Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency.

PURPOSE OF REVIEW: Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID. RECENT FINDINGS: Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.

Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort.

Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naïve CD4+CD45RA+CD27+ T-lymphocyte values at 3, 6, 9, 12months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p=0.002, p<0.001, p<0.001, p=0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.

Haematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.

T-lymphocyte depleted transplants for inborn errors of immunity.

INTRODUCTION: Hematopoietic stem cell transplantation is a curative treatment for many inborn errors of immunity (IEI). Incremental improvements and advances in care have led to high rates of >85% survival and cure in many of these diseases. Improvements in HLA-classification and matching have led to increased survival using HLA-matched donors, but survival using T-lymphocyte-depleted mismatched grafts remained significantly worse until fairly recently. Advances in T-lymphocyte depletion methods and graft engineering, although not specific to IEI, have been widely adopted and instrumental in changing the landscape of donor selection, such that a donor should now be possible for every patient. AREAS COVERED: A literature review focusing on T-lymphocyte depletion methodologies and treatment results was performed. The importance of early T-lymphocyte immunoreconstitution to protect against viral infection is reviewed. Two main platforms now dominate the field - immune-magnetic selection of specific cell types and post-transplant chemotherapeutic targeting of rapidly proliferating allo-reactive T-lymphocytes - the emerging literature on these reports, focusing on IEI, is explored, as well as the impact of serotherapy on early immunoreconstitution. EXPERT OPINION: Pharmacokinetic monitoring of serotherapy agents, and use of co-stimulatory molecule blockade are likely to become more widespread. Post-transplant cyclophosphamide or TCR depletion strategies are likely to become the dominant methods of transplantation for nonmalignant diseases.

Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome).

BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.

Clinical immunology review series: an approach to the patient with recurrent infections in childhood.

Recurrent or persistent infection is the major manifestation of primary immunodeficiency, which also results in atypical infection with opportunistic organisms. Young children are also vulnerable to infection and recurrent infection is common. While most children with recurrent infection have a normal immunity, it is important to recognize the child with an underlying primary immunodeficiency and investigate and treat appropriately and yet not over investigate normal children. Prompt, accurate diagnosis directs the most appropriate treatment, and early and judicious use of prophylactic antibiotics and replacement immunoglobulin can prevent significant end organ damage and improve long-term outlook and quality of life. This paper describes important presenting features of primary immunodeficiency and indicates when further investigation is warranted.

Mutations in CHD7 in patients with CHARGE syndrome cause T-B + natural killer cell + severe combined immune deficiency and may cause Omenn-like syndrome.

More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T-B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Ralpha and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T-B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized--CHARGE syndrome should now be added to the causes of T-B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome.

Value of bronchoalveolar lavage before haematopoietic stem cell transplantation for primary immunodeficiency or autoimmune diseases.

Pulmonary infection, often insidious, is frequent in primary immunodeficiency (PID) and acquired immunodeficiency. Pulmonary complications are serious obstacles to success of haematopoietic SCT (HSCT) for these conditions. Bronchoalveolar lavage (BAL) permits identification of lower respiratory tract pathogens that may direct specific treatment and influence prognosis. There are no reports about the utility of pre-HSCT BAL for immunodeficient patients. We prospectively studied the value of 'routine' BAL before commencing transplantation in patients undergoing HSCT for severe immunological disease. Routine non-bronchoscopic BAL was performed under general anaesthetic, a few days before commencing pre-HSCT cytoreductive chemotherapy. Patients were categorized as symptomatic or asymptomatic with respect to pulmonary disease or infection. Samples were sent for microbiological processing. Complications arising from the procedure, pathogens isolated and treatments instituted were recorded. Results were available from 69/75 patients transplanted during the study period; 26 (38%) had pathogens identified (six asymptomatic patients), 10 (14.5%) developed complications post-procedure (two asymptomatic patients)-all recovered, 21 had management changes. There was no statistically significant difference in the number of positive isolates from severe combined or other immunodeficient patients, or of symptomatic or asymptomatic patients. Routine non-bronchoscopic BAL is safe in immunodeficient patients about to undergo HSCT, and leads to management changes.

Outcome of boost haemopoietic stem cell transplant for decreased donor chimerism or graft dysfunction in primary immunodeficiency.

Haemopoietic stem cell transplants (HSCT) cure increasing numbers of primary immunodeficiencies (PID): residual recipient T-cell function increases risk of incomplete or decreasing immune reconstitution, which may resolve following a second, unconditioned, infusion from the same donor (boost infusion). We assessed the outcome of 20 boost infusions in 19/139 patients transplanted for PID patients at our centre since 1987. Boost infusion was given 64-1226 days after the original HSCT. Follow-up was 4-124 months. In all, 12 of 19 patients cleared viral infection (6), or showed sustained increase in donor chimerism, T- and B-cell numbers and function, or other markers (6). In 7/12 patients, immunoglobulin replacement has been discontinued. Four were partially successful with stable low-level chimerism (two patients) or improved T-cell function, but not B cell function (two patients). Four failed with no change in donor chimerism or cell number. No significant association with donor source, T-cell depletion, conditioning regimen, boost infusion stem cell dose or time from original HSCT to boost was found. One patient developed grade III acute graft-versus-host disease despite cyclosporine, and one developed severe pneumonitis; both have recovered. Boost infusion was successful or partially successful in 84% of patients. The risk of adverse effects is low.

