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Hydroxyurea (HU) is approved in EU and USA for preventing vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in adults, adolescents and children ≥2 years with sickle-cell disease (SCD). Further to the double blinded, randomized controlled Multicenter Study of Hydroxyurea administration (MSH) which provided the first data on clinical efficacy of HU (Charache 1995), a few follow-up studies suggested that long-term use of HU resulted in significant clinical benefit on patient outcome. This was reflected by lower mortality rates in HU-treated patients compared to conventionally treated patients (Steinberg 2003 & 2010, Voskaridou 2010, Lê 2015). Sustained hematological and clinical response after several years of follow-up at maximal tolerated dose was further shown in subsequent studies, especially the LaSHS study (Voskaridou 2010). Based on these data, the ESCORT-HU (European Sickle Cell Disease COhoRT - HydroxyUrea) study was launched aiming in the establishment of the safety and the sustainability of hematological and clinical benefits to HU administration in the prevention of sickle-cell vaso-occlusive crises in routine practice. We hereby present preliminary results from a large cohort of patients enrolled in the study between January 2009 and June 2017. 1920 patients were enrolled from 63 centers in France, Germany, Greece and Italy, For 147 of the 600 HU-naive patients (never treated with HU before enrolment) and started on HU for VOC or ACS, there was documented clinical outcome (number of VOC >48h and ACS episodes per year) over a 4-year follow-up period. These patients were selected for analysis to evaluate sustainability of clinical and hematological HU response in routine practice. Demographic data and Hb genotypes are displayed in table 1. The children group was mainly composed of βS/βS patients, while adults were mainly βS/βS and βS/β-thal patients. As shown in figure 1 and 2, there was a dramatic reduction in the number of VOC >48h and ACS episodes (-79%) from year 1 in adults and children, with results comparable to previous randomised clinical trials in adults (Charache et al., 1995) and children (Jain et al, 2012). Overall, the reduction in number of VOC (>48h) and ACS was stable over the 4 years of follow-up. This reduction is inversely proportional to the increase in HbF. There were however a moderate rebound in children from year 2 while adults remained stable. Similarly, there was reduction in the proportion of adults and children requiring transfusion (figure 3). The clinical benefit of HU was higher in severe forms of SCD, as displayed by the markedly reduced number of patients with ≥ 3 VOC episodes (>48h)/year at year 1 (figure 4). Hematological response to HU was evidenced as soon as year 1 with a marked increase in HbF% (+6-10) and were maintained over subsequent years of treatment (figure 1 and 2) as the dose of HU was further increased. While there was no striking differences in HbF% variation between age groups and genotypes, the requirement for increase in HU dose over the 4 years of follow-up was markedly higher in children, probably reflecting the different severity between the two population at entry (figure 5). The red cell red cell mean corpuscular volume (MCV) could be used as a measurement of compliance, showing differences between age group (figure 5). There was, as expected, an apparent negative correlation between induction of HbF synthesis and number of VOC >48h and ACS episodes at year 1, attesting to reduced effectiveness of treatment in some patients (figure 6). Improvement in blood parameters was accompanied by mild reduction of absolute neutrophil and platelet count although not to the point of myelosuppression (defined as ANC < 2 x 109/L), showing that MTD was not targeted in routine practice. Treatment-emergent adverse reactions occurring in the 147 patients of the cohort over the 4 years of follow-up were consistent with the known safety profile of hydroxyurea. The commonest effects included neutropenia and thrombocytopenia (25 events in 13 patients) and were easily manageable with temporary discontinuation of treatment. No tumorigenesis was reported. In conclusion, preliminary results from ESCORT-HU in 147 patients treated with HU showed sustained hematological and clinical response while MTD was not targeted, with differences between adults and children which may be attributed in part to reduced compliance in the latter group. Disclosures Voskaridou: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron: Membership on an entity's Board of Directors or advisory committees, Research Funding. Oevermann:Addmedica: Membership on an entity's Board of Directors or advisory committees. Thuret:Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Steschenko:Novartis: Membership on an entity's Board of Directors or advisory committees.

