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Hematopoietic cell transplantation for non-SCID inborn errors of immunity

Hematopoietic cell transplantation for non-SCID inborn errors of immunity
Author:
Rebecca Marsh, MD
Section Editor:
Jennifer M Puck, MD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Nov 2022. | This topic last updated: Jul 06, 2022.

INTRODUCTION — Inborn errors of immunity (IEI, includes the former term primary immunodeficiencies) are potentially life-threatening disorders caused by genetic defects that result in immune deficiency and/or immune dysregulation. Various treatments are available, depending upon the specific genetic defect and the parts of the immune system affected. Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for most cases of severe combined immunodeficiency (SCID) and is also a treatment option for several other forms of IEI including many combined immunodeficiencies, syndromic immunodeficiencies, immune dysregulatory disorders, phagocytic cell defects, some defects of innate immunity, and a few autoinflammatory disorders. Improvements in HCT procedures and supportive care have resulted in better outcomes.

This topic reviews aspects of HCT specific to patients with IEI other than SCID, which is discussed in greater detail separately. (See "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Numerous topics discuss other aspects of HCT:

(See "Sources of hematopoietic stem cells".)

(See "Donor selection for hematopoietic cell transplantation".)

(See "Evaluation for infection before hematopoietic cell transplantation".)

(See "Hematopoietic support after hematopoietic cell transplantation".)

(See "Prevention of graft-versus-host disease".)

(See "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Introduction' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)

The general aspects of medical therapy for immunodeficiency, including therapy with immune globulin, prophylactic antimicrobials, biologic therapies, vaccination recommendations, and gene therapy, are also discussed separately:

(See "Primary immunodeficiency: Overview of management".)

(See "Immune globulin therapy in primary immunodeficiency".)

(See "Immunizations in hematopoietic cell transplant candidates and recipients" and "Immunizations in patients with primary immunodeficiency".)

(See "Overview of gene therapy for primary immunodeficiency".)

INDICATIONS — Allogeneic HCT is indicated for treatment of typical SCID since it is the only potentially curative, nonexperimental therapy available for a condition that, if untreated, is almost always lethal in the first few years of life. However, use of HCT is less clear cut for other forms of IEI. Factors to consider include the type of IEI, the severity of the phenotype in a particular patient, the survival and quality of life with and without HCT of previously reported cases with the same condition, and whether the disease manifestations can be prevented or improved with HCT (table 1). Discussing the role of allogeneic HCT for each individual genetic disease is beyond the scope of this topic since there are more than 450 IEI. Rather, a broad overview regarding the types of IEI that are usually or sometimes treated with allogeneic HCT and nuances relative to certain disease types is presented in this topic.

The familial hemophagocytic lymphohistiocytosis (HLH) disorders are an example of a disease group for which allogeneic HCT is almost always used. HLH in these disorders is almost universally fatal if left untreated, and life-threatening hyperinflammation will generally keep reoccurring in patients with familial HLH without curative allogeneic HCT. Thus, the decision to perform allogeneic HCT is straightforward in these patients if the patient can tolerate the procedure and a suitable stem cell donor is available. Patients with chronic granulomatous disease (CGD) or Wiskott-Aldrich syndrome (WAS) also generally suffer repeated life-threatening complications of their diseases, and allogeneic HCT is often performed in these patients. On the other end of the spectrum, patients with predominantly antibody deficiencies are infrequently treated with allogeneic HCT since most of these patients can have an acceptable quality of life and life expectancy with medical management.

For some disorders, the indication for allogeneic HCT is less clear. As an example, the indication for allogeneic HCT in patients with CD40 ligand (CD40L) deficiency remains controversial. A large, retrospective study of 176 transplanted and nontransplanted patients was published in 2017 and observed no survival advantage for transplanted patients compared with untransplanted patients [1]. However, the study included patients who were diagnosed with CD40L deficiency as far back as 1964, and HCT outcomes have improved significantly since then. One-year survival following allogeneic HCT was close to 90 percent for patients who were transplanted between 2006 and 2013. In addition, surviving patients in another study who were treated with allogeneic HCT had higher quality-of-life scores than patients who were not transplanted [1,2].

PRETRANSPLANT CONSIDERATIONS — There are several considerations surrounding allogeneic HCT for IEI including the underlying diagnosis, patient health status, donor options, local transplant center practice preferences and experience, and parental/caregiver understanding and willingness. Practice patterns for patients with non-SCID IEI vary greatly among transplant centers.

Parent/caregiver preferences — A major challenge is that parents/caregivers may not agree to exposing their child to the risks of HCT early in life before onset of major infections or organ damage, but the risks of HCT increase after these complications have occurred.

