Introduction

Primary cellular immunodeficiencies are a group of inherited disorders characterized by severe impairment of the innate or adaptive immune systems, which generally leads to early death from infectious complications. These disorders can be further categorized by the cell lineage(s) primarily affected (Table 1). While improved supportive care has extended the life span of patients affected by these diseases, definitive cure is generally only achieved by allogeneic hematopoietic stem cell transplantation (HSCT), though recent advances in gene therapy hold significant promise that this may soon be a viable alternative.

Table 1 - Primary immunodeficiencies potentially treated with HSCT.

Full table

SCID

SCID is a rare disease caused by a group of genetic disorders with a shared phenotype of deficient T- and B-lymphocyte function (with or without abnormal natural killer (NK) cell development) that leads to early death from recurrent infections in affected children (Table 2). In addition, since SCID patients are unable to reject foreign cells, a significant percentage of patients will have evidence of maternally engrafted T lymphocytes, which often leads to clinical manifestations of GVHD.¹ Except for those patients with SCID due to deficiency of adenosine deaminase (ADA), for which a replacement enzyme exists, the only curative therapy for SCID is allogeneic HSCT. However, early results with gene insertion into autologous hematopoietic stem cells for children with X-linked SCID and ADA deficiency² suggest that eventually, this will become a more common form of curative treatment for many primary immunodeficiency diseases.

Table 2 - Genetic subtypes of severe combined immunodeficiency.

Full table

At the time of diagnosis, patients with SCID generally have already developed, or are at an extremely elevated risk of developing, a life-threatening infection. This necessitates rapid initiation of HSCT. For all stem cell sources, successful outcomes are more likely to be achieved when the patient is still very young, preferably less than 6 months of age.^{3, 4} Buckley et al.,⁵ demonstrated that infants transplanted less than 3.5 months of age had a 95% overall survival (OS), compared to only 76% OS in older children. This is likely due to the development of pulmonary infections prior to transplant, which have been associated with significantly poorer outcomes.^{4, 6} In addition, transplants performed within the first month of life are associated with more rapid T-cell reconstitution, perhaps due to superior thymic capacity.⁷

Impact of SCID phenotype

T-B+NK- SCID

The most common form of SCID, accounting for approximately 50% of all cases, is due to a defect in the gene for the common gamma chain (c) located on Xq13. Another defect, JAK3 deficiency, results in a similar T-B+NK- phenotype (Table 2). Post transplant, patients with c deficiency have been noted to have excellent rates of sustained thymic output, as measured by levels of T-cell receptor excision circles (TRECs). This may be due to a pre-transplant low level of thymic precursors in these patients, which post transplant allows for thymic seeding of very early progenitors.⁸

T-B-NK+ SCID

It has been estimated that 20–30% of all SCID cases have the T-B-NK+ phenotype with defects in RAG1 or RAG2 being the most common etiology. It has been reported that B-phenotypes (presumably NK+) of SCID have significantly poorer 3-year OS (36%) compared with B+ phenotypes (64%).⁶ Bertrand et al.⁴ demonstrated a worse disease-free survival after T-depleted haplocompatible transplant in patients with B- SCID (35%) compared with B+ SCID (60%). Haddad et al.⁹ has also shown a worse long-term outcome in children with B- SCID (NK cell phenotype unknown), who were more likely to die during the first 6 months post transplant (37%) compared with those who had B+ SCID (13%). This poor survival has been attributed to a diminished rate of engraftment, increased severity of GVHD, higher incidence of chronic GVHD⁴ and slower recovery of T-cell function.^{6, 9} The relatively poor engraftment in patients with T-B-NK+ SCID is in large part due to the presence of host NK cells, which are capable of mediating donor stem cell rejection.⁴ Studies in animal models of NK+ SCID,¹⁰ as well as unpublished data in our own laboratory with an Artemis-deficient mouse model, support the role of NK cells in graft resistance.

