Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC

Author:

Cuvelier Geoffrey D. E.1ORCID,Logan Brent R.2,Prockop Susan E.3ORCID,Buckley Rebecca H.4,Kuo Caroline Y.5ORCID,Griffith Linda M.6,Liu Xuerong2,Yip Alison7,Hershfield Michael S.4,Ayoub Paul G.8ORCID,Moore Theodore B.9,Dorsey Morna J.7ORCID,O’Reilly Richard J.10,Kapoor Neena11,Pai Sung-Yun12,Kapadia Malika13,Ebens Christen L.14ORCID,Forbes Satter Lisa R.15ORCID,Burroughs Lauri M.16,Petrovic Aleksandra16,Chellapandian Deepak17,Heimall Jennifer18,Shyr David C.19,Rayes Ahmad20,Bednarski Jeffrey J.21ORCID,Chandra Sharat22ORCID,Chandrakasan Shanmuganathan23,Gillio Alfred P.24,Madden Lisa25,Quigg Troy C.26,Caywood Emi H.27,Dávila Saldaña Blachy J.28ORCID,DeSantes Kenneth29,Eissa Hesham30,Goldman Frederick D.31,Rozmus Jacob32,Shah Ami J.19,Vander Lugt Mark T.33,Thakar Monica S.16,Parrott Roberta E.4,Martinez Caridad34,Leiding Jennifer W.35,Torgerson Troy R.36ORCID,Pulsipher Michael A.37ORCID,Notarangelo Luigi D.38ORCID,Cowan Morton J.7,Dvorak Christopher C.7,Haddad Elie39ORCID,Puck Jennifer M.7ORCID,Kohn Donald B.8ORCID

Affiliation:

1. 1Manitoba Blood and Marrow Transplant Program, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada;

2. 2Division of Biostatistics, Medical College of Wisconsin, Milwaukee, WI;

3. 3Stem Cell Transplant Service, Dana Farber Cancer Institute/Boston Children’s Hospital, Boston, MA;

4. 4Duke University Medical Center, Durham, NC;

5. 5Division of Allergy, Immunology, Rheumatology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA;

6. 6Division of Allergy, Immunology and Transplantation, National Institutes of Allergy, National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD;

7. 7University of California San Francisco Benioff Children’s Hospital, San Francisco, CA;

8. 8Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, CA;

9. 9Department of Pediatric Hematology-Oncology, Mattel Children’s Hospital, University of California, Los Angeles, CA;

10. 10Stem Cell Transplantation and Cellular Therapy, MSK Kids, Memorial Sloan-Kettering Cancer Center, New York, NY;

11. 11Division of Hematology, Oncology and Blood and Marrow Transplant, Children’s Hospital, Los Angeles, CA;

12. 12Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD;

13. 13Boston Children’s Hospital, Dana-Farber Cancer Institute, Boston, MA;

14. 14Division of Pediatric Blood and Marrow Transplant and Cellular Therapy, MHealth Fairview Masonic Children’s Hospital, Minneapolis, MN;

15. 15Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX;

16. 16Fred Hutchinson Cancer Research Center, University of Washington, Department of Pediatrics and Seattle Children’s Hospital, Seattle, WA;

17. 17Center for Cell and Gene Therapy for Non-Malignant Conditions, Johns Hopkins All Children’s Hospital, St Petersburg, FL;

18. 18Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA;

19. 19Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Lucile Packard Children’s Hospital, Stanford School of Medicine, Palo Alto, CA;

20. 20Primary Children’s Hospital, University of Utah, Salt Lake City, UT;

21. 21Washington University, St. Louis Children’s Hospital, St. Louis, MO;

22. 22Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH;

23. 23Bone Marrow Transplantation and Immune Deficiency, Children’s Hospital of Atlanta, Atlanta, GA;

24. 24Children’s Cancer Institute, Hackensack University Medical Center, Hackensack, NJ;

25. 25Methodist Children’s Hospital of South Texas, San Antonio, TX;

26. 26Pediatric Blood and Marrow Transplant and Cellular Therapy Program, Helen DeVos Children’s Hospital, Michigan State University College of Human Medicine, Grand Rapids, MI;

27. 27Nemours Children’s Health, Thomas Jefferson University, Wilmington, DE;

28. 28Division of Blood and Marrow Transplantation, Children’s National Hospital, Washington, DC;

29. 29Division of Pediatric Hematology-Oncology & Bone Marrow Transplant, University of Wisconsin, American Family Children’s Hospital, Madison, WI;

30. 30Division of Pediatric Hematology-Oncology-BMT, Aurora, CO;

31. 31Division of Pediatric Hematology and Oncology and Bone Marrow Transplant, University of Alabama at Birmingham, Birmingham, AL;

32. 32British Columbia Children’s Hospital, Vancouver, BC, Canada;

33. 33Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI;

34. 34Hematology/Oncology/BMT, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX;

35. 35Division of Allergy and Immunology, Johns Hopkins University, St Petersburg, FL;

36. 36Allen Institute for Immunology, Seattle, WA;

37. 37Division of Pediatric Hematology and Oncology, Intermountain Primary Children’s Hospital, Huntsman Cancer Institute at the University of Utah Spencer Fox Eccles School of Medicine, Salt Lake City, UT;

38. 38Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD; and

39. 39Department of Pediatrics, Centre Hospitalier Universitaire (CHU) Sainte-Justine, University of Montreal, Montreal, QC, Canada

Abstract

Abstract Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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