Conditioning chemotherapy — SCID is the only immunodeficiency in which the complete absence of T cell immunity sometimes allows HCT to be performed without chemotherapy in selected cases. In all other conditions, there is sufficient host immunity to resist engraftment of allogeneic cells. Thus, some type of pretransplant conditioning is always required to allow engraftment of donor-derived stem cells in non-SCID combined immunodeficiencies (eg, Wiskott-Aldrich syndrome [WAS], X-linked hyperimmunoglobulin M syndrome); disorders of phagocytic cell function (eg, chronic granulomatous disease [CGD], leukocyte-adhesion deficiency [LAD]); diseases of immune dysregulation (eg, familial hemophagocytic lymphohistiocytosis [HLH]); and other categories of IEI. The patient's underlying genetic defect, health status, available donor human leukocyte antigen (HLA) match, and other factors influence the type of conditioning chemotherapy used.

Conditioning regimens were historically classified as myeloablative (MAC), nonmyeloablative (NMA), or reduced intensity (RIC) [3]. MAC regimens irreversibly ablate recipient hematopoietic stem cells (HSCs), and exogenous HSCs must be given in order to achieve count recovery. NMA regimens do not result in irreversible marrow destruction, and autologous marrow recovery can occur. RIC regimens fall somewhere in between MAC and NMA regimens and can also allow some autologous marrow recovery following transplant, which may result in mixed chimerism. MAC regimens have the benefit of increased success of engraftment but are associated with higher toxicities compared with RIC regimens, which have fewer toxicities but can be associated with decreased stable engraftment. Subsequently, conditioning regimens that are myeloablative but reduced in intensity compared with traditional fully myeloablative busulfan (16 mg/kg) and cyclophosphamide regimens have come into use in some IEIs. As an example, a regimen that targets busulfan exposure to achieve myeloablation but reduce toxicities using pharmacokinetic-guided dosing and includes fludarabine is often used in patients with CGD and some other IEIs. This type of approach is sometimes referred to as a "reduced toxicity" regimen. (See "Preparative regimens for hematopoietic cell transplantation".)

Conditioning serotherapy — Conditioning regimens often also contain serotherapies such as alemtuzumab or antithymocyte globulin. These agents deplete recipient T cells and help prevent graft rejection. These agents often linger through the early peritransplant period and so also deplete donor graft T cells, which can help prevent graft-versus-host disease (GVHD).

Donor choice — As with all allogeneic HCT, an HLA-matched related donor (MRD), such as an unaffected brother or sister, is considered the optimal choice for non-SCID HCT [4]. However, fewer than 20 percent of patients in the US have such a donor, although this may not be the case in cultures with high degrees of consanguinity and large sibship sizes. Alternatives include a matched unrelated donor (MUD/MURD), a mismatched unrelated donor (MMUD), a mismatched related donor (MMRD), or an umbilical cord blood (UCB) donor. (See "Donor selection for hematopoietic cell transplantation".)

Matched related (sibling) donor — Historically, transplants with a matched related (sibling) donor (MRD/MSD) have had the highest rate of overall survival (see 'Long-term prognosis' below). For example, an older, large European study of 783 patients with non-SCID IEI transplanted between 1968 and 2005 observed a 71 percent 10-year survival among patients transplanted with a related, genotypically identical donor compared with 39 to 63 percent for all other donor types [5].

However, many non-SCID immunodeficiencies do not manifest early in life or are not diagnosed early in their course, and there can be considerable differences in severity. Thus, an essential part of screening for potential related donors is to test them for the condition affecting the patient. This process may identify an apparently healthy relative as genetically affected with the same condition as the patient, a circumstance that can cause distress not only by disqualifying a potential donor but also by revealing new, unwelcome information.

An additional issue is whether female carriers of X-linked conditions, even if HLA matched, should be used as related donors for their affected male relative. Females heterozygous for X-linked CGD themselves have a higher incidence of autoimmune disease than noncarriers, and, in addition, those who by chance have unbalanced X-chromosome inactivation in their hematopoietic cell lineages may themselves experience infections similar to those of affected males [6]. Use of such donors could result in engraftment of a new immune system that would not fully correct the patient's original defect. There is no consensus regarding whether or not to use carrier siblings, since there are no large studies that demonstrate the frequency with which recipients develop clinical problems related to the use of a carrier sibling in the various IEI. The risk probably also depends upon the degree of skewing of X-chromosome inactivation. The donor choice decision is often determined by the primary transplant clinician who considers other characteristics of the potential sibling donor (such as size of the sibling, which can affect the amount of the anticipated stem cell collection), what potential MUD options exist, urgency of transplant, and other factors.

