrelated donors. The main outcome was event-free survival. The effect of donor type, conditioning regimen intensity (myeloablative, non-myeloablative, and reduced-intensity regimens), age (≤12 or 13-49 years), sex, performance score, comorbidity index, recipient cytomegalovirus serostatus, graft type (bone marrow, peripheral blood, or umbilical cord blood), and transplantation period (2008-12 and 2013-17) on outcomes was studied using Cox regression models.FindingsOf 996 patients with sickle cell disease and who underwent transplantation in 2008-17, 910 (91%) were included (558 [61%] patients had HLA-matched sibling donors, 137 [15%] haploidentical related donors, 111 [12%] matched unrelated donors, and 104 [11%] mismatched unrelated donors). The median follow-up was 36 months (IQR 18-60) after transplantation from HLA-matched siblings, 25 months (12-48) after transplantation from haploidentical related donors, 37 months (23-60) after transplantation from HLA-matched unrelated donors, and 47 months (24-72) after transplantation from mismatched unrelated donors. Event-free survival was worse in recipients aged 13 years or older than in those younger than 13 years (hazard ratio 1·74, 95% CI 1·24-2·45; p=0·0014) and in those who received a transplant from haploidentical related donors (5·30, 3·17-8·86; p

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

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 (

In order to identify very early prognostic factors that can provide insights into subsequent clinical complications, we performed a comprehensive longitudinal multi-center cohort study on 57 infants with sickle cell anemia (55 SS; 2 Sβ°) during the first 2 years of life (ClinicalTrials.gov: NCT01207037). Time to first occurrence of a severe clinical event-acute splenic sequestration (ASS), vaso-occlusive (VOC) event requiring hospitalization, transfusion requirement, conditional/ abnormal cerebral velocities, or death-was used as a composite endpoint. Infants were recruited at a mean age of 4.4 ±1 months. Median follow-up was 19.4 months. During the study period, 38.6% of infants experienced ≥1 severe event: 14% ASS, 22.8% ≥ 1 VOC (median age: 13.4 and 12.8 months, respectively) and 33.3% required transfusion. Of note, 77% of the cohort was hospitalized, with febrile illness being the leading cause for admission. Univariate analysis of various biomarkers measured at enrollment showed that fetal hemoglobin (HbF) was the strongest prognostic factor of subsequent severe outcome. Other biomarkers measured at enrolment including absolute neutrophil or reticulocyte counts, expression of erythroid adhesion markers, % of dense red cells, cellular deformability or ϒ-globin genetic variants, failed to be associated with severe clinical outcome. Multivariate analysis demonstrated that higher Hb concentration and HbF level are two independent protective factors (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43), respectively). These findings imply that early measurement of HbF and Hb levels can identify infants at high risk for subsequent severe complications, who might maximally benefit from early disease modifying treatments.

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.

La drepanocytose, maladie genetique, peut desormais etre traitee et guerie par une allogreffe intrafamiliale de cellules souches hematopoietiques (CSH). Cette greffe a fait ses preuves sur le plan medical et est de plus en plus utilisee, notamment chez les jeunes enfants. Elle leur donne le statut de chimere biologique grâce a la moelle osseuse d’un frere ou d’une sœur. Comment vivent-ils alors cette experience medicale lourde et ses consequences sur le plan psychologique ? Cette etude prospective a permis de decrire le vecu de la greffe chez trois enfants drepanocytaires âges de 5 a 7 ans sur une duree d’un an par une methodologie qualitative a partir des dessins et du discours des enfants. Ces enfants sont confrontes a des modifications de la perception d’eux-memes et de la representation du temps entre rupture et continuite. Face a cette epreuve, on observe une oscillation entre un besoin de maitrise et au contraire de passivite. La greffe va mettre a mal les enveloppes psychiques et leurs qualites. De plus, une problematique du don et de la dette va emerger. En effet, la greffe entraine un bouleversement dans la construction de leur personnalite, avec une reminiscence de processus archaiques. La representation du changement pour ces enfants et le sentiment de guerison qui en decoule sont complexes, et impliquent un veritable travail de deuil de la maladie qui s’avere long et douloureux. Il s’agit d’une periode de vulnerabilite pour l’enfant qui necessite un accompagnement psychologique.

