Bone marrow transplant for immune deficiency and genetic disorders

Bone marrow transplant for immune deficiency and genetic disorders

What every physician needs to know about bone marrow transplantation for immune deficiency:

Most primary immune deficiencies (PIDs) result from genetic mutations that impair the generation, function, or regulation of a cellular constituent of the immune system. Since immune cells arise from bone marrow stem cells, bone marrow transplantation is a potentially curative option for these conditions. A matched sibling donor is optimal, but not necessary; successful transplants for immune deficiencies have been performed using marrow from haploidentical donors (relatives who share only one HLA haplotype with the patient) and marrow or cord blood from unrelated donors.

Most inherited diseases of the immune system involve loss of function, so it is not generally necessary to eliminate host hematopoiesis to cure these diseases. Timing is critical for patients with severe combined immune deficiency (SCID) undergoing bone marrow transplant (BMT), with those transplanted as neonates before the development of significant infections, having significantly better prognosis. This is the justification for newborn screening programs to identify these rare disorders that result from a wide range of gene defects. It is crucial to screen newborns with a family history of inherited immune deficiency, and an important consideration in those with a family history of early childhood death.

Early diagnosis of PID is essential to prevent exposure to acquired infections that may prove fatal or impair the ability to treat with bone marrow transplant. Referral for evaluation and identification of potential BMT donors should occur at the time of diagnosis of PID.

Initiation of disease-specific antimicrobial surveillance and empiric prophylaxis (trimethoprim-sulfamethoxazole, IVIG [intravenous immunoglobulin], G-CSF [granulocyte colony-stimulating factor] is essential. Aggressive treatment of active infections in the peri-transplant period should be pursued, including support such as granulocyte transfusions, if indicated.

What features of the presentation will guide me toward possible causes and next treatment steps:

Failure to thrive (FTT) is the most common presenting symptom of SCID, and although non-specific, must always trigger screening for congenital immune deficiency.

Chronic diarrhea usually accompanies FTT and results from inability to clear organisms that cause minor, self-limited infections in normal hosts.

Pneumonitis, although less common, is a striking finding that allows immediate recognition of an immune deficiency.

Persistent thrush is a common presentation that may be associated with other causes such as antibiotic use or hyperglycemia, but may reflect T cell dysfunction.

Recurrent bacterial infections are a common non-specific presentation of immune deficiency that becomes compelling if the patient lacks reactive lymph nodes or tonsillar tissue or if CBC (complete blood count) results are abnormal.

Graft-versus-host disease may occur in infants with SCID who have not had a bone marrow transplant, due to the engraftment of maternal T cells after maternal-fetal transfusion. A characteristic rash is a very striking finding that should be followed up with a skin biopsy, blood testing for T cell chimerism, and tests of immune function.

Severe eczema is a feature of immunodysregulation, polyendocrinopathy, and enteropathy X-linked syndrome (IPEX), Omenn syndrome, and other defects of immune regulation.

A positive family history of immune deficiency, autoimmunity, or early childhood death should raise the index of suspicion, even when symptoms are non-specific.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The most basic screening tests are a CBC with differential and an immunoglobulin profile.

The CBC may reveal lymphopenia in SCID, lymphocytosis inautoimmune lymphoproliferative syndrome (ALPS) or X-linked lymphoproliferative syndrome (XLP), thrombocytopenia in Wiskott-Aldrich Syndrome (WAS), neutropenia in severe congenital neutropenia (SCN), or leukocytosis in leukocyte adhesion deficiency (LAD).

The immunoglobulin profile may reveal hypogammaglobulinemia in SCID, low Ig (immunoglobulin) M and high IgA in WAS, or high IgM without IgG in hyper IgM syndrome.

Flow cytometry is important to evaluate T, B, and NK (natural killer) cells, and T cell subsets. Functional assays include mitogen and antigen-stimulated lymphocyte proliferation, assessment of specific vaccine responses (including responses to a neoantigen such as phage virus), NK cytotoxicity, and NBT (nitroblue tetrazolium) assays of oxidative burst. Genetic testing for specific conditions treated by BMT may be available. Genes associated with specific PIDs are shown in Table I.

