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Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) are problematic pathogens because infections caused by these organisms are associated with significant morbidity and mortality. These organisms often harbor multiple resistance mechanisms, which makes it difficult to treat their associated infections. Treatment typically consists of intravenous antibiotics that are selected based on the specific susceptibility pattern for the pathogen. Data on the use of oral antibiotics for the treatment of infections caused by CRE are sparse. Case Presentation: In this case, a 62-year-old female presented with a chronic left leg wound infection. She previously underwent surgical debridement and skin grafting, which were unsuccessful. She was initially prescribed minocycline for the infection, but the wound got re-infected. At this time, the wound had significant surrounding erythema, drainage, and slough. A wound culture was obtained and demonstrated growth of carbapenem-resistant Enterobacter cloacae and methicillin-resistant Staphylococcus aureus. The patient was initiated on oral omadacycline, and she responded with resolution of the cellulitis and wound drainage. Conclusion: This case demonstrates that omadacycline may be beneficial as an oral medication for the treatment of complicated acute bacterial skin and skin structure infections caused by carbapenem-resistant Enterobacter cloacae.

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

A 23-month old female with hypoplastic myelodysplastic syndrome underwent allogenic hematopoietic cell transplantation (HCT), complicated by development of acute exotropia. Bilateral chorioretinal scars and a ring enhancing brain lesion were identified in further workup. Disseminated toxoplasmosis post-allogeneic HCT was subsequently confirmed by serologic and polymerase chain reaction testing results.

Sinusoidal obstructive syndrome, also known as hepatic veno-occlusive disease, is a potentially life-threatening complication that occurs in children undergoing haemopoietic stem-cell transplantation (HSCT). Differences in the incidence of genetic predisposition and clinical presentation of sinusoidal obstructive syndrome between children and adults have rendered the historical Baltimore and Seattle diagnostic criteria insufficient for children. In 2017, the European Society for Blood and Marrow Transplantation (EBMT) proposed the first paediatric diagnostic and severity grading guidelines for sinusoidal obstructive syndrome, intended for implementation across European centres. However, universally accepted paediatric criteria are needed to ensure prompt diagnosis, definitive treatment, and improved outcomes for children, adolescents, and young adults with sinusoidal obstructive syndrome, and to facilitate international clinical research collaboration. We convened an international panel of multidisciplinary experts including physicians with expertise in HSCT, paediatric intensive care, nephrology, hepatology, radiology, pathology, and transfusion medicine; HSCT advanced-practice providers and medical trainees; pharmacists; and translational and basic science researchers from the Pediatric Acute Lung Injury and Sepsis Investigators Network, the EBMT, the Pediatric Blood and Marrow Transplant Consortia, and several other institutions with extensive experience in sinusoidal obstructive syndrome. Panellists convened at The University of Texas, MD Anderson Cancer Center (Houston, TX, USA) in February, 2019, to evaluate the available evidence. In this expert position statement paper, we provide consensus recommendations for the international implementation of guidelines for the diagnosis, severity grading, and treatment of sinusoidal obstructive syndrome among children, adolescents, and young adults. We endorse universal adoption of paediatric diagnostic guidelines for sinusoidal obstruction syndrome as proposed by the EBMT, and provide implementation guidance for standardisation across centres; we have further proposed adjunctive use of age-appropriate organ-specific toxicity criteria for severity grading and provided prophylaxis and treatment considerations among children and adolescent and young adult patients. Key recommendations include: (1) liver biopsy, portal venous wedge pressure, and reversal of portal venous flow on Doppler ultrasonography should not be used for the routine diagnosis of sinusoidal obstructive syndrome in children, adolescents, and young adults; (2) platelet refractoriness can be defined as a corrected count increment of less than 5000-7500 following at least two sequential ABO-compatible fresh platelet transfusions; (3) hepatomegaly is best defined as an absolute increase of at least 1 cm in liver length at the midclavicular line; and if a baseline measurement is not available, hepatomegaly can be defined as greater than 2 SDs above normal for age; and (4) the presence and volume of ascites can be categorised as mild (minimal fluid by liver, spleen, or pelvis), moderate (1 cm fluid), or severe (fluid in all three regions with1 cm fluid in at least two regions).

Systemic juvenile idiopathic arthritis (sJIA) is characterized by arthritis, fever, rash, lymphadenopathy, hepatosplenomegaly, and serositis. Macrophage activation syndrome is the most feared complication of sJIA with a high risk of mortality. We report a 16-year-old female diagnosed with refractory systemic juvenile idiopathic arthritis (sJIA) complicated by recurrent macrophage activation syndrome (MAS), severe joint disease, and lung involvement requiring prolonged immunosuppressive therapy. She received a matched unrelated allogeneic hematopoietic cell transplant (Allo-HCT) using a reduced-intensity conditioning regimen and is now, 3 years after the transplant, with complete resolution of sJIA symptoms, off immunosuppressants, and with significant improvement in the quality of life.