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.

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.

Sickle cell disease (SCD) is a chronic inflammatory disease associated with multiple organ damage, chronic anemia, and infections. SCD patients have a high rate of alloimmunization against red blood cells (RBCs) following transfusion and may develop autoimmune diseases. Studies in mouse models have suggested that regulatory T cells (Treg) play a role in alloimmunization against RBC antigens. We characterized the phenotype and function of the Treg cell population in a homogeneous cohort of transfused SCD patients. We found that the distribution of Treg subpopulations differed significantly between SCD patients and healthy blood donors. SCD patients have a particular Treg phenotype, with strong CTLA-4 and CD39 expression and weak HLA-DR and CCR7 expression. Finally, we show that this particular phenotype is related to SCD rather than alloimmunization status. Indeed, we observed no difference in Treg phenotype or function in vitro using autologous feeder cells between strong and weak responders to alloimmunization.

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.

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.

Considering the progress made in the management of sickle cell disease during the past 30 years, along with the excellent results obtained with hematopoietic stem cell transplantation (SCT), it is important to reexamine why, who, when and how to recommend allogeneic SCT in children with sickle cell disease. While sickle cell disease has a low risk of death in children and a high risk for morbidity during aging, SCT carries an early risk of death, graft-vs-host disease and infertility. Nevertheless, SCT offers at least 95% chance of cure with low risk of chronic graft-vs-host disease when a matched-sibling donor is available and the risks of infertility can be reduced by ovarian, sperm or testis cryopreservation. Thus, all available therapies such as hydroxyurea, transfusions and SCT should be presented to the parents, providers, and affected children and discussed with them from infancy. Furthermore, the use of these therapies should be adjusted to the severity of the disease and to local availabilities in order to choose the treatment offering the best benefit/risk ratio.

Background and Purpose— There is little evidence about characteristics of ischemic stroke (IS) occurring in adults with sickle-cell disease (SCD). The objective of this study was to assess characteristics of first-ever IS in adults with SCD and to assess whether they differ from those occurring in child patients with SCD. Methods— Adult and child individuals with SCD who had a first-ever IS were identified from cohorts of patients followed up in an adult and a child sickle cell referral center. Mechanisms of IS were determined by consensus meeting from all available explorations using the following predefined classification: Vasculopathy, cardioembolism, other defined cause, and undetermined. Treatment and stroke recurrences were recorded from prospective follow-up performed in the referral centers. Results— Twenty-nine adults and 26 children had a first-ever IS; mean age (SD) was 7.1 (4.3) and 32.3 (11.6), respectively. With regard to IS mechanism, vasculopathy was less often the cause of IS in adults (12/29, 41%) than in children (24/26, 92%; P P log rank=0.046) despite exchange-blood transfusion in patients with vasculopathy. Conclusions— First-ever IS occurring in adults with SCD has specificities that justify further studies conducted in adults with SCD to improve understanding and management.

Cerebral vasculopathy is the most severe complication to affect children with sickle cell anaemia and its pathophysiology is complex. Traditionally, small-vessel occlusion by intravascular sickling and sludging was considered to underlie the strokes but, in the last 20 years, progressive major cerebral vessel involvement has become recognized as the principal responsible factor. Macrovasculopathy is well detected by abnormally high velocities on transcranial Doppler and with magnetic resonance angiography (MRA), and is responsible for the majority of overt strokes. Silent infarcts are ischaemic lesions detected by magnetic resonance imaging (MRI) in patients without history of stroke. They are associated with compromised cognitive functioning. The present review discusses the pathophysiologal mechanisms that could be involved in the development of cerebral vasculopathy, such as inflammation and hypoxia, anaemia, haemolysis and the resulting decreased nitric oxide bioavailability, genetic factors, impaired blood rheology and particular local haemodynamic profiles.

