Hematopoietic Cell Transplantation for Primary Immunodeficiency Disorders

Number: 0830

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for primary immunodeficiency disorders.

Medical Necessity
1. Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the following primary immunodeficiency disorders (PID) (not an all-inclusive list):
  1. Adenosine deaminase deficiency
  2. Autoimmune lymphoproliferative syndrome
  3. Cartilage hair hypoplasia
  4. CD40 ligand deficiency
  5. Chediak-Higashi syndrome
  6. Chronic granulomatous disease
  7. Common variable immune deficiency (CVID)
  8. DiGeorge syndrome
  9. Griscelli syndrome type 2
  10. Hemophagocytic lymphohistiocytosis
  11. IL-10 receptor deficiency
  12. Immune dysregulation, poly-endocrinopathy, enteropathy, X-linked syndrome (IPEX)
  13. Kostmann syndrome (also known as severe congenital neutropenia, autosomal recessive type 3 [SCN3])
  14. Leukocyte adhesion deficiency type 1
  15. MHC class I deficiency
  16. MHC class II deficiency
  17. Purine nucleoside phosphorylase deficiency
  18. Severe combined immunodeficiency (SCID)
  19. Severe congenital neutropenia
  20. Wiskott-Aldrich syndrome (WAS)
  21. WAS X-linked thrombocytopenia
  22. X-linked lymphoproliferative syndrome
  23. Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency.
2. T-cell receptor excision circle (TREC) testing is considered medically necessary following allogeneic hematopoietic stem cell transplant for severe combined immunodeficiency (SCID).
Experimental, Investigational, or Unproven

Aetna considers hematopoietic cell transplantation experimental, investigational, or unproven for the following indications because the effectiveness of these approaches has not been established:
1. Allogeneic hematopoietic cell transplantation for the treatment of any of the following (not an all-inclusive list):
  1. Activated phosphoinositide 3-kinase delta syndrome;
  2. Complement deficiency;
  3. Granulomatous-lymphocytic interstitial lung disease;
  4. Inflammatory bowel disease;
  5. Juvenile idiopathic arthritis;
  6. Pulmonary alveolar proteinosis;
2. Autologous hematopoietic cell transplantation for primary immunodeficiency disorders.
Related Policies

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes covered if selection criteria are met:
38205	Blood derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogenic
38230	Bone marrow harvesting for transplantation; allogenic
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
CPT codes not covered for indications listed in the CPB:
38232	Bone marrow harvesting for transplantation; autologous
38241	Hematopoietic progenitor cell (HPC); autologous transplantation
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre- and post-transplant care in the global definition
ICD-10 codes covered if selection criteria are met:
D69.42	Congenital and hereditary thrombocytopenia purpura
D70.0	Congential agranulocytosis
D71	Functional disorders of polymorphonuclear neutrophils
D76.1	Hemophagocytic lymphohistiocytosis
D80.5	Immunodeficiency with increased immunoglobulin M [IgM]
D81.30 - D81.39	Adenosine deaminase [ADA] deficiency
D81.5	Purine nucleoside phosphorylase [PNP] deficiency
D81.6	Major histocompatibility complex class I deficiency
D81.9	Combined immunodeficiency, unspecified
D82.0	Wiskott-Aldrich syndrome
D82.1	DiGeorge's syndrome
D82.3	Immunodeficiency follow hereditary defective response to Epstein-Barr virus
D83.9	Common variable immune deficiency
D84.8	Other specified immunodeficiencies [leukocyte adhesion deficiency type1]
D84.89	Other immunodeficiencies [not covered for activated phosphoinositide 3-kinase delta syndrome]
D89.82	Autoimmune lymphoproliferative syndrome
E34.8	Other specified endocrine disorders [IPEX]
E70.330	Chediak-Higashi syndrome
ICD-10 codes not covered for indications listed in the CPB:
D84.1	Defects in the complement system
J84.01	Alveolar proteinosis
J84.89	Other specified interstitial pulmonary diseases [granulomatous-lymphocytic interstitial lung disease]
K50.00 - K50.919	Crohn’s disease [regional enteritis]
K51.00 - K51.919	Ulcerative colitis
M08.00 - M08.99	Juvenile arthritis, unspecified [juvenile idiopathic arthritis]
*T-cell receptor excision circle (TREC)*:
CPT codes covered if selection criteria are met:
T-cell receptor excision circle (TREC) - no specific code:
ICD-10 codes covered if selection criteria are met:
D81.0	Severe combined immunodeficiency [SCID] with reticular dysgenesis
D81.1	Severe combined immunodeficiency [SCID] with low T- and B-cell numbers
D81.2	Severe combined immunodeficiency [SCID] with low or normal B-cell numbers
D81.9	Combined immunodeficiency, unspecified
Z94.84	Stem cells transplant status [allogeneic hematopoietic stem cell transplant]

Background

Primary immunodeficiency disorders (PIDs) constitute a group of highly complex congenital disorders, most of which are characterized by poor prognosis with high mortality and morbidity (Al-Ghonaium, 2008). PIDs are genetically heterogenous, affecting distinct components of the innate and adaptive immune system. More than 120 distinct genes have been identified and the World Health Organization lists more than 150 different forms of primary immunodeficiencies (Geha et al, 2007). The most common forms of PID include ataxia telangiectasia, common variable immunodeficiency (CVID), DiGeorge syndrome, hypogammaglobulinemia, IgG subclass deficiency, severe combined immunodeficiency (SCID), selective IgA deficiency, and X-linked agammaglobulinemia (XLA).

Lindegren et al (2004), in a report of the findings of a November 2001 Centers for Disease Control (CDC) workshop convened to discuss means to improve health outcomes among persons with PID, reported that “approximately 100 separate [primary immunodeficiency (PI)] diseases have been described, but less than 20 probably account for greater than 90% of cases. Although diverse, PIDs share the common feature of susceptibility to infection and result in substantial morbidity and shortened life spans. Most important, prompt diagnosis and treatment can now lead to life-saving treatment and result in marked improvements in the quality and length of life for persons with PIDs.” The prevalence of PIDs increases as researchers discover novel immunodeficiency syndromes and as clinicians increasingly recognize and diagnose nuanced presentations of immunodeficiency (Savides and Shaker, 2010).

The goal of hematopoietic cell transplantation (HCT) in PID is to restore the number and/or function of lymphocytes or phagocytes through selection of matched, related or unrelated donors, or related haploidentical donors to minimize the risk of graft versus host disease (GVHD) and that prophylactic immunosuppression is performed to minimize risk of GVHD (Garcia et al, 2007). Allogeneic stem cell transplantation (allo-SCT) involves transplanting stem cells, most often obtained from bone marrow, from a compatible donor whereas autologous stem cell transplantation (auto-SCT) involves the use of stem cells harvested from the patient. Haploidentical donors share a haplotype; having the same alleles at a set of closely linked genes on one chromosome. Donor T-lymphocyte depletion is also performed in haploidentical and unrelated donors (Garcia et al, 2007). Pre-transplantation conditioning regimens, method and use of T-cell depletion, and/or GVHD prophylaxis vary widely among transplantation centers (Griffith et al, 2009).

The National Institute of Child Health and Human Development (NICHD) states that “for several life-threatening immunodeficiencies, bone marrow transplantation (BMT) offers the chance of a dramatic, complete, and permanent cure. Since the first BMT was performed in 1968, nearly 1,000 children with PI, including SCID, WAS, leukocyte adhesion defect, and other disorders, have shown a remarkable recovery. They recover from infections, gain weight, and move on to essentially normal lives.” It has also been noted by NICHD that BMT works especially well for SCID (NICHD, 2012).