Background Immunosuppressive prophylaxis is usually given to decrease the development of acute graft versus host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Belatacept is a Cytotoxic T-lymphocyte-associated protein 4, blocking agent, an immunosuppressive agent used for organ rejection prevention in adult renal transplant recipients. Methods We describe two children in whom belatacept was successfully used for GvHD prophylaxis. Case 1 was noncompliant with prior immunosuppressive therapy for aplastic anemia, and Case 2 developed severe thrombotic microangiopathy (TMA) precluding the use of calcineurin inhibitors (CNI) or mTOR inhibitors. Results and conclusion Belatacept was found to be a safe alternative in preventing GvHD in 2 patients in whom traditional prophylactic therapies were not possible to use.

RationaleLittle is known on the use of noninvasive ventilation (NIPPV) in pediatric hematopoietic cell transplant (HCT) patients.ObjectiveWe sought to describe the landscape of NIPPV use and to identify risk factors for failure to inform future investigation or quality improvement.MethodsThis is a multicenter, retrospective observational cohort of 153 consecutive children post-HCT requiring NIPPV from 2010-2016.Results97 (63%) failed NIPPV. Factors associated with failure on univariate analysis included: longer oxygen use prior to NIPPV (p=0.04), vasoactive agent use (p40 at 4 hours [aOR=6.3 9(95% CI: 2.4, 16.4), pConclusionsIn this cohort respiratory rate at 4 hours and vasoactive use are independent risk factors of NIPPV failure. An objective model to predict which children may benefit from a trial of NIPPV, may also inform the timing of both NIPPV initiation and uncomplicated intubation.

Vitamin D not only plays an important role in bone metabolism but is also involved in multiple immune-mediated processes in the body which may be adversely affected in those with low levels. Most pediatric studies evaluating the association of vitamin D in patients undergoing allogeneic HSCT are single-center studies. We present the results of retrospective study at 5 centers across the United States in pediatric patients undergoing allogeneic HSCT. (VDD) and (VDI) were defined by vitamin D levels of

Pediatric HSCT patients endure complicated treatment regimens, lifestyle modifications, and a lifetime of long-term follow-up. Treatment adherence in this population is understudied and prevalence unknown. Providers (physicians and advanced practice nurses) in this study completed an online-structured questionnaire about definition, assessment, and perceived rates of adherence. Researchers' extracted 187 statements from participants' responses. The majority (n = 12, 71%) of providers reported adherence as a primary concern in outpatient HSCT. The major concern for providers was the potential of non-adherence to negatively affect outcomes. Providers also shared clinical examples of non-adherence. This study contributes to a better understanding of providers' perceptions of adherence within pediatric HSCT. Additional research is needed to describe, define, and improve adherence in pediatric HSCT to ultimately improve outcomes and quality of life for this vulnerable population.

Hepatic VOD is a potentially fatal complication during stem cell transplantation and is rarely seen in the non-transplant setting. We report the case of a five-year-old boy who presented with visual complaints during delayed intensification phase of treatment for ALL. He was found to have bilateral retinal hemorrhages associated with profound thrombocytopenia due to chemotherapy. VOD was diagnosed based on EBMT criteria and was managed with supportive care. Despite resolution of VOD, his vision progressively deteriorated and resulted in blindness. This case highlights the significance of close monitoring of ALL patients in delayed intensification when they are at risk for developing VOD, the importance of refractory thrombocytopenia as a diagnostic feature and the potential for VOD to manifest with intraocular bleeding.

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy., Chimeric antigen receptor (CAR) T cell therapies have impressive activity in the treatment of cancer but are associated with potentially fatal toxicities. In light of the approval of CAR T cell therapy for paediatric patients, a panel of experts from the Hematopoietic Stem Cell Transplantation (HSCT) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, the CAR T Cell Therapy-Associated Toxicity (CARTOX) Program at The University of Texas MD Anderson Cancer Center, and several other institutions have developed consensus guidelines for the use and management of these treatments in paediatric patients, which are presented herein.

Hematopoietic cell transplant (HCT) is associated with a proinflammatory, procoagulant environment that places recipients at increased risk of venous thromboembolism (VTE). Although the incidence of VTE in adult HCT recipients has been extensively studied, similar data for children are lacking. We conducted a multicenter retrospective study to analyze the prevalence of VTE and associated risk factors in a large cohort of patients who underwent HCT at tertiary care US children's hospitals. The Pediatric Health Information System database, a large administrative database that contains clinical and resource utilization data from 49 freestanding children's hospitals in the United States, was used to extract data. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients, VTE events, post-HCT complications, and associated risk factors up to 1 year post-transplant. Data on patients who received HCT from January 2010 through September 2014 were collected. A total of 4158 unique patients mean ± standard deviation age at transplant admit, 8.8 ± 6.5 years; range, birth to 33.4 years) were identified. After HCT 290 subjects (6.9%) developed VTE. VTE prevalence was greater in patients aged ≥ 13 versus13 years (8.54% versus 6.33%; P = .01) and in recipients of allogeneic versus autologous grafts (7.7% versus 5%; P ≤ .01). VTE was associated with prolonged median duration of hospitalization (81 versus 54 days; P ≤.01) and increased 1-year mortality (13.9% versus 5.9%; P ≤ .01). Infections and presence of any graft-versus-host disease (GVHD) were significantly associated with VTE occurrence in recipients of allogenic grafts. Prevalence of VTE in patients who underwent HCT at pediatric tertiary care hospitals is about 7%. Age ≥ 13 years and allogeneic grafts were significant pre-HCT VTE risk factors, with GVHD and infections seen more frequently in patients with VTE.