Other donor types — Options for patients without a matched sibling donor include an adult MUD, an adult MMUD, an MMRD such as a haploidentical parent, or UCB that has been cryopreserved in a cord blood repository. Historically, success rates have been lower with these donor sources due to graft rejection and GVHD. However, improvements in graft processing, conditioning regimens, and prevention of posttransplant complications have made MUD HCT outcomes almost as good as patients transplanted with an MRD. As an example, a study of reduced-toxicity conditioning in CGD observed a two-year overall survival of 100 percent for MRD transplants and 94 percent for MUD transplants [7]. For patients who lack an MRD or MUD, mismatched donor transplantation can be pursued, but the degree of mismatch directly affects survival [8]. There are several options to attenuate the risks of GVHD and mortality, including graft engineering or the use of aggressive GVHD prophylaxis strategies such as including posttransplant cyclophosphamide. Several centers have reported success with the use of T cell-depleted MUD or MMRD grafts [9-13]. In a large series of 98 patients, overall survival was 86 percent in the MUD group and 87 percent in the MMRD group [13]. In two reports of haploidentical transplantation with posttransplant cyclophosphamide that included sizable groups of non-SCID IEI, two-year overall survival was 65 to 78 percent [14,15].

Unrelated donor registries, including the US National Marrow Donor Program (publicized with the "Be the Match" campaign) have enlisted millions of volunteers who have given blood samples for HLA typing and indicated willingness to donate bone marrow or peripheral mobilized HSCs anonymously if a patient needing a transplant of their HLA type is identified. Although not all ethnicities are equally represented, the unrelated donor registry now provides donors for the majority of patients lacking an unaffected matched sibling.

There are also large repositories of donated, cryopreserved UCB. In the past, GVHD was less of a problem with UCB transplants than adult MUD transplants, but the gap has closed with graft engineering of adult donor cells. In addition, UCB units have a limited cell number and no possibility of returning to the same donor for additional cells if a boost is needed, making UCB a less viable option for older, larger patients.

Graft engineering — Removal of T cells from the graft decreases the risk of GVHD. However, this process can result in higher rates of graft failure and increase the time to immune recovery, resulting in increased rates of infection and viral reactivation and lower rates of survival. T cell receptor (TCR) alpha beta/CD19 depletion removes these T cells (and CD19+ B cells) but leaves behind TCR gamma delta T cells and natural killer (NK) cells that should improve immune recovery and infection control compared with other methods of T cell depletion [16]. Grafts can also undergo CD34+ selection to select out only the CD34+ stem cells for infusion. Other graft manipulation techniques also exist.

COMPLICATIONS OF HCT — Complications during and following HCT include infections, toxicities from cytoreductive chemotherapy, graft failure, graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy, and posttransplant lymphoproliferative disease. Late effects such as endocrinopathies and fertility problems also occur. The incidence of these adverse events varies with the type of HCT, conditioning regimen, and underlying disease.

Infections — Infection is one of the most common causes of mortality after HCT. All patients who undergo allogeneic HCT are at risk of bacterial, fungal, and viral infections and should receive appropriate prophylactic antimicrobial treatments during allogeneic HCT. However, there are some unique situations that can occur in IEI patients depending on the underlying disorder. At the time of HCT, for example, patients with chronic granulomatous disease (CGD) may have refractory fungal or bacterial infection, and patients with interferon gamma receptor deficiencies may have refractory atypical mycobacterial infections. Unique situations such as these require experienced teams of care providers, and all patients with IEI should be thoroughly evaluated for infections prior to transplant. Control and prevention of infections are discussed in greater detail separately. (See "Early complications of hematopoietic cell transplantation", section on 'Prevention of infection' and "Overview of infections following hematopoietic cell transplantation" and "Prevention of infections in hematopoietic cell transplant recipients" and "Prevention of viral infections in hematopoietic cell transplant recipients".)

Management of toxicity from cytoreductive chemotherapy — Patients can experience a variety of early complications related to allogeneic HCT. An expected complication of cytoreductive chemotherapy is myelosuppression with attendant cytopenias. Patients may have bleeding, anemia, or suffer infections related to leukopenia. Blood and platelet transfusions are usually required during the period of marrow aplasia. Mucositis may occur and limit oral nutrition. Patients often require enteral or intravenous nutrition supplementation. Hepatic veno-occlusive disease or transplant-associated thrombotic microangiopathy can occur. (See "Early complications of hematopoietic cell transplantation" and "Kidney disease following hematopoietic cell transplantation", section on 'Thrombotic microangiopathy' and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults", section on 'Introduction'.)

