Juliana Silva

Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant

Cidofovir is preemptively used for controlling adenoviremia and preventing disseminated viral disease in hematopoietic cell transplant (HCT) recipients but does not lead to resolution of viremia without T-cell immune-reconstitution. The lipid-conjugated prodrug of cidofovir, brincidofovir, has improved oral bioavailability and achieves higher intracellular concentrations of active drug. We present retrospective multicenter data comparing the kinetics of viremia and toxicities following preemptive treatment with and brincidofovir in children and adolescents diagnosed with HCT-related adenoviremia. Forty-one episodes (18 = brincidofovir; 23 = cidofovir) of antiviral therapy were observed in 27 patients. The 2 groups had comparable immune-reconstitution and viral burden. Major (≥2 log-reduction in 2 weeks; n = 13) and minor (≥1 to ≤2 log-reduction in 2 weeks; n = 2) virological responses were observed in 15 (83%) brincidofovir episodes compared to only 2 (9%) major virological responses with cidofovir (P < .0001). Brincidofovir mediated major responses in 9 of 11 cidofovir-unresponsive patients and resulted in complete responses (CR) despite significant lymphopenia (Brincidofovir vs cidofovir; CR = 13 (80%) vs 8 (35%); median lymphocyte count = 320/μl vs 910/μl; P < .05). One patient experienced abdominal cramps and diarrhea necessitating interruption of brincidofovir and none developed nephrotoxicity with brincidofovir. Thus, brincidofovir is well-tolerated and highly efficacious in controlling adenoviremia during the lymphopenic phase of HCT.

Stem cell transplantation for tetratricopeptide repeat domain 7A deficiency: long-term follow-up.

To the editor: Mutations in the tetratricopeptide repeat domain 7A ( TTC7A) gene cause a severe form of very early onset inflammatory bowel disease (VEOIBD).[1][1] TTC7A has a crucial role in chaperoning the enzyme phosphatidylinositol-4-kinase-3-α from the trans-Golgi apparatus to the plasma

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.

Use of the complement inhibitor Coversin to treat HSCT-associated TMA

Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor.Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.

Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future

ABSTRACT Primary immunodeficiencies (PID) are rare inherited disorders affecting immune function and can be life-threatening if not treated. Haematopoietic stem cell transplantation (HSCT) offers a curative approach for many of these disorders and gene therapy is increasingly used as an alternative therapeutic strategy for patients lacking a suitable donor. Early diagnosis, improved supportive care and advances in gene and cell therapies have resulted in increased survival rates and improved quality of life. This review describes current strategies employed to improve outcomes in PID, focusing on new developments in HSCT, gene and cell therapy. We also address the challenges associated with newborn screening (NBS) programmes and novel mutations identified through improved diagnostic technology.

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.

Outcome of domino hematopoietic stem cell transplantation in human subjects: An international case series

This multicenter cohort study demonstrates that at a median follow up of ten years, domino-HSCT results in overall survival of 80%, event-free survival of 49%, and low risk of GvHD. Domino-HSCT can be considered, weighed against other available transplantation strategies.

Stem Cell Transplantation for Primary Immunodeficiency

Primary immunodeficiency diseases (PID) are a group of heterogeneous inherited disorders affecting the development and function of the innate and acquired immune system. The disorders are characterized by increased susceptibility to recurrent and severe infections, autoimmunity and in some cases malignancies. Allogeneic haematopoietic stem cell transplant (HSCT), and in some cases gene therapy, is the only curative approach for many of these disorders. With the expanding field of molecular genetics, new immune disorders are being identified, but the role of HSCT or other therapy in these disorders remains to be determined. This chapter will review the current indications for HSCT in PID and will examine the specific challenges associated with HSCT in (1) severe combined immunodeficiency (SCID) where the landscape is changing due the introduction of newborn screening; (2) other combined immune deficiencies, some of which have only very recently been described; and (3) phagocytic and haemophagocytic cell disorders. The role of alternative therapies including gene therapy and thymic transplantation will also be discussed.

Multicenter phase 1/2 application of adenovirus-specific T cells in high-risk pediatric patients after allogeneic stem cell transplantation

BACKGROUND Adenovirus (ADV) reactivation can cause significant morbidity and mortality in children after allogeneic stem cell transplantation. Antiviral drugs can control viremia, but viral clearance requires recovery of cell-mediated immunity. METHOD This study was an open-label phase 1/2 study to investigate the feasibility of generating donor-derived ADV-specific T cells (Cytovir ADV, Cell Medica) and to assess the safety of pre-emptive administration of ADV-specific T cells in high-risk pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT) to treat adenoviremia. Primary safety endpoints included graft-versus-host disease (GvHD), and secondary endpoints determined antiviral responses and use of antiviral drugs. RESULTS Between January 2013 and May 2016, 92 donors were enrolled for the production of ADV T cells at three centers in the United Kingdom (UK), and 83 products were generated from 72 mobilized peripheral blood harvests and 20 steady-state whole blood donations. Eight children received Cytovir ADV T cells after standard therapy and all resolved ADV viremia between 15 and 127 days later. ADV-specific T cells were detectable using enzyme-linked immunospot assay (ELISpot) in the peripheral blood of all patients analyzed. Serious adverse events included Grade II GvHD, Astrovirus encephalitis and pancreatitis. CONCLUSION The study demonstrates the safety and feasibility of pre-emptively manufacturing peptide pulsed ADV-specific cells for high-risk pediatric patients after transplantation and provides early evidence of clinical efficacy.

Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-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. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. 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 quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. 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. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.