title: Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report.
abstract: 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.
authors.affiliation: 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.
authors.forename: Barbara C
authors.initials: BC
authors.lastname: Engel
authors.forename: Greg M
authors.initials: GM
authors.lastname: Podsakoff
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Ireland
authors.forename: E Monika
authors.initials: EM
authors.lastname: Smogorzewska
authors.forename: Denise A
authors.initials: DA
authors.lastname: Carbonaro
authors.forename: Kathy
authors.initials: K
authors.lastname: Wilson
authors.forename: Ami
authors.initials: A
authors.lastname: Shah
authors.forename: Neena
authors.initials: N
authors.lastname: Kapoor
authors.forename: Mirna
authors.initials: M
authors.lastname: Sweeney
authors.forename: Mark
authors.initials: M
authors.lastname: Borchert
authors.forename: Gay M
authors.initials: GM
authors.lastname: Crooks
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
authors.forename: Robertson
authors.initials: R
authors.lastname: Parkman
authors.forename: Howard M
authors.initials: HM
authors.lastname: Rosenblatt
authors.forename: Shi-Qi
authors.initials: SQ
authors.lastname: Wu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Hershfield
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Donald B
authors.initials: DB
authors.lastname: Kohn
mesh_terms: 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
chemical_list: D000243:Adenosine Deaminase