Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

Sylvie Chevret¹, Suzanne Verlhac², Elisabeth Ducros-Miralles³, Jean-Hugues Dalle⁴, Regis Peffault de Latour⁵, Mariane de Montalembert⁶, Malika Benkerrou⁷, Corinne Pondarré⁸, Isabelle Thuret⁹, Corinne Guitton¹⁰, Emmanuelle Lesprit¹¹, Maryse Etienne-Julan¹², Gisèle Elana¹³, Jean-Pierre Vannier¹⁴, Patrick Lutz¹⁵, Bénédicte Neven¹⁶, Claire Galambrun¹⁷, Catherine Paillard¹⁸, Camille Runel¹⁹, Charlotte Jubert²⁰, Cécile Arnaud²¹, Annie Kamdem²², Valentine Brousse²³, Florence Missud²⁴, Marie Petras²⁵, Lydia Doumdo-Divialle²⁶, Claire Berger²⁷, Françoise Fréard²⁸, Olivier Taieb²⁹, Elise Drain³⁰, Monique Elmaleh³¹, Manuela Vasile³², Yacine Khelif³³, Myriam Bernaudin³⁴, Philippe Chadebech³⁵, France Pirenne³⁶, Gérard Socié³⁷, Françoise Bernaudin³⁸

Affiliations

¹ Statistical, Methodology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: sylvie.chevret@paris7.jussieu.fr.
² Medical Imaging Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Créteil, France; Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: suzanne.verlhac@chicreteil.fr.
³ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: ducros.miralles@free.fr.
⁴ Pediatric Hematology Department, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: jean-hugues.dalle@aphp.fr.
⁵ Hematology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: regis.peffaultdelatour@aphp.fr.
⁶ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: mariane.demontal@aphp.fr.
⁷ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: malika.benkerrou@aphp.fr.
⁸ Pediatric Hematology Department, Lyon Léon Bérard Center, Lyon, France; Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: corinne.pondarre@chicreteil.fr.
⁹ Pediatric Hematology Department, Marseille-la Timone Hospital, Aix-Marseille University, France. Electronic address: Isabelle.THURET@ap-hm.fr.
¹⁰ Pediatric Department, Referral Center for Sickle Cell Disease, Bicêtre Hospital, Paris-Sud University, France. Electronic address: corinne.guitton@aphp.fr.
¹¹ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Trousseau Hospital, Paris-Diderot University, France. Electronic address: emmanuelle.lesprit@aphp.fr.
¹² Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: maryse.etienne-julan@chu-guadeloupe.fr.
¹³ Pediatric Department, Referral Center for Sickle Cell Disease, Fort de France Hospital, Antilles University, Martinique, France. Electronic address: gisele.elana@chu-fortdefrance.fr.
¹⁴ Pediatric Hematology Department, Rouen-Charles-Nicolle Hospital, Rouen University, France. Electronic address: Jean-Pierre.Vannier@chu-rouen.fr.
¹⁵ Pediatric Onco-Hematology Department, Strasbourg-Hautepierre Hospital, Strasbourg University, France. Electronic address: Patrick.Lutz@chru-strasbourg.fr.
¹⁶ Pediatric Immuno-Hematology Department, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: Benedicte.neven@aphp.fr.
¹⁷ Pediatric Hematology Department, Marseille-la Timone Hospital, Aix-Marseille University, France. Electronic address: Claire.GALAMBRUN@ap-hm.fr.
¹⁸ Pediatric Onco-Hematology Department, Strasbourg-Hautepierre Hospital, Strasbourg University, France. Electronic address: catherine.paillard@chru-strasbourg.fr.
¹⁹ Pediatric Hematology Department, Bordeaux-Hospital, Bordeaux University, France. Electronic address: camille.runel@chu-bordeaux.fr.
²⁰ Pediatric Hematology Department, Bordeaux-Hospital, Bordeaux University, France. Electronic address: charlotte.jubert@chu-bordeaux.fr.
²¹ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: cecile.arnaud@chicreteil.fr.
²² Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: annie.kamdem@chicreteil.fr.
²³ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: valentine.brousse@chicreteil.fr.
²⁴ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: florence.missud@aphp.fr.
²⁵ Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: eleonore.petras@chu-guadeloupe.fr.
²⁶ Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: lydia-divialle.doumdo@chu-guadeloupe.fr.
²⁷ Onco-Hematology Department, St-Etienne Hospital, St-Etienne University, France. Electronic address: claire.berger@chu-st-etienne.fr.
²⁸ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: francoise.freard@wanadoo.fr.
²⁹ Ethno-Psychiatry Department, Avicenne-Hospital, Paris-13 University, France. Electronic address: olivier.taieb@aphp.fr.
³⁰ Ethno-Psychiatry Department, Avicenne-Hospital, Paris-13 University, France. Electronic address: elise.drain@aphp.fr.
³¹ Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: monique.elmaleh@aphp.fr.
³² Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: Manuela.Vasile@chicreteil.fr.
³³ Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000 Caen, France. Electronic address: khelif@cyceron.Fr.
³⁴ Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000 Caen, France. Electronic address: bernaudin@cyceron.Fr.
³⁵ EFS Ile de France, IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, France. Electronic address: philippe.chadebech@efs.sante.fr.
³⁶ EFS Ile de France, IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, France. Electronic address: france.pirenne@efs.sante.fr.
³⁷ Hematology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: gerard.socie@aphp.fr.
³⁸ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: Francoise.Bernaudin@chicreteil.fr.

PMID: 28821470
DOI: 10.1016/j.cct.2017.08.008

Clinical Trial

Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

Sylvie Chevret et al. Contemp Clin Trials. 2017 Nov.

. 2017 Nov:62:91-104.

doi: 10.1016/j.cct.2017.08.008. Epub 2017 Aug 15.