The first stem cell transplants for PID were performed in 1968 and Filipovich (2008) reports that “significant progress has been made since that time due to

the ability to phenotype and quantitate (CD34+) hematopoietic cells,
the advent of high-resolution tissue typing,
availability of closely matched unrelated donor bone marrow, peripheral blood, stem cells, and cord blood, and
the application of reduced intensity conditioning regimens pre-transplant.”

Antoine et al (2003) reported on PID data collected from 37 European stem-cell transplantation registries in 18 countries, with a total of 1082 transplants studied in 919 patients (566 in 473 SCID patients and 512 in 333 non-SCID patients). Four procedures were excluded owing to insufficient data. For SCID patients, 3-year survival was significantly better following HLA-identical than after mismatched transplantation (77% vs 54%; p = 0.002). Survival in these patients improved over time. In the non-SCID study population, 3-year survival after genotypically and phenotypically human leukocyte antigen (HLA)-matched, HLA-mismatched related, and unrelated donor transplantation was 71%, 42%, and 59%, respectively (p = 0.0006). Acute GVHD predicted poor prognosis regardless of donor origin with the exception of related HLA-identical transplantation in SCID. The authors hypothesized that the improvement in survival over time indicates more effective prevention and treatment of disease-related and procedure-related complications such as infections and GVHD, which can be better prevented in the HLA-non-identical setting through use of improved efficiency in T-cell depletion. The authors concluded that the improvement in survival over time indicates more effective prevention and treatment of disease-related and procedure-related complications such as infection and GVHD.

Land et al (2007) reported that the therapeutic options for DiGeorge syndrome (DGS) with profound T-cell deficiency are very limited. Although not readily available, thymic transplantation has shown promising results. The authors further stated that "HCT has been successful in restoring immune competence in the short term". Land et al conducted a long-term follow-up of 2 patients with complete DGS who received bone marrow transplants in the neonatal period from HLA-matched siblings, and performed a multicenter survey to document the status of other patients with DGS who have undergone HCT. Among reported patients with DGS receiving HCT, the authors found survival was greater than 75% among reported patients with DGS receiving HCT. Their hematopoietic compartment showed continuous engraftment with mixed chimerism, normal T-cell function, and humoral immunity. Thus, the authors concluded that bone marrow transplant in complete DGS using an HLA-matched sibling donor provides long-lasting immunity and is a suitable and more available alternative to thymic transplantation.

Diaz de Heredia et al (2008) studied fifteen PID children with a median age of 11.6 months (SCID 11, X-linked lymphoproliferative syndrome 2, Omenn's syndrome 1, WAS 1), who received an umbilical cord blood (UCB) transplant where the donor was unrelated in 14 cases and related in 1 case. All patients engrafted and the authors found that eight patients developed acute GVHD grades II-IV and one chronic GVHD, and that viral and fungal infections were frequent. Four patients died during the follow up period, three from GVHD grade IV complicated by infection and one from progressive interstitial lung disease. All surviving patients presented complete immunologic reconstitution with a five year survival rate of 0.73 +/- 0.12 for the overall study population.

Petrovic et al (2009) retrospectively analyzed the transplantation outcomes of 31 patients with PIDs treated from 1986 - 2009 at All Children's Hospital, University of South Florida. Study subjects ranging in age from 1 month to 19 years with SCID, WAS, X-linked hyper-IgM syndrome, and chronic granulomatous disease were included. In 23 patients, the graft source was bone marrow, 4 patients received umbilical cord blood grafts, and 4 patients received peripheral blood stem cell grafts. The authors concluded that better survival rates were observed in those patients transplanted at a younger age and free of infections, demonstrating that transplantation at an early age before significant infections, autoimmune manifestation and malignant transformation have occurred is beneficial.

Friedrich et al (2009) reported on an analysis of 39 WAS patients treated by HCT with a mean follow-up time of 11 years. Fifteen patients received transplants from HLA-identical unrelated donors, 15 from nonidentical parental donors, and 9 from matched siblings, with an overall survival rate is 90% in patients with matched donors and 50% in patients after nonidentical transplantation. Treatment failures in the latter group were mainly related to graft rejections, GVHD, and infections following repeat transplants. Long-term survivors in both patient groups remain with few exceptions, free of late complications and with stable graft function and complete donor cell chimerism. The authors concluded that early and prompt treatment of each diagnosed WAS patient if an HLA-matched, related, or unrelated donor can be identified is recommended. If this is not the case, HLA-nonidentical donor transplantation represents an alternative to be considered early in patients with severe disease.

Griffith et al (2009) described results of a survey conducted by a collaborative network of North American investigators caring for patients with PID. The network of investigators have formed the Primary Immune Deficiency Treatment Consortium (PIDTC), which is a part of the National Institutes of Health Rare Diseases Clinical Research Network (PIDTC, 2012). The PIDTC, although acknowledging the challenges of determining formal guidelines given the rare nature of PID and its many sub-types, are continuing to work toward the development of a database sufficiently robust that evidence-based guidelines can be provided. The PIDTC recommends early diagnosis and definitive therapy for SCID as essential, including referral to a center with experience in HCT. The forms of non-SCID the PIDTC has determined are correctable by means of HCT are presented in Table 1.

Straathof et al (2009) conducted a Phase I/II study of HCT with antibody-based minimal intensity conditioning. The authors stated that stem-cell transplantation can cure primary immunodeficiencies, but in patients with pre-existing organ toxicity, younger than 1 year, or with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated. They evaluated a minimal-intensity conditioning regimen in 16 high-risk PID patients. The conditioning treatment consisted of antibodies YTH 24.5 and YTH 54.12 combined with alemtuzumab, fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings, or matched and mismatched unrelated donors. The investigators found that their conditioning regimen was well tolerated and reported their rates of clinically significant acute (36%) and chronic (31%) GVHD as acceptable. Only one patient required re-transplantation. Thus, the authors concluded that their conditioning regimen may reduce toxicity and late effects and enable HCT in virtually any PID patient with a matched donor.

Gennery et al (2010) evaluated the long-term outcome of patients with SCID and non-SCID PID treated between 1968 and 2005. Patients with SCID who had geno-identical donors (n = 25) had survival rates of 90%. Multivariate analysis showed that transplantation after year 1995, younger age, B (+) phenotype, geno-identical or pheno-identical donors, and absence of respiratory impairment or viral infection before transplantation were associated with better prognosis. Non-SCID PID patients using an unrelated donor (n = 124) were found to have a 3-year survival rate similar to that of a genoidentical donor (n = 73), at 76% for both. Survival was 76% in phenoidentical transplants (n = 23) and 46% (n = 47) in mismatched related donor transplants. The authors concluded that individual disease categories should be analyzed to aid in specifying disease-specific prognosis and optimizing treatment planning.

Morio et al (2011) performed UCB transplantation in 88 PID patients. The forms of PID included SCID (n = 40), WAS (n = 23), chronic granulomatous disease (n = 7), severe congenital neutropenia (n = 5), and other immunodeficiencies (n = 13). Five-year overall survival was 69% (95% confidence interval, 57 - 78%). The cumulative incidence of grade 2 - 4 acute GVHD at day 100 was 28% (95% confidence interval, 19 - 38%). The authors concluded that UCB transplantation should be considered for PID patients without an HLA-matched sibling.