Detection of maternal lymphocytes in blood is pathognomonic for SCID.

Table I.

Primary immune deficiencies treated by bone marrow transplant, gene(s), inheritance, cellular phenotype, special features
Disease Gene(s) Inheritance Cellular phenotype Special features Non-BMT Rx Preparatory regimen considerations
Severe combined immune deficiency Cytokine receptor common γ chain (IL2RG) XLR T-B+NK-
Adenosine deaminase (ADA) AR T-B-NK- PEG-ADA replacement
T cell receptor subunits CD3D/CD3E/CD247/CD3G AR T-B+NK+
Artemis (DCLRE1C) AR T-B-NK+ EBV lymphoma Radiation sensitivity
DNA ligase IV (LIG4) AR T-B-NK+ Microcephaly EBV lymphoma T-ALL Radiation sensitivity
DNA-PKcs (PRKDC) AR T-B-NK+ Radiation sensitivity
Omenn syndrome RAG1/RAG2/Artemis hypomorphic mutation AR Variable Lymphadenopathy Autoimmunity Some radiation sensitive
Nijmegen breakage syndrome Nibrin (NBN) AR Decreased CD4 T cells Hypogammaglobulinemia Bird-like facies B lymphomas Radiation sensitivity
Reticular dysgenesis Adenylate kinase 2 (AK2) AR T-B-NK-Neutropenia
Cernunnos/X-linked lymphoproliferative disease (XLF) deficiency Nonhomologous end-joining factor 1 (NHEJ1) XLR T-B-NK+ Elevated IgM Microcephaly Immune cytopenia
Purine nucleoside phosphorylase (PNP) deficiency PNP AR T-B+/-NK+ Neurologic degeneration Autoimmune hemolytic anemia
Major histocompatibility class II (MHC II) deficiency CIITARFXANKRFX5RFXAP AR CD4 lymphopenia Sclerosing cholangitis
Zeta-chain-associated protein-70 (ZAP-70) deficiency ZAP70 AR CD8 lymphopenia CD4 hypoproliferation
CD8 deficiency TAP1/TAP2/TAPBP AR CD8 lymphopenia Midline granulomatous lesions Vasculitis
Store operated calcium channel activation defects STIM1ORAI1 AR T lymphopenia Myopathy
DiGeorge syndrome 22q11 deletion 10p13-14 deletion T lymphopenia Thymic aplasia Cardiac defects Facial dysmorphism Hypoparathyroidism
Wiskott-Aldrich syndrome WASWIPF1 XLR AR Thrombocytopenia Eczema Autoimmunity B cell lymphoma
Hyper IgM CD40LGCD40UNGAICDA XLR AR Neutropenia Leukemia Lymphoma
X-linked lymphoproliferative disease XLP1 (SH2D1A) XLP2 (XIAP) XLR NKT cell deficiency EBV-induced HLH
Immunodysregulation, polyendocrinopathy, and enteropathy X-linked (IPEX) FOXP3 XLR FoxP3+ regulatory CD4 T cell deficiency Eczema Diarrhea Immunosuppression with cyclosporin A or sirolimus
CD25 deficiency IL2RA AR FoxP3+ regulatory CD4 T cell deficiency Autoimmunity
NF-kappaB Essential Modulator (NEMO) deficiency IKBKG XLR Ectodermal dysplasia Hypohydrosis Hypotrichosis Hypodontia
Immunodeficiency, centromeric instability, facial dysmorphism (ICF) syndrome DNMT3B AR T-B-NK+ Facial anomalies Growth retardation Psychomotor retardation
Autoimmune lymphoproliferative syndrome (ALPS) FASFASLGCASP8CASP10 AR Lymphadenopathy B cell lymphoma Immunosuppression with sirolimus
Familial hemophagocytic lymphohistiocytosis Perforin 1 (PRF1) UNC13D Syntaxin 11 (STX11) Syntaxin-binding protein 2 (STXBP2) AR HLH Immunosuppression with steroid, etoposide, cyclosporin A
Cartilage hair hypoplasia RMRP AR Short-limbed dwarfism Sparse hair Bone marrow failure
Hyper IgD syndrome Mevalonate kinase (MVK) AD Periodic fever syndrome
Hyper IgE syndrome STAT3TYK2DOCK8 AD AR Eczema Defective loss of teeth Hyperextensible joints Vascular abnormalities Autoimmunity Vasculitis
Chronic granulomatous disease CYBBCYBANCF1NCF2NCF4 XLR AR Gastric outlet obstruction Non-infectious colitis Hydronephrosis
Severe congenital neutropenia /cyclical neutropenia ELANEHAX1G6PC3 Glycogen storage disease Ib (G6PT1)p14GFI1 AR AD Neutropenia Increased risk for myelodysplastic syndrome and acute myeloid leukemia G-CSF replacement
Schwachman Diamond syndrome SBDS AR Neutropenia Exocrine pancreatic insufficiency Bone marrow failure Metaphyseal chondrodysplasia
Leukocyte adhesion deficiency 1 ITGB2 AR Neutrophilia
Leukocyte adhesion deficiency 2 GDP-fucose transporter 1 (SLC35C1) AR Neutrophilia Short stature Facial dysmorphisms Mental retardation Bombay blood-type phenotype
Leukocyte adhesion deficiency 3 Kindlin-3 (KIND3) AR Neutrophilia Abnormal platelet function
Chediak-Higashi syndrome LYST AR Cellular inclusions (giant lysosomes) Silver-gray hair Neuropathy HLH
Griscelli syndrome, type 2 RAB27A AR Partial albinism HLH
Interferon-γ receptor (IFN-γR) signaling deficiencies IFNGR1IFNGR2STAT1IL12RB1IL12B AR or AD Increased susceptibility to mycobacteria

