Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients.

Graft versus host disease (GVHD) is one of the most serious complications following stem cell transplant in children and is a major cause of morbidity and mortality. Corticosteroids remain the mainstay of treatment, and although a majority of children respond to systemic steroids, those refractory to or dependent upon corticosteroids suffer from complications secondary to long-term steroid administration. This problem has prompted consideration of steroid-sparing treatment strategies, although the time to clinical remission can be variable. Intraarterial corticosteroid delivery has been used in adults as a rescue therapy in steroid-resistant patients, but its use in children has been limited. We investigated the feasibility of intraarterial steroid administration into the bowel and/or liver in a cohort of six pediatric patients with acute GVHD. All patients successfully underwent treatment with no serious adverse effects. Five of five (100%) patients with gastrointestinal bleeding due to GVHD had rapid symptom improvement by 48 h, which was durable up to three weeks. Three of four (75%) patients with hepatic GVHD had improved cholestasis following intraarterial steroid administration. Our experience with this small cohort preliminarily demonstrated the feasibility and safety of intraarterial steroid administration in children with acute GVHD. This approach warrants consideration as a rescue therapy in steroid-refractory cases and as a "bridge" therapy for children with severe acute GVHD who are transitioning to steroid-sparing regimens.

Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients.

Type 1 regulatory T (Tr1) cells are inducible, interleukin (IL)-10+FOXP3− regulatory T cells that can suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have optimized an in vitro protocol to generate a Tr1-enriched cell product called T-allo10, which is undergoing clinical evaluation in patients with hematological malignancies receiving a human leukocyte antigen (HLA)­mismatched allo-HSCT. Donor-derived T-allo10 cells are specific for host alloantigens, are anergic, and mediate alloantigen-specific suppression. In this study, we determined the mechanism of action of T-allo10 cells and evaluated survival of adoptively transferred Tr1 cells in patients. We showed that Tr1 cells, in contrast to the non-Tr1 population, displayed a restricted T cell receptor (TCR) repertoire, indicating alloantigen-induced clonal expansion. Tr1 cells also had a distinct transcriptome, including high expression of cytotoxic T lymphocyte­associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Blockade of CTLA-4 or PD-1/PD-L1 abrogated T-allo10­mediated suppression, confirming that these proteins, in addition to IL-10, play key roles in Tr1-suppressive function and that Tr1 cells represent the active component of the T-allo10 product. Furthermore, T-allo10­derived Tr1 cells were detectable in the peripheral blood of HSCT patients up to 1 year after T-allo10 transfer. Collectively, we revealed a distinct molecular phenotype, mechanisms of action, and in vivo persistence of alloantigen-specific Tr1 cells. These results further characterize Tr1 cell biology and provide essential knowledge for the design and tracking of Tr1-based cell therapies.

Tissue-specific telomere shortening and degenerative changes in a patient with TINF2 mutation and dyskeratosis congenita.

Dyskeratosis congenita is a disease of impaired tissue maintenance downstream of telomere dysfunction. Characteristically, patients present with the clinical triad of nail dystrophy, oral leukoplakia, and skin pigmentation defects, but the disease involves degenerative changes in multiple organs. Mutations in telomere-binding proteins such as TINF2 (TRF1-interacting nuclear factor 2) or in telomerase, the enzyme that counteracts age related telomere shortening, are causative in dyskeratosis congenita. We present a patient who presented with severe hypoxemia at age 13. The patient had a history of myelodysplastic syndrome treated with bone marrow transplant at the age of 5. At age 18 she was hospitalized for an acute pneumonia progressing to respiratory failure, developed renal failure and ultimately, she and her family opted to withdraw support as she was not a candidate for a lung transplant. Sequencing of the patient's TINF2 locus revealed a heterozygous mutation (c.844C > T, Arg282Cys) which has previously been reported in a subset of dyskeratosis congenita patients. Tissue sections from multiple organs showed degenerative changes including disorganized bone remodeling, diffuse alveolar damage and small vessel proliferation in the lung, and hyperkeratosis with hyperpigmentation of the skin. Autopsy samples revealed a bimodal distribution of telomere length, with telomeres from donor hematopoietic tissues being an age-appropriate length and those from patient tissues showing pathogenic shortening, with the shortest telomeres in lung, liver, and kidney. We report for the first time a survey of degenerative changes and telomere lengths in multiple organs in a patient with dyskeratosis congenita.

The Binns Program for Cord Blood Research: A novel model of cord blood banking for academic biomedical research.

Umbilical cord blood is an important graft source in the treatment of many genetic, hematologic, and immunologic disorders by hematopoietic stem cell transplantation. Millions of cord blood units have been collected and stored for clinical use since the inception of cord blood banking in 1989. However, the use of cord blood in biomedical research has been limited by access to viable samples. Here, we present a cost-effective, self-sustaining model for the procurement of fresh umbilical cord blood components for research purposes within hospital-affiliated academic institutions.