ESCORT-HU (European Sickle Cell Disease (SCD) COhoRT - HydroxyUrea) is a multicenter prospective non interventional study implemented in Europe, following the European Medical Agency's request to collect more information focused on long-term safety profile of hydroxycarbamide (HU) in SCD patients treated with HU. Primary endpoint of the study is to determine the frequency of adverse events (AEs) under HU treatment Secondary endpoints include the efficacy of HU in labeled indications (prevention of vaso-occlusive complications and of acute thoracic syndrome), frequency of hospitalizations due to SCD events and frequency of blood transfusions. Data collection on the reason for HU initiation permitted to identify in-label (in the therapeutic indication of the European marketing authorization, group 1, G1) and off-label (other therapeutic indication, group 2, G2) prescriptions of HU. Frequency of AEs (including not related to SCD and infections) was compared between adults and children, both in G1 and G2, with focus on the following subclasses: blood and lymphatic system disorders, fever, gastrointestinal disorders, infection, nervous system disorders, skin and subcutaneous tissue disorders and others. As of 6th June 2016 (cut-off date), a cohort of 1047 sickle cell patients have been enrolled in 3 European countries (Greece, 11.4%, Germany, 13.4%, and France, 75.2%). Of the 1047 patients, 845 (80.7%) have an in-label prescription (478 adults and 367 children), 170 (16.2%) an off-label prescription (61 adults and 109 children), and 32 reported unknown or no indication (Table 1a). As usually observed in any disease, the off-label use is more frequent in children compared to adults (p=0.01). Main reasons for off-label prescription were anemia (31%) (n=9 in adults and n=44 in children), abnormal Transcranial Doppler (TCD) values/cerebral vasculopathy (15%) (n=2 in adults and n=24 in children) and sickle cell organopathy including renal impairment (15%) (n=14 in adults and n=12 in children) (Table 1b). These three indications follow recommendations issued by European clinicians and are in accordance with the last version of US guidelines (JAMA 2014). Mean HU daily doses at initiation were respectively 18 mg/kg (G1) and 17.3 mg/kg (G2) in children, and 16.2 mg/kg (G1) and 13.5 mg/kg (G2) in adults. Not SCD-related AEs were respectively reported in 25% and 27.6% of patients in G1 and G2 groups (Table 2a). Focusing on the number of not-SCD related AE reported in each group, 355 AE have been reported in 211 patients in G1 and 73 AE have been reported in 47 patients in G2. Within G1 group, more AEs were reported in adults (30.8%) vs. children (17.4%) (p < 0.01) (Table 2b) but not in G2 group (NS) (Table 2c). When compared by AE type in G1, significant differences appeared between children and adults for the following AE subclasses (p < 0.01): infections more frequent in children as usually observed, renal & urinary disorders, immune system disorders more common in adults. Regarding neoplasms benign, immune system disorders, no malignancy has been reported, but mainly cysts (1 ovary, 2 breast), 1 renal tumor and 1 cutaneous lesion (histological types not provided), 1 other (location not reported) (Table 3). All AEs were more frequent in adults except infections. In conclusion, the current ESCORT-HU data confirm the more frequent off-label use of HU in children, a similar frequency of patients reporting not SCD-related AE between the in-label and off-label groups despite a higher number of AE reported in the in-label group, and a significant difference between children and adults in frequency of AEs in the in-label group. Disclosures De Montalembert: Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Ribeil:Bluebirdbio: Consultancy; Addmedica: Research Funding.

