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506 Probability of TCD-Normalization in the “Drepagreffe” Trial Comparing Transplantation to Chronic Transfusion in Sickle Cell Anemia Children with Abnormal-Transcranial Doppler Is Associated with Lower Ang-2 and BDNF Plasma Levels

Program: Oral and Poster Abstracts
Type: Oral
Session: 114. Hemoglobinopathies, Excluding Thalassemia—Clinical: Novel or Improved Approaches To Treating Sickle Cell Disease
Hematology Disease Topics & Pathways:
Biological, sickle cell disease, Diseases, Non-Biological, Therapies, Pediatric, Technology and Procedures, Hemoglobinopathies, Study Population, Clinically relevant, transfusion, transplantation, molecular testing
Monday, December 3, 2018: 7:15 AM
Room 28D (San Diego Convention Center)

Myriam Bernaudin, PHD1*, Yacine Khelif1*, Philippe Chadebech, PhD2*, Gwellaouen Bodivit3*, Alicia Jouard2*, Suzanne Verlhac, MD4*, Catherine Paillard, MD, PhD5*, Isabelle Thuret, MD6*, Corinne Guitton, MD7*, Camille Runel, MD8*, Florence Missud, MD9*, Cécile Arnaud, MD10*, Annie Kamdem, MD10*, Corinne Pondarré, MD, PhD10*, France Pirenne, MD, PhD2 and Francoise Bernaudin, MD11

1Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, Caen, France
2EFS, Île-de-France IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, Créteil, France
3EFS, Île-de-France IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, Créteil France, Créteil, France
4Medical Imagery, Referral Center for Sickle Cell Disease, CHIC Hospital, Créteil, France
5University of strasbourg, Strasbourg, France
6Pediatric Hematology, Hôpital de la Timone, Marseille, France
7Referral Center for Sickle Cell Disease, Kremlin Bicetre Hospital, Kremlin Bicetre, France
8Pediatrics, CHU-Bordeaux, Bordeaux, France
9Referral Center for Sickle Cell Disease, Robert Debré Hospital, Paris, France
10Referral Center for Sickle Cell Disease, CHIC, Créteil, France
11Hopital Intercommunal de Creteil, Creteil, France

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<170cm/sec) was significantly higher in transplanted patients than in those maintained on chronic transfusion (27/32 (84%) vs 17/35 (49%), respectively; p=0.001). As shown (Table), leukocytes, neutrophils, platelets, reticulocytes, LDH, bilirubin, ferritin, HbS% were highly significantly lower in transplanted children than in those maintained on chronic transfusion, while hemoglobin and HbA% were highly significantly higher. Ang-2 and HGF were significantly lower in transplanted children than in those on chronic transfusion (p<0.001 and p=0.002, respectively). Velocities recorded in the artery with the highest values were significantly positively correlated with Ang-2 (r=0.385, p=0.015) and BDNF (r=0.444, p=0.005). Logistic regression analysis showed that TCD-normalization was significantly associated with the transplantation arm (OR=5.72 (95%CI:1.79-18.27); p=0.003). High hemoglobin (OR=1.49 per 1g/dL increase; 95%CI: 1.08-2.06; p=0.014) and HbA% (OR=1.05 per1% increase; 95%CI: 1.01-1.10; p=0.014) were significantly positively associated with TCD-normalization, but not independently. Higher levels of Ang-2 (OR=0.51 per 1 pg/mL increase, 95%CI:0.29-0.91; p=0.023) and BDNF (OR=0.69 per 1 pg/mL increase, 95%CI:0.50-0.94; p=0.02) were negatively and independently significantly associated with TCD-normalization. Multivariate analysis, also including the treatment arm, showed that BDNF remained an independent risk factor for a lack of TCD-normalization (OR=0.65, 95%CI:0.45-0.92: p=0.017).

This study confirms the association between high levels of BDNF and high velocities, and suggests that transplantation increases the likelihood of TCD-normalization compared to transfusion, and is associated with reduced Ang-2 expression in plasma, which may reflect improved brain oxygenation.

Disclosures: Thuret: Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Pondarré: Addmedica: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Blue Bird Bio: Honoraria. Bernaudin: AddMedica: Honoraria; Pierre fabre: Research Funding; Cordons de Vie: Research Funding; BlueBirdBio: Consultancy.

*signifies non-member of ASH