INTRODUCTION — An extreme form of severe combined immunodeficiency disease (SCID) is the T cell-negative (T-), B cell-negative (B-), natural killer cell-positive (NK+) SCID phenotype, which accounts for approximately one-quarter of all cases of SCID [1]. Children with T-B-NK+ SCID present early in life with serious infections, failure to thrive, low-to-absent T and B cell numbers and function, and normal numbers and function of NK cells. Typical SCID, by definition, leads to early death from overwhelming infection in the first year or two of life in the absence of definitive treatment.
Autosomal-recessive defects in several genes, all involved in V(D)J recombination that randomly combines variable, diverse, and joining gene segments in lymphocytes, result in this form of SCID. Some of the proteins encoded by these genes are also involved in DNA repair. Defects in all ubiquitously expressed DNA repair genes are associated with radiation/alkylating agent chemotherapy sensitivity, and some of them are associated with growth and developmental abnormalities.
The management of T-B-NK+ SCID is reviewed here. The primary treatment is hematopoietic cell transplantation (HCT). The pathogenesis, genetic defects, clinical manifestations including radiation sensitivity, and diagnosis are discussed in detail separately. An overview of SCID and the different forms of SCID are also presented separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis".)
MANAGEMENT PRIOR TO DIAGNOSIS AND TRANSPLANTATION — Infants suspected of immunodeficiency require special care and treatment before definitive diagnosis is made and correction is performed. This includes protective isolation, avoidance of live vaccines, and prophylaxis against infection (antimicrobials and immune globulin replacement therapy). For those patients suspected of radiation-sensitive SCID (RS-SCID), avoidance of exposure to unnecessary radiation is also important. These measures are discussed in greater detail separately. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
APPROACH TO DEFINITIVE THERAPY — Typical SCID is universally fatal in infancy without definitive treatment. These patients require definitive therapy to have a chance at survival. Hematopoietic cell transplantation (HCT) is the only confirmed curative therapy for children with T-B-NK+ SCID (table 1), but outcomes depend upon the donor type available and the conditioning used [2-5]. Gene therapy (GT) for T-B-NK+ SCID remains experimental and in the early stages of clinical investigation. We recommend HCT with a human leukocyte antigen (HLA) matched related donor, if available, for infants with T-B-NK+ SCID. For patients without an HLA-matched related donor, we suggest HCT with an alternative donor, preferably a matched unrelated donor or, if one is not available, a haploidentical related donor or an unrelated cord blood donor. Patients without a matched related donor who have Artemis-deficient SCID (ART-SCID) are eligible for GT as part of a clinical trial. (See 'Hematopoietic cell transplantation' below and 'Gene therapy' below.)
HEMATOPOIETIC CELL TRANSPLANTATION
Outcomes — As with all SCID hematopoietic cell transplantation (HCT) recipients, the outcome for T-B-NK+ SCID is best in those who have a human leukocyte antigen (HLA) matched related donor, usually a sibling [6-8]. T and B cell immune reconstitution appears better in patients with T-B-NK+ SCID who do not have radiation sensitivity (ie, recombinase-activating gene SCID [RAG-SCID]) and who receive myeloablative or reduced-intensity conditioning. However, outcomes are not as good in patients with radiation-sensitive SCID (RS-SCID), who have a higher rate of infections, poorer survival, and more long-term complications when treated with alkylating therapy and/or ionizing radiation than those with T-B-NK+ SCID without radiation sensitivity [9]. In fact, it appears that patients with certain genotypes of RS-SCID (eg, ligase IV deficiency) do more poorly if treated with myeloablative and reduced-intensity conditioning [9]. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies" and "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Radiation-sensitive SCID due to DNA repair defects'.)
HLA-matched related donor — In a multicenter, retrospective study of 145 children with either Artemis or RAG 1 and 2-deficient T-B-NK+ SCID, 88 percent of the 63 recipients of an HLA-matched related donor transplant without conditioning were long-term survivors (median follow-up 51 months for Artemis and 32 months for RAG defects) [7]. Similar results were seen in an earlier study of 16 patients with Artemis-deficient SCID (ART-SCID), who had an overall 75 percent long-term survival (median follow-up seven years) [6]. Patients were generally transplanted at an early age (mean 2.3 months) and had a relatively short interval between diagnosis and HCT (mean of 1.5 months). As an example, 7 of the 16 infants were diagnosed either in utero or at birth (because of a positive family history) with early transplantation prior to the onset of serious infections. The use of nonmyeloablative conditioning regimens in 14 of 16 initial transplants also likely contributed to the absence of mortality in the immediate posttransplant period and subsequent long-term survival, although the patients who received alkylating therapy as conditioning had increased late effects and poorer survival beyond two years compared with patients with non-RS-SCID [7]. (See 'Conditioning regimens' below.)
