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

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.

Review of Treatment for Adenosine Deaminase Deficiency (ADA) Severe Combined Immunodeficiency (SCID)

“…Trials with lentiviral vectors report no mutagenesis to date with follow-up at 4–5 years post treatment. 25 , 45 …”

“…1 , 10 , 11 , 23 An update to the 2012 publication was published in 2022 and reported that for ADA SCID patients treated by HSCT or gene therapy after 2000 who had no active infection at the time of treatment there was no difference in five-year event-free survival or overall survival regardless of ERT use or pretreatment regimen. 25 …”

Correcting inborn errors of immunity: From viral mediated gene addition to gene editing

“…These excellent results prompt a reconsideration of the hierarchy of treatment options, which needs to be supported by long-term studies comparing HSCT and GT outcomes. A recent report comparing HSCT and viral mediated gene addition outcomes, preceded or not by ERT, in 131 ADA-SCID patients [160] showed higher five-year overall and event-free survival rates in patients receiving ERT-GT (100%, 75.3%) than ERT-HSCT (79.6%, 73%) and HSCT (72.5%, 49.5%). Excellent and comparable survival rates were found between viral mediated gene addition and patients treated by MSD-HSCT and without infection.…”

“…Excellent and comparable survival rates were found between viral mediated gene addition and patients treated by MSD-HSCT and without infection. Moreover, alternative donor HSCT (particularly HLA-matched unrelated donor and cord blood) for young infants without infection should be considered an alternative when MSD/MFD HSCT and viral mediated gene addition are not available [160] .…”

National experience with adenosine deaminase deficiency related SCID in Polish children

“…Based on data on HSCT performed between 1981 and 2009 in 16 centers worldwide, an overall survival rate (OS) in ADA-SCID depends on type of HSCT, being 86% for MSD, 81% for MFD, 66% for MUD and 43 for Haplo(13). Recent studies on large groups of patients: 131 ADA-SCID diagnosed in 1982-2017(14) and 152 patients with SCID, including 43 ADA-SCID treated in 2006-2014(15), showed higher OS in patients transplanted from MSD/MFD under 3.5 months of age and without active infections. According to the European Society for Immunodeficiencies (ESID), the European Society for Blood and Marrow Transplantation (EBMT), and European Reference Network on Rare Primary Immunodeficiency Autoinflammatory Autoimmune diseases (RITA), gene therapy should be considered in absence of a matched family donor (…”