Table 6.
Overview of HSCT in individual PID.
| Indication | Main PID features | Evidence summary | Level of evidence based on published patients (<10; 10–100; >100) |
|---|---|---|---|
| X-linked SCID and JAK3 deficiency; IL7R deficiency |
Impaired γc signaling resulting in SCID T– B+ NK–; Impaired IL7R signaling resulting in SCID T- B+ NK+ |
HSCT required for survival. Conditioning is not required to attain T cell reconstitution. However, in the absence of conditioning, functional B and NK cell reconstitution is typically not achieved in X-linked SCID and JAK3 deficiency. In IL7R deficiency B and NK cells are functional, thus no or low-dose conditioning is indicated | >100 (X-linked SCID and JAK3 deficiency); 10–100 (IL7R deficiency) |
| RAG deficiency | Impaired VDJ recombination, leading to defective T and B cell development. Clinical presentation: autosomal recessive T- B- NK+ SCID, Omenn syndrome, atypical SCID, combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) | Patients with SCID and Omenn: HSCT required for survival. Use of RIC was associated with better T and B cell reconstitution. Patients with CID-G/A: HSCT + conditioning should be considered early in the course of the disease | >100 (SCID, Omenn and leaky SCID); 10–100 (CID-G/AI) |
| Adenosine deaminase (ADA) deficiency | Metabolic disease that may affect different tissues and organs; decreased cell survival | HSCT is curative. Gene therapy is an alternative option. ERT can be used as bridge to HSCT or gene therapy. Survival is superior after unconditioned HSCT than after MAC or RIC | 10–100 |
| Reticular Dysgenesis | T- B- NK- SCID, agranulocytosis, and sensorineural deafness due to mutations in AK2 gene | HSCT required for survival. Myeloablative components in the conditioning regimens required to achieve high-level donor myeloid engraftment and avoid post-transplant neutropenia | 10–100 |
| DNA double-strand break repair disorders | Heightened sensitivity to ionizing radiation due to defects in components of the non-homologous end joining (NHEJ) DNA repair mechanism | Associated immunodeficiency can be resolved by HSCT. Increased short- and long-term sensitivity to the alkylator-based conditioning regimens. Better survival with RIC than MAC | 10–100 |
| MHC class II (MHC-II) deficiency | Lack of MHC-II expression is associated with low CD4+ cell count, impaired antibody production, defective T cell priming | Without successful HSCT, most patients succumb in the first decade of life. Indication to HSCT depends on clinical status of the patient and availability of a matched donor, but survival is lower than in other forms of PID | >100 |
| CD40 ligand and CD40 deficiency | Defective CD40 signaling, leading to impaired immunoglobulin class switch and defective dendritic cell activation and T cell priming | HSCT is curative. Event-free survival: best with MAC and absence of pre-existing organ damage (in particular sclerosing cholangitis) | >100 |
| DOCK8 deficiency | Deficiency in DOCK8 is responsible for abnormal cytoskeletal rearrangement. Patients present with severe eczema, immunodeficiency, autoimmunity, severe allergies and increased risk for malignancy | HSCT curative, best outcome with RIC | 10–100 |
| DOCK2 deficiency | Deficiency in DOCK2 lead to early-onset severe bacterial and viral infections with T cell lymphopenia, reduced naïve T cells, defective antibody responses and impaired NK cell function | HSCT curative, no conclusive data regarding preferred conditioning regimens | <10 |
| Functional T cell immunodeficiencies | Defective pre-TCR and TCR signaling | HSCT is required for survival in patients with CD3δ, CD3ε, or CD3ζ defects. CD3γ deficiency may only require HSCT in most severe cases. There is limited experience in other TCR signaling defects. Overall, conditioning is beneficial to achieve immune reconstitution, but its intensity must be tailored to minimize risks of organ toxicity | 10–100 |
| Wiskott-Aldrich Syndrome and other immunodeficiencies with thrombocytopenia (WIP, ARPC1B) | WAS: X-linked disorder with immunodeficiency, eczema and thrombocytopenia. WIP: autosomal recessive immunodeficiency with mutations in the WIPF1 gene. Patients display a WAS-like phenotype. ARPC1B: autosomal recessive CID with immune dysregulation and platelet abnormalities | HSCT curative. Low myeloid engraftment is associated with increased risk of persistent thrombocytopenia. High intensity conditioning regimens result in reliable donor chimerism | >100 (WAS); <10 (WIP); <10 (ARPC1B) |
| Cartilage hair hypoplasia (CHH) | Caused by mutations of the RMRP gene involved in ribosomal RNA processing, mitochondrial DNA replication and control of gene transcription. Syndromic combined immunodeficiency, with short stature, sparse hair, and increased risk of autoimmunity, Hirschsprung disease, bone marrow failure and malignancies | HSCT can cure the immune deficiency and help prevent infections, bone marrow failure and malignancy. However, growth, cutaneous and intestinal manifestations of the disease are not cured | 10–100 |
| AD hyper-IgE syndrome due to dominant negative STAT3 mutations (Job's syndrome) | Mutation in the STAT3 gene. The disease is characterized by hyper-IgE, increased occurrence of bacterial and Aspergillus infections, mucocutaneous candidiasis, somatic features (distinctive facies, scoliosis, coronary and cerebral aneurysms) and deficiency of Th17 and T follicular helper cells | There is inconclusive evidence that HSCT is beneficial, although clinical and immunological improvement has been reported in several cases. However, the impact of transplantation on other features (aneurysms, bone anomalies and possibly intrinsic lung abnormalities) is not clear | 10–100 |