HLA-matched unrelated donors — Matched unrelated donors with varying conditioning regimens have been used to treat T-B-NK+ SCID. Anecdotal evidence suggests that these patients respond similarly to other SCID genotypes. However, there are no comparative data published in peer-reviewed literature to indicate any preferred alternative donor for T-B-NK+ SCID. As discussed below, the major concern for this type of SCID regardless of the donor is conditioning and whether the patient is radiation sensitive. (See 'Conditioning regimens' below.)
Haploidential related donor — Survival is lower in patients without an HLA-matched related donor. Only 52 percent of the 82 recipients of haploidentical related donor transplants in the first study discussed above were long-term survivors [7]. Survival in the haploidentical transplant group was 67 percent in patients who received myeloablative conditioning.
Successful engraftment of haploidentical T cell-depleted parental grafts is significantly reduced in children with T-B-NK+ SCID (unless maternal chimerism is present) compared with those with T-B+NK- SCID [6-8]. This is presumed to be due to the presence of normal functioning NK cells, which are known to mediate graft resistance.
Conditioning regimens — The best approach for conditioning for HCT in children with T-B-NK+ SCID is not yet defined, although ongoing studies in North America by the Primary Immune Deficiency Treatment Consortium (PIDTC), a consortium of 47 centers focused on HCT, gene therapy (GT), and enzyme replacement therapy for children with SCID, should help to shed light on this problem [10].
In an analysis of 640 children in North America with typical or leaky SCID who received HCT between 1968 and 2010, the PIDTC found that, in general, patients with SCID had the best T cell immune reconstitution and were more likely to come off of immune globulin replacement therapy when they received either reduced-intensity or myeloablative conditioning rather than no conditioning or only immunosuppression [8]. However, those with ART-SCID did significantly worse when compared with other genotypes such as interleukin 2 receptor common gamma chain (IL2RG; X-linked SCID [X-SCID]), Janus kinase 3 (JAK3), interleukin 7 receptor alpha chain (IL7RA), and RAG.
Myeloablative preparative regimens facilitate engraftment and immune reconstitution. However, these regimens also significantly increase transplant morbidity and mortality, especially in young infants with RS-SCID. As an example, patients with ART-SCID who are exposed to alkylating agents are at risk for late complications, such as pulmonary alveolar hemorrhage, absence of secondary teeth and other dental abnormalities, endocrinopathies, chronic graft-versus-host disease (GVHD), short stature, and decreased survival, that are not seen in other forms of SCID [6,7,11]. Patients with other genotypes of RS-SCID also have poorer survival when exposed to high-dose alkylating therapy [12].
General approach in T-B-NK+ SCID — Whether or not to provide pre-HCT conditioning of any form in patients with T-B-NK+ SCID to a large degree depends upon donor availability, presence of maternal chimerism, and genotype [3,5-7,13-19]. In general, conditioning therapy is not needed to achieve at least T cell reconstitution when HLA-matched related donors are available. Some form of immunosuppression with an alkylating agent is generally necessary for transplantation with haploidentical T cell-depleted stem cells (unless maternal cells are present) and possibly unrelated donor grafts.
HLA-matched donor — No conditioning is necessary for transplantation with HLA-matched related donors (and possibly with a perfectly matched unrelated donor) in order to achieve durable T cell reconstitution and, in limited cases, B cell reconstitution. An HLA-matched related donor may be used without conditioning therapy even with maternal engraftment.
Maternal engraftment and no HLA-matched relative — Patients with maternal engraftment are already tolerant of maternal cells. Thus, the mother should be used as the donor if maternal engraftment is present and an HLA-matched relative is unavailable. Under these circumstances, conditioning is not required, but T cell depletion of the graft (either by CD34 cell selection or T cell receptor [TCR] alpha/beta depletion) should be performed along with administration of pretransplant serotherapy with antithymocyte globulin (ATG) or alemtuzumab to minimize the risk of fatal GVHD [20,21].
