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Ferrata Storti Foundation
Red Cell Biology & its Disorders
Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion
Chantal Lagresle-Peyrou,1,2,3* François Lefrère,4* Elisa Magrin,1,4* Jean-Antoine Ribeil,1,4* Oriana Romano,3,5,6 Leslie Weber,2,3,7 Alessandra Magnani,1,4 Hanem Sadek,1,2,3 Clémence Plantier,1,4 Aurélie Gabrion,1,4 Brigitte Ternaux,1,4 Tristan Félix,3,5 Chloé Couzin,1,4 Aurélie Stanislas,1,4 Jean-Marc Tréluyer,8 Lionel Lamhaut,9,10 Laure Joseph,4 Marianne Delville,2,3,4 Annarita Miccio,3,5# Isabelle André-Schmutz1,2,3# and Marina Cavazzana1,2,3,4#
1Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, France; 2Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, Paris, France: 3Paris Descartes University – Sorbonne Paris Cité, Imagine Institute, France 4Department of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, France; 5Laboratory of Chromatin and Gene Regulation during Development, INSERM UMR1163, Imagine Institute, Paris, France; 6Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 7Paris Diderot University – Sorbonne Paris Cité, France; 8Mère-Enfant Clinical Investigation Center, Groupe Hospitalier Necker Cochin, Assistance Publique-Hôpitaux de Paris, France; 9Intensive Care Unit, Anaesthesia and SAMU de Paris, Necker Hospital, Assistance Publique- Hôpitaux de Paris, France and 10Paris Descartes University – Sorbonne Paris Cité, France.
ABSTRACT
Sickle cell disease is characterized by chronic anemia and vaso-occlu- sive crises, which eventually lead to multi-organ damage and pre- mature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autolo- gous transplantation of lentiviral-corrected hematopoietic stem and pro- genitor cells was shown to be efficacious in one patient. However, alter- ations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients’ stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of hematopoietic stem and progenitor cells into the circulation has been associated with severe adverse events in sickle cell patients. Thus, broad- er application of the gene therapy approach requires the development of alternative mobilization methods. We set up a phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients undergoing red blood cell exchange to decrease the hemoglobin S level to below 30%. The secondary objective was to measure the efficiency of mobilization and isolation of hematopoietic stem and progenitor cells. No adverse events were observed. Large numbers of CD34+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of hematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize hematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing. Clinicaltrials.gov identifier: NCT02212535.
Haematologica 2018 Volume 103(5):778-786
*CLP, FL and EM and JAR contributed equally to this work, in alphabetical order #AM, IAS and MC contributed equally to this work
Correspondence:
isabelle.andre-schmutz@inserm.fr
Received: November 15, 2017. Accepted: February 13, 2018. Pre-published: February 22, 2018.
doi:10.3324/haematol.2017.184788
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/5/778
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