Zohreh Nademi

Treosulfan-based conditioning regimens for hematopoietic stem cell transplantation in children with primary immunodeficiency: United Kingdom experience

Children with primary immunodeficiency diseases, particularly those less than 1 year of age, experience significant toxicity after hematopoietic stem cell transplantation, with busulfan- or melphalan-based conditioning. Treosulfan causes less veno-occlusive disease than busulfan and does not require pharmacokinetic monitoring. We report its use in 70 children. Children received 42 g/m(2) or 36 g/m(2) with cyclophosphamide 200 mg/kg (n = 30) or fludarabine 150 mg/m(2) (n = 40), with alemtuzumab in most. Median age at transplantation was 8.5 months (range, 1.2-175 months); 46 (66%) patients were 12 months of age or younger. Donors were as follows: matched sibling donor, 8; matched family donor, 13; haploidentical, 4; and unrelated, 45. Median follow-up was 19 months (range, 1-47 months). Overall survival was 81%, equivalent in those age less or greater than 1 year. Skin toxicity was common. Veno-occlusive disease occurred twice with cyclophosphamide. Eighteen patients (26%) had graft-versus-host disease, and only 7 (10%) greater than grade 2. Two patients rejected; 24 of 42 more than 1 year after transplantation had 100% donor chimerism. The remainder had stable mixed chimerism. T-cell chimerism was significantly better with fludarabine. Long-term follow-up is required, but in combination with fludarabine, treosulfan is a good choice of conditioning for hematopoietic stem cell transplantation in primary immunodeficiency disease.

Comparison of interferon-{gamma} release assays and tuberculin skin test in predicting active tuberculosis (TB) in children in the UK: a paediatric TB network study

Background The value of interferon-γ release assays (IGRA) to diagnose active tuberculosis (TB) in children is not established, but these assays are being widely used for this purpose. The authors examined the sensitivity of commercially available IGRA to diagnose active TB in children in the UK compared with the tuberculin skin test (TST). Methods The authors established a paediatric tuberculosis network and conducted a retrospective analysis of data from children investigated for active TB at six large UK paediatric centres. All centres had used TST and at least one of the commercially available IGRA (T-Spot.TB or Quantiferon-Gold in Tube) in the diagnostic work-up for active TB. Data were available from 333 children aged 2 months to 16 years. The authors measured the sensitivity of TST and IGRA in definite (culture confirmed) and probable TB in children, agreement between TST and either IGRA, and their combined sensitivity. Results Of 333 children, 49 fulfilled the criteria of definite TB, and 146 had probable TB. Within the definite cohort, TST had a sensitivity of 82%, Quantiferon-Gold in tube (QFT-IT) had a sensitivity of 78% and T-Spot.TB of 66%. Neither IGRA performed significantly better than a TST with a cut-off of 15 mm. Combining the results of TST and IGRA increased the sensitivity to 96% for TST plus T-Spot.TB and 91% for TST plus QFG-IT in the definite TB cohort. Conclusions A negative IGRA does not exclude active TB disease, but a combination of TST and IGRA increases the sensitivity for identifying children with active TB.

Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency

Background Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder. Objective To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment. Methods A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK+ (n = 24) and NK− (n = 53) forms of SCID. Results Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK−SCID were more likely to survive than NK+ recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK+SCID required additional transplantation procedures compared with only 8% of children with NK−SCID (P < .005). Conclusions NK−SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.

Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome.

Zohreh Nademi, PhD, Mary A. Slatter, MD, Christopher C. Dvorak, MD, Benedicte Neven, MD, Alain Fischer, MD, Felipe Suarez, MD, Claire Booth, MD, Kanchan Rao, MD, Alexandra Laberko, MD, Julia Rodina, MD, Yves Bertrand, MD, Sylwia Kołtan, MD, Robert Dębski, MD, Terence Flood, MD, Mario Abinun, MD, Andrew R. Gennery, MD, Sophie Hambleton, DPhil, Stephan Ehl, MD, Andrew J. Cant, MD, on behalf of the Inborn Errors Working Party of EBMT and ESID

Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

Single centre experience of haematopoietic SCT for patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection

Background Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity. Methods Children <15 years old were recruited from 11 sites in the UK between January 2011 and December 2014 if exposed in their home to a source case with sputum smear or culture positive TB. Demographic details were collected and TST and IGRA undertaken. The impact of BCG vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity. Results Of 422 children recruited (median age 69 months; IQR: 32–113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child. Discussion BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children.