No HLA-matched relative or maternal engraftment — Immunosuppressive conditioning is generally used for those children without maternal engraftment or an HLA-matched relative, although, in one study, approximately one-third of children with NK+ SCID without maternal engraftment and with no conditioning engrafted with haploidentical donors [20]. Thus, it is reasonable to attempt a haploidentical transplant without conditioning under certain circumstances, such as while searching for an unrelated donor, and to consider immunosuppression only if the graft is rejected, especially if the child has no active infections. In a retrospective review of 10 newly diagnosed patients with SCID, nine of whom had either ART-SCID or RAG-SCID, low-exposure busulfan (median dose 5.9 mg/kg, range 4.8 to 9.1) was used along with other nonalkylating agents, although three patients with non-RS-SCID also received 10 mg/kg thiotepa [22]. Six of the 10 patients had full T and B cell reconstitution, including three patients with ART-SCID.
Most transplant centers use either busulfan or melphalan with fludarabine regimens for myeloablation when an HLA-matched related donor is not available for a child with SCID [20,23,24]. Fludarabine (a nonalkylating agent) has more specific T cell immunosuppressive activity, although it has little to no effect on NK cells. In addition, it is less toxic than cyclophosphamide, the previous drug of choice for immunosuppressive conditioning [7]. These myeloablative regimens are more likely to result in B cell reconstitution [25], but they are also associated with a higher mortality than the immunosuppressive regimens or no conditioning approaches, at least in patients with RS-SCID who have active infection at the time of HCT [7,13,17,25].
In one European study, for example, none of the T-B- SCID recipients who did not receive busulfan conditioning developed B cell function [26]. The failure to reconstitute B cell immunity in T-B-NK+ SCID suggests a more complex maturation process for the B cell lineage and absence of the selective advantage that appears to exist for donor T cells. The higher mortality seen with myeloablation is largely because children with SCID who are ill at the time of diagnosis with opportunistic infections and/or failure to thrive are more susceptible to toxic chemotherapy [25]. At one center, preliminary experience in this patient population that included newborns suggests that targeting lower exposures of busulfan using pharmacokinetic models in infants under 10 kg may achieve sufficient levels of donor stem cell chimerism to restore both T and B cell immunity while reducing toxicity [22,27].
There is some evidence in patients with DNA double-stranded break (DSB) repair defects other than ART-SCID that using regular doses of fludarabine with reduced doses of cyclophosphamide is effective in overcoming the NK cell-mediated graft resistance seen with fludarabine alone [8]. A potential alternative approach is the use of monoclonal antibodies (eg, alemtuzumab) or ATG that bind to NK cells and induce apoptosis as well as suppress NK function, therefore reducing graft resistance mediated by NK cells [28,29]. However, neither alemtuzumab nor ATG appears effective in suppressing NK cell graft resistance in this patient population. The other agent that appears to be effective for NK cell-mediated rejection is thiotepa. Although it is an alkylating agent, it has been used at reduced dosing (8 mg/kg) with low-dose-exposure busulfan to successfully reconstitute T and B cell immunity in a small number of patients with ART-SCID [30].
Approach in radiation-sensitive SCID — Alkylating agents such as cyclophosphamide are more toxic in patients with RS-SCID (table 1), even without preexisting infection and at any age [7,9]. Thus, the goal for these patients is to minimize the use of alkylators and, if possible, to avoid using more than one alkylator and minimize dosing [6,9,12]. The use of either no conditioning or immunosuppressive conditioning alone (eg, low-dose cyclophosphamide or possibly thiotepa) for the initial HCT with an alternative donor in children with non-RAG1 or RAG2 types of T-B-NK+ SCID is suggested to minimize the exposure to alkylating agents. Donor marrow "boosts" or repeat HCT with myeloablative conditioning are reserved for those cases in which the initial procedure results in inadequate T cell immune reconstitution or graft failure. A combination of fludarabine, low-dose cyclophosphamide (or thiotepa), and serotherapy with antithymocyte globulin (ATG) or alemtuzumab (a monoclonal antibody that binds to CD52 on mature lymphocytes, leading to their destruction) can be used if immunosuppression is felt to be necessary. However, this regimen has not been formally evaluated to any degree in patients with RS-SCID and therefore should be used with caution. (See 'General approach in T-B-NK+ SCID' above.)
It is unknown whether a matched unrelated donor will engraft in this patient population without some immunosuppressive conditioning therapy. Published data indicate that this type of transplant can be performed successfully in some forms of SCID, mostly X-SCID and adenosine deaminase SCID (ADA-SCID) [31]. Unpublished results in a limited number of T-B-NK+ SCID are variable, and more studies are needed in these patient populations. If T cell reconstitution can be obtained with a transplant without conditioning, especially in infants, then there is the option to do a boost transplant with therapy directed at opening marrow niches when the child is older and possibly less susceptible to alkylating agents to achieve B cell reconstitution.