Background: Tacrolimus, commonly used for graft versus host disease prophylaxis is usually administered via a dedicated central venous line (CVL) and trough levels drawn from the unexposed lumen. Being an oil-based medication, it may be adsorbed to the inner lumen of the CVL and result in falsely high levels drawn from an inadvertently exposed lumen. There is no treatment for decontamination of such CVLs, and natural decay occurs over months before the CVL can be used to draw reliable trough levels. Objective: The primary objective of the study was to estimate the effectiveness of 70% ethanol locks for decontaminating CVLs exposed to tacrolimus. Methods: We studied the efficacy of 70% ethanol lock in decontaminating CVLs exposed to tacrolimus in patients during transplant. Trough tacrolimus levels were drawn from the exposed and unexposed (control) lumens at 8:00 am, followed by a 2-mL 70% ethanol lock instilled for a 2-hour dwell into the exposed (intervention) lumen. Trough tacrolimus levels were again drawn from both lumens at 8:00 pm and levels compared for efficacy. Results: All 20 sets showed a high 8 am trough level in the exposed intervention arm (median = 30 ng/mL), significantly greater ( P < 0.0001) than that in the control arm (median = 9.05 ng/mL), and were contaminated. After the 2-hour ethanol lock, 65% of the lumens were decontaminated. The difference between the control and intervention arms was no longer found to be statistically significant ( P = 0.0826). Conclusion: A 2-hour 70% ethanol lock is effective for decontamination of CVLs exposed to tacrolimus.

Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for year after allogeneic myeloablative HCT for hematologic malignancy at = 1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P

BACKGROUNDRisk factors for impairment in psychosexual development and satisfaction among adult survivors of childhood cancer are poorly understood. The authors compared psychosexual outcomes between survivors and healthy controls, and tested whether at-risk survivors can be identified by 1) treatment neurotoxicity or 2) diagnosis.METHODSA total of 144 young adult survivors of childhood cancer and 144 matched controls completed questionnaires regarding psychosexual development, sexual satisfaction, and satisfaction with relationship status. Survivors were aged 20 to 40 years and were 5 to 34 years after diagnosis. Using medical chart data, survivors were divided into non-neurotoxic (48 survivors), low-dose (36 survivors), and high-dose (58 survivors) neurotoxic treatment groups.RESULTSApart from having fewer lifetime sex partners, survivors did not appear to differ from controls. However, survivors of brain tumors and any survivor who received high-dose neurotoxic treatment reported the lowest rates of achieving milestones of psychosexual development, whereas sexual and relationship status satisfaction were found to be related to relationship status. Neurotoxic treatment intensity further distinguished between survivors of brain tumors with and without psychosexual impairment.CONCLUSIONSThe intensity of neurotoxic treatment may be a valuable indicator of risk for psychosexual impairment relative to diagnosis alone. Health care providers should assess romantic/sexual problems among survivors at risk and make referrals if needed. Cancer 2017;123:1869-1876. (c) 2017 American Cancer Society.The results of the current study indicate that adult survivors of childhood cancer do not differ from healthy controls with regard to their psychosexual development, sexual satisfaction, and relationship status satisfaction. However, more intense neurotoxic treatment appears to be associated with a higher risk of psychosexual impairment, and may be a more meaningful risk indicator than diagnostic category alone.

Hematopoietic cell transplantation (HCT) and cellular therapy (CT) are potentially lifesaving treatments for children with malignant and nonmalignant diseases. Advancements in care have led to expanding patient eligibility, with overall reduced morbidity and improved survival. Survival for HCT patients requiring pediatric intensive care unit (PICU) admission have improved. While almost half of pediatric patients receiving CAR-T therapy may require intensive care support, overall survival remains promising. However, patients undergoing HCT remain at risk for debilitating and life-threatening complications such as sinusoidal obstructive syndrome (S0S), infection, and graft-versus-host disease (GVHD); patients receiving chimeric antigen receptor (CAR) and other T-cell therapies are at risk for unique toxicities such as cytokine release syndrome (CRS) and CAR-T-related encephalopathy syndrome (CRES). Judicious patient and treatment selection, vigilant monitoring, and prompt interventions may reduce the need for PICU admission among HCT and CAR-T recipients. When PICU intervention is required, early intervention, excellent interdisciplinary communication, prognostication, and intensive support may improve outcomes.

