Use of Teduglutide in the Management of Gastrointestinal Graft-versus-Host Disease in Children and Young Adults.

Loss of intestinal L cells and reduced levels of glucagon-like peptide-2 (GLP-2) have been implicated in acute graft-versus-host disease (GVHD) in murine models. Teduglutide, a human recombinant GLP-2 analog, may be beneficial in acute gastrointestinal (GI) GVHD owing to its known tissue protective and regenerative functions. We retrospectively reviewed patients who received teduglutide for treatment of GI GVHD. Endoscopy was performed at diagnosis and at completion of the teduglutide course. GLP-1 immunohistochemistry (IHC) was performed at diagnosis and the end of teduglutide therapy in 2 patients to evaluate L cells. We initiated daily teduglutide 0.05 mg/kg subcutaneously as adjunctive therapy in 3 pediatric patients with refractory GI GVHD. All 3 patients had resolution of GI GVHD following completion of the teduglutide course, as evidenced by reduced apoptosis and regenerative changes on post-treatment endoscopy. Reportable GLP-1 IHC in 2 patients demonstrated increased L cells at the end of teduglutide treatment compared to at diagnosis. No adverse effects to teduglutide were observed. Teduglutide is a promising adjunctive and non-immune suppressive agent for managing acute GI GVHD.

A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults.

ABSTRACT: Vitamin A plays a key role in the maintenance of gastrointestinal homeostasis and promotes a tolerogenic phenotype in tissue resident macrophages. We conducted a prospective randomized double-blinded placebo-controlled clinical trial in which 80 recipients of hematopoietic stem cell transplantation (HSCT) were randomized 1:1 to receive pretransplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 IU/kg, maximum 250 000 IU was given before conditioning. The primary end point was incidence of acute graft-versus-host disease (GVHD) at day +100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in the vitamin A arm and 20% in the placebo arm (P = .5). Incidence of acute gastrointestinal (GI) GVHD was 2.5% in the vitamin A arm (P = .09) and 12.5% in the placebo arm at day +180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in the placebo arm (P = .02) at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day +180 was 0% and 12.5% in recipients of vitamin A and placebo, respectively (P = .02), and cumulative incidence of chronic GVHD was 2.7% and 15% in recipients of vitamin A and placebo, respectively (P = .01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in 1 recipient of vitamin A at day +30, which self-resolved. Absolute CCR9+ CD8+ effector memory T cells, reflecting gut T-cell trafficking, were lower in the vitamin A arm at day +30 after HSCT (P = .01). Levels of serum amyloid A-1, a vitamin A transport protein with proinflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower interleukin-6 (IL-6), IL-8, and suppressor of tumorigenicity 2 levels and likely a more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity, and reduces GVHD. This trial was registered at www.ClinicalTrials.gov as NCT03202849.

The Development of Neuroimaging Biomarkers for Cognitive Decline in Sickle Cell Disease.

Sickle cell disease (SCD) is complicated by neurologic complications including vasculopathy, hemorrhagic or ischemic overt stroke, silent cerebral infarcts and cognitive dysfunction. Patients with SCD, even in the absence of vasculopathy or stroke, have experience cognitive dysfunction that progresses with age. Transcranial Doppler ultrasound and structural brain MRI are currently used for primary and secondary stroke prevention, but laboratory or imaging biomarkers do not currently exist that are specific to the risk of cognitive dysfunction in patients with SCD. Recent investigations have used advanced MR sequences assessing cerebral hemodynamics, white matter microstructure and functional connectivity to better understand the pathophysiology of cognitive decline in SCD, with the long-term goal of developing neuroimaging biomarkers to be used in risk prediction algorithms and to assess the efficacy of treatment options for patients with SCD.

Pharmacogenomics insights into precision pediatric oncology.

