ALBERT

Description: 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 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.

Description: 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

Description: Sickle cell anemia (SCA) is a chronic illness that causes an increased risk of stroke and progressive brain and cognitive dysfunction. SCA-related cerebral vasculopathy includes vascular remodeling, abnormal arterial velocities and infarction. We studied the relationship between cytokines, velocities, and blood parameters in SCA-children enrolled in the "Drepagreffe" trial, a French prospective, Mendelian-randomized trial with 2 arms (transfusions/transplantation) defined by random-availability of a HLA-matched sibling. This trial enrolled SCA-children younger than 15, regularly transfused for abnormal-TCD history, with at least one non-SCA sibling, and parents agreeing to HLA-typing and transplantation. Between 12/2010 and 6/2013, 67 SCA-children (7 with stroke history) were enrolled. Thirty-two had a matched-sibling donor (MSD) and were transplanted, while 35 (no donor) were included in the transfusion arm. Hypoxia/angiogenesis and brain injury-related factor expression at 1-year was one of the trial secondary outcome. Elevated plasma BDNF and PDGF-AA have been shown to be significantly associated with high cerebral velocities (Hyacinth 2012). Chronic transfusion has been shown to reduce vascular endothelial activation and thrombogenicity in SCA-children with abnormal-TCD (Hyacinth 2014) but no study has been performed in transplanted SCA-children. Plasma samples were obtained at enrollment and 1-year post-enrollment and stored frozen. The expression of the following cytokines (VEGF, Ang-1, Ang-2, FGFb, HGF, PDGF-BB, BDNF) was assessed with a multiplex immunoassay (Bio-Techne). Ang-2, and BDNF levels were confirmed with specific enzyme-linked immunosorbent assays (ELISA, Bio-Techne). Blood parameters, velocities, ischemic lesions and stenoses were assessed at enrollment and 1-year post-enrollment. At 1-year, the percentage of patients with normalized-TCD (velocities