SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID

Abstract

A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T−B−NK+SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T−B−NK+SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…Artemis SCID in particular is associated with poor transplant outcomes. Late effects are seen in 70% of Artemis patients with high rates of growth failure (particularly in those who receive alkylator-based conditioning), severe or recurrent infections, cGVHD/ autoimmunity, need for nutritional support, and death occurring greater than 2 years post-HSCT 30 . Effects uniquely observed in Artemis patients include dental anomalies, growth hormone deficiency, central hypothyroidism, type 1 diabetes mellitus, renal tubulopathy, exocrine pancreatic insufficiency, and pulmonary fibrosis 34 .…”

“…Myeloablative conditioning is expected to result in greater long-lasting toxicity compared to reducedintensity conditioning, and busulfan in particular has been implicated in a number of late adverse effects, including dental anomalies, thyroid dysfunction, growth failure, and delayed puberty [28][29][30][31] . Conversely, many of these longterm complications are rare in SCID patients who do not receive preparative conditioning or post-transplant GVHD prophylaxis 32 .…”

Eliminating SCID row: new approaches to SCID

“…Other confounding variables that may affect success include the presence of recipient NK function (which may mediate graft rejection), infants with engraftment of maternal T cells, or with autologous auto-reactive T cells as in Omenn's syndrome, and SCID-related radiosensitivity (Artemis, DNA PKcs defects); in these cases, standard conditioning can have devastating late effects. 3 To a large STEMWARE: STEM CELL THERAPY FOR CONGENITAL BLOOD DISORDERS extent, the choice of conditioning has related to the choice of HSC source, with conditioning more likely to be used with UCB, variably with adult unrelated donors, less often with haploidentical donors, and almost never with matched sibling donors. The molecular defect causing SCID may also influence the choice of conditioning regimen, if used, with the presence of active NK cells, as in recombinase-deficiency etiologies (T Ϫ /B Ϫ /NK ϩ ) sometimes taken as an indication for conditioning to overcome allograft resistance.…”

Cytoreductive conditioning for severe combined immunodeficiency – help or hindrance?

“…Osteomedullary and thymic niches are occupied by proliferating lymphocyte progenitors, blocked at the pre-B-1 and DN3 stages, respectively. Infusion of haplo-identical T-lymphocyte-depleted donor inoculum without clearing either niche generally leads to graft failure, which is resolved if chemotherapy conditioning is given [15]. Infusion of unmanipulated HLA-matched donor cells has a better outcome, although T-lymphocyte counts remain low and B-lymphocyte engraftment is variable.…”

“…Infusion of unmanipulated HLA-matched donor cells has a better outcome, although T-lymphocyte counts remain low and B-lymphocyte engraftment is variable. However, use of alkylating agents in patients with artemis-deficient SCID, while improving engraftment, results in significant long-term sequalae, including growth deficiency, requirement for nutritional support and dental abnormalities [15].…”