Graft failure — Graft failure can be observed in patients with non-SCID IEI, and a variety of factors may contribute to the risk. Primary graft failure is typically defined as a failure to engraft following allogeneic HCT [17]. Patients may require an emergent second transplant in the absence of autologous recovery. Secondary graft failure is typically said to have occurred if engraftment initially occurred but was subsequently lost, resulting in cytopenias in at least two blood cell lineages [17]. Graft failure can be due to immune-mediated rejection and is sometimes referred to as graft rejection in this situation. Secondary graft failure can also be said to have occurred in the setting of having only low-level donor chimerism in either whole blood or within a particular cell type relevant to the underlying IEI. For instance, a patient with CGD who is nine months posttransplant with normal complete blood count parameters but only 4 percent donor chimerism in peripheral blood and 2 percent in myeloid cells is considered to have secondary graft failure. (See "Hematopoietic support after hematopoietic cell transplantation" and "Early complications of hematopoietic cell transplantation".)

Graft T cell depletion can lead to increased rates of graft failure [18]. Nonmyeloablative (NMA) and reduced-intensity conditioning (RIC) regimens are associated with increased rates of graft failure. Underlying disease can also increase the risk, and patients with immune dysregulatory diseases such as immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and gain-of-function signal transducer and activator of transcription 1 (STAT1) mutations have increased rates of graft failure.

Mixed chimerism — Following allogeneic HCT, especially if patients receive NMA conditioning or RIC, recipient marrow can recover alongside donor marrow engraftment. Mixed chimerism is often defined as having donor-derived cells that account for less than 95 percent of peripheral blood samples. Patients with most IEI do not require complete donor chimerism for cure of the underlying disease but may develop symptoms of disease with ill-defined low levels of donor chimerism (generally less than 5 to 20 percent) within relevant cell types. (See "Hematopoietic support after hematopoietic cell transplantation", section on 'Chimerism'.)

Graft-versus-host disease prophylaxis — Immunosuppressive agents, such as calcineurin inhibitors, are often given posttransplant to prevent GVHD in patients who receive unmanipulated graft products. Certain chemotherapeutic agents can be given following transplant as part of acute GVHD prophylaxis (such as methotrexate or cyclophosphamide). These agents target proliferating T cells that are responding to recipient alloantigens. In settings where donor grafts are manipulated to remove donor T cells, it may be possible to avoid GVHD prophylaxis. GVHD is discussed in greater detail separately (See "Prevention of graft-versus-host disease" and "Treatment of acute graft-versus-host disease" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Treatment of chronic graft-versus-host disease" and 'Conditioning serotherapy' above and 'Graft engineering' above.)

RECONSTITUTION OF IMMUNE FUNCTION — Immune reconstitution following allogeneic HCT takes time, and infection remains a significant cause of mortality and morbidity following allogeneic HCT until this takes place.

Neutrophils – Neutrophils usually recover within one month [19].

Natural killer (NK) cells – NK cells recover within one to three months [19].

T cells – Development of new T cells from the allogeneic graft typically takes at least three months, but recovery of T cell function may begin earlier in patients who have received nonablative conditioning or in those who have human leukocyte antigen (HLA) matched grafts not fully depleted of T cells. Complete T cell reconstitution generally takes 6 to 12 months [19]. T cell reconstitution can be delayed in patients who receive serotherapy or who develop graft-versus-host disease (GVHD). Patients are kept in isolation and are given prophylactic antimicrobial medicines and immune globulin infusions until adequate T cell recovery has been demonstrated. (Immune globulin replacement continues until B cell recovery has also occurred.)

B cells – B cell recovery after HCT for non-SCID IEI is generally slower than T cell recovery. Patients receive immune globulin infusions intravenously or subcutaneously to maintain protective immunoglobulin G (IgG) levels, and replacement may be needed for one to two years or even longer. Patients are monitored for appearance of donor B cells and serum immunoglobulin A (IgA) and immunoglobulin M (IgM) following HCT (immune globulin products do not contain a significant amount of IgA or IgM). In addition, isohemagglutinins, natural antibodies to blood group antigens A and B, are specific antibodies of the IgM class that can be found in persons whose B cell function has recovered, depending upon their blood type. Isohemagglutinin titers of 1:8 or higher are associated with intact specific antibody production. After immune globulin infusions are stopped, vaccination against childhood illnesses is undertaken, first with killed vaccines. Live vaccines should not be given until there has been demonstration of specific antibody production to killed vaccines and freedom from infections.

LONG-TERM PROGNOSIS — The largest European collective report regarding allogeneic HCT outcomes for patients with a non-SCID IEI included 783 patients treated at 37 European centers [5]. The patients had various disorders including Wiskott-Aldrich syndrome (WAS), non-SCID T cell deficiencies, chronic granulomatous disease (CGD), leukocyte-adhesion deficiency (LAD), and hemophagocytic lymphohistiocytosis (HLH) disorders. The four-year probability of survival for all non-SCID patients who were transplanted between the years 2000 and 2005 was 69 percent (95% CI 60-78 percent). Patients who were transplanted with completely human leukocyte antigen (HLA) matched, unaffected sibling donors had the highest survival (79% CI 69-89 percent). A history of respiratory impairment and malnutrition adversely affected survival. A report from the Center for International Blood and Marrow Transplant Research (CIBMTR) included 1902 patients with non-SCID IEI [20]. Three-year overall survival in the 816 non-SCID patients transplanted between 2010 and 2016 was 75 percent.