Martin-Nalda et al (2011) conducted a retrospective review of 189 PID patients diagnosed in a pediatric tertiary care hospital over a period of 10 years. In all but 2 SCID patients, stem cell transplantation was performed. There were positive outcomes in all but 8 SCID patients (2 prior and 6 after transplantation), 3 WAS patients, 1 complete DiGeorge patient, 1 chronic granulomatous disease patient, and 1 ataxia-telangiectasia patient, who died during follow-up. The authors concluded that the vast majority of patients in this series presented with typical clinical features, reinforcing that education of primary care providers allowing earlier diagnosis of PID leads to proper treatment and monitoring and results in improved prognosis.

Kohn (2010), in discussing autologous stem cell transplantation for PID as an alternative to allogeneic transplantation, stated that use of genetically corrected autologous stem cells represents an alternative treatment for patients with PID and could avoid the immunological risks of allogeneic HCT and confer similar benefits. However, Kohn reports that despite the initial successes that have been achieved utilizing gene therapy as an alternative to allogeneic HCT, there have been some serious complications and that additional challenges remain to the broad application of gene therapy for PID. Kohn further noted that “each specific disorder requires a dedicated effort to produce the relevant reagents, perform the pre-clinical efficacy and safety studies and develop the clinical trial protocol and reagents. These are relatively expensive activities that take several years to bring to fruition. However, the human as well as medical costs incurred by severe PID makes these efforts worthwhile and of high importance.”

Table 1: Management of Non-SCID PIDs
Disorder	Indication for HSCT	Chimerism
Cartilage hair hypoplasia	Recommended in patients with severe T-cell deficiency, especially if MFD or MUD is available. Haploidentical transplants might also have a role in the management of this disease, when clinically appropriate. Importantly, HCT will not improve skeletal abnormalities.	Mixed donor chimerism is not expected to have negative consequences in this disease.
CD40 ligand deficiency	HCT is recommended if matched family donor (MFD) is available. Transplants from other donor sources such as a matched unrelated donor (MUD) or haploidentical donors should be strongly considered in the presence of severe disease complications.	Mixed donor chimerism is likely to be beneficial.
Chediak-Higashi syndrome	HCT is recommended if MFD or MUD is available. Haploidentical transplants might also have a role in the management of this disease when clinically appropriate.	Mixed donor chimerism is likely to be beneficial.
Chronic granulomatous disease	HCT is recommended for gp91phox-deficient patients (X-CGD) if MFD is available. Transplants of X-CGD from MUD or of other genetic variants from MFD or MUD are considered in the presence of severe disease complications or poor compliance to medical management. Haploidentical transplants might also have a role in the management of this disease, when clinically appropriate.	Mixed donor chimerism is likely to be beneficial.
Griscelli syndrome type 2	HCT from any available donor source is recommended for all patients who have not experienced severe neurologic involvement. Haploidentical transplants might also have a role in the management of this disease, when clinically appropriate.	Mixed chimerism is sufficient to stabilize disease.
Hemophagocytic lymphohistiocytosis	HCT from any available donor source is recommended as soon as the hemophagocytic syndrome is controlled. Neurologic disease is associated with a poor outcome.	Mixed chimerism with ≥ 20% of donor leukocytes is associated with sustained remission of the disease.
Immune dysregulation, poly-endocrinopathy and enteropathy, X-linked syndrome (IPEX)	HCT from MFD or MUD is recommended and should preferably be performed early, before onset of diabetes.	Partial donor chimerism can result in sustained remission of the disease.
Leukocyte adhesion deficiency, Type 1	HCT from MFD or MUD is recommended because of long-term disease risks. Haploidentical transplants might also have a role in the management of this disease, when clinically appropriate.	Mixed donor chimerism at even relatively low levels is likely beneficial for infection control and can result in lack of significant symptoms.
Wiskott-Aldrich syndrome	HCT from MFD or MUD is recommended. The preferred donors are MFD/MUD (70% to 80% survival) versus haploidentical donors (40% survival).	Long-term mixed chimerism is undesirable because it is associated with autoimmune complications.
WAS-X-linked thrombocytopenia	The decision to perform HCT might be made based on biomarkers (WAS protein expression levels, response to vaccination, and immune laboratory values) or case-specific clinical reasons.	N/A
X-linked lymphoproliferative syndrome	HCT from MFD or MUD is recommended, preferably before development of lymphoma, hemophagocytic syndrome, or other disease complications. Haploidentical transplants might also have a role in the management of this disease, when clinically appropriate.	Mixed donor chimerism is likely to be beneficial and is not expected to have negative consequences in this disease.
Severe congenital neutropenia	G-CSF resistance leaves no alternative therapy. MFD or MUD has proven successful in the European experience.	Mixed chimerism might be beneficial.
MHC class II deficiency	Early demise without HCT prompts treatment but poor survival (54% with MFD and 32% with haploidentical donors) at 1 year after HCT.	Mixed chimerism is beneficial.

Adapted from Griffith et al (2009). J Allergy Clin Immunol. 2009;124(6):1164.

Ganaiem et al (2013) stated that veno-occlusive disease with immunodeficiency (VODI) is an autosomal recessive disorder of CID and hepatic injury. Hematopoietic stem cell transplantation (HSCT) -- the only definitive treatment for CID -- appeared to have a high rate of complications in a previous report. In this study, these investigators described a new group of patients with VODI high-lighting further clinical and immunologic aspects of this disease and re-evaluating the effectiveness of HSCT for the treatment of this disorder. They reviewed clinical data, immunologic features, molecular studies, treatment, and final outcome of 8 kindred members with VODI. The patients described had clinical and immunologic findings consistent with VODI. The molecular studies revealed a new mutation in the SP110 gene. Hematopoietic stem cell transplantation was carried out in 5 patients and was successful in 3. The authors concluded that the diagnosis of VODI should be considered in all patients regardless of ethnicity with a SCID-like presentation, especially with a normal mitogen response, or with signs of hepatic injury. They stated that VODI is a primary immune deficiency, which can be successfully corrected by bone marrow transplantation if applied early in the course of disease using appropriate conditioning.

Mitchell et al (2013) performed a retrospective analysis on the outcomes of 135 HSCTs for PIDs in Australian and New Zealand Children's Hematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were SCID, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72 % for the entire cohort. Disease-specific 5-year OS was 70 % for SCID, 81 % for Wiskott-Aldrich syndrome, and 69 % for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10 % at day +100. Transplantation-related mortality and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. Interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. The authors concluded that this large series supported the use of HSCT as curative therapy for a range of PIDs, demonstrating excellent survival after both related and unrelated donor transplantation.

Choi and colleagues (2005) stated that severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the pro-myelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. These researchers reported results for 6 patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at 2 transplant centers. Two patients transplanted for MDS survived; both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. The authors concluded that patients with SCN should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. Moreover, they stated that for SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.

Ferry et al (2005) studied the outcome of allogeneic HSCT in patients with SCN. Among 101 cases of SCN included in the French Severe Chronic Neutropenia Registry, 9 patients received HSCT between 1993 and 2003, in 7 institutions. The indications were non-response to G-CSF therapy in 4 cases, bone marrow failure in 1 case, and MDS or leukemia in 4 cases. The conditioning regimen consisted of total body irradiation in 2 cases and chemotherapy alone in the other 7 cases. Seven patients received stem cells from unrelated donors and 2 from identical siblings. Engraftment occurred in all but 1 of the patients; 3 patients died. The respective causes of death were GVHD, infection, and Epstein-Barr virus (EBV) post-transplant lympho-proliferative disease. Six patients are alive and in complete remission, with a median follow-up of 3.1 years. The authors concluded that these findings indicated that HSCT is feasible for patients with SCN who do not respond to G-CSF, who have malignant transformation, or who are at a high risk of malignant transformation, even if an HLA-identical sibling donor is not available.