SCID due to DNA repair defects

A subset of T-B-NK+ SCID patients have increased cellular sensitivity to alkylating agents and ionizing radiation, mainly due to a deficiency in the gene for Artemis, a critical protein in the nonhomologous DNA repair pathway.¹¹ Unlike other forms of B- SCID, patients with Artemis deficiency have undergone HSCT with an excellent OS of 75%.¹¹ A new type of radiosensitive T-B-NK+ SCID has been recently described with a defect in DNA ligase IV, an enzyme in the nonhomologous DNA repair pathway distal to Artemis.¹²

T-B+NK+ SCID

Another subset of SCID patients is characterized by the presence of both B cells and NK cells. A variety of cellular defects have been reported to result in this phenotype, including deficiencies of IL-7 receptor-, CD45 and the CD3, CD3 and CD3 subunits. Most of these deficiencies have only recently been discovered and very small numbers of these patients have been followed long term after HSCT, making definitive statements regarding their clinical course difficult.

T+ SCID

Rare forms of SCID are characterized by the selective absence of CD4+ T cells (for example, HLA class II deficiency) or CD8+ T cells (for example, ZAP70 deficiency). Due to partial T-cell function, children with these diseases are often diagnosed later than other patients with SCID. A high incidence of preexisting viral infections has been associated with high rates of severe GVHD and poor outcomes after HLA-identical HSCT in patients with HLA class II deficiency.^{6, 13}

Stem cell sources

The preferred choice of stem cell donor for a patient with SCID is an HLA-identical sibling, in which the OS now exceeds 90% if the transplant is performed promptly.^{5, 14} In patients without a matched sibling, the choice is whether to use an immediately available T cell-depleted haplocompatible family member or to perform a search for an HLA-matched unrelated donor or cord blood unit. Some of the reports on transplantation with different stem cell sources are summarized in Table 3. In cases with a known genetic mutation, recent improvements in preimplantation genetics raise the possibility of creation of a SCID-free HLA-matched sibling for possible cord blood transplantation. However, both the cost and time needed to produce stem cells from this source makes this option unfeasible for most cases of SCID, in which HSCT is urgently indicated.

Table 3 - Survival following HSCT for SCID based on stem cell source and conditioning regimen.

Full table

Haplocompatible-related donors

With the advent of effective T-cell depletion strategies, the use of haplocompatible family members as donors for children with SCID has become a viable strategy. Three-year survivals of 53–79% have been reported, with significantly better success rates in more recent years and in more experienced centers,^{3, 5, 6, 14} especially if the transplant is performed early before the development of life-threatening infections. In SCID patients with evidence of maternal engraftment,¹ the mother is typically utilized as the stem cell source (unless an HLA-matched sibling is available), since the recipient is already tolerant to the maternal cells. A potential risk with this approach is the development of GVHD by the maternally engrafted T cells following the infusion of maternal bone marrow cells. In our own experience this has not been a significant problem provided the donor graft is adequately T-cell depleted. A significant problem with haplocompatible transplants is that the required T-cell depletion can lead to a slow rate of T-cell reconstitution and a prolonged time of risk of opportunistic infections and EBV-related lymphoproliferative disease. The median time to achieve normal T-cell numbers is 8.5–10 months,^{3, 19} only slightly slower than that seen following HSCT from an HLA-identical sibling (6 months).¹⁹ However, functional T cells generally take 4–9 months to be detected following haplocompatible HSCT, as opposed to 2 months following HLA-identical sibling HSCT.^{3, 9, 19} B-cell numbers generally recover by 3–12 months post transplant, while their function can take 6–15 months to return to normal.^{3, 9} In addition, the slow recovery of regulatory T cells may explain the increased risk for the development of autoimmune hemolytic anemia.¹⁹