What conditions can underlie abnormality?

What inherited abnormalities of the immune system are indications for transplantation?

Table I. Primary immune deficiencies treated by bone marrow transplant, gene(s), inheritance, cellular phenotype, special features.

When do you need to get more aggressive tests?

In SCID, IPEX, familial HLH (hemophagocytic lymphohistiocytosis) and XLP (X-linked lymphoproliferative disease), a positive family history warrants aggressive screening, so that BMT can be performed before the development of persistent infections or inflammatory states occur, that impair organ function.

A characteristic presentation combined with abnormal screening tests should prompt an attempt to make a specific genetic diagnosis. HLA typing and identification of an appropriate donor can begin immediately in response to the clinical presentation of SCID, IPEX, or HLH.

What imaging studies (if any) will be helpful?

A CT (computed tomography) scan of the chest may demonstrate absence of the thymus in DiGeorge syndrome. Pneumonitis is a common presentation of SCID.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

For pneumonitis, empiric therapy should cover Pneumocystis jirovecii pneumonia (PCP), Cytomegalovirus (CMV), influenza, adenovirus, and, Mycoplasma, in addition to standard bacterial and fungal pathogens, pending results of a BAL (bronchoalveolar lavage).

For HLH, prompt treatment with glucocorticoids, a calcineurin inhibitor, and etoposide may be indicated to stabilize the patient.

What other therapies are helpful for reducing complications?

Empiric antibiotic prophylaxis for PCP has reduced fatal P. jirovecii in WAS and X-linked hyper IgM, IVIG replacement decreases sinopulmonary infections in hyper IgM syndrome, and G-CSF treatment dramatically reduces infection in SCN.

Pegylated adenosine deaminase therapy can allow normalization of immune function in ADA (adenosine deaminase)-deficient SCID for months to years. Granulocyte transfusions may help treat severe bacterial or fungal infections in conditions such as LAD and SCN.

When is the best time to proceed with bone marrow transplantation?

