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

Highlights • Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections. • MRD is the best source for HSC, but MMRD, MRD, and UCB have all been successfully used to treat SCID. • Autoimmunity and cGVHD are seen in a minority of patients overall, but ar...

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Published inBiology of blood and marrow transplantation Vol. 23; no. 3; pp. 379 - 387
Main Authors Heimall, Jennifer, Puck, Jennifer, Buckley, Rebecca, Fleisher, Thomas A, Gennery, Andrew R, Neven, Benedicte, Slatter, Mary, Haddad, Elie, Notarangelo, Luigi D, Baker, K. Scott, Dietz, Andrew C, Duncan, Christine, Pulsipher, Michael A, Cowan, Mort J
Format Journal Article Conference Proceeding
LanguageEnglish
Published United States Elsevier Inc 01.03.2017
Subjects
Adolescent
Adult
B-Lymphocytes
Child
Child, Preschool
Graft Survival - immunology
Hematology, Oncology and Palliative Medicine
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cell Transplantation - methods
Humans
Infant
Late effects
Pediatric allogeneic bone marrow transplantation
Research - trends
Severe combined immunodeficiency
Severe Combined Immunodeficiency - therapy
T-Lymphocytes - pathology
Time Factors
Transplantation Conditioning - methods
Young Adult
Severe combined immunodeficiency
Pediatric allogeneic bone marrow transplantation
Late effects
Online AccessGet full text

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Abstract Highlights • Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections. • MRD is the best source for HSC, but MMRD, MRD, and UCB have all been successfully used to treat SCID. • Autoimmunity and cGVHD are seen in a minority of patients overall, but are more commonly seen in those with poor long-term outcomes. • Use of pre-HCT conditioning is controversial in SCID, and further studies are needed to determine the best agents and doses to use in young infants, with particular attention to those with radiosensitive SCID who are more susceptible than others to experience poor growth and other adverse effects with use of alkylator-based chemotherapy. • B cell engraftment is associated with higher likelihood of B cell function in most forms of SCID.
AbstractList •Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections.•MRD is the best source for HSC, but MMRD, MRD, and UCB have all been successfully used to treat SCID.•Autoimmunity and cGVHD are seen in a minority of patients overall, but are more commonly seen in those with poor long-term outcomes.•Use of pre-HCT conditioning is controversial in SCID, and further studies are needed to determine the best agents and doses to use in young infants, with particular attention to those with radiosensitive SCID who are more susceptible than others to experience poor growth and other adverse effects with use of alkylator-based chemotherapy.•B cell engraftment is associated with higher likelihood of B cell function in most forms of SCID. 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.
Severe Combined Immunodeficiency (SCID) is one of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency (PID). 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 U.S., the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life, although in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for transplanted SCID patients currently is >70% at 3 years post-transplant, 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 prior to transplant, GVHD prophylaxis, type of conditioning (if any) utilized and underlying genotype of SCID. In at least one study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) post-transplantation. While 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, while 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 non-immunologic 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.
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.
Highlights • Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections. • MRD is the best source for HSC, but MMRD, MRD, and UCB have all been successfully used to treat SCID. • Autoimmunity and cGVHD are seen in a minority of patients overall, but are more commonly seen in those with poor long-term outcomes. • Use of pre-HCT conditioning is controversial in SCID, and further studies are needed to determine the best agents and doses to use in young infants, with particular attention to those with radiosensitive SCID who are more susceptible than others to experience poor growth and other adverse effects with use of alkylator-based chemotherapy. • B cell engraftment is associated with higher likelihood of B cell function in most forms of SCID.
Author Gennery, Andrew R
Baker, K. Scott
Dietz, Andrew C
Pulsipher, Michael A
Neven, Benedicte
Puck, Jennifer
Notarangelo, Luigi D
Buckley, Rebecca
Duncan, Christine
Slatter, Mary
Cowan, Mort J
Fleisher, Thomas A
Haddad, Elie
Heimall, Jennifer
AuthorAffiliation 3 Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC, USA
9 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
5 Department of Paediatric Immunology, Newcastle upon Tyne, United Kingdom Institute of Cellular Medicine, Newcastle upon Tyne University, United Kingdom
6 Department of Immunology, Bone Marrow Transplantation, Hopital Necker Enfants Malades, Paris, France
10 Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles, Los Angeles, California, United States of America
11 Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, United States of America
1 Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2 UCSF Department of Pediatrics, Allergy, Immunology, and Blood and Marrow Transplant Division, San Francisco California, USA
7 Department of Pediatrics, Depar
AuthorAffiliation_xml – name: 8 Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, MD
– name: 9 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/28068510$$D View this record in MEDLINE/PubMed
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Keywords Severe combined immunodeficiency
Pediatric allogeneic bone marrow transplantation
Late effects
Language English
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Copyright © 2017 The American Society for Blood and Marrow Transplantation. All rights reserved.
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Snippet Highlights • Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections. • MRD is the best source for HSC, but...
•Survival after HCT for SCID is >70% and can be higher in those treated prior to the onset of infections.•MRD is the best source for HSC, but MMRD, MRD, and...
Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary...
Severe Combined Immunodeficiency (SCID) is one of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary...
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elsevier
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Publisher
StartPage 379
SubjectTerms Adolescent
Adult
B-Lymphocytes
Child
Child, Preschool
Graft Survival - immunology
Hematology, Oncology and Palliative Medicine
Hematopoietic Stem Cell Transplantation - adverse effects
Hematopoietic Stem Cell Transplantation - methods
Humans
Infant
Late effects
Pediatric allogeneic bone marrow transplantation
Research - trends
Severe combined immunodeficiency
Severe Combined Immunodeficiency - therapy
T-Lymphocytes - pathology
Time Factors
Transplantation Conditioning - methods
Young Adult
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
URI https://www.clinicalkey.es/playcontent/1-s2.0-S1083879116311764
https://dx.doi.org/10.1016/j.bbmt.2016.12.619
https://www.ncbi.nlm.nih.gov/pubmed/28068510
https://www.proquest.com/docview/1857379481/abstract/
https://pubmed.ncbi.nlm.nih.gov/PMC5659271
Volume 23
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