There are several complications of allogeneic HCT that manifest late after transplant. Following intensive chemotherapy, endocrine problems such as hypothyroidism, growth issues, and delayed puberty or infertility can occur, and patients are at increased risk of secondary malignancies. Patients with IEI remain at risk of death from transplant-related complications for as long as six years or longer following allogeneic HCT [21]. Chronic graft-versus-host disease (GVHD) is the biggest contributor to this risk of late death. (See "Long-term care of the adult hematopoietic cell transplantation survivor" and "Clinical manifestations and diagnosis of chronic graft-versus-host disease" and "Treatment of chronic graft-versus-host disease".)

Another consideration in non-SCID immunodeficiency is that the underlying disorder may not be fully corrected by HCT, particularly in patients whose gene defects cause impairments in multiple organ systems, such as signal transducer and activator of transcription 3 (STAT3) haploinsufficient hyper-immunoglobulin E (IgE) syndrome, a multisystem disorder. Diabetes caused by immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) or other immune dysregulatory disorders does not resolve. Food allergies associated with dedicator of cytokinesis 8 (DOCK8) deficiency or other disorders may persist. Organ damage due to infections prior to HCT, especially bronchiectasis or other lung disease, may not improve post-HCT.

For all of these reasons, patients who have received HCT must be followed indefinitely in survivors' clinics. As with recipients of HCT for malignancy, those with IEI disorders may suffer long-term consequences from both the transplant chemotherapy and their underlying condition that may raise their risk for malignancies later in life.

GENOTYPE-SPECIFIC CONSIDERATIONS — IEI encompass over 450 different genetic diseases, which have a wide spectrum of manifestations [14,15]. Diseases are often grouped phenotypically [22]. Some IEI are characterized predominantly by risk of life-threatening infections, and the range of infections can be broad or limited to only a few specific pathogens. Other IEI are characterized predominantly by immune dysregulation and manifest as life-threatening autoimmunity or hyperinflammation. The variability in disease pathophysiology and clinical manifestations among different IEI results in nuanced approaches to some specific IEI or IEI phenotypic groups. The frequency at which HCT is used also varies by phenotypic category (table 1). Specific genotypes may require different approaches to HCT and have distinct outcomes and complications. Awareness of these differences will help optimize the approach to HCT.

Non-SCID combined immunodeficiencies — The indications for HCT for non-SCID combined immunodeficiency primarily depend upon the severity of the specific disorder. Combined immunodeficiencies for which HCT is often used include CD40 ligand (CD40L) deficiency, dedicator of cytokinesis 8 (DOCK8) deficiency, zeta chain-associated protein kinase of 70 kD (ZAP-70) deficiency, and major histocompatibility complex class II (MHC-II) deficiency, among others.

Combined immunodeficiencies that are due to congenital athymia such as DiGeorge syndrome/velocardiofacial syndrome/chromosome 22q11.2 deletion syndrome and diseases due to pathogenic variant(s) in T-box transcription factor 1 (TBX1), T-box transcription factor 2 (TBX2), chromodomain helicase DNA-binding protein 7 (CHD7), forkhead box N1 (FOXN1), and paired box 1 (PAX1) should not be treated by allogeneic HCT, since allogeneic HCT does not replace thymic tissue. Patients with combined immunodeficiencies due to congenital athymia disorders are optimally treated with cultured thymus tissue implantation [23]. (See "DiGeorge (22q11.2 deletion) syndrome: Management and prognosis", section on 'Cultured thymic transplant'.)

CD40L deficiency — The indication for allogeneic HCT in patients with CD40L deficiency remains somewhat controversial because data from earlier decades showed similar survival outcomes for transplanted and untransplanted patients [1]. However, data from more recent transplants reveal higher quality-of-life scores and better survival in those who underwent HCT [1,2]. Similar to Wiskott-Aldrich syndrome (WAS), younger age at allogeneic HCT is associated with better outcomes [24]. Liver disease is a common complication observed in patients with CD40L deficiency and is a predictor of poor outcome when present at the time of allogenic HCT. Analyses reveal that history of liver disease, Cryptosporidium infection, and sclerosing cholangitis all significantly adversely affect survival [24]. More experience and longer follow-up will be required to determine if HCT can prevent liver disease associated with CD40L deficiency. Successful sequential/combined liver transplantation and HCT has been reported [25,26]. An international collaborative effort that published outcomes for 130 patients in 2019 observed overall and disease-free survival of 78.2 and 72.3 percent five years after HCT, respectively [24]. (See "Hyperimmunoglobulin M syndromes", section on 'Hematopoietic cell transplantation'.)

