How I treat ADA deficiency

Abstract

Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably. Unlike other SCID forms, 2 other options are available for ADA-SCID: enzyme replacement therapy (ERT) with pegylated bovine ADA, and autologous haematopoietic stem cell gene therapy (GT). Due to the rarity of the condition, the lack of large scale outcome studies, and availability of different treatments, guidance on treatment strategies is limited. We have reviewed the currently available evidence and together with our experience of managing this condition propose a consensus management strategy. Matched sibling donor transplants represent a successful treatment option with high survival rates and excellent immune recovery. Mismatched parental donor transplants have a poor survival outcome and should be avoided unless other treatments are unavailable. ERT and GT both show excellent survival, and therefore the choice between ERT, MUD transplant, or GT is difficult and dependent on several factors, including accessibility to the different modalities, response of patients to long-term ERT, and the attitudes of physicians and parents to the short- and potential long-term risks associated with different treatments.

Figure 1

Survival of patients receiving HSCT for ADA-SCID (preliminary results from an international multicenter retrospective study).

Figure 2

Fate of patients who received ERT between April 1986 and September 2008.

Figure 3

Estimated probability of survival while receiving ERT. Patients who discontinued ERT to undergo stem cell transplantation or GT were censored at the time ERT was stopped, except for 5 patients who developed refractory hemolytic anemia and subsequently died after attempted stem cell transplantation. In these latter 5 cases, death was attributed to ERT at the time PEG-ADA was discontinued.

Figure 4

Flow chart for treatment of patients with ADA-SCID.