e22523 Background: The Institute of Medicine (IOM) report on childhood cancer survivorship specified the need to create and evaluate standards and alternative models of care delivery, including collaborative practices between oncologists and primary care physicians (PCP).1 We aimed to examine the utilization of primary care physicians by childhood cancer and bone marrow transplant (BMT) survivors, as well as identify barriers to non-oncology follow-up care. Methods: Survivors and caregivers were recruited from a cancer and bone marrow transplant survivorship clinic at a large Midwestern pediatric hospital. Participants completed a demographic survey and an 8-item semi-structured interview in clinic or online. Results: A total of 472 participants (211 survivors, 259 caregivers, 2 left unanswered) completed the survey (Survivors Mage= 26.11, SD= 7.32). Most participants were Caucasian (89%) and female (58%). Only 57 (12.3%) survivors received a BMT. There were no significant differences in PCP utilization between BMT survivors and those who did not receive a BMT, t(448) = -.519, p = .604. In addition, there were no significant group differences in PCP utilization between oncological and hematologic survivors, t(387) = 1.144, p = .253. Most survivors (87%) had a PCP, but 43% sought care for ill visits only. Survivors most commonly chose their PCP through referral from family or friends (45%), with only 4% obtaining a recommendation from their oncology provider. Top reasons for not having a PCP included being unsure who to see (52%), lack of insurance (20%), and not perceiving a need for a PCP (18%). In a logistic regression, greater annual family income ( β= .209, p< .001) and having health insurance ( β= .161, p< .01) were predictive of having a PCP. The frequency of PCP visits was also positively correlated with annual family income ( r= .13, p= .014). Conclusions: While most survivors had a PCP, higher income and insurance coverage were important predictors of having a PCP. There is a clear need for education and formal transition programs to primary care, as survivors and their family identified the need for guidance in choosing a PCP. Stronger partnerships between oncology and primary care providers may improve surveillance and outcomes for these survivors. 1. Blaauwbrock R, Zwart, N., Bouma, M., Meyboom-de Jung, B., Kamps, W., & A. Postma. The willingness of general practitioners to be involved in the follow up of adult survivors of childhood cancer. Journal of Cancer Survivors. 2007;1:292-297.

We present here a case of MIRAGE syndrome due to novel variant (c.2318T>C) in the sterile α motif domain-containing protein 9 (SAMD9) gene. Previous reports have described the clinical phenotype, which includes myelodysplasia, recurrent infections, restriction of growth and development, adrenal insufficiency, genitourinary abnormalities, and enteropathies, often resulting in fatality within the first few years of life. This report illustrates the variability in phenotype by describing an 11-year-old male, diagnosed with MIRAGE at age 9 years when his novel variant was identified through whole exome sequencing. A brief review of previously published cases of MIRAGE syndrome and the genotypic and phenotypic spectrum are presented.

Background Data on adrenal function following pediatric allogeneic hematopoietic cell transplantation (HCT) is limited. Therefore, a single-institution retrospective study was performed to determine the prevalence of secondary adrenal insufficiency (AI) and identify associated risk factors in pediatric HCT recipients. Methods All allogeneic HCT patients from January 2007 through December 2014, with a minimum of two years of post-HCT follow up were included. AI was diagnosed when testing done at either clinical presentation of AI or routine yearly screening in the long term follow up clinic, revealed a morning cortisol level Results Eighty patients (48 male, 32 female) with malignant (n=38) and non-malignant diagnoses (n=42) were included. Median age at HCT and length of follow up were 7.6 years (range 0.1- 20.5 years) and 4.1 years (range 2-10 years), respectively. Twelve (12, 15%) patients developed secondary AI at a median of 16 months post-HCT (range 2-61 months), with an equal number presenting with clinical AI (n=6) and biochemical AI (n=6) respectively. In univariate analysis (Table 1), occurrence of graft-versus-host disease (GvHD), and post-HCT corticosteroid exposure were significant risk factors for development of secondary AI. Age, gender, type of diagnosis, total body irradiation (TBI)-containing and myeloablative conditioning were not. Conclusion: GvHD, and post-HCT steroid exposure were significant risk factors for AI, with one-third patients with post-HCT corticosteroid exposure diagnosed with AI. As half of patients with AI in this cohort were asymptomatic, routine screening for AI should be performed in pediatric allogeneic HCT recipients for timely diagnosis of AI to prevent morbidity associated with this complication.

Vitamin D deficiency (VDD) has been linked to multiple autoimmune disorders because of its importance in self-tolerance and effect on multiple immune system cells. A few studies have shown that patients with VDD may have increased risk of GvHD, CMV infection and decreased overall survival after HSCT, conversely, a study from Brazil showed no such correlations. To better identify the role of vitamin D in children undergoing HSCT, we present the results of a retrospective multicenter study. Records of patients who underwent allogeneic HSCT from January 1, 2012 until June 2017 were reviewed. VDD and insufficiency was defined by vitamin D levels of ≤20 ng/mL and 21-30 ng/mL, respectively. A total of 316 patients were enrolled on the study, of these 276 had at least 1 vitamin D level (pre or post HSCT) and 192 patients had two levels (pre and post HSCT). Patient characteristics and survival graphs are shown in Table 1, Figure 1 and 2 respectively. Severe chronic GvHD was more commonly seen in patients with VDD (p=0.0237). There was no correlation of VDD with the rate of infections (viral, bacterial or fungal), length of hospitalization, neutrophil engraftment, graft failure, or acute GvHD; there were more relapses in patients with normal Vitamin D levels. This retrospective study found that patients with VDD have a slightly higher incidence of severe chronic GvHD, which may explain the lower relapse rate in the VDD group, higher relapse rate in those with normal vitamin D levels but no correlation with all other patient outcomes after HSCT. A small sample size, variability in the accuracy of the assay used to test for vitamin D levels may be some of the limitations. A larger prospective study is needed to help understand the role of vitamin D in children undergoing allogeneic HSCT.