Authors

Affiliations

¹ Statistical, Methodology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: sylvie.chevret@paris7.jussieu.fr.
² Medical Imaging Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Créteil, France; Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: suzanne.verlhac@chicreteil.fr.
³ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: ducros.miralles@free.fr.
⁴ Pediatric Hematology Department, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: jean-hugues.dalle@aphp.fr.
⁵ Hematology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: regis.peffaultdelatour@aphp.fr.
⁶ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: mariane.demontal@aphp.fr.
⁷ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: malika.benkerrou@aphp.fr.
⁸ Pediatric Hematology Department, Lyon Léon Bérard Center, Lyon, France; Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: corinne.pondarre@chicreteil.fr.
⁹ Pediatric Hematology Department, Marseille-la Timone Hospital, Aix-Marseille University, France. Electronic address: Isabelle.THURET@ap-hm.fr.
¹⁰ Pediatric Department, Referral Center for Sickle Cell Disease, Bicêtre Hospital, Paris-Sud University, France. Electronic address: corinne.guitton@aphp.fr.
¹¹ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Trousseau Hospital, Paris-Diderot University, France. Electronic address: emmanuelle.lesprit@aphp.fr.
¹² Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: maryse.etienne-julan@chu-guadeloupe.fr.
¹³ Pediatric Department, Referral Center for Sickle Cell Disease, Fort de France Hospital, Antilles University, Martinique, France. Electronic address: gisele.elana@chu-fortdefrance.fr.
¹⁴ Pediatric Hematology Department, Rouen-Charles-Nicolle Hospital, Rouen University, France. Electronic address: Jean-Pierre.Vannier@chu-rouen.fr.
¹⁵ Pediatric Onco-Hematology Department, Strasbourg-Hautepierre Hospital, Strasbourg University, France. Electronic address: Patrick.Lutz@chru-strasbourg.fr.
¹⁶ Pediatric Immuno-Hematology Department, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: Benedicte.neven@aphp.fr.
¹⁷ Pediatric Hematology Department, Marseille-la Timone Hospital, Aix-Marseille University, France. Electronic address: Claire.GALAMBRUN@ap-hm.fr.
¹⁸ Pediatric Onco-Hematology Department, Strasbourg-Hautepierre Hospital, Strasbourg University, France. Electronic address: catherine.paillard@chru-strasbourg.fr.
¹⁹ Pediatric Hematology Department, Bordeaux-Hospital, Bordeaux University, France. Electronic address: camille.runel@chu-bordeaux.fr.
²⁰ Pediatric Hematology Department, Bordeaux-Hospital, Bordeaux University, France. Electronic address: charlotte.jubert@chu-bordeaux.fr.
²¹ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: cecile.arnaud@chicreteil.fr.
²² Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: annie.kamdem@chicreteil.fr.
²³ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Necker Hospital, Paris-Descartes University, France. Electronic address: valentine.brousse@chicreteil.fr.
²⁴ Pediatric Department, Referral Center for Sickle Cell Disease, Paris-Debré Hospital, Paris-Diderot University, France. Electronic address: florence.missud@aphp.fr.
²⁵ Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: eleonore.petras@chu-guadeloupe.fr.
²⁶ Referral Center for Sickle Cell Disease, Pointe à Pitre Hospital, Antilles University, Guadeloupe, France. Electronic address: lydia-divialle.doumdo@chu-guadeloupe.fr.
²⁷ Onco-Hematology Department, St-Etienne Hospital, St-Etienne University, France. Electronic address: claire.berger@chu-st-etienne.fr.
²⁸ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: francoise.freard@wanadoo.fr.
²⁹ Ethno-Psychiatry Department, Avicenne-Hospital, Paris-13 University, France. Electronic address: olivier.taieb@aphp.fr.
³⁰ Ethno-Psychiatry Department, Avicenne-Hospital, Paris-13 University, France. Electronic address: elise.drain@aphp.fr.
³¹ Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: monique.elmaleh@aphp.fr.
³² Pediatric Imaging Department, Robert-Debré Hospital, Paris-Diderot University, France. Electronic address: Manuela.Vasile@chicreteil.fr.
³³ Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000 Caen, France. Electronic address: khelif@cyceron.Fr.
³⁴ Normandie Univ, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, 14000 Caen, France. Electronic address: bernaudin@cyceron.Fr.
³⁵ EFS Ile de France, IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, France. Electronic address: philippe.chadebech@efs.sante.fr.
³⁶ EFS Ile de France, IMRB INSERM U955 équipe 2 (Créteil), GR-Ex (Paris) and Paris-Est-Créteil University, France. Electronic address: france.pirenne@efs.sante.fr.
³⁷ Hematology Department, Paris-St-Louis Hospital, Paris-Diderot University, France. Electronic address: gerard.socie@aphp.fr.
³⁸ Pediatric Department, Referral Center for Sickle Cell Disease, Créteil-CHIC Hospital, Paris-Est University, Créteil, France. Electronic address: Francoise.Bernaudin@chicreteil.fr.

PMID: 28821470
DOI: 10.1016/j.cct.2017.08.008

Abstract

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 15years receiving chronic transfusion due to a history of abnormal transcranial Doppler (velocities ≥200cm/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 1year. 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.

Keywords: Cerebral vasculopathy; Chronic transfusion; Genetic randomization; Hematopoietic stem cell transplantation; Sickle cell anemia; Transcranial Doppler.

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Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

Affiliations

Design of the DREPAGREFFE trial: A prospective controlled multicenter study evaluating the benefit of genoidentical hematopoietic stem cell transplantation over chronic transfusion in sickle cell anemia children detected to be at risk of stroke by transcranial Doppler (NCT 01340404)

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