Welte et al (2006) noted that SCN includes a variety of hematologic disorders characterized by severe neutropenia, with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L, and associated with severe systemic bacterial infections from early infancy. One subtype of CN, Kostmann syndrome, is an autosomal recessive disorder, characterized histopathologically by early-stage maturation arrest of myeloid differentiation. Severe congenital neutropenia with similar clinical features occurs as an autosomal dominant disorder and many sporadic cases also have been reported. This genetic heterogeneity suggests that several pathophysiological mechanisms may lead to this common clinical phenotype. Recent studies on the genetic bases of SCN have detected inherited or spontaneous point mutations in the neutrophil elastase gene (ELA 2) in about 60 % to 80 % of patients and, less commonly, mutations in other genes. Acquisition of additional genetic defects during the course of the disease, for example, G-CSF receptor gene mutations and cytogenetic aberrations, indicates an underlying genetic instability as a common feature for all congenital neutropenia subtypes. Data on more than 600 patients with SCN collected by the Severe Chronic Neutropenia International Registry (SCNIR) demonstrated that, regardless of the particular SCN subtype, more than 95 % of these patients respond to r-HuG-CSF with ANCs that can be maintained above 1.0 x 10(9)/L. Adverse events include mild splenomegaly, osteoporosis, and malignant transformation into MDS/leukemia. If and how G-CSF treatment impacts on these adverse events is not fully understood. In recent analyses the influence of the G-CSF dose required to achieve neutrophil response (ANC greater than 1,000/microL) in the risk of developing AML has been reported. The authors stated that HSCT is still the only treatment available for patients who are refractory to G-CSF treatment.

Elhasid and Rowe (2010) stated that until further progress will occur in the field of gene therapy, the only curative treatment available in SCN, leukocyte adhesion deficiency, and chronic granulomatous disease is allogeneic HSCT.

Carlsson et al (2011) noted that SCN is an immunodeficiency characterized by disturbed myelopoiesis and an ANC less than 0.5 × 10(9)/L. Severe congenital neutropenia is also a pre-malignant condition; a significant proportion of patients develop myelodysplastic syndrome or leukemia. Allogeneic HSCT is the only curative treatment for SCN.

Furthermore, an UpToDate review on “Congenital neutropenia” (Coates, 2014) states that “Hematopoietic cell transplantation (HCT) is curative and should be considered for all patients, particularly those with a high requirement for G-CSF”.

Complement Deficiency

Lee et al (2006) reported that 124 patients (from 120 families) diagnosed as PIDs were enrolled from 5 tertiary medical centers. The distribution by an update 8 categories showed 45 patients (13 females/32 males; 36.3 %) with "predominant antibody deficiencies", 27 patients (6/21; 21.8 %) with "T- and B-cell immunodeficiency", 25 patients (9/16; 20.2 %) with "congenital defects of phagocyte", 25 patients (4/21; 20.2 %) with "other well-defined immunodeficiency syndromes", 1 boy (0.8 %) with "disease in immune deregulation" (Chediak-Higashi syndrome) and another with "complement 3 deficiency". None had "defects in innate immunity" or "auto inflammatory disorders". Pseudomonas and Salmonella spp. were the 2 most identified microorganisms in septicemia (39.7 %; 27/68 episodes). Twenty-three patients (18.5 %) had mortality. Stem cell transplantation succeeded in 7 of 12 patients. In addition to 9 patients with DiGeorge syndrome recognized by FISH, direct sequencing identified 12 unique mutations from 20 families, reflecting distinct Taiwan geography, although a selection bias may exist.

Lee et al (2011) stated that PIDs are a group of rare diseases with wide geographic and ethnic variations in incidence, prevalence, and distribution patterns. These researchers examined the distribution pattern and clinical spectrum of PIDs in Taiwan at a national referral institute. From 1985 to 2010, a total of 215 patients from 183 families were diagnosed and grouped according to the updated classification of PIDs. Eighty-one (37.7 %) patients had "other well-defined immunodeficiency syndromes", followed by "predominantly antibody deficiencies" (54 patients; 25.1 %), "T- and B-cell immunodeficiencies" (34; 15.8 %), "congenital defects of phagocytes" (25; 20.2 %), "complement deficiencies" (15; 7.0 %), and "disease in immune dysregulation" (5; 2.3 %). The last category included 2 patients with Chediak-Higashi syndrome, and 1 each with familial hemophagocytosis, IPEX, and hypo-gammaglobulinemia and albinism. One female had cold-induced auto-inflammatory disease. There were no cases of "defects in innate immunity". Pseudomonas and Streptococcus pneumoniae were the 2 most identified microorganisms in septicemia (42.7 %; 44/103 episodes). Stem cell transplantation was successful in 13 of 22 patients, while 34 patients (15.8 %) died. Molecular defects were identified in 109 individuals (from 90 families). There were relatively fewer cases of "predominantly antibody deficiencies" due to there being only a few patients with adult-onset PIDs, implying certainty bias rather than ethnic variation. Awareness of under-diagnosis among physicians rather than pediatricians is vital for timely diagnosis and consequently adequate treatment.

Furthermore, UpToDate reviews on “Inherited disorders of the complement system” (Liszewski and Atkinson, 2015) and “Primary humoral immune deficiencies: An overview“ (Bonilla, 2015) do not mention stem cell transplant as a management tool.

Autoimmune Lymphoproliferative Syndromes

Benkerrou et al (1997) stated that an inherited syndrome characterized by nonmalignant lymphoproliferation with autoimmune manifestations, caused by mutations of the Fas (CD95) receptor gene has been described. Because of disease severity, i.e. unremitting lymphoproliferation in a child with complete Fas deficiency, a haploidentical bone marrow transplantation (BMT) was performed despite the known resistance of Fas-deficient lpr mice to bone marrow transplantation. Marrow graft was rejected early; however, a second attempt using bone marrow from the mother led to engraftment and to control of lymphoproliferation and of autoimmune thrombocytopenia up to the last follow-up at 24 months after BMT. The investigators stated that this single case shows that resistance to bone marrow engraftment caused by survival of Fas-deficient cells can be overcome.

Sleight et al (1998) reported on a child with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) who developed progressive disease requiring stem cell transplantation. This severe form of ALPS was associated with a novel Fas gene splice site mutation that resulted in functional deletion of exons 8 and 9. While this child shared many clinical features with previously described ALPS cases, including massive lymphadenopathy and circulating alphabeta+ CD3+CD4-CD8-T cells, his disease progressed despite immunosuppressive therapy to a clinically aggressive oligoclonal lymphoproliferation which resembled a diffuse large cell non-Hodgkin's lymphoma. After partial remission was achieved with cytotoxic therapy the patient underwent BMT from an unrelated donor. The investigators noted that this was the first reported case of ALPS in which BMT was successfully attempted for correction of a Fas deficiency.

IL-10 Receptor Deficiency

Inherited deficiencies of IL-10 or IL-10 receptor (IL-10R) lead to immune dysregulation with life-threatening early-onset enterocolitis.