DOCK8 deficiency — Dedicator of cytokinesis 8 (DOCK8) deficiency is a typically moderate-to-severe IEI, and less than half of patients survive into their 20s [27]. Allogeneic HCT is often indicated. Preexisting infections or other complications such as malignancy or central nervous system complications can impact care. Survival was 84 percent after a median follow-up of 26 months in a 22-center retrospective study of allogeneic HCT outcomes for 81 patients with DOCK8 deficiency transplanted between 1995 and 2015 [28]. Survival was higher with matched related compared with unrelated donors (89 versus 81 percent), reduced-intensity compared with fully myeloablative conditioning (RIC versus MAC; 97 versus 78 percent), and transplantation at <8 years compared with ≥8 years of age (96 versus 78 percent). There appeared to be a selective advantage for donor-derived T cells and switched memory B cells in patients with mixed chimerism. The frequency and severity of infections decreased and eczema improved or resolved in nearly all patients, but food allergies and failure to thrive were slower to improve and persisted in some patients. (See "Combined immunodeficiencies".)

Syndromic combined immunodeficiencies — Allogeneic HCT is often indicated for certain syndromic immunodeficiencies, including WAS, nuclear factor (NF) kappa-B essential modifier (NEMO) deficiency, and cartilage-hair hypoplasia with significant immune compromise. Decisions regarding HCT for these conditions must weigh the risks of continued medical management versus HCT to arrive at the best treatment for each patient.

Wiskott-Aldrich syndrome — Allogeneic HCT is typically indicated in WAS due to the life-threatening complications of infection, malignancy, and bleeding. The majority of patients with WAS are transplanted with myeloablative regimens because they need durable donor lymphoid and myeloid engraftment for correction of both the lymphocyte and the platelet defects [29-33]. Donor myeloid chimerism of less than 50 percent has been associated with thrombocytopenia and autoimmunity [29]. (See "Wiskott-Aldrich syndrome", section on 'Hematopoietic cell transplantation'.)

A collaborative report of 196 patients with WAS who underwent HCT from 1980 to 2009 observed survival of greater than 80 percent in all patients [29]. The five-year survival of patients who were transplanted in the year 2000 or later was 90 percent. Better outcomes were associated with age <5 years at transplant and achievement of full donor chimerism [29-33]. Historically, use of a matched sibling donor (MSD) rather than a T cell-depleted mismatched family donor was associated with superior outcomes, but this gap is closing.

Graft failure occurred in 7 percent of patients in the largest series, most of whom had received T cell-depleted mismatched family donor grafts [29]. Other reported complications included serious infections (28 percent), grade III to IV acute graft-versus-host disease (GVHD; 11 percent), chronic GVHD (6 percent), autoimmune cytopenias or endocrinopathies (14 percent), and malignancy (3 percent).

Anhidrotic ectodermal dysplasia with immunodeficiency (NEMO deficiency) — Nuclear factor kappa-B essential modulator (NEMO) deficiency has a wide phenotypic variability, and allogeneic HCT is often but not always performed for that reason. Both myeloablative and reduced-intensity approaches have been used. Reported survival was 74 percent overall (median follow-up 57 months) and 100 percent in those with MSDs in a series of 29 patients with NEMO pathogenic variants who underwent allogeneic HCT [34]. Allogeneic HCT may not cure colitis, possibly due to lack of NEMO-dependent gastrointestinal epithelial cell function. (See "Combined immunodeficiencies", section on 'Treatment' and "Syndromic immunodeficiencies".)

Diseases of immune dysregulation — These include disorders with increased susceptibility to Epstein-Barr virus (eg, X-linked lymphoproliferative disease [XLP]), familial forms of hemophagocytic lymphohistiocytosis (HLH), regulatory T cell defects (eg, immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX]), and HLH disorders with hypopigmentation (eg, Chediak-Higashi syndrome).

X-linked lymphoproliferative disease — Most patients with X-linked lymphoproliferative disease type 1 (XLP1) due to SH2 domain-containing 1A (SH2D1A) pathogenic variants undergo allogeneic HCT because of their high risk of developing fatal HLH due to Epstein-Barr virus and lymphoma, also most often associated with Epstein-Barr virus. Survival was 81 percent in a larger, older study of 43 patients, with better survival in patients without a history of HLH [35]. The indications for transplantation in patients with XLP2 (due to pathogenic variants in X-linked inhibitor of apoptosis [XIAP]) are less clear as there is a wider phenotypic spectrum of disease [36]. Patients with XIAP deficiency do poorly with fully myeloablative conditioning regimens [37]. Patients appear to do well with reduced-intensity and reduced-toxicity regimens when in remission of HLH [36-38]. Patients are at increased risk of GVHD complications based upon murine and observational human data [39-41]. (See "X-linked lymphoproliferative disease", section on 'Curative therapy'.)

