Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

Monica S Thakar; Brent R Logan; Jennifer M Puck; Elizabeth A Dunn; Rebecca H Buckley; Morton J Cowan; Richard J O'Reilly; Neena Kapoor; Lisa Forbes Satter; Sung-Yun Pai; Jennifer Heimall; Sharat Chandra; Christen L Ebens; Deepak Chellapandian; Olatundun Williams; Lauri M Burroughs; Blachy Davila Saldana; Ahmad Rayes; Lisa M Madden; Shanmuganathan Chandrakasan; Jeffrey J Bednarski 2nd; Kenneth B DeSantes; Geoffrey D E Cuvelier; Pierre Teira; Alfred P Gillio; Hesham Eissa; Alan P Knutsen; Frederick D Goldman; Victor M Aquino; Evan B Shereck; Theodore B Moore; Emi H Caywood; Mark T Vander Lugt; Jacob Rozmus; Larisa Broglie; Lolie C Yu; Ami J Shah; Jeffrey R Andolina; Xuerong Liu; Roberta E Parrott; Jasmeen Dara; Susan Prockop; Caridad A Martinez; Malika Kapadia; Soma C Jyonouchi; Kathleen E Sullivan; Jack J Bleesing; Sonali Chaudhury; Aleksandra Petrovic; Michael D Keller; Troy C Quigg; Suhag Parikh; Shalini Shenoy; Christine Seroogy; Tamar Rubin; Hélène Decaluwe; John M Routes; Troy R Torgerson; Jennifer W Leiding; Michael A Pulsipher; Donald B Kohn; Linda M Griffith; Elie Haddad; Christopher C Dvorak; Luigi D Notarangelo

doi:10.1016/S0140-6736(23)00731-6

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium

Lancet. 2023 Jul 8;402(10396):129-140. doi: 10.1016/S0140-6736(23)00731-6. Epub 2023 Jun 20.

Authors

Monica S Thakar¹, Brent R Logan², Jennifer M Puck³, Elizabeth A Dunn⁴, Rebecca H Buckley⁵, Morton J Cowan³, Richard J O'Reilly⁶, Neena Kapoor⁷, Lisa Forbes Satter⁸, Sung-Yun Pai⁹, Jennifer Heimall¹⁰, Sharat Chandra¹¹, Christen L Ebens¹², Deepak Chellapandian¹³, Olatundun Williams¹⁴, Lauri M Burroughs¹⁵, Blachy Davila Saldana¹⁶, Ahmad Rayes¹⁷, Lisa M Madden¹⁸, Shanmuganathan Chandrakasan¹⁹, Jeffrey J Bednarski 2nd²⁰, Kenneth B DeSantes²¹, Geoffrey D E Cuvelier²², Pierre Teira²³, Alfred P Gillio²⁴, Hesham Eissa²⁵, Alan P Knutsen²⁶, Frederick D Goldman²⁷, Victor M Aquino²⁸, Evan B Shereck²⁹, Theodore B Moore³⁰, Emi H Caywood³¹, Mark T Vander Lugt³², Jacob Rozmus³³, Larisa Broglie³⁴, Lolie C Yu³⁵, Ami J Shah³⁶, Jeffrey R Andolina³⁷, Xuerong Liu³⁸, Roberta E Parrott⁵, Jasmeen Dara³, Susan Prockop³⁹, Caridad A Martinez⁸, Malika Kapadia³⁹, Soma C Jyonouchi¹⁰, Kathleen E Sullivan¹⁰, Jack J Bleesing¹¹, Sonali Chaudhury⁴⁰, Aleksandra Petrovic¹⁵, Michael D Keller⁴¹, Troy C Quigg⁴², Suhag Parikh¹⁹, Shalini Shenoy²⁰, Christine Seroogy⁴³, Tamar Rubin⁴⁴, Hélène Decaluwe²³, John M Routes⁴⁵, Troy R Torgerson⁴⁶, Jennifer W Leiding⁴⁷, Michael A Pulsipher¹⁷, Donald B Kohn³⁰, Linda M Griffith⁴⁸, Elie Haddad²³, Christopher C Dvorak³, Luigi D Notarangelo⁴⁹

