Page 80 - Haematologica May 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1240-1247
Red Cell BIology & its Disorders
Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease:
insight into hematopoiesis and engraftment thresholds for gene therapy
Alessandra Magnani,1,2 Corinne Pondarré,3,4 Naïm Bouazza,5 Jeremy Magalon,6
Annarita Miccio,7,8 Emmanuelle Six,8,9 Cecile Roudaut,1 Cécile Arnaud,3 Annie
Kamdem,3 Fabien Touzot,10 Aurélie Gabrion,1 Elisa Magrin,1,2 Chloé Couzin,1
11 8,9 12 13 Mathieu Fusaro, Isabelle André, Jean-Paul Vernant, Eliane Gluckman,
Françoise Bernaudin,3 Dominique Bories14* and Marina Cavazzana1,2,8,9*
1Department of Biotherapy, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; 2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM CIC 1416, Paris, France; 3Centre de référence de drépanocytose, CHIC Centre Hospitalier Intercommunal de Créteil, Créteil, France; 4Inserm U955, Paris XII University, Créteil, France; 5Université Paris Descartes, EA7323, Sorbonne Paris Cité, CIC-1419 Inserm, Cochin-Necker, Paris, France; 6Cell Therapy Unit, Hôpital de la Conception, AP-HM, INSERM CIC BT 1409, Marseille, France; 7Laboratory of Chromatin and gene regulation during development, Imagine Institute, Paris, France; 8Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris; 9Human Lymphohematopoiesis Laboratory, Inserm UMR 1163, Imagine Institute, University Paris Descartes Sorbonne Paris Cité, Paris, France; 10Department of Immunology-Allergy-Rheumatology, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada; 11Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker-Enfants Malades University Hospital, Paris, France; 12Hematology Department, Pitié-Salpêtrière Hospital, Paris, France; 13Monacord Hôpital Saint Louis Paris, Centre Scientifique de Monaco, Monaco and Eurocord, Hôpital Saint Louis, Université Paris Diderot, Paris, France and 14Hématologie Moléculaire, Hôpital Henri Mondor, Université Paris Est, Créteil, France
*These authors are co-senior authors
ABSTRACT
Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may pro- vide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lack- ing. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lympho- cytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism <50% had hemolysis (reticulocytosis) and higher HbS than their donor. Four of them had donor chimerism <30%, including a patient with AA donor (hemoglobin >10 g/dL) and three with AS donors (hemoglobin <10 g/dL). However, only one vaso-occlusive crisis occurred with 68.7% HbS. Except in the patients with the lowest chimerism, the donor engraft- ment was lower for T cells than for the other lineages. In a context of mixed chimerism after hematopoietic stem cell transplantation for SCD, myeloid (rather than T cell) engraftment was the key efficacy criterion. Results show that myeloid chimerism as low as 30% was sufficient to prevent a vaso- occlusive crisis in transplants from an AA donor but not constantly from an AS donor. However, the correction of hemolysis requires higher donor chimerism levels (i.e. ≥50%) in both AA and AS recipients. In the future, this group of patients may need a different therapeutic approach.
Correspondence:
ALESSANDRA MAGNANI
alessandra.magnani@aphp.fr
Received: May 24, 2019.
Accepted: September 18, 2019. Pre-published: September 19, 2019.
doi:10.3324/haematol.2019.227561
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