Familial hemophagocytic lymphohistiocytosis and related pigmentary disorders associated with HLH — Allogeneic HCT is performed for most patients with primary HLH disorders due to pathogenic variants in perforin 1 (PRF1); unc-13 homolog D (UNC13D); syntaxin-binding protein 2 (STXBP2); syntaxin 11 (STX11); RAB27A, member RAS oncogene family (RAB27A); and lysosomal trafficking regulator (LYST) due to the risk of recurrent life-threatening HLH. Many transplant clinicians recommend performing allogeneic HCT in asymptomatic individuals diagnosed with a genetic HLH disorder because of a family history since data suggest that post-HCT outcomes are better in patients who have never developed HLH [35]. However, HCT in asymptomatic patients remains controversial.

The presence of refractory HLH at the time of transplant can adversely affect outcomes, although transplantation should not be unduly delayed if remission cannot be attained, because death may ensue. Survival has improved significantly since conditioning regimens were switched from myeloablative to reduced intensity. However, RIC regimens are associated with high rates of mixed chimerism and need for interventions including donor lymphocyte infusion, stem cell boosts, and second transplants [42,43]. An analysis from the Center for International Blood and Marrow Transplant Research (CIBMTR) including 261 patients with HLH disorders transplanted between 2005 and 2018 revealed event-free survival of only 44 percent in those who received fludarabine and melphalan RIC, and this approach has fallen out of use [44]. The optimal approach in HLH disorders is not known, though experience with reduced-toxicity approaches such as busulfan and fludarabine or fludarabine, melphalan, and thiotepa is increasing, and event-free survival observed in the aforementioned study with those approaches was 70 to 79 percent [44]. HCT may halt central nervous system (CNS) disease, but fixed neurologic defects may not improve [45]. In addition, early relapse of HLH, particularly with CNS disease, can occur following HCT. Low donor chimerism is associated with relapse. Monitoring for CNS disease and donor engraftment is indicated. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Allogeneic hematopoietic cell transplant'.)

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) — IPEX is typically a severe disease, and allogeneic HCT is usually performed. A 2018 collaborative examination of 96 patients observed that 60 percent of patients had been treated with allogeneic HCT at the time of writing [46]. Preexisting multiorgan autoimmunity can make allogeneic HCT challenging in patients with IPEX, with higher rates of organ involvement associated with lower rates of survival [46]. Endocrinopathies frequently persist after HCT in those with preexisting organ damage. Mixed chimerism is common in IPEX patients but can still result in disease resolution, particularly in patients with high levels of regulatory T cell donor chimerism. Uniquely, mixed chimerism in these patients is not correlated with the use of RIC. A variety of conditioning approaches are used in IPEX. Some patients with IPEX required a second transplant. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked", section on 'Hematopoietic cell transplantation'.)

Phagocyte defects — Phagocytic cell defects that can be treated with HCT commonly include chronic granulomatous disease (CGD) and leukocyte-adhesion deficiency (LAD).

Chronic granulomatous disease — Allogeneic HCT for patients with CGD is often indicated to prevent or resolve life-threatening infections or other complications such as inflammatory bowel disease. Allogeneic HCT can be challenging in patients with CGD due to the presence of refractory fungal or other microbial infections or preexisting pulmonary, liver, or gastrointestinal disease, all of which are more common in patients with an older age at diagnosis or HCT. Historically, MAC regimens were used for allogeneic HCT in CGD [47,48]. However, it has become clear that MAC regimens were not always required and had a higher risk of peritransplant mortality. Thus, reduced-toxicity/reduced-intensity approaches that are often still myeloablative/submyeloablative are more commonly being used. These approaches have resulted in improved survival with limited toxicity and low rates of GVHD, although graft failure has occurred in some patients, and others have required additional interventions to maintain donor chimerism [7,49-52]. A large collaborative allogeneic HCT study of 712 patients observed three-year overall and event-free survival of 86 and 76 percent, respectively [53]. Choice of conditioning regimen did not influence outcomes. Patients transplanted after age 18 years or with HLA-mismatched donors had inferior outcomes [53]. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Hematopoietic cell transplantation'.)

Leukocyte-adhesion deficiency — The severe forms of LAD are usually treated with allogeneic HCT. Survival is lowest with haploidentical donors compared with matched related or unrelated donors [54]. A variety of conditioning approaches have been used. Three-year survival among a large cohort of 84 patients with LAD type I and type III was 83 percent, and transplant before 13 months of age and receipt of a MSD graft were associated with superior outcomes [55]. (See "Leukocyte-adhesion deficiency", section on 'Severe phenotype' and "Leukocyte-adhesion deficiency", section on 'Treatment and prognosis'.)