Karaca et al (2016) observed that alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. The authors noted that IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

Engelhardt et al (2013) sought to gather clinical data of IL-10/IL-10R-deficient patients and devise guidelines for diagnosis and management, including hematopoietic stem cell transplantation (HSCT). The investigators enrolled 40 patients with early-onset enterocolitis and screened for mutations in IL10/IL10R using genetic studies, functional studies, or both of the IL-10 signaling pathway. Medical records of IL-10/IL-10R-deficient patients were reviewed and compiled. Of 40 patients, investigators identified 7 with novel mutations, predominantly in consanguineous families with more than 1 affected member. IL-10/IL-10R-deficient patients had intractable enterocolitis, perianal disease, and fistula formation. HSCT was carried out in 2 patients with IL-10 deficiency and 1 patient with IL-10R α chain deficiency and proved to be an effective therapy, leading to rapid improvement of clinical symptoms and quality of life. The investigators concluded that, because the defect in patients with IL-10/IL-10R deficiency resides in hematopoietic lineage cells and their colitis is resistant to standard immunosuppressive therapy, HSCT should be considered early as a potentially curative therapeutic option.

Common Variable Immune Deficiency

Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigators have examined more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT).

Abolhassani et al (2013) commented that common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. As symptoms of CVID are usually heterogeneous and unspecific, diagnosis and follow-up of CVID can be challenging. In light of this, the authors performed a broad review of advances in management and treatment of CVID in order to reach a distinct protocol. However, it should be noted that owing to the nature of the disease, it can only be treated symptomatically but not cured. There is little evidence to guide appropriate or universal guidelines to improve the current status of management of the disease. The most satisfactory treatments of CVID could be achieved by the use of immunoglobulin replacement, antibiotics, immunosuppressants and hematopoietic stem cell transplantation.

Wehr et al (2015) sought to define the outcomes of HSCT for patients with CVID. Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. The investigators concluded that this multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.

Cambray-Gutierrez and colleagues (2017) noted that patients with common variable immunodeficiency show higher incidence of sino-pulmonary and GI infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin; and HSCT is a non-conventional therapeutic modality. These researchers reported the case of a 26-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum anti-microbials and macrolides. At 22 years of age, she underwent HSCT owing to continued severe infections. At 4 months post-transplantation, she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud's disease and upper respiratory tract persistent infections. At the moment of this report she was being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol. The authors concluded that given the high rate of morbidity and mortality associated and immune reconstitution failure, HSCT should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders. The clinical value of HSCT for the treatment of common variable immunodeficiency needs to be further investigated.

Other Indications

Patiroglu et al (2016) reported the outcomes of HSCT in patients with PIDs (n = 20). The disease distribution of the 20 patients were as follows: SCID (n = 6), hemophagocytic lymphohistiocytosis (n = 4), CGD (n = 2), Griscelli syndrome type 2 (n = 2), B-cell deficiency plus bone marrow failure (n = 2) , severe congenital neutropenia (n = 1), X-linked lymphoproliferative disease (n = 1), T-cell deficiency plus relapsed non-Hodgkin lymphoma (n = 1), leukocyte adhesion deficiency type 1 (n = 1). Of the 20 patients, 11 received related HLA-matched, 6 received haploidentical, 2 received unrelated HLA-matched, and 1 received HLA-mismatched transplant. The median age at transplant was 21 months, and median follow-up was 5 months; OS rate was 65 %. Mean engraftment times for neutrophils and platelets were 14.25 ± 3.08 and 24.7 ± 11.4 days; GVHD was observed in 30 % of patients. The authors concluded that patients with PID treated at their center had acceptable transplant outcomes. The findings of this study supported the use of HSCT in patients with PIDs.

Allogeneic Hematopoietic Stem Cell Transplantation for Inflammatory Bowel Disease

Bakhtiar and co-workers (2017) noted that inflammatory bowel disease (IBD) in young children can be a clinical manifestation of various PID syndromes. Poor clinical outcome is associated with poor quality of life (QOL) and high morbidity from the complications of prolonged immunosuppressive treatment and mal-absorption. In 2012, mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene were identified as the cause of an autoimmunity and immunodeficiency syndrome. Since then, several LRBA-deficient patients have been reported with a broad spectrum of clinical manifestations without reliable predictive prognostic markers. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been performed in a few severely affected patients with complete or partial response. These investigators presented a detailed course of the disease and the transplantation procedure used in a LRBA-deficient patient suffering primarily from infantile IBD with immune enteropathy since the age of 6 weeks, and progressive autoimmunity with major complications following long-term immunosuppressive treatment. At 12 years of age, allo-HSCT using bone marrow of a fully matched sibling donor -- a healthy heterozygous LRBA mutant carrier -- was performed after conditioning with a reduced-intensity regimen. During the 6-year follow-up, these researchers observed a complete remission of enteropathy, autoimmunity, and skin vitiligo, with complete donor chimerism. The authors concluded that the genetic diagnosis of LRBA deficiency was made after allo-HSCT by detection of 2 compound heterozygous mutations, using targeted sequencing of DNA samples extracted from peripheral blood before the transplantation.

The authors stated that due to the lacking genotype-phenotype correlation in LRBA-deficient patients, further data are needed to establish predictive and prognostic biomarkers that would allow the reliable identification of candidates for early allo-HSCT. Moreover ,they stated that further studies on transplantation in LRBA deficiency are needed to evaluate the optimal conditioning regimen and determine the necessary level of chimerism for disease remission.

Allogeneic Hematopoietic Stem Cell Transplantation for Juvenile Idiopathic Arthritis

Silva and colleagues (2018) noted that patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying anti-rheumatic drugs (DMARDs) including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allo-HSCT is a potentially curative immunomodulatory strategy for patients with such refractory disease. These investigators treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor (RF)-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab; 14 of 16 patients were alive with a median follow-up of 29 months (range of 2.8 to 96 months). All patients had hematological recovery; 3 patients had grade II to IV acute GVHD. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved QOL early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. The authors concluded that allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Moreover, they stated that long-term follow-up is needed to determine if disease control following HSCT continues indefinitely. These researchers stated that prospective studies are needed to harmonize selection of patients and indications for transplant, to evaluate conditioning regimens that could promote robust engraftment with even lower toxicity, to assess potential biomarkers, and to investigate immunological mechanisms of remission following allo-HSCT.

Allogeneic Hematopoietic Stem Cell Transplantation for Pulmonary Alveolar Proteinosis

Tanaka-Kubota and associates (2018) stated that pulmonary alveolar proteinosis (PAP) is a rare disorder that is characterized by the excessive accumulation of surfactant-like materials in the alveoli, leading to hypoxemic respiratory failure. These researchers described 2 Japanese infants with PAP associated with hypo-gammaglobulinemia and mono-cytopenia. These patients may have underlying PID and were successfully treated with allo-HSCT. The authors concluded that this report indicated that allo- HSCT may provide a curative treatment for PAP associated with PID.

UpToDate reviews on “Pulmonary alveolar proteinosis in children” (Carmona, 2018) and “Treatment and prognosis of pulmonary alveolar proteinosis in adults” (Chan and King, 2018) do not mention allo-HSCT as a therapeutic option.

