Implementation of a European Cohort to Follow Sickle Cell Children and Adults Treated with Hydroxycarbamide

Abstract

Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is a multicenter prospective non interventional study implemented in Europe to collect more information about the safety profile of HU and morbi-mortality in SCD patients treated with HU. The study responds to EMA (European Medicines Agency) request and has been approved by the Ethical of Necker Enfants Malades Hospital (Paris, France).The ongoing study involves the largest number so far of patients with SCD treated with HU. Primary endpoints of ESCORT HU are to determine frequency of adverse events, and possible consequent changes of HU treatment. Secondary endpoints are to evaluate morbi-mortality of the disease although in the absence of control group.From June 2008 to June 2014, 483 patients (255 females; 228 males) were enrolled from 3 European countries, Greece (24%), Germany (19%), and France (56%). 67% patients were adults, median aged 37.35 yrs (17-83.5) and 33% were children, median aged 11.06 yrs (2.6-16.9). genotypes were HbS/HbS in 71.4% cases, and compound heterozygotous HbS/β-thalassemia in 22.8 % (Table 1).137 (28.4%) patients experienced 421 events (Table 2). 132 (32.2%) of these events may be attributed to HU. The safety profile is roughly similar in children and adults. As expected the most frequent side effects were firstly blood disorders (n=86 events, 42.4%) such as neutropenia or thrombocytopenia. In all cases, these cytopenias were rapidly resolved with the transitory stop of HU. 71 events related to skin and subcutaneous tissue disorders were observed, mostly cutaneous dryness, skin reactions, alopecia and nails or skin pigmentation; 4 patients had a leg ulcer (34.8%). Most of these events are ongoing or stabilized despit the decrease of HU. No secondary cancer has been reported until now.Even if HU is an old drug with a relatively well-known safety profile, some uncertainties remain in terms of long-term safety as well as tolerance in the youngest people. The main interest of ESCORT HU is to offer the possibility of safety surveillance of hydroxycarbamide in European sickle cell patients.Table 1Demographic dataAdultsChildren < 17 years oldTotalNumber of patients322 (67%)161 (33%)483Females/Males183/13972/89255/228Median age (yrs) (range)37.35 (17-83.5)11.06 (2.6-16.9)28.58GenotypeSS206 (64%)139 (86.3%)345 (71.4%)SC1 (0.3%)3 (1.86%)4 (0.8%)Sβ051 (15.8%)11 (6.8%)62 (12.8%)Sβ+46 (14.2%)2 (1.2%)48 (9.9%)Other18 (5.5%)6 (3.7%)24 (4.9%)Treatment with HU before enrollment in ESCORT HUNo of pts23283315 (65%)Median duration (range) of HU treatment before ESCORT HU8.2 yrs (0.5 ans-24 yrs)3. 1 yrs ( 71 days – 8.9 yrs)6.85 (71 days-24 years)]HU ESCORT Daily mean dose (mg/kg/d)16.11 ± 4.7919.63 ± 4.6917.32 ± 4.94Abstract 564. Table 2The most frequent events of hydroxycarbamide in the two populations of SCD patientsADULTSCHILDRENNo ofGerman(%)No of adultsNo ofEpisodes(%)No of childrenTotal(% /411)Events Related to HU treatment (Siklos®)(%**)Blood and lymphatic system disorders (%)32 (17.7)2254 (31.03)2886 (20.9)56 (65.1)Skin and subcutaneous tissue disorders (%)42 (23.2)2829 (16.7)1971 (17.3)46 (64.8)Nervous system disordersHeadache (24), Dizziness/vertigo (14),32 (17.7)2312(6.9)1044 (10.7)11 (25)Gastrointestinal disordersNausea (14), diarrhea (8), other (14)20 (11)1723 (13.2)1643 (10.4)7 (16.3)Metabolic and nutrition disorders: vit D deficiency (17), weight gain (5)13 (7)1118 (18.3)1836 (8.75)4 (11.1)Fever11 (6)1012(6.9)723 (5.6)1 (4.3)Cardiac disorders (hypertension, bradycardia, chest pain, cardiomegaly)442261 (16.6)General disorders : fatigue550050Hepatobiliary disorders220020Neoplasms benign, malignant and unspecified (incl. cysts and polyps)Harmatoma, benign vulvar sebaceous cyst220020Renal & urinary disorders220020Reproductive system and breast disorders330030Other13132114346 (17.1%)18180 /181(24.8%)17457 / 174(35.4%)411132/411 (32.2%)**compared to the total number of “system organ class” events DisclosuresNo relevant conflicts of interest to declare.