The best time to treat a PID with BMT is influenced by the particular disease, its accumulated complications/morbidity, and the availability of a suitable donor. Earlier is better for severe combined immunodeficiency (SCID). In a single institution series of 166 patients, infants transplanted at less than 3.5 months of age demonstrated overall survival of 94%, versus 69% for those transplanted at an older age. Young infants had more robust T cell reconstitution as marked by numbers of circulating CD3+ and CD45RA+ cells and higher numbers of T cell receptor excision circles (TRECs), found in recent thymic emigrants. Analysis of European transplants for SCID similarly showed superior 10 year survival of 68% if less than 6 months old, versus 51% if greater than 12 months old at time of transplant. More recent outcome data regarding 240 patients transplanted for SCID between 2000 and 2009 bear these findings out, with children older than 3.5 months doing nearly as well as younger infants if the older children are free of infection or have had infection resolve before BMT, with 90% and 82% overall survival, respectively. Older children with active infection fared far worse with only 50% survival.

Implicit in this relationship of outcome and time of transplant is the increased risk of fatal infectious complications in patients who are older at BMT, largely due to common viruses such as Cytomegalovirus, adenovirus, Epstein Barr virus, enterovirus, parainfluenza, varicella, HSV (herpes simplex virus), and RSV (human respiratory syncytial virus) in order of frequency. Conversely, children with prompt neonatal diagnosis of SCID due to family history benefited with substantially lower overall mortality (60% in probands, 10% in second affected children), associated with both fewer pre-transplant infections. This observation suggested that neonatal diagnosis of lymphopenia by screening Guthrie cards using quantitative PCR (polymerase chain reaction) for TRECs (T-cell receptor excision circles) could help to improve overall survival for SCID and other diseases with neonatal lymphopenia, by allowing earlier diagnosis and transplantation. Early data regarding success of newborn screening has recently been published. In 11 states that were the first to implement universal screening, 52 cases have been identified, leading to an estimated incidence of SCID of 1 in 58,000 live births in the US. Survival outcomes of these children identified at a very young age by universal screening has been 82%, supporting the view that early diagnosis prior to infection is critical to the best treatment outcomes.

For other PIDs where supportive measures can treat or delay onset of infection, bone marrow transplant may be deferred successfully until children are older. As examples: empiric antibiotic prophylaxis for PCP has reduced fatal P. jirovecii in WAS and X-linked Hyper IgM; IvIg replacement decreases sinopulmonary infections in Hyper IgM syndrome; and G-CSF treatment dramatically reduces infection in SCN. However, longer-term follow-up of registry data have demonstrated that such measures may only delay early mortality in these conditions into the second or third decade. Moreover, eventual complications of the underlying PID significantly reduce the chance for successful cure by transplantation.

Another subset of the inherited immune disorders includes autoimmunity (IPEX, ALPS) or severe inflammatory states triggered by infection (familial HLH, or the HLH-like states due to EBV and other infections in XLP or Chediak-Higashi syndrome). These inflammatory states may cause irreversible and sometimes fatal end-organ damage. Immunosuppressive therapy with cyclosporine or sirolimus can reduce symptoms for some patients with IPEX or ALPS, and chemotherapy and steroids can induce temporary remissions of HLH and related inflammatory states.

While chronic immunosuppressive therapy may temporize, it clearly increases infectious risk and requires monitoring and antibiotic prophylaxis. Furthermore, recurrence of HLH or the accelerated phase in XLP and Chediak-Higashi often fails to respond to further immune modulation with chemotherapy.

In each of these diseases, BMT outcomes are superior when performed during a period of good disease control. Therefore, it is important for all children with PIDs to have early referral to a center familiar with BMT to treat PID, in order to discuss treatment options and perform HLA typing at the time of diagnosis.

Donor selection and transplant outcomes

Transplants from HLA-identical sibling donors have produced the best results, but results with alternative donor transplants are improving.

Haploidentical (typically parent) donors have been used successfully in PID transplantation following in vitro T cell depletion of marrow grafts by a factor of 10-4to 10-5. Although this approach may carry an increased risk for graft rejection in PID patients who are not lymphopenic, the ready donor availability and ability to collect a second product or donor lymphocytes to boost engraftment are advantages for patients without a fully matched sibling donor. The primary disadvantage to this approach is related to the delay in T cell immune reconstitution after rigorous T cell depletion of the graft, leading to increased mortality from opportunistic infection. Alternatives to deplete T cells in vivo using Campath, anti-thymocyte globulin, or post-transplant cyclophosphamide are discussed under "Transplant preparative regimens" below.