Matched unrelated donors

Due to a slow rate of immune reconstitution following T cell-depleted haplocompatible HSCT as well as the inability to do T-cell depletion, some centers have advocated utilization of matched unrelated donors. Despite a later median age of transplant due to the time needed to perform a search, some groups report good outcomes (OS 63–67%) with the use of unrelated donors.^{6, 15} Grunebaum et al.¹⁴ reported that matched unrelated donors had superior 2-year OS (81%) compared with mismatched related donors (53%). In those patients tested, evidence of functional T cells was seen as early as 2 months post-HSCT, and specific antibody production by 5 months.¹⁵ It should be noted that in the recipients of the unrelated donor transplants, conditioning with high-dose chemotherapy such as busulfan was utilized. Since it has been shown that the use of a conditioning regimen for haplocompatible donors produces faster recovery of T-cell numbers,¹⁹ it is difficult to directly compare the immune reconstitution following HSCT from unrelated donors with that of nonconditioned haplocompatible donors. In addition, the long-term complications with the utilization of high-dose chemotherapy-based conditioning regimens have not been reported in any detail. Thus, until a prospective randomized trial comparing haplocompatible-related donors to matched unrelated donors has been performed, the optimal choice of stem cell source is not clear. However, some recent success with reduced intensity conditioning regimens demonstrates that this may prove to be a feasible alternative to fully myeloablative conditioning prior to transplant of unrelated donor stem cells, especially in patients who begin transplant with a known infection or organ dysfunction.¹⁷

Cord blood

Utilization of cord blood for HSCT for SCID has been advocated over adult-unrelated donors due to more rapid availability of the product, increased permissiveness of HLA mismatch with a reduced risk of GVHD. Most reports describing this strategy include only small numbers of patients, but demonstrate rapid recovery of T-, B- and NK cell function.^{5, 16, 20, 21} However, these types of transplants required high-dose chemotherapy to achieve successful engraftment, further raising the issue of conditioning therapy in very young infants. In one report of 10 cord blood transplants for children with SCID, 3 transplants did not use conditioning and were from 6/6 or 8/8 HLA-matched unrelated cord blood units, all of whom engrafted.¹⁸ The same could prove to be true for perfectly matched unrelated donor transplants for SCID as well and needs to be further evaluated.

Conditioning

One unique feature of HSCT for the treatment of SCID is the lack of an absolute requirement for conditioning, which has been demonstrated to restore antigen-specific T-cell function within 8 weeks (for unfractionated marrow recipients)¹⁹ to 4–8 months (for T cell-depleted marrow recipients).^{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 ILc deficiency.⁸ As with ILc 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.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 ILc 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 thymus⁸ or (3) mature donor T cells expand to fill a homeostatic niche. In the latter case, it might be expected that eventually thymic output would diminish and holes would appear in the T-cell receptor repertoire, leading to recurrence of opportunistic infections later in life.²⁵ Some groups do not report a significant difference in late infectious complications regardless of thymic output,⁸ while others have reported that some long-term survivors of HSCT for SCID do show a propensity for the development of chronic human papillomavirus disease, though a link to the presence or absence of a conditioning regimen has not been established.²⁶ At least two studies have identified donor stem cells in the marrow of recipients of unconditioned haplocompatible transplants.^{23, 27} In one, a sibling was diagnosed with SCID and was HLA matched with her sister who had previously undergone a successful haplocompatible transplant from their father. The sibling received a bone marrow transplant from the older sister and successfully engrafted without any conditioning being given. Donor cells were shown to contain stem cells from the father at the time of the second transplant.²³

It has been argued that SCID phenotypes with preservation of NK cells, which have been shown to mediate graft rejection in murine models, would benefit from conditioning regimens that are designed to inhibit NK activity.⁴ Grunebaum et al.¹⁴ was not able to detect a difference in outcome based on B-cell phenotypes, possibly due to a high use of unrelated donors, for whom busulfan and cyclophosphamide was utilized. However, some forms of B-NK+ SCID have increased sensitivity to alkylating agents and ionizing radiation, and are at significant risk of increased short- and long-term toxicity from conditioning regimens utilizing these agents.^{4, 11} Alternative approaches need to be considered for these genotypes.

When conditioning is utilized, complete donor chimerism in all cell lines is frequently accomplished.^{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.²⁸

For those patients requiring conditioning, the ideal regimen has not been defined. Many groups utilize a conventional 16 mg/kg of busulfan plus 200 mg/kg of cyclophosphamide.^{3, 14, 15} It has been proposed that fully ablative regimens utilizing 16 mg/kg of busulfan may have poor outcomes due to increased infectious complications. Bertrand et al.⁴ reported that their best outcomes follow a reduced intensity regimen utilizing 8 mg/kg of busulfan plus 200 mg/kg of cyclophosphamide, however other groups have reported that 8 mg/kg of busulfan is not sufficient to obtain myeloid chimerism.^{24, 28} Table 3 summarizes the survival rates in recent reports that indicate the type of conditioning regimen administered based on the stem cell source utilized.