T-Cell Receptor Excision Circle (TREC) Testing Following Allogeneic Hematopoietic Stem Cell Transplant for Severe Combined Immunodeficiency (SCID)

Myers and colleagues (2002) stated that all genetic types of severe combined immunodeficiency (SCID) could be cured by hematopoietic stem cell transplantation (HSCT) from related donors. The survival rate approaches 80 %, and most deaths resulted from opportunistic infections acquired before transplantation. It was hypothesized that the survival rate and kinetics of immune reconstitution would be improved for infants receiving transplants in the neonatal period (first 28 days of life), prior to the development of infections. A 19.2-year retrospective / prospective analysis compared immune function in 21 SCID infants receiving transplants in the neonatal period with that in 70 SCID infants receiving transplants later. Lymphocyte phenotypes, proliferative responses to mitogens, immunoglobulin levels, and T-cell receptor excision circles (TREC) were measured before transplantation and sequentially after transplantation. Of 21 SCID infants with transplantations in the neonatal period, 20 (95 %) survived. Neonates were lymphopenic at birth (1,118 ± 128 lymphocytes per cubic millimeter). Infants receiving transplants early developed higher lymphocyte responses to phytohemagglutinin and higher numbers of CD3+ and CD45RA+ T cells in the first 3 years of life than those receiving transplants late (p < 0.05); TRECs peaked earlier and with higher values (p < 0.01) in the neonatal transplantations (181 days to 1 year) than in the late transplantations (1 to 3 years); SCID recipients of allogeneic, related hematopoietic stem cells in the neonatal period had higher levels of T-cell reconstitution and thymic out-put and a higher survival rate than those receiving transplants after 28 days of life. The authors concluded that an improved outcome for this otherwise fatal syndrome could be achieved with newborn screening for lymphopenia so that transplantation could be performed under favorable thymopoietic conditions.

Pirovano and associates (2004) noted that in-utero HSCT allows immune reconstitution of fetuses with SCID. These researchers examined the quality of T-cell reconstitution following this procedure. They evaluated the kinetics and extent of T-cell reconstitution in 5 infants with SCID, 3 with a B+ and 2 with a B- phenotype, who received haplo-identical stem cell transplantation before birth. These investigators measured the frequency of TREC and the diversity of the T-cell repertoire. In-utero HSCT led to engraftment of donor-derived T lymphocytes which attained normal numbers in 4 infants, who were in good health. In the 3 patients with a B+ phenotype, generation of a heterogeneous T-cell repertoire was associated with development of TREC levels comparable to those of SCID patients treated by post-natal transplantation and of healthy babies. Of the 2 patients with a B- phenotype, 1 developed mixed T-cell chimerism and a substantial number of circulating T cells, associated with a variable heterogeneity of the T-cell repertoire; TREC levels were normal soon after birth, but declined thereafter. The remaining B- patient remained lymphopenic with a skewed T-cell repertoire and very low TREC levels. This patient eventually required transplantation from a matched unrelated donor at 5 years of age, but died of EBV-related lymphoproliferative disease. The authors concluded that these data indicated that in-utero HSCT of fetuses with B+ SCID allowed generation of newly diversified T lymphocytes and ensured long-term reconstitution of cell-mediated immunity.

The authors stated that in evaluating these data, however, it must be considered that TREC levels can also be influenced by other variables, such as an elevated cell division rate or the induction of apoptosis. Whether the impact of these variables is different in in-utero HSCT and post-natal HSCT remained to be established. Moreover, these data suggested that quality of T-cell reconstitution following in-utero HSCT was better for B+ than for B- SCID. They stated that a long-term analysis of a larger series of patients is needed to confirm these results and to compare the quality of immune reconstitution following in-utero HSCT with that obtained with post-natal transplantation in the neonatal period or later in life.

Fu and colleagues (2007) examined the relationship between pre-transplantation host thymic recent out-put function and prognosis in HLA-matched sibling bone marrow transplantation (MSD-BMT) and examined if pre-transplantation host thymic recent out-put function could act as a marker for predication of prognosis after HSCT. TREC in DNA of pre-transplantation peripheral blood mononuclear cells from 64 patients who underwent MSD-BMT was detected by real-time quantitative PCR. The content of TREC in 70 normal donors was detected as well. All clinical data of patients after HSCT were collected and studied. Survival rates of patients after HSCT were estimated with Log-rank test. Uni-variate and multi-variate analysis of prognostic factors were carried out by COX's proportional hazard regression model. The mean value of TREC in normal donors was (3,351 +/- 3,711) copies/10(5) cells. There was an inverse correlation between TREC and age in the donor groups. Before transplantation, all patients were detected TREC, with a mean TREC number of (180 +/-332) copies/10(5) cells being significantly lower than that of normal donors. The results of uni-variate analysis showed that the counts of pre-HSCT TREC were closely correlated with long-term survival and chronic GVHD (cGVHD) (p < 0.05) and with cytomegalovirus (CMV) infection (p = 0.084); but not with acute GVHD (aGVHD). The results of multi-variate analysis showed the same thing as that of uni-variate analysis. The authors concluded that pre-transplantation host thymic recent out-put function was closely correlated with prognosis in MSD-BMT and could be a factor for predicting the outcome of HSCT.

The 2nd Pediatric Blood and Marrow Transplant Consortium International Conference provided recommendations for screening and management of late effects in patients with SCID after allogenic hematopoietic cell transplantation (Heimall et al, 2017):

Minimal recommended testing should include assessment of T, B, and NK cell numbers, naïve (CD4+CD45RA+) T cells, TREC, T cell function via proliferation, and B cell function via immunoglobulin levels and isohemagglutinin titers, as well as lineage-specific engraftment.

Gaballa and colleagues (2018) noted that reconstitution of the adaptive immune system following allogeneic HSCT is crucial for beneficial outcome and is affected by several factors, such as GVHD and graft source. The impact of these factors on immune reconstitution has been examined during the early phase following transplantation. However, little is known regarding their long-term effect. Similarly, leukocyte telomere length (TL) shortening has been reported shortly after transplantation. However, whether TL shortening continues in long-term aspect is still unsettled. These researchers evaluated TREC, kappa deleting recombination excision circle (KREC) and leukocyte TL in recipients and donors several years post-transplantation (median of 17 years). The analysis showed that, recipients who received bone marrow (BM) as the graft source had higher levels of both TREC and KREC. Furthermore, cGVHD affected TREC levels and TL but not KREC levels. Finally, these investigators showed that recipient's TL was longer than respective donors in a group of young age recipients with high KREC levels. The authors concluded that these findings suggested that BM can be beneficial for long-term adaptive immune recovery; they also presented supporting evidence for recipient telomere homeostasis, especially in young age recipients, rather than telomere shortening.

Manor and associates (2019) stated that allogeneic HSCT is the effective mean of immune restoration in SCID. Usually, HSCT without cytoreductive conditioning is attempted. Nevertheless, conditioning procedures are still preferred in a subset of patients. In a retrospective study, these investigators described the immunological outcome in a cohort of conditioned and un-conditioned patients, from diagnosis, through transplantation, to follow-up. This trial was conducted on 17 patients with SCID (10 conditioned, 7 un-conditioned) who later underwent HSCT. Immune reconstitution was assessed in the post-transplant year by quantification of TRECs and KRECs, among additional laboratory and clinical evaluations. Un-conditioned patients were diagnosed and transplanted earlier; TREC and KREC quantification showed a gradual increase in both groups, with higher levels in the conditioned group. Engraftment percentages differed drastically between groups, favoring the conditioned group. Un-conditioned patients were significantly more dependent on intravenous immunoglobulins (IVIGs). One patient from each group succumbed to disease complications. Conditioning demonstrated superior laboratorial outcomes. Patients with unique characteristics (i.e., consanguinity, Bacillus Calmette-Guerin [BCG] vaccination, impaired access to IVIG) may require personalized considerations. The effort to implement secondary prevention of SCID with newborn screening should continue.

Furthermore, an UpToDate review on “Hematopoietic cell transplantation for severe combined immunodeficiencies” (Dvorak, 2019) states that “Following HCT, T cell precursors develop from donor stem cells and repopulate the native thymus, a previously vestigial organ in patients with SCID. Thymic T cell development can be monitored by measuring T cell receptor excision circles (TRECs) in the blood”.