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.

BACKGROUND: The recent in vitro demonstration that inositol hexaphosphate–loaded red blood cells (IHP-RBCs) may reduce the risks of sickling of sickle RBCs (SS RBCs) exposed to hypoxia make these modified RBCs potentially useful in transfused sickle cell anemia (SCA) patients. STUDY DESIGN AND METHODS: Hemorheologic properties of IHP-RBCs, normal RBCs (AA RBCs), SS RBCs, SS RBCs plus AA RBCs, and SS RBCs plus IHP-RBCs were compared under normoxia and/or after hypoxic challenges. RESULTS: Although IHP-RBCs have reduced deformability compared with SS RBCs or AA RBCs, IHP-RBCs exhibited lower aggregability than AA RBCs and SS RBCs and, when mixed with SS RBCs, the aggregation level was below the one of SS RBCs alone or SS RBCs plus AA RBCs. Blood viscosity of SS RBC plus IHP-RBC suspension was lower than the viscosity of SS RBCs alone and greater than viscosity of SS RBCs plus AA RBCs. The hypoxic challenge was detrimental for deformability and viscosity of SS RBCs alone or SS plus AA RBC suspension but not for SS plus IHP-RBC suspension. CONCLUSION: Our results support the fact that IHP-RBCs could be useful in SCA by decreasing RBC aggregation and blunting the adverse effects of hypoxia on RBC deformability and blood viscosity.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Acute splenic sequestration crisis (ASSC) is an unpredictable life-threatening complication of sickle cell disease (SCD) in infants. Here, our objective was to update available clinical information on ASSC. We retrospectively studied the 190 patients who were diagnosed at birth with SS or Sbeta(0) in the Paris conurbation between 2000 and 2009 and who experienced ASSC. They had 437 ASSC episodes (0.06/patient-year). Median age at the first episode was 1.4 years (0.1-7) and 67% of patients had more than one episode. Age was the only factor predicting recurrence: the risk was lower when the first episode occurred after 2 years versus before 1 year of age (hazard ratio, 0.60; 95% confidence interval, 0.41-0.88; P=0.025). A concomitant clinical event was found in 57% of episodes. The mortality rate was 0.53%. The treatment consisted in watchful waiting without prophylactic blood transfusions or splenectomy in 103 (54%) patients and in a blood transfusion programme in 55 (29%) patients. Overall, splenectomy was performed in 71 (37%) patients, at a median age of 4.5 years (range, 1.9-9.4). In conclusion, aggressive treatment may be warranted in patients experiencing ASSC before 2 years of age. Randomized controlled trials are needed to define the best treatment modalities.

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.

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

SummaryBackgroundThe decline in lung volumes associated with sickle cell disease (SCD) may begin in childhood. Risk factors for early restrictive lung disease may include SCD severity markers such as leukocytosis.ObjectiveWe examined the relationship between early alteration of lung function and extra-pulmonary markers of SCD severity.MethodsWe analyzed pulmonary function test results for 184 SCD children (mean age 12.6 y) enrolled in a pediatric cohort.Main resultsTotal lung capacity (TLC) and vital capacity (VC) were not associated with a history of acute chest syndrome. Lower TLC values were significantly associated with three independent factors: older age, previous acute episodes of anemia

Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children ( In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