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome, is a potentially fatal complication, which occurs in 7–27% of children undergoing hematopoietic stem cell transplantation. In this article, we review commonly accepted diagnostic criteria, atypical diagnostic features as well as preventative and treatment measures associated with VOD. Reversal of portal venous flow by Doppler ultrasound is often a late finding; many patients with anicteric VOD may never develop hyperbilirubinemia, and yet perish from severe VOD. Transjugular liver biopsy is usually not available and/or is often avoided. Prophylactic therapies with ursodeoxycholic acid, heparin and defibrotide are discussed. Supportive care with fluid restriction and diuretic therapy, analgesia, blood and platelet transfusions, paracentesis as well as other pulmonary and renal therapies remain imperative to superior outcomes. Specific therapy with thrombolytics such as defibrotide and recombinant tissue plasminogen activator is discussed and a classification of severity of VOD is proposed.

Some patients with veno-occlusive disease (VOD) have multiorgan dysfunction, and multiple teams are involved in their daily care in the pediatric intensive care unit. Cardiorespiratory dysfunction is critical in these patients, requiring immediate action. The decision of whether to use a noninvasive or an invasive ventilation strategy may be difficult in the setting of mucositis or other comorbidities in patients with VOD. Similarly, monitoring of organ functions may be very challenging in these patients, who may have fulminant hepatic failure with or without hepatic encephalopathy complicated by delirium and/or infections. In this final guideline of our series on supportive care in patients with VOD, we address some of these questions and provide evidence-based recommendations on behalf of the Pediatric Acute Lung Injury and Sepsis Investigators and Pediatric Blood and Marrow Transplantation Consortium Joint Working Committees.

Veno-occlusive disease (VOD) is a common and potentially fatal complication in children undergoing hematopoietic cell transplantation (HCT). It occurs in about one-third of all patients undergoing transplantation and is fatal in 50% of patients with severe disease. Early intervention and specific treatment with defibrotide are associated with improved outcomes. However, there is a lack of supportive care guidelines for management of the multiorgan dysfunction seen in most cases. There is high variability in the management of VOD, which may contribute to the increased morbidity and mortality. Although there is ample research in the specific treatment of VOD, there is paucity of literature regarding the management of ascites, transfusions requirements, fluids and electrolyte dysfunction, delirium, and investigations in children with VOD. The joint working committees of the Pediatric Acute Lung Injury and Sepsis Investigators and the Pediatric Blood and Marrow Transplantation Consortium collaborated to develop a series of evidence-based supportive care guidelines for management of VOD. The quality of evidence was rated and recommendations were made using Grading of Recommendations, Assessment, Development and Evaluation criteria. This manuscript is part 1 of the series and focuses on the need to develop these guidelines; methodology used to establish the guidelines; and investigations needed for diagnosis, prophylaxis, and treatment of VOD in children.

Even though hepatic veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic cell transplantation (HCT), there is paucity of research on the management of associated multiorgan dysfunction. To help provide standardized care for the management of these patients, the HCT Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators and the Supportive Care Committee of the Pediatric Blood and Marrow Transplant Consortium, collaborated to develop evidence-based consensus guidelines. After conducting an extensive literature search, in part 2 of this series we discuss the management of fluids and electrolytes, renal dysfunction; ascites, pleural effusion, and transfusion and coagulopathy issues in patients with VOD. We consider the available evidence using the GRADE criteria.

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.

Pre-existing endothelial dysfunction and vascular injury sustained during allogeneic hematopoietic stem cell transplantation (HCT) increases risk for endothelial injury-related complications like posterior reversible encephalopathy (PRES) and transplant-associated thrombotic microangiopathy (TA-TMA) in patients with sickle cell disease (SCD). Herein, we report two SCD HCT recipients in whom PRES-related symptoms resolved only after eculizumab therapy was initiated for underlying TA-TMA. Case 1 25-year-old male with SCD developed PRES-related seizures and headaches on Day+30 following matched sibling donor bone marrow transplant (BMT) and reduced-intensity conditioning (RIC) with fludarabine/melphalan/alemtuzumab and graft-versus-host disease (GvHD) prophylaxis with tacrolimus and methotrexate (MTX). Symptoms initially resolved after discontinuing tacrolimus. However, on Day+60, he presented with hypertension (HTN), status epilepticus, and right intracranial hemorrhage. Despite adequate HTN control and maximal anti-epileptic therapy, his symptoms persisted. Two weeks later, laboratory testing confirmed TA-TMA. Both PRES and TA-TMA symptoms and signs resolved after five weeks of eculizumab therapy (Figure 1). Case 2 Eight-year-old female with SCD underwent 10/10 matched unrelated BMT following RIC with fludarabine/melphalan/thiotepa/alemtuzumab and MTX/tacrolimus/abatacept for GvHD prophylaxis. She developed altered mental status, seizures, and HTN and Day+74 MRI brain confirmed PRES. Her symptoms also persisted despite tacrolimus cessation and effective HTN control. One week later, laboratory testing confirmed TA-TMA. Complete resolution of neurological symptoms occurred after three weeks of eculizumab therapy. (Figure 2). Conclusion Our cases highlight maintaining a high level of clinical suspicion for TA-TMA in SCD patients presenting with PRES post-HCT and consideration for eculizumab therapy in such patients.