Long-term outcomes

Failure to develop adequate T-cell immunity at 2 years after HSCT is the most common indication for retransplantation, though B- SCID may require retransplant at an earlier time point.⁹ Repeat transplant has been required more often following haplocompatible HSCT.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. Radiosensitive forms of SCID may be at increased risk of other abnormalities, such as failure of secondary tooth development.¹¹ Otherwise, reports generally show few significant long-term sequelae of HSCT in infants with SCID^{8, 14} although detailed careful long-term follow-up studies evaluating growth and developmental and other major organ functions have not been done in the large majority of patients with SCID.

Newborn screening

Recent work has led to the development of two tests for T-cell lymphopenia: IL-7 levels²⁹ and a polymerase chain reaction test to detect low numbers of TRECs,³⁰ which can be performed on dried blood spots as part of a population-based screening program at birth. Since HSCT is most likely to be successful when performed at a young age prior to the onset of life-threatening infections,⁷ plans are underway in a number of states to test whether implementation of such a program will prove to be a cost-effective strategy to improve OS in these infants. However, large-scale screening programs must be designed with a high degree of specificity in order to avoid the generation of a large number of false positive results that would result in excessive evaluations for the presence of SCID and undue parental anxiety.

Other primary immunodeficiencies

In addition to SCID, many other primary immunodeficiencies have been treated with allogeneic HSCT. These include syndromes with T-cell defects (for example, Wiskott–Aldrich syndrome (WAS) and hyper IgM1 syndrome), inherited predispositions to development of hemophagocytic lymphohistiocytosis (HLH) (for example, familial HLH, Chediak–Higashi syndrome (CHS), Griscelli syndrome and X-linked lymphoproliferative disease) and phagocytic disorders (for example, severe congenital neutropenia (SCN), leukocyte adhesion deficiency and chronic granulomatous disease (CGD)). Because of the rarity of most of these disorders, many of the descriptions of treatment with HSCT include very small numbers of patients. When these patients are combined into a single large group for analytical purposes, not surprisingly patients with genotypically identical-related donors had significantly improved 3-year OS (71%) compared to other donor types (42–59%).⁶

Wiskott–Aldrich syndrome

Wiskott–Aldrich syndrome is characterized by the triad of thrombocytopenia with small platelets, eczema and recurrent infections. The T-cell immunodeficiency predisposes to the development of autoimmune phenomena and lymphomas. A defect at Xp11 in the gene for the WAS protein leads to defective cytoskeletal interactions with CDC42, a regulator of signaling pathways that controls diverse cellular functions, including migration and cell cycle progression. Affected males rarely survive past the second decade of life.

The only curative strategy for treatment of WAS is allogeneic HSCT. A report from the International Bone Marrow Transplant Registry and National Marrow Donor Program demonstrated in 170 patients that while the 5-year OS of patients transplanted from HLA-identical siblings was 87%, the results for unrelated HSCT were significantly related to the age at transplant.³¹ Unrelated donors less than 5 years of age had an 85% 5-year OS, while all 15 patients greater than 5 years of age died.³¹ This may be at least partly related to the presence of infection prior to conditioning, which significantly decreased the survival of patients with unrelated donors.³¹ No difference was noted between TBI- and chemotherapy-based conditioning regimens.³¹ Haplocompatible-related transplants have been less successful for WAS, with an OS of 45–52%.^{6, 31}

Familial hemophagocytic lymphohistiocytosis

Familial HLH is characterized by episodes of fever, hepatosplenomegaly and cytopenias. An autosomal recessive defect in one of several genes, including those encoding perforin or Munc13, causes reduced NK and T-cell cytotoxicity. This leads to a widespread accumulation of lymphocytes and mature macrophages with hypercytokinemia. Familial HLH is invariably fatal.