Affiliations

¹ Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA. Electronic address: msthakar@fredhutch.org.
² Division of Biostatistics, Medical College of Wisconsin, WI, USA; Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.
³ Division of Pediatric Allergy, Immunology, and Blood and Marrow Transplantation, University of California San Francisco, CA, USA; UCSF Benioff Children's Hospital, San Francisco, CA, USA.
⁴ Division of Pediatric Allergy, Immunology, and Blood and Marrow Transplantation, University of California San Francisco, CA, USA.
⁵ Department of Allergy and Immunology, Department of Pediatrics and Immunology, Duke University Medical Center, Durham, NC, USA.
⁶ Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Transplant and Cell Therapy Program and Laboratory, Department of Pediatrics, Keck School of Medicine, University of Southern California, CA, USA; Hematology, Oncology and TCT, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁸ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Immunology Allergy and Retrovirology, Center for Human Immunobiology, Texas Children's Hospital Infusion Center, Houston, TX, USA.
⁹ Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute (NCI)/NIH, Bethesda, MD, USA.
¹⁰ Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, PA, USA; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
¹² Department of Pediatrics, Division of Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.
¹³ Pediatric Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for Cell and Gene Therapy for Nonmalignant Conditions, Johns Hopkins All Children's Hospital, St Petersburg, FL, USA.
¹⁴ Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA; Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, New York-Presbyterian Morgan Stanley Children's Hospital, New York, NY, USA.
¹⁵ Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁶ Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington DC, USA; Division of Blood and Marrow Transplantation and Center for Cancer and Immunology Research, Children's National Hospital, Washington DC, USA.
¹⁷ Pediatric Immunology and Blood and Marrow Transplant Program, University of Utah, Salt Lake City, UT, USA; Intermountain Primary Children's Hospital, Salt Lake City, UT, USA.
¹⁸ Pediatric Bone Marrow Transplant Program, Texas Transplant Institute, San Antonio, TX, USA.
¹⁹ Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA; Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA.
²⁰ Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
²¹ Department of Pediatrics, University of Wisconsin, Madison, WI, USA.
²² University of Manitoba, Winnipeg, MB, Canada; Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, Winnipeg, MB, Canada.
²³ Department of Pediatrics and Department of Microbiology, Immunology and Infectious Diseases, University of Montreal, Montreal, QC, Canada; Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.
²⁴ Pediatric Stem Cell and Cellular Therapy Division, Joseph M Sanzari Children's Hospital at HMH Hackensack University Medical Center, Hackensack, NJ, USA.
²⁵ Department of Pediatrics, University of Colorado, Aurora, CO, USA; Bone Marrow Transplant and Cellular Therapeutics, Children's Hospital of Colorado, Aurora, CO, USA.
²⁶ Pediatric Allergy and Immunology, St Louis University, St Louis, MO, USA; Jeffrey Modell Diagnostic & Research Center for Primary Immunodeficiencies, Cardinal Glennon Children's Hospital, St Louis, MO, USA.
²⁷ Division of Hematology/Oncology/BMT, Department of Pediatrics, University of Alabama, Birmingham, AL, USA.
²⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁹ Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA.
³⁰ Pediatric Blood and Marrow Transplant Program, Division of Pediatric Hematology/Oncology in the Department of Pediatrics, University of California Los Angeles, Los Angeles, CA, USA.
³¹ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA; Nemours Children's Health, Delaware, Wilmington, DE, USA.
³² Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
³³ Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada; British Columbia Children's Hospital, Vancouver, BC, Canada.
³⁴ Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
³⁵ Louisiana State University Health New Orleans School of Medicine, New Orleans, LA, USA; Children's Hospital of New Orleans, New Orleans, LA, USA.
³⁶ Division of Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Palo Alto, CA, USA.
³⁷ Department of Pediatrics, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY, USA.
³⁸ Division of Biostatistics, Medical College of Wisconsin, WI, USA.
³⁹ Department of Pediatrics, Harvard University Medical School, Boston, MA, USA; Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
⁴⁰ Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
⁴¹ Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington DC, USA; Division of Blood and Marrow Transplantation and Center for Cancer and Immunology Research, Children's National Hospital, Washington DC, USA; Intermountain Primary Children's Hospital, Salt Lake City, UT, USA.
⁴² Pediatrics, Michigan State University College of Human Medicine, Grand Rapids, MI, USA; Pediatric Blood and Marrow Transplant and Cellular Therapy Program, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
⁴³ Division of Allergy, Immunology, and Rheumatology, University of Wisconsin, Madison, WI, USA.
⁴⁴ Division of Pediatric Allergy and Immunology, University of Manitoba, Winnipeg, MB, Canada.
⁴⁵ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
⁴⁶ Experimental Immunology, Allen Institute for Immunology, Seattle, WA, USA.
⁴⁷ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
⁴⁸ Division of Allergy, Immunology and Transplantation, (NIAID)/NIH, Bethesda, MD, USA.
⁴⁹ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID)/NIH, Bethesda, MD, USA.

Abstract

Background: Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010-18.

Methods: We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982-89, 1990-99, 2000-09, and 2010-18. Categorical variables were compared by χ² test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity.

Findings: For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%-73% for 28 years until 2010-18, when it increased to 87% (95% CI 82·1-90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8-96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5-87·0] and 85·4% [71·8-92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56-3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38-3·24; p=0·001), Black or African-American race (2·33, 1·56-3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43-1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival.

Interpretation: Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID.

Funding: National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Graft vs Host Disease*
Hematopoietic Stem Cell Transplantation* / methods
Humans
Infant, Newborn
Longitudinal Studies
Neonatal Screening
Proportional Hazards Models
Severe Combined Immunodeficiency* / diagnosis
Severe Combined Immunodeficiency* / genetics
Severe Combined Immunodeficiency* / therapy

Abstract

Publication types

MeSH terms

Grants and funding