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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 685-705 |
| Number of pages | 21 |
| Journal | Blood |
| Volume | 140 |
| Issue number | 7 |
| DOIs | |
| State | Published - Aug 18 2022 |
Bibliographical note
Funding Information:The authors thank PIDTC Project Managers Sharon Kidd, Elizabeth Dunn, and Kiana Soriano for their dedicated work to advance the research goals of the consortium; all study coordinators at PIDTC sites for collection of clinical data from medical records; the clinical teams who provided medical care for patients; and all the patients and families who have made this work possible. This work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) (grant U54AI082973, MPI: J.M.P. C.C.D. E.H.; grants U54NS064808 and U01TR001263). The PIDTC is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium is supported by the U54 grants listed, along with support of the PBMTC Operations Center by the St. Baldrick's Foundation and grant U10HL069254. Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant U24CA076518, grant U01HL069294, contracts HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration, and grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research. L.D.N. is supported by the Division of Intramural Research, NIAID, NIH (grant 1 ZIA AI001222-02, PI: L.D.N). S.-Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute, Center for Cancer Research. The content and opinions expressed are solely the responsibility of the authors and do not represent the official policy or position of the NIAID, ORDR, NCATS, NIH, HRSA, or any other agency of the US Government. The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Funding Information:
This work was supported by the Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases (NIAID), the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) (grant U54AI082973, MPI: J.M.P., C.C.D., E.H.; grants U54NS064808 and U01TR001263). The PIDTC is a part of the Rare Diseases Clinical Research Network of ORDR, NCATS. The collaborative work of the PIDTC with the Pediatric Transplantation and Cellular Therapy Consortium is supported by the U54 grants listed, along with support of the PBMTC Operations Center by the St. Baldrick's Foundation and grant U10HL069254. Collaborative work of the PIDTC with the Center for International Blood and Marrow Transplant Research is supported by grant U24CA076518, grant U01HL069294, contracts HHSH250201200016C and HHSH234200637015C with the Health Resources and Services Administration, and grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research. L.D.N. is supported by the Division of Intramural Research, NIAID, NIH (grant 1 ZIA AI001222-02, PI: L.D.N). S.-Y.P. is supported by funding from the Intramural Research Program, NIH, National Cancer Institute, Center for Cancer Research.
Funding Information:
Conflict-of-interest disclosure: G.D.E.C. has received consultancy fees from Miltenyi Biotech. D.B.K. is an inventor for the UC Regents on a lentiviral vector for gene therapy of ADA SCID and is a member of the DSMB for Revcovi PEG-ADA (Chiesi, USA). S.E.P. has received clinical trial support from Atara Biotherapeutics, Jasper Pharmaceuticals, and AlloVir; is an inventor of IP licensed to Atara Biotherapeutics by Memorial Sloan-Kettering (all rights assigned to MSK); and has been part of advisory boards for ADMA and Neovii. J.M.P. has received royalties from Up-To-Date, and her spouse is employed by and owns stock in Invitae (a DNA sequencing company). E.H. has received consultancy fees from Chiesi, USA (producers of Revcovi PEG-ADA), has received adboard meeting fees for CSL-Behring and Takeda and DSMB fees for Jasper Therapeutics and Rocket Pharmaceutical, and is involved in Immugenia, a biotech company. M.J.D. has received institutional research support from Chiesi, USA. C.C.D. is a member of the DSMB for Revcovi PEG-ADA (Chiesi, USA) and has received consultancy fees from Orchard Therapeutics. J.J.B. has served on the advisory board for Sobi and Horizon Therapeutics. M.S.H has received grant support for his laboratory from Chiesi, USA (producers of Revcovi PEG-ADA) and Orchard Therapeutics. M.A.P. has served on the advisory boards of Novartis, Medexus, Equillium, and Mesoblast; has received clinical study support from Adaptive and Miltenyi Biotech; and has received financial support for educational lectures for Miltenyi Biotech and Novartis. M.S.T. has been a consultant for the Infectious Disease Research Institute (nonprofit). L.R.F.S. has received consultancy fees from Enzyvant, CSL Behring, Takeda, ADMA, and Grifols. B.J.D.S. has received consultancy fees from Sobi and Orchard. J.H. has received clinical trial support from Regeneron, an investigator-initiated grant, and participated on an advisory board for CSL Behring; has received royalties from Up-To-Date; and has participated on an advisory board for ADMA Biologics. J.W.L. has been a speaker and consultant for Horizon Therapeutics, speaker for Sobi, consultant for ADMA Biologics, and is an employee and shareholder of Bluebird Bio. A.P. has participated in advisory boards for Orchard, Horizon, and Enzyvant and serves on the DSMB for ExCellThera. L.M.B. has received clinical trial support through the Fred Hutchinson Cancer Research Center by Medac GmbH (including supply of treosulfan), is a member of the DSMB for a clinical trial with Jasper Therapeutics, and has served on an advisory board for Horizon Therapeutics USA. E.H.C. has received royalties for participation in advisory boards from Pfizer. M.J.C. has received royalties from Up-To-Date, is on the Scientific Review Board of Homology Medicines with equity interest, and is on the DSMB for clinical trials with Bluebird Bio, Rocket Pharmaceuticals, and Chiesi, USA. The remaining authors declare no competing financial interests.
Publisher Copyright:
© 2022 American Society of Hematology
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