Single centre experience of umbilical cord stem cell transplantation for primary immunodeficiency.

Primary immunodeficiencies (PID) are an important cause of childhood mortality. Haematopoietic stem cell transplantation (HSCT) is the best treatment for many PID. Umbilical cord stem cells are an alternative source of HSC. There is little data regarding outcome of umbilical cord stem cell transplantation (UCSCT) for PID. Our single centre experience is reported. A retrospective study of 14 of 148 patients transplanted for PID, who have received 15 UCSCT was performed, with specific regard to graft-versus-host disease (GvHD) and immune reconstitution. Eight patients with severe combined immunodeficiency (SCID), and six with other combined immunodeficiencies were treated. Of the patients, 12 received unrelated cords, and two had sibling transplants. Median age at transplant was 3.5 months, median nucleated cell dose was 0.8 x 10(8)/kg. All engrafted. Median time to neutrophil engraftment was 22 days, median time to platelet engraftment was 51 days. One developed significant grade III GvHD post transplantation. In total, 11 patients had full donor T and six full donor B-cell chimerism, six of nine patients >1 year post-BMT had normal IgG levels and specific antibody responses to tetanus and Hib vaccines; two are being assessed. Two patients died of multi-organ failure related to pre-existing infection and inflammatory complications respectively. UCSCT should be considered for patients requiring stem cell therapy for PID.

Treosulfan-based conditioning regimens for allogeneic haematopoietic stem cell transplantation in children with non-malignant diseases.

An increasing number of children with non-malignant diseases can be cured by allogeneic haematopoietic stem cell transplantation (HSCT). Treosulfan (L-treitol-1,4-bis-methanesulfonate) is being used more frequently for conditioning, owing to its' lower toxicity profile compared with conventional myeloablative regimens. A retrospective analysis was performed of children registered in the EBMT database, who received treosulfan before HSCT between January 2005 and 2010, to identify possible dose-related toxicity and determine the incidence of engraftment, treatment-related mortality and overall survival (OS). Results from 316 transplants from 11 different countries are presented. Ninety-five (30%) were under 1 year of age at the time of transplant. OS was 83% and event-free survival was 76%; 3-year OS and event-free survival of infants below 1 year were 79% and 73%, respectively. No association was found with age at transplant, dose of treosulfan given, other agents used in combination with treosulfan, donor type, stem cell source, or second or subsequent transplant. In this report of the largest number of children to date receiving treosulfan for non-malignant diseases, treosulfan is shown to be a safe and effective agent even for those under 1 year of age at the time of transplant. Further prospective studies are needed using precisely defined protocols with pharmacokinetic monitoring and detailed chimerism analysis. In addition, long-term studies will be vital to determine long-term effects, for example, on fertility in comparison with other regimens.

Thyroid dysfunction after bone marrow transplantation for primary immunodeficiency without the use of total body irradiation in conditioning.

Thyroid dysfunction, a common long-term complication following bone marrow transplantation (BMT), is frequently associated with total body irradiation (TBI) given in the pre-BMT conditioning protocol. We report our preliminary observation of the prevalence of thyroid dysfunction in children transplanted for primary immunodeficiency (PID) who were given cytoreductive conditioning with busulphan and cyclophosphamide, but without TBI. We evaluated thyroid-stimulating hormone (TSH) and free thyroxine (fT4) in 83 survivors transplanted between 1987 and 2002. We found nine children (10.8%) with clinical and/or biochemical thyroid dysfunction at 4 months to 4.5 years post-BMT of which three had positive antithyroid microsomal antibodies. Two patients were classified as primary and seven as compensated hypothyroidism (hyperthyrotropinaemia). Four patients with clinical features of hypothyroidism received replacement thyroxine, while five of the seven patients with compensated hypothyroidism remain off thyroxine because we suspect this may be a transient phenomenon. Abnormalities of thyroid function including severe primary hypothyroidism may occur post-BMT in children receiving chemotherapy conditioning without TBI. Thyroid function should be assessed regularly in this group of patients.

Polysaccharide antibody responses are impaired post bone marrow transplantation for severe combined immunodeficiency, but not other primary immunodeficiencies.

