Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.
A patient with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.
Engel
Barbara C
BC
Division of Research Immunology/Bone Marrow Transplantation, General Clinical Research Center, Department of Pathology, Children's Hospital Los Angeles, CA 90027, and Baylor College of Medicine, Houston, TX, USA.
Podsakoff
Greg M
GM
Ireland
Joanna L
JL
Smogorzewska
E Monika
EM
Carbonaro
Denise A
DA
Wilson
Kathy
K
Shah
Ami
A
Kapoor
Neena
N
Sweeney
Mirna
M
Borchert
Mark
M
Crooks
Gay M
GM
Weinberg
Kenneth I
KI
Parkman
Robertson
R
Rosenblatt
Howard M
HM
Wu
Shi-Qi
SQ
Hershfield
Michael S
MS
Candotti
Fabio
F
Kohn
Donald B
DB
D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics; D002675:Child, Preschool; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D020732:Cytogenetic Analysis; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D009030:Mosaicism; D010198:Pancytopenia / Q000209:etiology / Q000628:therapy*; D012189:Retrospective Studies; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000628:therapy*; D014314:Trisomy
D000243:Adenosine Deaminase