T-B+NK-
SCID-XL (IL2RG)
JAK3 |
Generally reconstitute T cell immunity from any type of donor without any conditioning required. When using donors other than matched siblings, usually fail to regain B cell function, unless conditioning is provided. Increased risk of late HPV infection, which is likely related to abnormal γc / JAK3-dependent signaling in keratinocytes.(41). Gene therapy (GT) is being evaluated in SCID-XL patients.
|
T-B-NK-
ADA |
When a MSD is not available, enzyme replacement therapy (ERT) is a potential option and should be pursued over a mismatched unrelated HSCT.(26) The underlying defect in purine metabolism may lead to increased susceptibility to certain hemotherapeutic agents, which may explain why survival is lower in those patients getting conditioning.(26) Matched related or unrelated donors may not require a conditioning regimen (12). For mismatched related or unrelated donors, most centers have used a conditioning regimen, as rejection is seen more commonly without conditioning in these transplants compared to IL2RG-deficiency patients, despite absence of NK cells.(52) B cell function is often recovered after matched sibling donor transplant, even without conditioning, but is more variable in unconditioned unrelated donors or mismatched related donors.(12) 50% of patients will have cognitive abnormalities following either transplantation or ERT (46, 53). This has not been linked to either the use of conditioning or the degree of myeloid engraftment. For patients without a MSD, GT has a lower risk of immediate complications, but it is not widely available
|
T-B+NK+
IL7Rα
CD45
CD3 subunits |
Conditioning is not required if a MSD donor is available. Limited data exist on the role of conditioning for HLA-matched unrelated donors. For haploidentical transplants, conditioning is not usually necessary, especially if using a maternal graft in the setting of transplacental maternal chimerism. As there is no intrinsic B cell defect, B cell recovery in these patients is not dependent on conditioning and is expected in most cases providing T cell reconstitution is achieved.(14)
|
T-B-NK+
RAG1/2
Artemis
DNA ligase IV
Cernunnos-XLF
DNA-PKcs |
RAG1/2 defects can present with a clinical spectrum dependent on the functionality of the mutations. Complete loss of function results in typical SCID, while hypomorphic mutations can produce a leaky SCID phenotype, with detectable non-maternal circulating T cells that, if autoreactive, result in Omenn Syndrome. In patients with RAG1 or RAG2-SCID, there is no increased sensitivity to alkylating chemotherapy as seen in defects of DNA repair.(42) For donors other than MSDs, there is an increased risk of rejection if no conditioning is used.(7, 13) For donors other than MSD's, there is very poor B cell recovery if conditioning is not used. Hypomorphic mutations typically require conditioning, regardless of donor type.
|
DNA repair defects are reviewed elsewhere.(27) If maternal engraftment is present, a maternal donor is strongly preferred, since T-cell engraftment will generally occur without the need for alkylating chemotherapy. High rate of regimen-related toxicity and late effects when DNA-damaging agents are used.(42, 54) In order to avoid alkylating therapy, it is advisable to proceed with an unconditioned transplant, even with haploidentical or matched unrelated donors. If conditioning is used, attempts to minimize the number of alkylators and the dosing are recommended. B cell recovery is rare if conditioning is not used. Reduced intensity conditioning that includes fludarabine may be used if rejection occurs following unconditioned HSCT.(13)
|
|
|