T-cell receptor αβ+ and CD19+ cell–depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA‐matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft‐versus‐host disease (GvHD) and rejection associated with such transplants. Objective: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD‐causing T‐cell receptor (TCR) &agr;&bgr; CD3+ cells from the graft. Methods: CD3+TCR&agr;&bgr;+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti‐thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. Results: Twenty‐five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow‐up of 20.8 months (range, 5 month‐3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event‐free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant‐related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). Conclusion: CD3+TCR&agr;&bgr;+ and CD19+ cell–depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.

Treosulfan and Fludarabine Conditioning for Hematopoietic Stem Cell Transplantation in Children with Primary Immunodeficiency: UK Experience

We previously published results for 70 children who received conditioning with treosulfan and cyclophosphamide (n = 30) or fludarabine (n = 40) before undergoing hematopoietic stem cell transplantation (HSCT) for primary immunodeficiency (PID). Toxicity was lower and T cell chimerism was better in the patients receiving fludarabine, but cohort numbers were relatively small and follow-up was short. Here we report outcomes of 160 children who received homogeneous conditioning with treosulfan, fludarabine, and, in most cases, alemtuzumab (n = 124). The median age at transplantation was 1.36 years (range, .09 to 18.25 years). Donors included 73 matched unrelated, 54 1 to 3 antigen-mismatched unrelated, 12 matched sibling, 17 other matched family, and 4 haploidentical donors. Stem cell source was peripheral blood stem cells (PBSCs) in 70, bone marrow in 49, and cord blood in 41. Median duration of follow-up was 4.3 years (range, .8 to 9.4 years). Overall survival was 83%. No patients had veno-occlusive disease. Seventy-four patients (46%) had acute GVHD, but only 14 (9%) greater than grade II. Four patients underwent successful retransplantation for graft loss or poor immune reconstitution. Another patient experienced graft rejection and died. There was no association between T cell chimerism >95% and stem cell source, but a significant association was seen between myeloid chimerism >95% and use of PBSCs without an increased risk of significant GVHD compared with other sources. All 11 patients with severe combined immunodeficiency diagnosed at birth were alive at up to 8.7 years of follow-up. Long-term studies are needed to determine late gonadotoxic effects, and pharmacokinetic studies are needed to identify whether specific targeting is advantageous. The combination of treosulfan, fludarabine, and alemtuzumab is associated with excellent results in HSCT for PID.

Haploidentical hematopoietic stem cell transplantation can lead to viral clearance in severe combined immunodeficiency

compassionate use of immunoglobulins in our study was for neurologic diseases. This is similar to results of other studies. This is interesting because some of the neurologic diseases may have an autoimmune background. Several other diseases are treated with immunoglobulins despite lack of scientific data, and this seems to be similar in our study as previously described. Most of the children were treated for immune disorders or other approved indications. Our results seem to be in concordance with other reports. Interestingly, more women than men received immunoglobulin therapy during the study period. This difference was largely related to more unapproved use in women. Although women have a higher incidence of many autoimmune diseases and neurologic disorders than do men, we do question whether this entirely explains this observed difference in the sex ratio. It is important to use immunoglobulin treatment cautiously but sensibly. Treatment with immunoglobulins is often very effective, but the cost can be high andmust be taken into consideration. Unapproved use can certainly be accepted, but at the same time, the need for a better understanding of these diseases and the treatment is evident. It is hoped that research in the near future will facilitate this development.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Background: Immunodysregulation polyendocrinopathy enteropathy x‐linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective: This analysis sought to evaluate disease onset, progression, and long‐term outcome of the 2 main treatments in long‐term IPEX survivors. Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow‐up of 2.7 years (range, 1 week‐15 years). Patients receiving chronic IS (n = 34) had a median follow‐up of 4 years (range, 2 months‐25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4–83.0) and after IS was 65.1% (95% CI, 62.8–95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long‐term disease‐free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.