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017.

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

The Cost of Hematopoietic Stem-Cell Transplantation in the United States.

BACKGROUND: Hematopoietic stem-cell transplantation (HSCT) requires highly specialized, resource-intensive care. Myeloablative conditioning regimens used before HSCT generally require inpatient stays and are more intensive than other preparative regimens, and may therefore be more costly. OBJECTIVE: To estimate the costs associated with inpatient HSCT according to the type of the conditioning regimen used and other potential contributors to the overall cost of the procedure. METHOD: We used data from the Truven Health MarketScan insurance claims database to analyze healthcare costs for pediatric (age <18 years) and adult (age ≥18 years) patients who had autologous or allogeneic inpatient HSCT between January 1, 2010, and September 23, 2013. We developed an algorithm to determine whether conditioning regimens were myeloablative or nonmyeloablative/reduced intensity. RESULTS: We identified a sample of 1562 patients who had inpatient HSCT during the study period for whom the transplant type and the conditioning regimen were determinable: 398 patients had myeloablative allogeneic HSCT; 195 patients had nonmyeloablative/reduced-intensity allogeneic HSCT; and 969 patients had myeloablative autologous HSCT. The median total healthcare cost at 100 days was $289,283 for the myeloablative allogeneic regimen cohort compared with $253,467 for the nonmyeloablative/reduced-intensity allogeneic regimen cohort, and $140,792 for the myeloablative autologous regimen cohort. The mean hospital length of stay for the index (first claim of) HSCT was 35.6 days in the myeloablative allogeneic regimen cohort, 26.6 days in the nonmyeloablative/reduced-intensity allogeneic cohort, and 21.8 days in the myeloablative autologous regimen cohort. CONCLUSION: Allogeneic HSCT was more expensive than autologous HSCT, regardless of the regimen used. Myeloablative conditioning regimens led to higher overall costs than nonmyeloablative/reduced-intensity regimens in the allogeneic HSCT cohort, indicating a greater cost burden associated with inpatient services for higher-intensity preparative conditioning regimens. Pediatric patients had higher costs than adult patients. Future research should involve validating the algorithm for identifying conditioning regimens using clinical data.

A pediatric case of T-cell prolymphocytic leukemia.

T-cell Prolymphocytic Leukemia (T-PLL) is a rare entity, and to date has never been reported in children. Here, we describe the first pediatric case of T-PLL in a 16-year old male and review his clinical course through treatment. He underwent therapy with alemtuzumab and pentostatin, which was successful in inducing initial remission. He then underwent an allogeneic matched sibling stem cell transplant following a myeloablative conditioning regimen and remains disease-free 1.5 years after diagnosis.

Improved outcomes after autologous bone marrow transplantation for children with relapsed or refractory Hodgkin lymphoma: twenty years experience at a single institution.

The purpose of this study is to evaluate the survival of pediatric patients undergoing autologous bone marrow transplantation (auBMT) for relapsed or refractory Hodgkin lymphoma (rrHL) and to identify factors that might contribute to their outcome. We reviewed the records and clinical course of 89 consecutive rrHL patients ≤ 21 years old who underwent auBMT at Stanford Hospitals and Clinics and the Lucile Packard Children's Hospital, Stanford between 1989 and 2012. We investigated, by multiple analyses, patient, disease, and treatment characteristics associated with outcome. Endpoints were 5-year overall and event-free survival. Our findings include that cyclophosphamide, carmustine, and etoposide (CBV) as a conditioning regimen for auBMT is effective for most patients ≤ 21 years old with rrHL (5-year overall survival, 71%). Transplantation after the year 2001 was associated with significantly improved overall survival compared with our earlier experience (80% compared with 65%). Patients with multiply relapsed disease or with disease not responsive to initial therapy fared less well compared with those with response to initial therapy or after first relapse. Administration of post-auBMT consolidative radiotherapy (cRT) also appears to contribute to improved survival. We are able to conclude that high-dose chemotherapy with CBV followed by auBMT is effective for the treatment of rrHL in children and adolescents. Survival for patients who undergo auBMT for rrHL has improved significantly. This improvement may be because of patient selection and improvements in utilization of radiotherapy rather than improvements in chemotherapy. Further investigation is needed to describe the role of auBMT across the entire spectrum of patients with rrHL and to identify the most appropriate preparative regimen with or without cRT therapy in the treatment of rrHL in young patients.

Cytokine and chemokine patterns across 100 days after hematopoietic stem cell transplantation in children.

We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory "signature" provided by a multicytokine assay may be predictive.