The study has been approved by ESID.
Proposed by: Tiphaine ARLABOSSE, Sujal GHOSH
Adenosine deaminase is a key enzyme in purine metabolism. Its deficiency causes the accumulation of toxic metabolites (dAXP/dATP), which leads to a T-B-NK- severe combined immunodeficiency (SCID). Patients present with failure to thrive, life-threatening infections and non-immunological manifestations such as neurological deficits, sensorineural hearing loss, skeletal abnormalities, and non-infectious lung disease, among others.
ADA-deficient SCID (ADA-SCID) is one of the most frequent forms of autosomal recessive SCID and is fatal within the first months of life if left untreated. There are three approved therapeutic approaches for ADA-SCID to date: enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT) and gene therapy (GT).
ERT with PEGylated bovine ADA was first used in 1986 and it was reported to maintain higher levels of ADA activity in plasma than those achieved with red blood cell transfusions2,3. This first product (Adagen®, pegademase bovine) was approved by the FDA in 1990 and was replaced by a recombinant product of bovine ADA conjugated to PEG (Revcovi®, elapegdemase-lvlr) 2018. There is consensus that ERT should be administered to all newly diagnosed patients with ADA-SCID as an immediate stabilizing measure and to use it as a “bridge” therapy before undergoing HSCT or GT4. It achieves a rapid metabolic detoxification, an improvement of the clinical state of the patient and, in most cases, immune reconstitution in the short term, although the long-term response seems to be suboptimal5. Recently, GT is recommended over HSCT in case there is no available match family donor6. However, only a few centres perform GT, and waiting time for ADA-SCID GT can be up to 5 years for lentiviral GT. For this waiting time to be safe – immune reconstitution has to be achieved with ERT. If ERT yields insufficient response, urgent HSCT should be prioritized over GT when the latter is unavailable within a short timeframe. The available data on immune reconstitution is sparse, and mainly comes from single-centre retrospective studies7,8,9. Further investigation is needed to determine the role of ERT in the management of ADA-SCID, especially, timing of immune reconstitution, and when to consider ERT treatment failure.
The aim is to carry out a multicentre research project to evaluate the level of immune reconstitution achieved by patients with ADA-SCID on ERT while awaiting a more definitive treatment with HSCT or GT. Because GT is now recommended over HSCT if there is no matched sibling donor, but it is associated with a significantly longer waiting time, precise knowledge about timing of immune reconstitution, and when to consider treatment failure and plan an „urgent“ HSCT is important in the management of patients with ADA-SCID.