For patients with DBA who are transfusion dependent, HSCT is the only cure. Chronic transfusions can lead to cirrhosis secondary to iron overload, making them poor candidates for myeloablative HSCT. RIC regimens are associated with lower morbidity and mortality compared to myeloablative regimens, but use of RIC in DBA has been limited. Here we present a 14-yr-old girl with DBA and multiple comorbidities including liver cirrhosis, who underwent MUD HSCT utilizing a RIC regimen that is novel to this condition. She tolerated the regimen well, and at 21 months, she remains transfusion independent with chimerisms at 99%.

Key Points HCT prior to onset of neurologic symptoms in children with OSTM1 osteopetrosis does not halt neurologic progression.

Veno-occlusive disease (VOD) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT). Patients with VOD are often critically ill and require close collaboration between transplant physicians and intensivists. We surveyed members of a consortium of pediatric intensive care unit (PICU) and transplant physicians to assess variability in the self-reported approach to the diagnosis and management of VOD. An internet-based self-administered survey was sent to pediatric HSCT and PICU providers from September 2014 to February 2015. The survey contained questions relating to the diagnosis and treatment of VOD. The response rate was 41% of 382 providers surveyed. We found significant variability in the diagnostic and management approaches to VOD in children. Even though ultrasound is not part of the diagnostic criteria, providers reported using reversal of portal venous flow seen on abdominal ultrasound in addition to Seattle criteria (70%) or Baltimore criteria to make the diagnosis of VOD. Almost 40% of respondents did not diagnose VOD in anicteric patients (bilirubin2 mg/dL). Most providers (75%) initiated treatment with defibrotide at the time of diagnosis, but 14%, 7%, and 6% of the providers waited for reversal of portal venous flow, renal dysfunction, or pulmonary dysfunction, respectively, to develop before initiating therapy. Only 50% of the providers restricted fluids to 75% of the daily maintenance, whereas 21% did not restrict fluids at all. Albumin with diuretics was used by 95% of respondents. Platelets counts were maintained at 20,000 to 50,000/mm(3) and 10,000 to 20,000/mm(3) by 64% and 20% of the respondents, respectively. Paracentesis was generally initiated in the setting of oliguria or hypoxia, and nearly 50% of the providers used continuous drainage to gravity, whereas the remainder used an intermittent drainage approach. Nearly 73% of the transplant providers used VOD prophylaxis, whereas the remainder did not use any medications for VOD prophylaxis. There was also considerable variation in the management strategies among the transplant and critical care providers. We conclude that there is considerable self-reported variability in the diagnosis and management of VOD in children. The practice variations reported in this study should encourage the development of standard practice guidelines, which will be helpful in improving the outcome of this potentially fatal complication.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

MS and endocrine dysfunction(s) are common well-recognized complications after HSCT. We retrospectively analyzed our data on 160 patients with a median age at transplant of five yr (0.3-23), who had been followed for a median of seven yr (range 3-18) at Nationwide Children's Hospital after transplant. Dyslipidemia and MS were seen in 13% and 7.5% patients, respectively, and 58% of these patients were

Tacrolimus is routinely administered for GVHD prophylaxis as a 24-h continuous infusion that requires a dedicated i.v. line and thus becomes logistically difficult to administer, especially in young pediatric patients. We investigated the safety and efficacy of twice daily bolus infusions of i.v. tacrolimus in 33 children undergoing hematopoietic stem cell transplantation (HSCT) at our institution. Tacrolimus was started at an initial dose of 0.015 mg/kg i.v. bolus administered as a 2-h infusion and then given at every 12 h to maintain a trough drug level between 5-15 ng/mL. Patients also received short-course MTX (66%) or mycophenolate mofetil (34%) in combination with tacrolimus. No acute infusional toxicities were observed with bolus infusions of i.v. tacrolimus. Nephrotoxicity occurred in 14/33 (42%) patients and 48% developed hypertension (HT). Almost all (94%) patients required magnesium supplements to maintain magnesium (Mg) levels 1.5 mg/dL. In all, 3 (9%) patients developed severe sinusoidal obstruction syndrome (SOS). One patient developed posterior reversible leuko-encephalopathy syndrome (PRES) and one additional patient had tremors. The prevelance of these side-effects was similar to those reported for continuous i.v. administration. In all, 28% of the evaluable patients developed acute GVHDgrade II, though the incidence of severe (grade III-IV) GVHD was only 7%. These results suggest that intermittent bolus i.v. tacrolimus administration is a safe and effective method of GVHD prophylaxis in children.