PURPOSE OF REVIEW: Pharmacogenomic insights provide an opportunity to optimize medication dosing regimens and patient outcomes. However, the potential for interindividual genomic variability to guide medication dosing and toxicity monitoring is not yet standard of care. In this review, we present advances for the thiopurines, anthracyclines and vincristine and provide perspectives on the actionability of pharmacogenomic guidance in the future. RECENT FINDINGS: The current guideline on thiopurines recommends that those with normal predicted thiopurine methyltransferase and NUDT15 expression receive standard-of-care dosing, while 'poor metabolizer' haplotypes receive a decreased 6-mercaptopurine starting dose to avoid bone marrow toxicity. Emerging evidence established significant polygenic contributions that predispose to anthracycline-induced cardiotoxicity and suggest this knowledge be used to identify those at higher risk of complications. In the case of vincristine, children who express CYP3A5 have a significantly reduced risk of peripheral neuropathy compared with those expressing an inactive form or the CYP3A4 isoform. SUMMARY: The need for adequately powered pediatric clinical trials, coupled with the study of epigenetic mechanisms and their influence on phenotypic variation and the integration of precision survivorship into precision approaches are featured as important areas for focused investments in the future.

Outcomes of pediatric patients with therapy-related myeloid neoplasms.

Long-term outcomes after allogeneic hematopoietic cell transplantation (HCT) for therapy-related myeloid neoplasms (tMNs) are dismal. There are few multicenter studies defining prognostic factors in pediatric patients with tMNs. We have accumulated the largest cohort of pediatric patients who have undergone HCT for a tMN to perform a multivariate analysis defining factors predictive of long-term survival. Sixty-eight percent of the 401 patients underwent HCT using a myeloablative conditioning (MAC) regimen, but there were no statistically significant differences in the overall survival (OS), event-free survival (EFS), or cumulative incidence of relapse and non-relapse mortality based on the conditioning intensity. Among the recipients of MAC regimens, 38.4% of deaths were from treatment-related causes, especially acute graft versus host disease (GVHD) and end-organ failure, as compared to only 20.9% of deaths in the reduced-intensity conditioning (RIC) cohort. Exposure to total body irradiation (TBI) during conditioning and experiencing grade III/IV acute GVHD was associated with worse OS. In addition, a diagnosis of therapy-related myelodysplastic syndrome and having a structurally complex karyotype at tMN diagnosis were associated with worse EFS. Reduced-toxicity (but not reduced-intensity) regimens might help to decrease relapse while limiting mortality associated with TBI-based HCT conditioning in pediatric patients with tMNs.

Driving the precision medicine highway: community health workers and patient navigators.

The general public is currently bombarded with direct-to-consumer advertising, real time "medical" guidance through the internet, access to digital devices that capture health information, and science-based adds that promote foods, cosmetics, and dietary supplements. Unfortunately, much of this information relies on terminology and concepts not well-understood by consumers, particularly those with lower levels of health and genomic literacy. Such constraints align with the limitations of the American public to obtain and process the basic medical information needed to make appropriate healthcare decisions. Low levels of health and genomic literacy render the American public ill-equipped to make informed decisions, use and interpret genomic information, or appreciate the benefits afforded by genomics-based technologies. We propose that coordinated expansion of the roles of community health workers and patient navigators within the precision medicine space can be effectively used to disseminate the knowledge required for the public to benefit from precision medicine advances in healthcare. A well-organized and trained community health worker and patient navigator workforce will provide a voice for the disadvantaged, especially among recent immigrants likely to be experiencing social isolation, language barriers, and economic deprivation. Armed with this knowledge, community health workers and patient navigators can advance the precision medicine agenda and empower disadvantaged communities to take advantage of major advances in the precision medicine era.

Genetics and epigenetics of pediatric leukemia in the era of precision medicine.

Pediatric leukemia represents a heterogeneous group of diseases characterized by germline and somatic mutations that manifest within the context of disturbances in the epigenetic machinery and genetic regulation. Advances in genomic medicine have allowed finer resolution of genetic and epigenetic strategies that can be effectively used to risk-stratify patients and identify novel targets for therapy. This review discusses the genetic and epigenetic mechanisms of leukemogenesis, particularly as it relates to acute lymphocytic leukemias, the mechanisms of epigenetic control of leukemogenesis, namely DNA methylation, histone modifications, microRNAs, and LINE-1 retroelements, and highlights opportunities for precision medicine therapeutics in further guiding disease management. Future efforts to broaden the integration of advances in genomic and epigenomic science into the practice of pediatric oncology will not only identify novel therapeutic strategies to improve clinical outcomes but also improve the quality of life for this unique patient population. Recent findings in precision therapeutics of acute lymphocytic leukemias over the past three years, along with some provocative areas of epigenetics research, are reviewed here.