Ashley Teusink-Cross

Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients

We describe our retrospective clinical experience with ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of ruxolitinib from response analysis. Patients were called a treatment failure if ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of ruxolitinib that will achieve efficacy without significant adverse effects.

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children

Vitamin A promotes development of mucosal tolerance and enhances differentiation of regulatory T cells. Vitamin A deficiency impairs epithelial integrity, increasing intestinal permeability. We hypothesized that higher vitamin A levels would reduce the risk of graft-versus-host disease (GVHD) through reduced gastrointestinal (GI) permeability, reduced mucosal injury, and reduced lymphocyte homing to the gut. We tested this hypothesis in a cohort study of 114 consecutive patients undergoing allogeneic stem cell transplant. Free vitamin A levels were measured in plasma at day 30 posttransplant. GI GVHD was increased in patients with vitamin A levels below the median (38% vs 12.4% at 100 days, P = .0008), as was treatment-related mortality (17.7% vs 7.4% at 1 year, P = .03). Bloodstream infections were increased in patients with vitamin A levels below the median (24% vs 8% at 1 year, P = .03), supporting our hypothesis of increased intestinal permeability. The GI mucosal intestinal fatty acid-binding protein was decreased after transplant, confirming mucosal injury, but was not correlated with vitamin A levels, indicating that vitamin A did not protect against mucosal injury. Expression of the gut homing receptor CCR9 on T-effector memory cells 30 days after transplant was increased in children with vitamin A levels below the median (r = -0.34, P = .03). Taken together, these data support our hypothesis that low levels of vitamin A actively promote GI GVHD and are not simply a marker of poor nutritional status or a sicker patient. Vitamin A supplementation might improve transplant outcomes.

Combination of High-Dose Methylprednisolone and Defibrotide for Veno-Occlusive Disease in Pediatric Hematopoietic Stem Cell Transplant Recipients

Veno-occlusive disease (VOD) is a serious complication of hematopoietic stem cell transplant (HSCT), with high mortality in severe cases and until recently very limited therapeutic options consisting largely of supportive care. Defibrotide was recently approved in the United States for the treatment of severe VOD in patients with renal or pulmonary dysfunction after HSCT. Our group previously published on the use of high-dose methylprednisolone (500 mg/m2 per dose every 12 hours for 6 doses) in patients with VOD, showing good success. A small subset of these individuals were also treated with defibrotide, but additional studies using the combination of high-dose methylprednisolone and defibrotide for the treatment of VOD are lacking. We present a single-institution retrospective chart review of 15 HSCT patients with VOD treated with the combination of high-dose methylprednisolone and defibrotide. VOD developed at a median of 17 days post-HSCT, and combination therapy was initiated within 1 day of VOD diagnosis. Twelve of 15 patients (80%) had multiorgan failure. Our single-center experience using both high-dose methylprednisolone and defibrotide showed a day +100 survival rate of 73% and an overall VOD complete resolution rate of 66.7%, higher than the rates reported in the recent literature using defibrotide alone (40% to 50% day +100 overall survival). These data suggest that the combination of high-dose steroids and defibrotide may be superior to defibrotide alone and warrant further investigation.

Restrictive Palivizumab Use Does Not Lead to Increased Morbidity and Mortality in Pediatric Hematopoietic Stem Cell Transplantation Patients