| Phosphoglucomutase 3 (PGM3) deficiency | Glycosylation defect presenting with variable immunodeficiency, skeletal dysplasia, neurodevelopmental delay, tendency to bone marrow failure and organ (kidney, intestine, heart) defects | HSCT may be curative, but limited experience. Other manifestations of the disease: unlikely to be resolved by HSCT. Intermediate intensity conditioning recommended | <10 |
| Chronic granulomatous disease (CGD) | Mutations that affect the functionality of the nicotinamide adenine dinucleotide phosphate (NADPH) complex, with defective production of microbicidal reactive oxygen species. The most common form is X-linked | HSCT curative. Adequate level of donor myeloid chimerism is fundamental to successfully correct the clinical phenotype. To limit toxicity, alkylator-based RIC are used | >100 |
| Immuno-dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX syndrome) | Mutations in the FOXP3 gene, a master transcriptional regulator for development of CD4 regulatory T-cells. Patients experience severe, multi-organ autoimmune phenomena including enteropathy, chronic dermatitis, endocrinopathy, hepatitis, nephritis and cytopenia | Patients do not survive long-term without HSCT, HSCT curative. Important to transplant before organ damage develops. Medium-high RIC regimen may suffice to correct the disease, unclear whether serotherapy is needed | 10–100 |
| Activated PI3kinase delta syndrome (APDS) | GOF mutations of PIK3CD or LOF mutations of the PIK3R1 gene, encoding the regulatory subunit p85a. Patients manifest defects in T-cell function with deficiency of naive T cells and an excess of senescent effector T cells, defects in B-cell function with increased IgM, reduced IgG2, and impaired vaccine responses, recurrent sinopulmonary infections, lymphoproliferation | HSCT can be curative. Serotherapy may help prevent graft failure/rejection. Medium/high RIC regimens are associated with improved chimerism and immune function | 10 - 100 |
| STAT1 GOF | STAT-1 GOF mutations impair STAT1 dephosphorylation or result in increased STAT1 phosphorylation. Patients experience chronic mucocutaneous candidiasis, severe viral infections, bacterial and mycobacterial infections, and autoimmunity | There is need to improve approach to HSCT for this disease. A sub-myeloablative regimen may be needed. The role of serotherapy has to be evaluated | 10–100 |
| STAT3 GOF | Mutations confer GOF in STAT3 leading to secondary defects in STAT5 and STAT1 phosphorylation and the regulatory T-cell compartment. Patients experience infections, lymphoproliferation and autoimmunity | There is very limited experience with HSCT for this disease. HSCT can be curative, and RIC with serotherapy may suffice | <10 |
| CTLA-4 deficiency | Heterozygous mutations in CTLA4 leading to haploinsufficiency and impaired CTLA4 dimerization or impaired ligand binding, result in an autosomal dominant immune dysregulation syndrome with immunodeficiency | There is very limited experience with HSCT for this disease. HSCT can be curative, and RIC with serotherapy may suffice | <10 |
| LRBA deficiency | Immune dysregulation syndrome due to mutations in LPS-responsive, beige-like anchor (LRBA), resulting in hypogammaglobulinemia with B-cell deficiency, functional T-cell defects, aberrant autophagy, autoimmunity and chronic diarrhea | There is very limited experience with HSCT for this disease. HSCT can be curative | <10 |
| X-linked lymphoproliferative disease (XLP) 1 and 2 | XLP1 (due to mutations of the SH2D1A gene) affects cytotoxic T and NK cell function. Affected males are at high risk for fulminant infectious mononucleosis, HLH, EBV-driven lymphoma, bone marrow aplasia, and hypogammaglobulinemia. XLP2 (with mutations of XIAP) is characterized by increased incidence of HLH and inflammatory disease (especially of the gut), but not of EBV-related lymphoma | HSCT can be curative. RIC is preferable to MAC. There is a need to improve outcome for patients with XLP2, and these patients may continue to experience inflammatory intestinal disease even after successful transplant | >100 (XLP1); 10–100 (XLP2) |
PID, primary immunodeficiency; HSCT, hematopoietic stem cell transplantation; SCID, severe combined immunodeficiency; CID, combined immunodeficiency; JAK3, Janus kinase 3; IL7R, interleukin-7 receptor; RAG, recombination activating gene; CD40, cluster of differentiation 40; DOCK8, dedicator of cytokinesis 8; DOCK2, dedicator of cytokinesis 2; WAS, Wiskott-Aldrich syndrome; WIP, WASP interacting protein; ARPC1B, actin related protein 2/3 complex subunit 1B; AD, autosomal dominant; STAT3, signal transducer and activator of transcription 3; GOF, gain of function; STAT1, signal transducer and activator of transcription 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; LRBA, lipopolysaccharide (LPS)-responsive and beige-like anchor protein; AK2, adenylate kinase 2; TCR, T-cell receptor; RMRP, RNA component of mitochondrial RNA processing endoribonuclease; FOXP3, Forkhead box P3; LOF, loss of function; PIK3CD, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; STAT5, signal transducer and activator of transcription 5; SH2D1A, SH2 domain containing 1A; HLH, hemophagocytic lymphohistiocytosis; EBV, Epstein-Barr virus; RIC, reduced intensity conditioning; ERT, enzyme replacement therapy; MAC, myeloablative conditioning.