Specific defects
RAG1/2 defects — Patients with defects in recombinase-activating gene (RAG) 1 or 2 tolerate aggressive conditioning regimens compared with non-RAG1 or RAG2 types of T-B-NK+ SCID because those with RAG1 or RAG2 defects are defective in T and B cell V(D)J recombination but do not have a defect in double-stranded DNA repair [7]. Most transplants for Omenn syndrome due to RAG pathogenic variants or other defects have used intensive myeloablative and immunosuppressive conditioning, regardless of the donor-recipient match or donor source [14-16]. This is because Omenn syndrome patients have T cells, some of which are activated and can mediate a hyperinflammatory and autoimmune reaction [32]. Myeloablative regimens with reduced toxicity, such as those using targeted busulfan and fludarabine, may significantly improve long-term outcomes for these patients. However, if there is incomplete replacement of host with donor immunity, there is an increased likelihood of late effects from autoimmune and hyperinflammatory reactions. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical variants'.)
DCLRE1C (Artemis) defects — Patients with ART-SCID (due to pathogenic variants in DNA cross-link repair protein 1C [DCLRE1C], the gene encoding Artemis) are more susceptible to adverse effects, particularly late toxicities, from conditioning regimens that include alkylating therapy and/or ionizing radiation. In one series, there was no difference in survival or the incidence of acute GVHD in patients with ART-SCID, regardless of exposure to alkylators, although a higher incidence of infection was seen. However, in patients surviving more than two years post-HCT, there was a significant association among short stature, abnormal dental development including absent secondary teeth, and late endocrine effects in patients with ART-SCID who received high-dose alkylator therapy prior to their transplant. In addition, these patients are at least theoretically at higher risk for malignancy secondary to radiotherapy due to their inability to effectively repair DNA, although no increased incidence of malignancy has been reported in children with ART-SCID to date [6,7]. One patient with ART-SCID who received high-dose cyclophosphamide prior to a matched sibling transplant died of hepatic carcinoma 25 years posttransplant [30].
Conditioning with busulfan or some other alkylating agent that opens marrow niches appears to be required for adequate B cell reconstitution in children with ART-SCID. In a previously discussed study, two of the three Athabascan-speaking patients with ART-SCID who achieved B cell reconstitution received myeloablative conditioning regimens [6]. Unfortunately, only one is a long-term survivor, with complications including short stature, multiple endocrinopathies, and absence of permanent tooth development. The use of an immunosuppressive conditioning regimen or no conditioning resulted in T cell, but not B cell, reconstitution in 11 of 12 initial transplants for Athabascan-speaking ART-SCID patients [6].
Non-DCLRE1C double-stranded DNA break repair defects — Results were reported in 87 patients from 38 centers in Europe and North America who received HCT for primary immunodeficiency (PID) and/or malignancy associated with defective genes involving DNA DSB repair including DNA ligase IV (LIG4), nibrin (NBN), nonhomologous end joining factor 1 (NHEJ1), and ATM serine/threonine kinase (ATM) [12]. Of the 77 patients with DNA ligase IV deficiency, Cernunnos-XRCC4-like factor (XLF) deficiency, or Nijmegen breakage syndrome, survival was only 41 percent for those who received myeloablative conditioning (high-dose alkylator therapy) compared with 79 percent for those receiving reduced-intensity conditioning (including low-dose cyclophosphamide). The incidence of acute GVHD was high in this group of 87 patients, with 37 percent having grade 3 to 4 disease and 18 percent with chronic GVHD. Long-term outcomes other than survival and chronic GVHD were not reported in this retrospective multicenter study.
Avoiding conditioning with alkylating agents is the optimal goal in treating all patients with SCID and, in particular, those with RS-SCID. The possibility of using a monoclonal antibody (anti-c-Kit) that targets hematopoietic stem cells (HSCs) and opens marrow niches is being tested in an ongoing clinical trial for SCID (NCT02963064). Preliminary results in patients who previously received an allogeneic HCT but had poor immune reconstitution and were boosted following an infusion of anti-c-Kit suggest that the approach is safe, with enhancement of T cell immunity in some patients. Study in additional patients, including newly diagnosed patients with SCID, is needed to determine whether B cell engraftment occurs. Studies in animal models suggest that the use of immunotoxins targeting CD45+ cells or the combination of anti-c-Kit with a monoclonal antibody targeting the "don't eat me" receptor on phagocytic cells, CD47, may also be effective [33].