Another means to overcome lack of a fully matched related or unrelated donor is use of unrelated cord blood transplants matched for only four of the HLA-A and B antigens and DRB1-alleles.

Transplant preparative regimen

The risks of graft failure and of treatment-related mortality depend strongly on the underlying host immune function, the presence of opportunistic infection at the time of transplant, and the presence of underlying end-organ damage prior to BMT.

For SCID patients who have minimal T cell mediated immunity, one approach to transplant is to infuse the graft without any prior preparative regimen. Because an important goal is to transplant such patients at as young an age as possible, avoiding the toxicity of chemotherapy and irradiation on brain development, growth, and gonadal function in this susceptible age group is a distinct advantage of this approach. The disadvantage lies in a somewhat increased incidence of graft failure and less complete immune reconstitution, particularly of the B cell compartment, often requiring lifelong IgG replacement.

Myeloablative BMT is possible for such patients and results in more complete donor engraftment and better B and T cell reconstitution at the expense of somewhat greater transplant-related mortality. Nevertheless, with improved HLA matching and aggressive treatment of acute GVHD (graft-versus-host disease), long term overall survival of up to 80% has been achieved in a recent cohort of 41 patients from Canada and Italy.

Efforts to improve upon these results, for SCID and other PID, have taken several approaches. One has been the development of treosulfan, an alkylating agent with reduced risk of hepatic veno-occlusive disease (VOD) following myeloablative preparative dosing, particularly when given with fludarabine.

Another approach has been to avoid high-dose chemotherapy entirely, by using immunosuppressive, but non-myeloablative preparative regimens to shorten the duration of neutropenia and avoid organ toxicity. Such regimens may include anti-thymocyte globulin or monoclonal antibodies to deplete host lymphocytes to promote engraftment. Depending on timing of administration, such antibodies may persist and also deplete donor-derived T cells infused with the graft and thereby help prevent GVHD. These agents are typically combined with lymphocytotoxic doses of cyclophosphamide, fludarabine, or melphalan, and regimens may include low doses of total body irradiation.

No systematic comparison of these approaches is available. In general, non-myeloablative preparative regimens appear to have higher graft rejection rates, and ATG (antithymocyte globulin) and monoclonal antibody-containing regimens may result in delayed T cell reconstitution and higher rates of infection, due to depletion of mature T cells within the graft.

An alternative approach for haploidentical donor BMT is to use a non-myeloablative preparative regimen, and to administer high dose cyclophosphamide (50mg/kg on day +3 and +4) after infusion of an unmanipulated graft. This approach results in depletion of activated alloreactive T cells, while sparing resting non-alloreactive T cells. This strategy has been used with success in both hematologic malignancies and non-malignant conditions.

What should you tell the patient and the family about prognosis?

Success of BMT for immunodeficiency is affected by the complications related to the underlying diagnosis, such as preexisting severe infection or preexisting autoimmunity from diseases involving immune dysregulation, and the risk of graft rejection depends on the preservation of partial host immune function in some conditions. When SCID patients have failure-to-thrive due to persistent viral infection, only a minority survive BMT, but of SCID patients transplanted as newborns from a matched sibling donor, over 90% survive.


Most primary immune deficiencies (PIDs) arise from genetic mutations that result in defects in the generation, function, or regulation of a cellular constituent of the immune system.

Lymphocyte disorders result from defects in cytokine signaling, generation of antigen receptors, signaling from antigen receptors, costimulatory pathways, apoptotic pathways, and cytotoxic effector mechanisms.

Granulocyte disorders result from defects in cytokine signaling, trafficking, and cytotoxic effector mechanisms.

What’s the evidence?

Buckley, RH. "Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes". Immunol Res. vol. 49. 2011. pp. 25-43.

