title: Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT.
abstract: Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.
authors.affiliation: Division of Allergy and Immunology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heimall
authors.affiliation: Department of Pediatrics, Allergy, Immunology, and Blood and Marrow Transplant Division, University of California San Francisco, San Francisco, California.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Puck
authors.affiliation: Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buckley
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: Department of Paediatric Immunology, Newcastle upon Tyne, United Kingdom Institute of Cellular Medicine, Newcastle upon Tyne University, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
authors.affiliation: Department of Immunology, Bone Marrow Transplantation, Hopital Necker Enfants Malades, Paris, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Neven
authors.affiliation: Department of Paediatric Immunology, Newcastle upon Tyne, United Kingdom Institute of Cellular Medicine, Newcastle upon Tyne University, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: Slatter
authors.affiliation: Department of Pediatrics, Department of Microbiology, Infection and Immunology, University of Montreal, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
authors.affiliation: Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: K Scott
authors.initials: KS
authors.lastname: Baker
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Dietz
authors.affiliation: Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts.
authors.forename: Christine
authors.initials: C
authors.lastname: Duncan
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California. Electronic address: mpulsipher@chla.usc.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.affiliation: Department of Pediatrics, Allergy, Immunology, and Blood and Marrow Transplant Division, University of California San Francisco, San Francisco, California.
authors.forename: Mort J
authors.initials: MJ
authors.lastname: Cowan
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes; D002648:Child; D002675:Child, Preschool; D006085:Graft Survival / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D007223:Infant; D012106:Research / Q000639:trends*; D016511:Severe Combined Immunodeficiency / Q000628:therapy*; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D019172:Transplantation Conditioning / Q000379:methods; D055815:Young Adult
keywords: Late effects; Pediatric allogeneic bone marrow transplantation; Severe combined immunodeficiency