GENE THERAPY — Gene therapy (GT) has been successful for other forms of SCID such as X-linked SCID (X-SCID) and SCID due to adenosine deaminase (ADA) deficiency, but its use is still experimental for forms of T-B-NK+ SCID. (See "Overview of gene therapy for primary immunodeficiency".)
Artemis-deficient SCID (ART-SCID) GT may prove advantageous given the relatively poor outcomes of allogeneic transplants for this condition. In addition, autologous GT only requires low-dose conditioning, which is better tolerated in these patients than myeloablative conditioning due to their sensitivity to ionizing radiation and alkylating chemotherapy.
A lentiviral Artemis vector containing DCLRE1C cDNA driven by the natural human Artemis promoter sequence from the 5' region of the human DCLRE1C locus was tested in human fibroblasts in vitro and in mouse and humanized mouse models [34-36]. Fibroblasts from patients with ART-SCID transduced with the vector showed correction of radiosensitivity. Hematopoietic stem cells (HSCs) from ART-SCID mice and patients had restored in vitro T and B cell development after gene transduction. In safety testing, transduced murine HSCs showed no increase in potential for immortalization, and insertion sites showed no predilection to activate oncogenes.
An investigational clinical trial of GT for ART-SCID is ongoing (NCT03538899). Ten newly diagnosed infants have received autologous Artemis gene-transduced CD34+ HSC following conditioning with very-low-exposure busulfan (cumulative area under the curve [cAUC] of 20 mg*hour/L). The standard cAUC for myeloablative therapy is 70 to 90 mg*hour/L. All 10 patients are making T and B cells, with T cell immunity normalizing by six months postinfusion. Three of four patients who are at least 24 months postinfusion have full T and B cell reconstitution and are off immune globulin replacement, with normal responses to vaccines. Several of the other patients are making immunoglobulin M (IgM), with evidence of normal B cell maturation. There have been no adverse events related to the GT or busulfan exposure [30].
For patients with recombination-activating gene (RAG) deficiency, including Omenn syndrome, successful GT should be curative, although studies in mouse models suggest a more complex process than with ART-SCID [37].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)
SUMMARY AND RECOMMENDATIONS
●Initial management – Infants suspected of having a primary immunodeficiency (PID) require special care and treatment before definitive correction is performed, including protective isolation, avoidance of live vaccines, and prophylaxis against infection (antimicrobials and immune globulin replacement therapy). (See 'Management prior to diagnosis and transplantation' above and "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures'.)
●Definitive therapy – Typical severe combined immunodeficiency (SCID) is universally fatal in infancy without definitive treatment. Hematopoietic cell transplantation (HCT) is the only confirmed curative therapy for children with T-B-NK+ SCID (table 1), but outcomes depend upon the donor type available and conditioning regiment used. Gene therapy (GT) for Artemis-deficient T-B-NK+ SCID (ART-SCID) is still experimental and in the early stages of clinical investigation.
We recommend HCT with a human leukocyte antigen (HLA) matched related donor, if available, for infants with T-B-NK+ SCID (Grade 1B). For patients without an HLA-matched related donor, we suggest HCT with a matched unrelated donor (Grade 2C). Alternatives include HCT with an haploidentical related donor or cord blood donor or, in patients with ART-SCID, GT as part of a clinical trial.
•Hematopoietic cell transplantation (HCT) – For patients who have an HLA-matched related donor, survival at two years posttransplant is approximately 75 to 90 percent. Survival after HLA-nonidentical transplantation is less favorable (approximately 35 to 50 percent at two years). (See 'Outcomes' above.)
Myeloablative preparative regimens facilitate engraftment and immune reconstitution. However, these regimens may increase transplant morbidity and mortality, especially in young infants and those with radiation sensitivity. In general, conditioning therapy is not needed to achieve at least T cell reconstitution when HLA-matched donors are available. Depending on the genotype, some form of immunosuppression with an alkylating agent is generally necessary for transplantation with haploidentical T cell-depleted stem cells (unless maternal cells are present). However, patients with radiation-sensitive SCID (RS-SCID) are at increased risk of toxicity from alkylating agents, and, therefore, use of alkylators is avoided or at least minimized in these patients. (See 'General approach in T-B-NK+ SCID' above and 'Approach in radiation-sensitive SCID' above.)
•Gene therapy – GT has been successful for other forms of SCID such as X-linked SCID (X-SCID) and SCID due to adenosine deaminase (ADA) deficiency, and the early experience in ART-SCID is encouraging. (See 'Gene therapy' above and "Overview of gene therapy for primary immunodeficiency".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.