Established treatment of severe combined immunodeficiencies (SCID) and other primary immunodeficiencies (PID) is bone marrow transplantation (BMT). Normal lymphocyte numbers and protein antigen responses are present within 2 years of BMT, polysaccharide antibody responses appear last. Streptococcus pneumoniae infection causes significant morbidity and mortality post-BMT. Previous studies have shown good protein antigen responses post-BMT for SCID and PID, but had not examined the polysaccharide responses. We retrospectively analysed pneumococcal polysaccharide (PPS) responses in our patient series. In total, 22 SCID and 12 non-SCID PID were evaluated, all >2 years post BMT: 17 SCID, 12 PID received chemotherapy conditioning; 17 SCID, three PID had T-cell depleted (TCD) BMT, others had nonconditioned whole marrow BMT. All had normal Haemophilus influenza B and tetanus antibody responses. Of 22 SCID, 13 vs 11/12 PID responded to PPS vaccine (P=0.05). There was no association with donor age, GvHD, B-cell chimerism, or IgG2 level. Fewer TCD marrow recipients responded to PPS (P=0.04). Analysis of the SCID group showed no association of PPS response with type of marrow received. This is the first study to specifically examine PPS antibody responses following SCID and PID BMT. Pneumococcal conjugate vaccine antibody responses should be examined in these children.

Outcome of children requiring intensive care following haematopoietic SCT for primary immunodeficiency and other non-malignant disorders.

Haematopoietic SCT (HSCT) is curative for many children with primary immunodeficiencies or other non-malignant conditions. Outcome for those admitted to intensive care following HSCT for oncology diagnoses has historically been very poor. There is no literature available specifically regarding the outcome for children with primary immunodeficiency requiring intensive care following HSCT. We reviewed our post-HSCT admission to intensive care over a 5-year period. A total of 111 children underwent HSCT. Median age at transplant was 1 year 4 months. The most common diagnosis was SCID. In all, 35% had at least one intensive care admission and 44% survived to be discharged from intensive care. Also, 73% of admission episodes requiring invasive ventilation but no inotropes or renal replacement therapy resulted in survival to discharge. Children undergoing HSCT for immunological diagnoses had a high rate of admission to intensive care. No factors were identified that could predict the need for admission. Invasive ventilation alone has a much better outcome than that in historical series. However, the need for multi-organ system support was still associated with a poor outcome. This information is useful when counselling families of children that have deteriorated and been admitted to intensive care during the HSCT procedure.

Umbilical cord stem cell transplantation for primary immunodeficiencies.

Primary immunodeficiencies (PIDs) are a rare but important cause of mortality and morbidity in childhood: the most severe--known as severe combined immunodeficiency (SCID)--are fatal within the first year of life; other PIDs are less immediately life-threatening, but have a poor long-term outlook. Haematopoietic stem cell transplantation (HSCT) is the best treatment for SCID and is increasingly offered for other PIDs. The best results are achieved with an HLA-matched family donor. Umbilical cord stem cells (UCSCs) are an alternative stem cell source. Results using UCSCs in the treatment of haematological disorders and malignancy are as good as those for which marrow is the stem cell source. Although PIDs make up a small proportion of disorders amenable to treatment by HSCT, UCSCs are an ideal source of haematopoietic stem cells for many of these patients. Of the 52 patients with SCID or other PIDs for whom detailed information on outcome is available, results of engraftment, immune reconstitution, incidence of graft-versus-host disease and survival are comparable with other stem cell sources. Small stem cell dose and prolonged time to viral immunity limit the patients for whom UCSCs can be used. Newer methods of achieving better engraftment, ex vivo expansion of stem cells and generation of antigen-specific cytotoxic T cells are being developed at present, and will widen the application of UCSCs as a viable source for more patients.

Use of two unrelated umbilical cord stem cell units in stem cell transplantation for Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome, an X-linked primary immunodeficiency can be cured by bone marrow transplantation. Umbilical cord haemopoietic stem cells are increasingly used as an alternative to bone marrow; advantages include ready availability, no risk to the donor, low rate of viral contamination, and low risk of graft versus host disease. Disadvantages include low stem cell dose for larger patients and lack of stem cells for boost infusions following the initial procedure. We report the case of a child with Wiskott-Aldrich syndrome who underwent cord blood stem cell transplantation with two separate cord blood units, 8 days apart.

The clinical and biological overlap between Nijmegen Breakage Syndrome and Fanconi anemia.

Fanconi anemia (FA), an autosomal recessive chromosomal instability syndrome, is characterized clinically by developmental abnormalities, growth retardation, progressive bone marrow failure, pancytopenia, and pronounced cancer predisposition. Nijmegen Breakage Syndrome (NBS) is a related disorder that shares overlapping clinical features, principally, developmental delay, microcephaly, and cancer predisposition. The diagnosis has relied on chromosomal instability following exposure to DNA cross-linking agents in FA and to ionizing radiation (IR) in NBS. We describe two patients who clinically had FA, but showed sensitivity to both DNA cross-linking agents and ionizing radiation, and who were found to have a rare mutation in the NBS gene. The importance of genetic diagnosis with respect to treatment and prognosis is discussed.