Respiratory syncytial virus (RSV) is a common cause of infection in immunocompromised patients and can lead to significant morbidity and mortality in pediatric hematopoietic stem cell transplantation (HSCT) patients and patients with a primary immune deficiency (PID). Palivizumab is a humanized monoclonal antibody that targets the F glycoprotein on the surface of the RSV virus, preventing RSV replication. Palivizumab was initially licensed for the prevention of RSV infections in children at high risk of severe disease. Since licensure, the American Academy of Pediatrics (AAP) has issued guidelines to help ensure appropriate use of palivizumab in pediatric patients. In the 2014 edition of the guidelines, the AAP recognizes that severe and fatal disease secondary to RSV can be seen in patients receiving chemotherapy or patients who are immunocompromised because of other conditions. However, they recognize that no large clinical trials exist to support the use of palivizumab, and efficacy and safety data in this population are limited. Despite this, the AAP recommends considering prophylaxis for children younger than 24 months who are profoundly immunocompromised during the RSV season. Because of the high cost of palivizumab, the uncertainty of its efficacy as prophylaxis in hospitalized pediatric HSCT and PID patients, and secondary to recent data from our center that suggested immunocompromised patients diagnosed with RSV did not have worse outcomes, we implemented very restrictive criteria for the use of palivizumab in the 2015 to 2016 RSV season in our pediatric HSCT population. Despite these strict criteria, there was no change in the number of patients developing RSV during this season compared with previous seasons, and there was no change in RSV course in those patients developing RSV compared with previous seasons. Restricted use also resulted in a significant dose and cost savings. Based on our experience, we recommend only administering prophylaxis palivizumab to the youngest and most high-risk HSCT patients during the RSV season.

A Pharmacokinetic and Pharmacodynamic Study of Maraviroc as Acute Graft-versus-Host Disease Prophylaxis in Pediatric Allogeneic Stem Cell Transplant Recipients with Nonmalignant Diagnoses

Maraviroc is an allosteric small molecule antagonist of chemokine receptor type 5 (CCR5) and has been used in adult allogeneic hematopoietic stem cell transplant (HSCT) recipients to prevent acute graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract and liver. The goal of this study was to establish feasibility and pharmacokinetic and pharmacodynamic profiles of maraviroc in pediatric HSCT recipients. Children ages 2 to 12 years were enrolled and maraviroc was added to standard GVHD prophylaxis, which included a calcineurin inhibitor and either steroids or mycophenolate mofetil. Maraviroc was started on day -3 and administered at a dose of approximately 300 mg/m(2) orally twice daily until day +30 after stem cell infusion. On days 0 and day +10, samples for pharmacokinetic analysis were collected before the dose and 1, 2, 4, 6, 8, and 12 hours after maraviroc administration. Additional trough concentrations were collected on days +7, 14, and 21. Patients were followed until day +100 for acute GVHD. Functional blockade of CCR5 was assessed in a pharmacodynamic assay by flow cytometry. Thirteen patients, median age of 4 years (range, 2 to 11 years), were prospectively enrolled. Underlying diagnoses included a primary immune deficiency (n = 6), hemoglobinopathy (n = 4), metabolic disorder (n = 1), and bone marrow failure syndrome (n = 2). Patients received either a myeloablative preparative regimen (n = 7) or a reduced-intensity conditioning regimen (n = 6). Cyclosporine and methylprednisolone (n = 7) was the predominant GVHD prophylactic regimen, followed by tacrolimus and mycophenolate mofetil (n = 4) and tacrolimus and steroids (n = 2). Two formulations of maraviroc (150-mg tablets and 20-mg/mL solution) were used on study. Mean (± SD) area under the concentration-time curve from 0 to 12 hours was 4805 ± 3265 hour * ng/mL on day 0 and 5917 ± 4048 hour * ng/mL on day +10. Four patients developed grade 1 or 2 acute skin GVHD before day +100 and were successfully treated. Two patients developed grade 3 acute GI GVHD on days +23 and +24 after HSCT and both had discontinued maraviroc before development of GI GVHD. No adverse effects attributable to maraviroc were observed and administration by enteral tubes was well tolerated by children and accepted by parents. All evaluable patients demonstrated functional CCR5 blockade on day 0. Administration of maraviroc is feasible in most pediatric HSCT recipients with good safety and tolerability profile.

Improving Time to Antibiotic Administration for Bone Marrow Transplant Patients With First Fever