AML with the RAM immunophenotype is associated with extremely poor prognosis. We report a rare case of monozygotic twins presenting simultaneously at the age of 2 years with RAM AML. Each twin underwent a myeloablative 7/10 unrelated umbilical cord blood transplant. Pretransplant Twin A's bone marrow was negative for MRD by flow cytometry (

Background Hematopoietic cell transplant (HCT) may be a risk factor for morbidity and mortality from respiratory syncytial virus (RSV). Previous studies have been limited by small sample size. We took a multicenter approach with the goal of better understanding the epidemiology, risk factors, treatment, morbidity, and mortality associated with RSV infections among children with HCT in the United States. Methods A retrospective, multicenter, cohort study of pediatric HCT recipients were diagnosed with RSV infection between January 2010 and December 2014. Results Of the 1522 HCT, 47 (3%) patients were diagnosed with RSV. Of those with RSV, 9 (19.1%) were admitted to the pediatric intensive care unit (PICU), 6 (12.8%) received invasive mechanical ventilation, and 1 died. Prophylactic palivizumab was uncommon. All who required critical care received ribavirin vs 7.3% of those who did not (P = .004). Cobacterial infections were found in 16 patients and were not associated with the need for critical care. We examined potential risk factors for severity of RSV disease. In those who received invasive ventilation, 100% had one of the preidentified risk factors. Half of those requiring mechanical ventilation were diagnosed with RSV during their conditioning for transplant as opposed to only 2.4% of those that did not require invasive mechanical ventilation (P = .005). Conclusions In this multicenter cohort, RSV was not common in children following HCT. Few children infected with RSV required critical care and mortality was low. Those diagnosed with RSV during conditioning for transplant were at higher risk for invasive mechanical ventilation.

Anti-seizure prophylaxis is routinely utilized during busulfan administration for HSCT. We evaluated the feasibility and efficacy of levetiracetam in children undergoing HSCT. A total of 28 children and young adults received levetiracetam during HSCT and the outcomes and costs were compared to a historical, but similar cohort of 25 patients who had received fosphenytoin. Levetiracetam was well tolerated and was efficacious in preventing seizures. Cost of drug, administration, and monitoring were also similar among the two groups. Due to non-induction of the hepatic cytochrome P450 enzymes, levetiracetam may lead to better dose assurance of busulfan in targeted dose regimens for HSCT.

Allogeneic HCT is curative for SCN; however, a standard conditioning regimen or intensity has not been established. We describe a patient with SCN associated with c.1A>G (M1V) mutation in ELANE gene resulting in refractoriness to G-CSF, who received reduced-intensity HCT and developed secondary graft failure requiring a second myeloablative HCT. This case suggests that M1V mutation confers a poor G-CSF response and HCT using the best available donor is beneficial.

Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.

Matched sibling donor hematopoietic stem cell transplantation is the standard of care for severe aplastic anemia, with an overall survival of 80% to 90%. Only 60% to 70% of patients respond to treatment with immunosuppressive therapy. The main life threatening complications are infections, graft failure, and graft versus host disease. A 10-year-old patient with severe aplastic anemia underwent matched sibling donor hematopoietic stem cell transplantation, but developed sudden onset of fatal multiorgan failure on day +12. The cause of death was found only after autopsy.

Background: Identifying factors that influence donor-derived immune response may ultimately enable its therapeutic redirection, lessening risk for complications following allogeneic hematopoietic cell transplantation (alloHCT) like acute graft-versus-host disease (aGvHD) and promoting protection against infection and malignant disease relapse. Viral reactivation seems poised to influence donor-derived immune response, potentially disrupting the balance between immune surveillance in eradicating malignancy and infection and immune tolerance in preventing aGvHD. Cytomegalovirus (CMV) is a clinically-significant virus with immunomodulatory capabilities. However, studies interrogating such effects are limited in the modern transplant era. The primary study aim was to estimate the cumulative incidence of initial CMV reactivation (RA) and aGvHD in alloHCT patients and to assess reciprocal influence between CMV RA and aGvHD. The secondary study aim was to define whether CMV RA predisposed alloHCT patients to infection or increased relapse risk. Methods: Consecutive adult patients (n=324) with acute lymphoblastic leukemia, acute myelogenous leukemia or myelodysplasia whom received initial matched sibling or unrelated donor (MUD) bone marrow (n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center comprised the study cohort. Patient-, transplant-, and infection-related data were retrospectively analyzed (Table 1). Initial CMV RA was defined as plasma quantitative CMV PCR≥1000 viral copies/ml for which CMV-directed antiviral therapy was started. Microbiologically-documented infections were recorded for the first year after alloHCT and categorized as bacterial blood stream infection, invasive fungal infection, human herpes virus 6 viremia, and respiratory viral infection. Cumulative incidences of CMV RA and aGvHD were estimated accounting for competing risks (death from any cause). Association between CMV RA and incidence of aGvHD was evaluated in a proportional sub-distribution hazards model, where CMV RA was treated as a time-dependent covariate with competing risk as death from any cause. Similarly, influence of aGvHD on incidence of CMV RA was evaluated where development of aGvHD was treated as the time-dependent covariate and CMVR RA as the end point of interest. Associations between CMV RA and subsequent infection or disease relapse were similarly analyzed. To evaluate impact of CMV and aGvHD on long-term outcomes, landmark analysis (LMA) at D100 and D365 were compared among four distinct patient groups: (1) No CMV RA, no aGvHD; (2) CMV RA, no aGvHD; (3) No CMV RA, aGvHD; and (4) CMV RA and aGvHD. Results: Most transplant patients had AML in CR1, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Patients who developed aGvHD grades 2 (HR=1.93, 95% CI 1.15-3.23, p=0.013) or grades 3 and 4 (HR=3.36, 95% CI 1.76-6.45, p Overall survival (OS) at 1, 2, and 3 years post-transplant were 63%, 53%, and 45%, respectively. Cumulative incidence rates for non-relapse mortality (NRM) at 1, 2, and 3 years were 16%, 19%, and 23%, respectively; for infection-related mortality (IRM), cumulative incidence rates were 10%, 13%, and 16%, respectively. OS, NRM and IRM were stratified by initial CMV RA and aGvHD status at D100 and D365 (Table 2). Among patients who were alive, patients whom had initial CMV RA and aGvHD by D100 were at higher risk for NRM (HR=2.85, 95% CI 1.24-6.56, p=0.014) and IRM (HR=3.65, 95% CI 1.39-9.57, p=0.008) than patients who experienced neither CMV RA nor aGvHD. D365 LMA did not reveal any statistically significant differences in OS, NRM, and IRM between groups. Conclusion: aGvHD associated with increased risk for CMV RA, but initial CMV RA did not associate with subsequent aGvHD risk. Furthermore, initial CMV RA did not associate with increased risk for disease relapse or infection, but did increase NRM and IRM, particularly in combination with aGvHD. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding. Hofmeister:Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Arno Therapeutics, Inc.: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