The only curative strategy for treatment of familial HLH is allogeneic HSCT. A report from a multicenter prospective trial, HLH-94, demonstrated a 62% 3-year EFS in 65 children undergoing allogeneic HSCT with a variety of stem cell sources.³²

Chediak–Higashi syndrome

Chediak–Higashi syndrome is characterized by oculocutaneous albinism, recurrent infections and the presence of giant granules in hematopoietic and other cells. A recessive defect at 1q42 in the lysosomal trafficking regulator gene leads to neutropenia, as well as defective phagocyte, NK cell and T-cell function. In those patients that survive the infectious complications, during the first or second decade of life, an accelerated phase develops, in which patients generally die from HLH.

A report from the Center for International Blood and Marrow Transplant Research demonstrated a 62% 5-year OS in 35 children undergoing allogeneic HSCT for CHS. Mortality was highest in those patients undergoing HSCT with an alternative related donor or with active disease at the time of HSCT, suggesting that early referral for HSCT prior to development of the accelerated phase may significantly improve survival.³³

Severe congenital neutropenia

Severe congenital neutropenia is characterized by an absolute neutrophil count less than 0.2 10⁹ per liter and an early onset of life-threatening bacterial infections. Both autosomal dominant and recessive forms of SCN exist, with the most common cause due to a defect in the neutrophil elastase gene at 19p13. The administration of G-CSF has significantly improved the survival of patients with SCN, however, these children also demonstrate an elevated risk of malignant transformation into AML. A recent study has demonstrated that approximately one-third of SCN patients are relatively unresponsive to G-CSF doses above 8 g/kg per day and that these patients have a 10-year incidence of AML of 40%, with a 14% incidence of death from sepsis.³⁴

A report from the SCN International Registry demonstrated an 82% OS in 11 children with nontransformed SCN undergoing allogeneic HSCT. The only two deaths seen in this cohort were in recipients of mismatched grafts.³⁵ Given the extremely elevated risk of AML and/or mortality in G-CSF poorly-responsive SCN patients, early referral for HSCT may significantly improve survival.

Chronic granulomatous disease

Chronic granulomatous disease is characterized by recurrent pyogenic infections in patients with normal neutrophil numbers. Patients present with deep tissue infections and sepsis due to catalase-positive organisms such as Staphylococcus aureus and Aspergillus fumigatus. A defect in one of the four genes encoding subunits of the nicotinamide adenine dinucleotide phosphate-oxidase complex leads to insufficient production of free protons from which to make hydrogen peroxide. With good supportive care, including therapy with interferon-, affected individuals can live up to the fourth decade of life, but suffer early mortality from recurrent pulmonary infections.

The only curative strategy for treatment of CGD is allogeneic HSCT. A report from the European Group for Blood and Marrow Transplantation demonstrated in 23 patients that myeloablative conditioning prior to matched sibling HSCT can be safely performed (85% OS), especially if the patients were free of infection at the time of HSCT (100% OS).³⁶

Conclusions

One overriding similarity between all primary immunodeficiencies is the importance of early transplantation before the development of serious infections that contribute to a significant increase in the risk of mortality following HSCT. In families with a history of primary immunodeficiency due to an identified genetic mutation prenatal diagnosis is available, which should enable initiation of HSCT in the first several months of life. In addition, several attempts at in utero HSCT have been performed for treatment of SCID, though progress with this technique to date has been limited due to poor engraftment and mixed chimerism.³⁷ A population-based screening program at birth may be able to identify children with T-cell lymphopenia and SCID prior to the onset of life-threatening infections and should also allow for prompt initiation of HSCT, when it is most likely to be successful.^{7, 29, 30} In the future, the success rates for T cell-depleted haplocompatible-related stem cells, as well as unrelated donor sources, for treatment of SCID and other primary immunodeficiencies will continue to improve as new strategies are discovered to enhance immune reconstitution, such as adoptive immunotherapy utilizing alloreactive-depleted donor T cells,³⁸ and to reduce short- and long-term side effects by the effective use of reduced toxicity regimens and possibly regimens that do not require alkylating agents or radiation. Finally, as efforts with gene therapy become more effective and safer, we will be able to move away from the use of allogeneic donors in favor of replacement with gene-corrected autologous hematopoietic progenitors.²

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