Defects in intrinsic and innate immunity — These disorders include defects that lead to Mendelian susceptibility to mycobacterial disease, such as GATA-binding protein 2 (GATA2) deficiency and signal transducer and activator of transcription 1 (STAT1) autosomal-recessive loss-of-function defects, as well as STAT1 gain-of-function (GOF) defects that cause increased susceptibility to a variety of severe infections, as well as autoimmunity.

GATA2 deficiency — Allogeneic HCT was performed in 22 patients with GATA2 deficiency, with 86 percent overall disease-free survival with a mean follow-up of 24 months [56]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'GATA2 deficiency (MonoMAC syndrome)'.)

STAT1 gain-of-function defects — Patients with STAT1 GOF pathogenic variants have been treated with allogeneic HCT, but survival was low (40 percent) in one series of 15 patients, and graft failure was common [57]. Preexisting HLH may have contributed to the observed mortality in two patients. More experience is needed to better understand the role of allogeneic HCT as well as develop optimal approaches. (See "Chronic mucocutaneous candidiasis", section on 'Signal transducer and activator of transcription (STAT1) dysfunction'.)

Complement deficiencies — Most complement deficiencies are not curable with allogeneic HCT, because most complement components are produced by the liver and not by hematopoietic cells. An exception is C1q deficiency. Hematopoietic cells are a major source of C1q, and there are case reports of cures with allogeneic HCT [58-60]. (See "Inherited disorders of the complement system", section on 'C1 deficiency'.)

EXPERIMENTAL APPROACHES AND ALTERNATIVES TO HCT — There are numerous developments in this rapidly moving field that may improve outcomes for the diseases discussed here.

Given the better outcomes of HCT from human leukocyte antigen (HLA) matched sibling donors (MSDs), some couples wishing to enlarge their families have opted for in vitro fertilization and preimplantation genetic testing of the resulting embryos in order to have a baby who is unaffected with the condition and is a perfect HLA match with the existing affected child. However, the probability of success with this approach is not high, and genetic counseling is essential. (See "In vitro fertilization: Overview of clinical issues and questions" and "Preimplantation genetic testing".)

Avoidance of toxic chemotherapy may be possible with biologic or small molecule therapies that specifically target patient hematopoietic stem cells (HSCs) for destruction. One such agent in clinical trials is a monoclonal antibody to the cell surface kinase cKit [61].

Gene therapy, in which patient HSCs are removed and treated ex vivo with addition of a correct copy of the mutated gene, has been successful in clinical trials for Wiskott-Aldrich syndrome (WAS) and X-linked chronic granulomatous disease (CGD) [62]. Autologous corrected cells do not have the problems of graft rejection or graft-versus-host disease (GVHD) that are seen with allogeneic transplants. (See "Overview of gene therapy for primary immunodeficiency" and "Wiskott-Aldrich syndrome", section on 'Gene therapy' and "Chronic granulomatous disease: Treatment and prognosis", section on 'Gene therapy/gene repair'.)

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

Indications – Allogeneic hematopoietic cell transplantation (HCT) is an option for definitive therapy for many inborn errors of immunity (IEI, includes the former term primary immunodeficiencies) (table 1). However, there are many life-threatening complications of allogeneic HCT. Thus, clinicians must weigh the risks and benefits of allogeneic HCT against the risks of the underlying IEI. (See 'Introduction' above and 'Indications' above.)

Parent/caregiver preferences – A major challenge with HCT for IEI other than severe combined immunodeficiency (SCID) is that parents/caregivers may not agree to expose their child to the risks of HCT early in life, before onset of major infections or organ damage, but the risks of HCT are greater after these complications have occurred. (See 'Parent/caregiver preferences' above.)

Conditioning chemotherapy – There is sufficient host immunity to resist engraftment of allogeneic cells in all non-SCID IEI. Thus, some type of pretransplant conditioning is always required to prevent graft failure. (See 'Conditioning chemotherapy' above.)

Donor choice – As with all allogeneic HCT, a matched related (sibling) donor (MRD/MSD) is considered the optimal choice. However, improvements in graft processing, conditioning regimens, and prevention of posttransplant complications have made matched unrelated donor (MUD) and mismatched related donor (MMRD) HCT viable options in patients without an MSD. (See 'Donor choice' above.)

Prognosis following HCT – Survival rates following allogeneic HCT for most non-SCID IEI are approximately 70 percent or higher, and, in general, younger age and better health status (particularly absence or control of severe infections and/or autoimmune disease) at the time of transplantation are associated with superior outcomes. (See 'Pretransplant considerations' above and 'Long-term prognosis' above.)

Genotype-specific considerations – Specific genotypes may require different approaches to HCT and have distinct outcomes and complications. (See 'Genotype-specific considerations' above.)

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Topic 3941 Version 19.0

References