In this study, we explore the interventions used to improve the time in which febrile BMT patients receive their first dose of antibiotic. BACKGROUND AND OBJECTIVE: Timely antibiotic administration in immunocompromised patients is associated with improved outcomes. The aim of our study was to decrease the mean time to administration of antibiotics in hospitalized bone marrow transplant patients with fever from 75 to <60 minutes. METHODS: By using the Model of Improvement, we performed plan-do-study-act cycles to design, test, and implement high-reliability interventions to decrease time to antibiotics. Nursing, physician, and pharmacy interventions were successfully applied to improve timely antibiotic administration. RESULTS: The study period was from April 2014 through March of 2017. Through heightened awareness, dedicated roles and responsibilities, a standardized order set specifically used for first fever patients, notification to the pharmacy about newly febrile first fever patients through a dedicated order, the creation of a dedicated sticker (“STAT first dose antibiotic, give directly to nurse”) to be printed when antibiotics were entered via the order set in the pharmacy, and prioritization of antibiotic delivery on arrival on the floor, we saw an increase in the percentage of patients receiving antibiotics within 60 minutes of documented fever from a mean of 40% to over 90%. Our mean time for antibiotic administration decreased from 75 to 45 minutes. CONCLUSIONS: Implementation of a standardized process for notifying providers of new fever in patients, prioritization of antibiotic preparation in the central pharmacy, and timely antibiotic order entry resulted in improved times to antibiotic administration in the febrile bone marrow transplant population.

Medications Commonly Used in Pediatric HSCT

This chapter contains charts of medication classes most commonly used in pediatric hematopoietic stem cell transplantation (HSCT). These include chemotherapeutics, immunosuppressants, SOS/VOD medications, antibacterials, antifungals, antivirals, anti-pneumocystis agents, pain medications, and diuretics. This chapter is designed to be a quick reference guide, and thus the detailed references provided should be consulted for more complete information. While the dosing provided is pediatric-based, more comprehensive references should be reviewed for neonatal/young infant dosing.

Micafungin antifungal prophylaxis in children undergoing HSCT: can we give higher doses, less frequently? A pharmacokinetic study

Background Micafungin has a distinct advantage for antifungal prophylaxis in HSCT owing to its better safety profile, specifically in terms of hepatic and renal toxicity. In children, prophylactic micafungin is given as either 1 mg/kg every day or 3 mg/kg every other day. Objectives We performed a prospective single-centre observational study that investigated the pharmacokinetics (PK) of a single 5 mg/kg dose of micafungin in young children undergoing HSCT, to ascertain the eventual feasibility of twice-weekly prophylactic administration. Methods Nine children, ≤10 years of age undergoing HSCT, were enrolled and received a single intravenous dose of 5 mg/kg micafungin. Blood samples were obtained for PK analysis. Micafungin plasma concentration of >0.2 mg/L was chosen for target attainment (i.e. considered adequate prophylactic concentration). In addition, a population PK model was developed based on current and our previous PK study data. We also evaluated PK model-based simulation of PK profiles and target attainment using Monte Carlo simulation, for several dosing scenarios. Results Mean clearance was 15.3 mL/h/kg (range 11.0-21.4 mL/h/kg) and the mean elimination half-life was 11.6 h (range 7.8-16.6 h). The mean concentration at 96 h was 0.11 mg/L (range 0.03-0.26 mg/L). Eleven percent (n = 1) of patients achieved target attainment at the end of 96 h. Simulation data showed that 1 mg/kg daily dosing and 3 mg/kg alternate-day dosing strategies achieved at least 99% and 81% target attainment, respectively, whereas a 5 mg/kg with 3 day-interval dosing strategy resulted in 64%, 72% and 84% target attainments in patients with body weights of 10, 20 and 30 kg, respectively. Conclusions Micafungin at 5 mg/kg dosing did not achieve target attainment at the end of 96 h for antifungal prophylaxis in children undergoing HSCT. Simulation data suggest that a dosing strategy of micafungin at 5 mg/kg every 72 h is more likely to achieve target attainment in children with a higher body weight in comparison with children with a lower body weight. A cautious approach is advisable when using a high, but less frequent, dosing strategy in very young children.