Allogeneic Hematopoietic Stem Cell Transplantation for Zeta-Chain Associated Protein Kinase 70 kDa (ZAP-70) Deficiency

Sharifinejad and colleagues (2020) stated that zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency is a rare CID caused by recessive homozygous/compound heterozygous loss-of-function mutations in the ZAP70 gene. Patients with ZAP-70 deficiency present with a variety of clinical manifestations, particularly recurrent respiratory infections and cutaneous involvements. Thus, a systematic review of ZAP-70 deficiency is helpful to achieve a comprehensive view of this disease. These investigators searched PubMed, Web of Science, and Scopus databases for all reported ZAP-70 deficient patients and screened against the described eligibility criteria. A total of 49 ZAP-70 deficient patients were identified from 33 articles. For all patients, demographic, clinical, immunologic, and molecular data were collected. ZAP-70 deficient patients had been reported in the literature with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8 %), cutaneous involvement (57.9 %), lympho-proliferation (32.4 %), autoimmunity (19.4 %), enteropathy (18.4 %), and increased risk of malignancies (8.1 %). The predominant immunologic phenotype was low CD8+ T cell counts (97.9 %). Immunologic profiling showed defective antibody production (57 %) and decreased lymphocyte responses to mitogenic stimuli such as phytohemagglutinin (PHA) (95 %). Mutations of the ZAP70 gene were located throughout the gene, and there was no mutational hotspot. However, most of the mutations were located in the kinase domain. Hematopoietic stem cell transplantation (HSCT) was applied as the major curative treatment in 25 (51 %) of the patients, 18 patients survived transplantation, while 2 patients died and 3 required a 2nd transplant in order to achieve full remission. The authors concluded that newborns with consanguineous parents, positive family history of CID, and low CD8+ T cell counts should be considered for ZAP-70 deficiency screening, since early diagnosis and treatment with HSCT could lead to a more favorable outcome. Based on the current evidence, there is no genotype-phenotype correlation in ZAP-70 deficient patients. Moreover, these researchers noted that 8 out of the 12 patients (66 %) with clinical complications post-HSCT were older than 6 months at the time of transplantation. It appeared that younger patients undergoing HSCT, experienced better outcomes and fewer complications; thus, early screening and HSCT could lower the burden of the disease. However, no study has yet directly examined the correlation between age at the time of transplantation and its outcome in ZAP-70-related CID. Therefore, more studies are needed to support this hypothesis.

An UpToDate review (Roifman, 2020) stated that patients with ZAP-70 deficiency require HSCT to cure their chronic immune deficiency. Bone marrow from a human leukocyte antigen (HLA)-matched sibling is the optimal choice, with excellent survival, as well as long-term immune reconstitution. However, most patients lack this option. In such situations, other histocompatible donors can be used.

Allogeneic Hematopoietic Stem Cell Transplantation for Activated Phosphoinositide 3-Kinase Delta Syndrome

Dimitrova and colleagues (2022) stated that activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allo-HSCT. In a retrospective study, these researchers characterized HSCT outcomes in APDS. Data were collected on 57 patients with APDS1/2 (median age of 13 years; range of 2 to 66 years) who underwent HSCT. Pre-HSCT co-morbidities such as lung, gastro-intestinal (GI), and liver pathology were common, with hematologic malignancy in 26 %. With median follow-up of 2.3 years, 2-year OS and graft failure-free survival probabilities were 86 % and 68 %, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following 1st HSCT was 17 % overall but 42 % if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the 1st year post-HSCT, compared with 9 % without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion (DCI) was overall 28 %, but 65 % in the context of mTORi receipt and 23 % without. Phenotype reversal occurred in 96 % of evaluable patients, of whom 17 % had mixed chimerism. Vulnerability to renal complications continued post-HSCT, adding new insights into potential non-immunologic roles of phosphoinositide 3-kinase not correctable through HSCT. The authors concluded that graft failure, graft instability, and poor graft function requiring unplanned DCI were major barriers to successful HSCT. Post-HSCT mTORi use may confer an advantage to residual host cells, promoting graft instability. These researchers stated that longer-term post-HSCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and evaluate the completeness of phenotype reversal over time.

Allogeneic Hematopoietic Stem Cell Transplantation for Granulomatous-Lymphocytic Interstitial Lung Disease (GLILD)

Lamers and colleagues (2021) stated that besides recurrent infections, a proportion of patients with CVID may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking. These investigators examined the published literature on the efficacy of treatments for GLILD in CVID. They carried out a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized. A total of 6,124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or HSCT. Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high. The authors could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a therapeutic option for GLILD in CVID, the risks related to the procedure are high. These researchers stated that based on this systematic review of the current literature, which was often of low quality with a high risk of bias, it is impossible to define which therapeutic option is optimal in treating GLILD in CVID. They noted that corticosteroid monotherapy appeared suboptimal for many patients, rituximab monotherapy and combination chemotherapy with rituximab and azathioprine were effective in most reported cases. The use of abatacept has so far been only implemented as therapy for patients with pathogenic CTLA-4 and LRBA mutations. HSCT is the only curative treatment for GLILD, yet not free of risks. These researchers stated that while much is left open and uncertain, what has become most evident throughout this review is that there remain many critical knowledge gaps concerning treatment of GLILD. Etiology and optimal treatment for the disease are questions that require urgent answers, as they may lead to better and more specific treatment regimens. In the future, larger well-designed studies examining therapeutic strategies should be performed, with uniform quantitative outcomes.

Allogeneic Hematopoietic Stem Cell Transplantation for Autoimmune Lymphoproliferative Syndromes

Hafezi et al (2021) noted that ALPS is a group of genetic disorders characterized by early-onset lymphoproliferation, autoimmune cytopenia, and susceptibility to lymphoma. The majority of ALPS patients carry heterozygous germline mutations in the TNFRSF6 gene. These researchers carried out a systematic review of patients with ALPS and ALPS-like syndrome. The literature search was conducted in Web of Science, Scopus, and PubMed databases to find eligible studies. Furthermore, the reference list of all included papers was hand-searched for additional studies. Demographic, clinical, immunological, and molecular data were extracted and compared between the ALPS and ALPS-like syndrome. A total of 720 patients with ALPS (532 genetically determined and 189 genetically undetermined ALPS) and 59 cases with ALPS-like phenotype due to mutations in genes other than ALPS genes were assessed. In both ALPS and ALPS-like patients, splenomegaly was the most common clinical presentation followed by autoimmune cytopenia and lymphadenopathy. Among other clinical manifestations, respiratory tract infections were significantly higher in ALPS-like patients than ALPS. The immunological analysis showed a lower serum level of IgA, IgG, and lymphocyte count in ALPS-like patients compared to ALPS. Most (85 %) of the ALPS and ALPS-like cases with determined genetic defects carry mutations in the FAS gene. Approximately 1/3 of patients received immunosuppressive therapy with conventional or targeted immunotherapy agents. A small fraction of patients (3.3 %) received HSCT with successful engraftment, and all except 2 patients survived following transplantation. The authors concluded that these findings showed that the FAS gene with 85 % frequency is the main etiological cause of genetically diagnosed patients with ALPS phenotype; thus, the genetic defect of the majority of suspected ALPS patients could be confirmed by mutation analysis of FAS gene.