Background: Primary malignant disease relapse, graft-versus-host disease (GvHD) and infection are the most common causes of death following allogeneic hematopoietic cell transplantation (alloHCT). We investigated whether infection following initial alloHCT influenced subsequent risk for hematologic malignant disease relapse. Methods: Consecutive adult patients (N=324) with acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML) or myelodysplasia (MDS) who received initial matched sibling (MSD) or unrelated donor (MUD) bone marrow (BM, n=33), peripheral blood stem cell (PBSC, n=253) or umbilical cord blood (UCB, n=38) grafts from January 2010 through December 2014 at The Ohio State University Comprehensive Cancer Center were included. Patient-, transplant-, and infection-related data were retrospectively obtained. Categories for microbiologically-documented infections included bacterial blood stream infection (BSI), viral reactivation (VRA), invasive fungal infection (IFI), and respiratory viral infection (RVI). Correlation between development of infection and relapse was assessed using multi-variable (MV) proportional sub-distribution hazards models, where infection was treated as a time‐dependent covariate and death from any cause as a competing risk. Landmark analyses (LMA) at D14, D28, D56 and D100, which included only those patients who survived without relapse at the indicated time and infection status as a covariate, were performed to predict future relapse. Results: Most transplant recipients had first complete remission AML, received MUD PBSC grafts following myeloablative conditioning, and were given methotrexate and calcineurin-based GvHD prophylaxis. Following alloHCT, 107 (33%) patients experienced disease relapse. Median progression-free survival (PFS) for the entire patient cohort was nearly two years (703 days). Grades 2-4 acute GvHD developed in 164 (51%) patients, and 145 (45%) patients developed limited or extensive chronic GvHD. One- and three-year overall survival (OS) rates for the entire cohort were 63% and 45%, respectively. Cumulative incidence of infection, overall and by infection type, is depicted in Table 1. Patient- and transplant-related factors affecting development of infection are listed in Table 2. Patients who developed infection post-transplant had future relapse risk that was 46% (HR 0.54, 95% CI: 0.36-0.80, p=0.003) less than those patients who did not develop infection, regardless of infection type, in MV proportional sub-distribution hazards model analyses. LMA showed similar patterns in reduced risk for relapse following infection. Although not all reached statistical significance, LMA showed reduced relapse risk associated with early infection: D14 (HR 0.54, 95% CI: 0.27-1.05, p=0.07), D28 (HR 0.53, 95% CI: 0.30-0.93, p=0.03), D56 (HR 0.57, 95% CI: 0.37-0.90, p=0.01), and D100 (HR 0.63, 95% CI: 0.37-1.09, p=0.10). Using infection as a time-dependent covariate, patients with infection had higher risk for infection-related mortality (IRM, HR 2.10, 95% CI: 1.45-3.05, p Conclusion: Early infection post-alloHCT may confer protection against hematologic malignant disease relapse, but also increases NRM and IRM. Further investigation is required to define underlying immunologic mechanisms that may mediate such putative protection in order to promote presumed enhancement in graft-versus-leukemia effect. Disclosures Auletta: Shire Pharmaceuticals: Consultancy. Lozanski:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding. Hofmeister:Arno Therapeutics, Inc.: Research Funding; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Celgene: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Andritsos:Hairy Cell Leukemia Foundation: Research Funding.

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant-related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven-month-old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.