High-dose Carboplatin/Etoposide/Melphalan increases risk of thrombotic microangiopathy and organ injury after autologous stem cell transplantation in patients with neuroblastoma

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant that can result in multi-organ failure (MOF). Patients undergoing high-dose chemotherapy with autologous stem cell transplant (aHCT) for neuroblastoma require good organ function to receive post-transplant radiation and immunotherapy. We examined TA-TMA incidence and transplant outcomes in patients with neuroblastoma receiving different transplant preparative regimens. Sixty patients underwent aHCT using high-dose chemotherapy: 41 patients received carboplatin/etoposide/melphalan (CEM), 13 patients busulfan/melphalan (Bu/Mel) and six patients received tandem transplant (cyclophosphamide/thiotepa and CEM). TA-TMA with MOF was diagnosed in 13 patients (21.7%) at a median of 18 days after aHCT. TA-TMA occurred in 12 patients receiving CEM and in 1 after cyclophosphamide/thiotepa. There were no incidences of TA-TMA after Bu/Mel regimen. Six of 13 patients with TA-TMA and MOF received terminal complement blocker eculizumab for therapy. They all recovered organ function and received planned post-transplant therapy. Out of seven patients who did not get eculizumab, two died from TA-TMA complications and four progressed to ESRD. We conclude that the CEM regimen is associated with a high incidence of clinically significant TA-TMA after aHCT and eculizumab can be safe and effective treatment option to remediate TA-TMA associated MOF.

Topical vitamin D analog for chronic graft versus host disease of the skin

Chronic graft versus host disease (cGVHD) is a significant cause of post-transplant morbidity and mortality. Chronic skin GVHD with associated sclerosis, pigmentation changes, alopecia, restricted joint mobility, and intense pruritus significantly affects quality of life and self-confidence. Topical therapy options for cGVHD of the skin are limited. Topical calcineurin inhibitors, steroid applications, and emollients are often only partially effective, and oily and inconvenient for long-term use. Medications used for pruritus are often sedating and ineffective, so there is significant need for alternative therapies for these patients. Systemic vitamin D deficiency has been linked to acute and chronic GVHD in multiple studies. We showed that over 70% of stem cell transplant recipients are vitamin D deficient, and severe vitamin D deficiency is associated with inferior survival [1–3]. The dermatology literature points to inadequate vitamin D receptors (VDR) in the skin in some immune mediated skin disorders [4]. Calcipotriene, a topical vitamin D analog, is thought to increase the number of VDR’s in epidermal nuclei. VDR agonists also contribute to control of the innate and adaptive immune system. Topical vitamin D analogs have been used for atopic dermatitis [5], vitiligo, morphea, and lichen sclerosus et atrophicus owing to its effects on immunoregulation, fibroblast proliferation, collagen synthesis, and endothelial cell function [6]. Vitamin D3 downregulates cellular adhesion molecule expression by inhibiting TNF-α mRNA expression, which has been suggested as a mechanism that alleviates pruritus in patients with steroid refractory prurigo [7]. Calcipotriene was approved by the FDA in 1994 for use in psoriasis only. It has proven to be effective in the treatment of other dermatoses, but there are no reports in the scientific literature using it for the treatment of skin GVHD. We proposed that topical vitamin D analog application would have a positive effect on chronic skin GVHD due to predominantly cutaneous metabolism. In 2016 we established uniform clinical guidelines to offer topical vitamin D treatment to patients with therapy refractory skin GVHD presenting with intractable pruritus, skin or scalp erythema/desquamation or altered skin pigmentation. Six patients were treated with topical calcipotriene for therapy refractory cGVHD of the skin and/or scalp from June 2016 to January 2017. Patient demographics, disease characteristics, and previous GVHD therapy used is summarized in Table 1. Chronic GVHD score at the initiation of topical vitamin D therapy was based on the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graftversus-Host Disease: I. The 2014 Diagnosis and Staging Working Group reported by Jagasia et al [8]. Response to therapy was documented by the treating physician using the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for each presenting symptom at least weekly. Serial skin and scalp photographs were obtained with caregiver consent. Clinically meaningful and objective response to therapy was counted as symptom reduction by at least one CTCAE grade. Time to response was documented as days from initiation of therapy. Patient and caregiver report about therapy tolerability and compliance were documented, but not scored due to subjectivity. Blood 25-OH vitamin D levels were monitored every 2 weeks in children below 15 kg of weight and those receiving near complete daily body application with calcipotriene. 25-OH vitamin D levels were monitored every 3 months in older children or those receiving partial body applications if levels remained * Gregory Wallace Gregory.Wallace@cchmc.org