(A comprehensive analysis of treatment outcomes for 166 patients with SCID who received stem cell transplantation at a single institution.)

Gennery, AR, Slatter, MA, Grandin, L, Taupin, P, Cant, AJ, Veys, P. "Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better?". J Allergy Clin Immunol. vol. 126. 2010. pp. 602-10.

(An analysis of transplant outcomes for SCID and non-SCID PID from the European registry spanning 37 years.)

Pai, SY, Logan, BR, Griffith, LM, Buckley, RH, Parrott, RE, Dvorak, CC. "Transplantation outcomes for severe combined immunodeficiency, 2000-2009". N Engl J Med. vol. 371. 2014. pp. 434-46.

(A comprehensive, multi-institutional analysis of contemporary treatment outcomes of transplantation for SCID.)

Baker, MW, Laessig, RH, Katcher, ML, Routes, JM, Grossman, WJ, Verbsky, J. "Implementing routine testing for severe combined immunodeficiency within Wisconsin's newborn screening program". Public Health Rep. vol. 125 Suppl 2. 2010. pp. 88-95.

(An analysis of the cost/benefit and effectiveness of newborn screening to permit early diagnosis of severe combined immunodeficiency.)

Kwan, A, Abraham, RS, Currier, R, Brower, A, Andruszewski, K, Abbott, JK. "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States". JAMA. vol. 312. 2014. pp. 729-38.

(A report on the outcomes of universal newborn screening for T cell lymphopenia in the United States with estimated incidence of SCID.)

Teachey, DT, Greiner, R, Seif, A. "Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome". Br J Haematol. vol. 145. 2009. pp. 101-6.

(Use of novel medical management with sirolimus to control symptoms of immunodeficiency from ALPs. Such approaches may permit more flexibility regarding timing of curative transplant and may also apply to other diseases with immune dysregulation such as IPEX.)

Henter, JI, Samuelsson-Horne, A, Arico, M. "Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation". Blood. vol. 100. 2002. pp. 2367-73.

(Successful cure of HLH with chemotherapy followed by BMT in a patient population traditionally challenging to successfully transplant, due to organ dysfunction from PID.)

Seidel, MG, Fritsch, G, Lion, T. "Selective engraftment of donor CD4+25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation". Blood. vol. 113. 2009. pp. 5689-91.

(A case report demonstrating that engraftment with regulatory T cells alone is sufficient to cure IPEX syndrome in humans.)

Dvorak, CC, Hassan, A, Slatter, MA, Hönig, M, Lankester, AC, Buckley, RH. "Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of severe combined immunodeficiency". vol. 134. 2014. pp. 935-43.

(Analysis of outcomes of transplantation without conditioning for SCID comparing matched related and unrelated donors.)

Bhattacharya, A, Slatter, MA, Chapman, CE. "Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency". Bone Marrow Transplant. vol. 36. 2005. pp. 295-9.

(Successful use of umbilical cord blood transplant for a variety of PIDs.)

Grunebaum, E, Roifman, CM. "Bone marrow transplantation using HLA-matched unrelated donors for patients suffering from severe combined immunodeficiency". Immunol Allergy Clin North Am. vol. 30. 2010. pp. 63-73.

(Successful matched unrelated donor transplantation (in contrast to maternal T cell depleted haploidentical transplantation) for severe combined immune deficiency.)

Slatter, MA, Rao, K, Amrolia, P. "Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency: United Kingdom experience". Blood. vol. 117. 2011. pp. 4367-75.

(The authors describe a method to reduce PID-transplant related morbidity and mortality using the novel alkylating agent treosulfan.)

Brodsky, RA, Luznik, L, Bolanos-Meade, J, Leffell, MS, Jones, RJ, Fuchs, EJ. "Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases". Bone Marrow Transplant. vol. 42. 2008. pp. 523-7.

(This author demonstrates the efficacy of post-transplant high-dose cyclophosphamide in permitting the use of mismatched (haploidentical) donors for BMT with favorable rates of engraftment and GVHD, expanding the potential donor pool for patients with immunodeficiency who require transplant.)
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