Background and hypothesis: Infancy is a critical time during which the first complications of sickle cell anemia (SCA) emerge. Very early prognostic factors of severity are needed to select high-risk children to offer precisely tailored therapy. Our hypothesis was that clinical, biological or genetic parameters measurable soon after birth (3 to 6 months of age) could predict severe outcomes in the first two years of life in SCA infants. Methods: Infants with SCA were offered to participate in a prospective study (ClinicalTrials.gov: NCT01207037) that included clinical and laboratory assessment at enrollment (3-6 months) and at 12, 18 and 24 months of age. The prognostic performance of conventional and SCA-specific biomarkers (notably erythroid adhesion markers, dense cells, ektacytometry indices) on disease severity was assessed using Cox's proportional hazard regression models. The disease severity was defined as time to first occurrence of either acute splenic sequestration (ASS), vaso occlusive (VOC) event requiring hospitalization, transfusion, conditional or abnormal Trans Cranial Doppler, acute chest syndrome and death. Hazard ratios (HRs) were calculated with 95% Cis. Results: Fifty-seven infants (55 SS; 2 Sβ°; 54.4% males), diagnosed through neonatal screening, were included in the study at a mean age of 4.4 ± 1 months and longitudinally assessed with a median follow-up of 19.4 months (range 3.1-23.2). Only 1 of 57 infants had experienced a SCA-related event prior to enrolment (dactilytis). At inclusion, clinical examinations were unremarkable except for pallor found in 15 (26,3%) and none of the infants had an enlarged or palpable spleen. Growth parameters were normal. Main biological characteristics were a mild hemolytic anemia (Hb 9.3 ±1.3 g/dL; reticulocytes count: 151.2 ±76 x 109/L), increased HbF level (3.8 ±1.3 g/dL. or 41.4 ±11.7%) and presence of dense red cells (23.1 % ±10.8). Genetic analysis showed one alpha globin deletion in 18 (32.1%) and a balanced distribution of beta globin haplotypes: 16 (30.8%), 18 (34.6%) and 18 (34.6%) in the favorable (SEN/SEN, BEN/SEN, CAM/SEN or SEN/ATYP), unfavorable (CAR/CAR, CAM/CAR, CAR/ATYP or BEN/CAR) and intermediate category (other) respectively. During the 2 years duration of the study, 44 of 57 (77%) infants required 157 hospital admissions, median (range): 2 (1-12) per patient. Infection was a leading cause of hospitalization although no serious adverse event related to pneumococcal infection was noted. Eight (14%) children experienced an episode of ASS at a median (range) age of 13.4 months (7.8- 15.9) while 13 infants (22.8%) experienced at least one VOC event at a median age of 12.7 months (7-22.5), with 6 experiencing ≥ 2 episodes. Nineteen infants (33.3%) required at least one transfusion with 10 (17.6%) requiring more than 2. Altogether, 22 (38.6%) infants of this cohort experienced a SCA-related severe clinical event by 24 months of age. The Kaplan Meier estimate of the 24-month event-free rate was 54.4% (95% CI, 39.7 to 74.5%) (Figure). Univariate analysis of potential prognostic markers at inclusion showed that higher HbF % and concentration were the strongest protective parameters for ASS in particular and for all severe outcomes, except for VOC (p < 0.001). Unfavorable haplotypes were also associated with severe outcome (HR (95% CI) 4.73 (1.31-17.01), p=0.017). Protective factors for VOC were higher Hb level (threshold > 8 g/dL) and low % of circulating dense cells (p=0.04 and 0.02, respectively). In a multivariate analysis, Hb level ≥ 8 g/dL and HbF ≥ 2.8 g/dL proved to be two independent prognostic factors of a SCA-related severe event (adjusted HRs (95% CI) 0.27 (0.11-0.73) and 0.16 (0.06-0.43) respectively). Interestingly, absolute neutrophil or reticulocyte counts, level of expression of known potentially pathogenic erythroid adhesion markers (CD36, Lu/B-CAM, ICAM-4/LW), % of red dense cell, or deformability parameters failed to be prognostic factors of specific complications or overall severity in this very young cohort. Conclusion: HbF and Hb levels measured between 3 and 6 months of age in SCA infants predict the risk of subsequent severe clinical outcome in the next 2 years. These events are frequent even in a high-income setting where neonatal screening is implemented. These findings further support the early use of HbF inducers such as hydroxyurea in high-risk infants to sustain a protective HbF level. Figure 1 Figure 1. Disclosures Brousse: Add Medica: Membership on an entity's Board of Directors or advisory committees. De Montalembert: Novartis: Consultancy, Honoraria, Research Funding; Addmedica: Consultancy, Honoraria, Research Funding.