Background. The TWiTCH multicentre randomised phase III trial showed recently non inferiority of hydroxyurea (HU) with phlebotomy versus transfusions with chelation for primary stroke prevention and management of iron overload in children with sickle cell anemia, having had abnormal transcranial Doppler but no severe vasculopathy and after at least one year of transfusion. Importantly, children in the HU arm received the drug at the maximum tolerated dose (MTD) with escalation of dosage until absolute neutrophil count (ANC) is Methods. We extracted data from the ESCORT-HU cohort, which is non-interventional, prospective, observational open-label study on the efficacy and safety of Siklos. The cut-off date was set as February 5th, 2016. Out of the global cohort of 992 patients, 386 patients were aged 2 to 18 years at the time of study initiation. Among them, 233 patients were HU treatment-naïve and initiated Siklos® treatment. A follow-up of at least 12 months and data allowing biological or clinical efficacy evaluations were available in a subgroup of 139 "naïve" (= not previously treated with HU) patients. Our objectives were 1) to collect the dosages of HU and to compare HbF% and ANC before and 12 months after initiation of Siklos® in the subgroup of naïve patients (table 1); 2) to assess the efficacy of HU in this cohort. We compared using Mac-Nemar paired t-test and Wilcoxon sign rank-test in the 12 months period before treatment and 12 months after initiation of treatment i) painful crises >48 hours, ii) acute chest syndromes (ACS), iii) hospitalizations, and iv) blood transfusion (% of patients having had at least 1 event and the total numbers of events); 3) to assess in the total cohort of 386 children the % of children with ANC count within the ranges recommended in the TWiTCH trial, underlining those treated with HU for cerebral vasculopathy (table 2). Results 1) HbF% and ANC in the subgroup of 139 children not previously treated with HU (table 1) 46.8% were males; mean age was 8.1 ± 3.9 years. Genotypes were HbSS, HbSC, HbSb0thalassemia, HbSb+ thalassemia, and unknown in respectively 86.5%, 1.4%, 7.8%, 2.1% and 2.1% of cases. 2) Efficacy data in this subgroup The % of patients having had at least 1 episode and the total numbers of painful crises > 48 hours, ACS, hospitalizations, and blood transfusion in the 12 months, decreased significantly under HU (P 3) ANC in the total cohort of children from ESCORT-HU cohort (table 2) The total cohort enrolled 386 children, 51.1 % were males, and mean age was 9.65 ± 4.26 years. Genotypes were HbSS, HbSC, HbSb0thalassemia, HbSb+ thalassemia, and unknown in respectively 89.1%, 2%, 4.7%, 2%, and 2.2% of cases. Only 159 patients had one HbF% determination 12 months after inclusion. Out of these, 138 (86.79%) had ANC > 3.0 x109/L, their mean HbF was 13.04 ± 8.6 %; 21 (13.20%) had ANC < 3.0 x109/L, their mean HbF was 21.02 ± 9.64 %. In conclusion We show that children included in the ESCORT-cohort received median HU dosage quite lower than the one given to children included in the TWiTCH trial which resulted in quite lower HbF %. This dosage was sufficient to very dramatically reduce SCD-related painful events. Whether it can exert the same brain protection as the one demonstrated in the TWiTCH study is so far not known. We encourage physicians to reach MTD when the indication for HU is brain protection. Disclosures De Montalembert: Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau.

Abstract 4680 One of the most common human chromosomal abnormalities, Down syndrome, is caused by trisomy 21. Transient myeloproloferative disorders (TMD) occur in 10-20 % of newborns with Down syndrome. About 30 % of those TMD patients develop Acute Megakaryoblastic Leukemia (AMKL) within 4 years. Therefore both disorders have their origin in the fetus. There is emerging evidence that the protein product of GATA1 mutations, GATA1s, directly contributes to leukemogenesis. Although an in utero origin of GATA1 mutations and consecutively TMD is established it was never analyzed if GATA1 mutations could be detected in maternal PBL collected before and after the delivery of a child with Down syndrome and TMD. We therefore initiated a study to detect mutant GATA1 in three pairs of mother and child (A, B, C). After the identification of the specific GATA1 mutations of the newborn with TMD, PBL samples of the mothers drawn 4 days after delivery (mother A), 7 days after delivery (mother B) and 4 week before as well as just before sectio cesarea ( mother C) were analyzed. Results All 3 patients had duplications in exon 2. Patient A had a duplication of 191 bp including the start codon,, patient B showed a duplication of 2 bp, and patient C had a duplication of 13 bp, respectively. The three mothers harbored the TMD specific GATA1 mutations in PBL analyzed around the birth of their children. The GATA1s signal in mother A and B had disappeared 1 month after birth. No analysis at this time point was done in mother C,whereas she was positive for the specific GATA1 mutation one month before delivery. At that time TMD was suggested by ultrasound which revealed clinical signs of hydrops in the fetus. In mother B and C the particular GATA1 mutations could also be detected in their plasma, in the plasma sample of mother C even 4 weeks before delivery (not done in mother A). Conclusion In our study we could show for the first time that GATA1 mutations of leukemic cells could be detected in PBL of the mothers around birth. Cell free GATA1 DNA was also detectable. The prenatal finding of TMD specific mutations in the mothers' blood suggests that feto-maternal transfer of leukemic cells and DNA may already occur up to 4 weeks before delivery. Disclosures: No relevant conflicts of interest to declare.