Allogeneic Hematopoietic Stem Cell Transplantation for Combined Immunodeficiency

Durkee-Shock et al (2022) stated that optimal management of patients with combined immunodeficiency, especially pertaining to HSCT, remains unclear. These researchers identified factors influencing HSCT and mortality in the population with combined immunodeficiency in North America. They identified 337 participants in the U.S. Immunodeficiency Network database with diverse forms of combined immunodeficiency and their characteristics, including demographic characteristics, laboratory values, infectious history, co-morbidities, and treatment strategies. Univariate analysis was carried out using logistic regression, whereas multi-variate analysis was carried out using multiple Cox proportional hazards. On univariate analysis, disseminated invasive viral infections and variants in STAT3, GATA2, and DOCK8 were associated with increased odds of HSCT. Mucocutaneous fungal infections and variants in STAT3 were associated with increased odds of survival, whereas disseminated/invasive fungal infections, disseminated/invasive viral infections, and parasitic infections were associated with decreased odds of survival. On multiple variable Cox proportional hazards analysis, variants in ZAP70, non-specific bacterial, and disseminated/invasive viral infections were associated with increased hazards of transplantation, whereas variants in multiple genes (RMRP, NEMO, DOCK8, CD40L, and CARD9), disseminated/invasive viral infections, autoimmune disease, and higher absolute lymphocyte count were associated with increased hazards of death. More importantly, demographic characteristics, basic lymphocyte subset counts, and absence of genetic diagnosis were not associated with HSCT or mortality. The authors determined that specific genetic diagnoses and infection burden impacted the decision to undergo HSCT in this cohort. Furthermore, certain genetic diagnoses and invasive viral infections carried an increased risk of mortality.

Allogeneic Hematopoietic Stem Cell Transplantation for Wiskott-Aldrich Syndrome

Albert et al (2022) noted that allo-HSCT is a potentially curative treatment for patients affected by WAS. Reported HSCT outcomes have improved over time with respect to OS; however, some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. These researchers analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year OS of 88.7 % and chronic GVHD-free survival (events included death, graft failure, and severe chronic GVHD) of 81.7 %. Chronic GVHD-free survival and OS were not significantly affected by conditioning regimen (busulfan- versus treosulfan-based), donor type (matched sibling donor/matched family donor versus matched unrelated donor/mismatched unrelated donor versus mismatched family donor), or period of HSCT (2006 to 2013 versus 2014 to 2017). Patients aged less than 5 years at HSCT had a significantly better OS. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6 % and 2.1 %, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (2nd HSCT, unconditioned stem cell boost, donor lymphocyte infusion [DLI], or splenectomy). The authors concluded that HSCT for WAS with conditioning regimens currently recommended by IEWP resulted in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age of 5 years or more remains a risk factor for OS.

Adenosine Deaminase Deficiency

Kohn et al (2019) stated that inherited defects in adenosine deaminase (ADA) cause a subtype of SCID known as severe combined immune deficiency caused by ADA defects (ADA-SCID). Most affected infants can receive a diagnosis while still asymptomatic by using an SCID newborn screening test, allowing early initiation of therapy. These investigators examined the available evidence and proposed a consensus management strategy. In addition to treatment of the immune deficiency observed in patients with ADA-SCID, patients should be followed for specific non-infectious respiratory, neurological, and biochemical complications associated with ADA deficiency. All patients should initially receive enzyme replacement therapy (ERT), followed by definitive treatment with either of 2 equal 1st-line options. If an HLA-matched sibling donor or HLA-matched family donor is available, allo-HSCT should be pursued. The excellent safety and effectiveness observed in more than 100 patients with ADA-SCID who received gamma retrovirus- or lentivirus-mediated autologous hematopoietic stem cell gene therapy (HSC-GT) since 2000 now positions HSC-GT as an equal alternative. If HLA-matched sibling donor/HLA-matched family donor HSCT or HSC-GT are not available or have failed, ERT could be continued or re-instituted, and HSCT with alternative donors should be considered. Moreover, these researchers noted that the outcomes of novel HSCT, ERT, and HSC-GT strategies should be prospectively examined in "real-life" conditions to further inform these management guidelines.

Grunebaum et al (2023) noted that inherited ADA gene typically cause severe combined immunodeficiency. In addition to infections, ADA-deficient patients can present with neurodevelopmental, behavioral, hearing, skeletal, lung, heart, skin, kidney, urogenital, and liver abnormalities. Some patients also suffer from autoimmunity and malignancies. In recent years, there have been remarkable advances in the management of ADA deficiency. Most ADA-deficient patients can be identified by newborn screening for SCID, which facilitates early diagnosis and treatment of asymptomatic infants. Most patients benefit from ERT. Allogeneic HSCT from an HLA-matched sibling donor or HLA-matched family member donor with no conditioning is currently the preferable treatment. When matched sibling donor or matched family member donor is not available, autologous HSC-GT with non-myeloablative conditioning and ERT withdrawal, which is reported in recent studies to result in 100 % OS and 90 % to 95 % engraftment, should be pursued. If HSC-GT is not immediately available, ERT can be continued for a few years. The recent improved outcome of HSCT using HLA-mismatched family-related donors or HLA-matched unrelated donors, after reduced-intensity conditioning (RIC), suggested that such procedures might also be considered rather than continuing ERT for prolonged periods. Long-term follow-up will further aid in determining the optimal therapeutic approach for ADA-deficient patients.

Furthermore, an UpToDate review on “Adenosine deaminase deficiency: Treatment and prognosis” (Grunebaum and Kohn, 2023) states that “Preferred definitive therapy -- Cure is possible with definitive therapy, which includes gene therapy and hematopoietic cell transplantation (HCT). We recommend gene therapy or HCT with a matched sibling donor (MSD) or matched family donor (MFD), if available, for infants with ADA-SCID (Grade 1B)”.

Purine Nucleoside Phosphorylase Deficiency

Dzulkarnain et al (2023) stated that purine nucleoside phosphorylase deficiency-SCID (PNP-SCID) is one of the rare autosomal recessive primary immunodeficiency diseases; and the data on epidemiology and outcome are limited. These investigators reported on the successful management of a child with PNP-SCID and presented a systematic literature review of published case reports, case series, and cohort studies on PNP-SCID listed in PubMed, Web of Science, and Scopus from 1975 until March 2022. A total of 41 studies were included from the 2,432 articles retrieved and included 100 PNP-SCID patients worldwide. Most patients presented with recurrent infections, hypo-gammaglobulinemia, autoimmune manifestations, as well as neurological deficits. There were 6 reported cases of associated malignancies, mainly lymphomas. A total of 22 patients had undergone allo-HSCT with full donor chimerism observed mainly in those receiving matched sibling donors and/or conditioning chemotherapy before the transplant. This research provided a contemporary, comprehensive overview on clinical manifestations, epidemiology, genotype mutations, and transplant outcome of PNP-SCID. These findings highlighted the importance of screening for PNP-SCID in cases presented with recurrent infections, hypo-gammaglobulinemia, and neurological deficits.

Furthermore, an UpToDate review on “Purine nucleoside phosphorylase deficiency” (Grunebaum, 2023) states that “The only curative procedure for PNP deficiency is hematopoietic cell transplantation (HCT), with success reported following use of reduced-intensity conditioning. Without successful transplantation, patients usually die within the first or second decade of life due to recurrent viral, fungal, or bacterial infections”.

References

The above policy is based on the following references:

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Last Review 11/13/2024

Effective: 10/02/2012

Next Review: 09/25/2025
Review History
Definitions

Hematopoietic Cell Transplantation for Primary Immunodeficiency Disorders

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Experimental, Investigational, or Unproven

Related Policies

CPT Codes / HCPCS Codes / ICD-10 Codes

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

T-cell receptor excision circle (TREC):