Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Abstract

Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome.

Hematopoietic stem cell transplantation for primary immunodeficiency disease

“…3,5,9 It is unclear, however, whether a true stem cell graft occurs in the recipient marrow when ablative conditioning is not used, as B cells, myeloid cells and erythroid cells generally remain of recipient origin. 3,5,8,22,23 Host myeloid chimerism has been associated with defective sustained thymopoiesis, except for patients with ILgc deficiency. 8 As with ILgc deficiency, in patients with JAK3 deficiency, HSCT without conditioning successfully reconstitutes T-cell immunity, but rarely accomplishes restoration of NK cell function, and does not produce donor B cells.…”

“…3,8,22 Patients with reticular dysgenesis present with the typical features of SCID, such as absent lymphocytes and thymus, but also demonstrate an early arrest of myeloid differentiation. Given the more global nature of the defect, it is not surprising that HSCT without conditioning results in treatment failure, while myeloablative conditioning can be successful.…”

“…14 Many centers have utilized a conditioning regimen during second transplant, especially when changing from a haplocompatible donor to an unrelated donor. 3,5,20,22 Others perform 'booster' transplants without conditioning with reported improvement in immune function. 5,23 While HSCT may correct some or all of the immunologic abnormalities in patients with SCID, it should be noted that nonimmunologic abnormalities, such as dwarfism and hypoplastic hair in cartilage-hair hypoplasia or neurologic abnormalities in ADA deficiency, 22 may persist.…”

“…20 Successful achievement of donor B-cell chimerism is usually associated with normal B-cell function, while recipient B cells only receive enough support from donor T cells for normal function in a fraction of cases, and none with ILgc deficiency. 9,22,24 In cases of inadequate B-cell reconstitution, prolonged administration of intravenous immunoglobulin is required to prevent infections. 5 Possible explanations for selective T-cell donor chimerism following unconditioned HSCT include: (1) engraftment of marrow stem cells does occur, but only selective T-lymphocyte lineage differentiation takes place; (2) early self-renewing progenitor cells seed the thymus 8 or (3) mature donor T cells expand to fill a homeostatic niche.…”

Outcome of hematopoietic stem cell transplantation for adenosine deaminase–deficient severe combined immunodeficiency

“…18 A series of 15 patients with ADA-SCID showed overall survival (OS) of 80%, but there were only 6 transplantations from mismatched family donors and 2 transplantations from unrelated donors in this series. 19 The paucity of formal outcome data has limited the ability to make informed choices about transplantation. There has also been a perception among transplantation physicians that patients with ADA are more difficult to transplant, especially from unrelated and haploidentical donors.…”