Pediatric Hematopoietic Cell Transplant Patients Research Articles

Impact of dexamethasone on transplant-related mortality in pediatric patients: a multi-site, propensity score-weighted, retrospective assessment.

Dexamethasone use during hematopoietic cell transplant (HCT) conditioning varies between pediatric centers. This study aimed to estimate the difference in 1-year treatment-related mortality (TRM) between patients who did or did not receive dexamethasone during HCT conditioning. Secondary objectives were to estimate the difference between dexamethasone-exposed and dexamethasone-unexposed groups in 1-year event-free survival (EFS), time to neutrophil engraftment, acute graft-versus-host disease (aGVHD), and invasive fungal disease (IFD) at day + 100. This was a seven-site, international, retrospective cohort study. Patients < 18years old undergoing their first allogeneic or autologous myeloablative HCT for hematologic malignancy or aplastic anemia between January 1, 2012, and July 31, 2017, were included. To control for potential confounders, propensity score weighting was used to calculate the standardized mean difference for all endpoints. Among 242 patients, 140 received dexamethasone during HCT conditioning and 102 did not. TRM was unaffected by dexamethasone exposure (1.7%; 95% CI - 7.4, 10.2%). Between-group differences in secondary outcomes were small. However, dexamethasone exposure significantly increased possible, probable, and proven IFD incidence (9.0%, 95% CI 0.8, 17.3%). TRM is not increased in pediatric patients who receive dexamethasone during HCT conditioning. Clinicians should consider potential IFD risk when selecting chemotherapy-induced vomiting prophylaxis for pediatric HCT patients.

Timing of intubation of pediatric hematopoietic cell transplant patients: an international survey.

Retrospective data suggest that pediatric hematopoietic cell transplant (HCT) patients placed on non-invasive ventilation (NIV) prior to intubation have increased risk of mortality compared to patients who are intubated earlier in their course. The HCT-CI subgroup of the PALISI Network set out to gain a better understanding of factors that influence clinician's decisions surrounding timing of intubation of pediatric HCT patients. We validated and distributed a brief survey exploring potential factors that may influence clinician's decisions around timing of intubation of pediatric HCT patients with acute lung injury (ALI). One hundred and four of the 869 PALISI Network's members responded to the survey; 97 of these respondents acknowledged caring for HCT patients and were offered the remainder of the survey. The majority of respondents were PICU physicians (96%), with a small number of Advanced Practice Providers and HCT physicians. As expected, poor prognosis categories were perceived as a factors that delay timing to intubation whereas need for invasive procedures was perceived as a factor shortening timing to intubation. Concerns for oxygen toxicity or NIV-associated lung injury were not believed to influence timing of intubation. Our survey indicates increased risk of ALI from prolonged NIV and oxygen toxicity in HCT patients are not a concern for most clinicians. Further education of pediatric ICU clinicians around these risk factors could lead to improvement in outcomes and demands further study. Additionally, clinicians identified concerns for the patient's poor prognosis as a common reason for delayed intubation.

Intrapulmonary administration of recombinant activated factor VII in pediatric, adolescent, and young adult oncology and hematopoietic cell transplant patients with pulmonary hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a devastating disease process with 50-100% mortality in oncology and hematopoietic cell transplant (HCT) recipients. High concentrations of tissue factors have been demonstrated in the alveolar wall in acute respiratory distress syndrome and DAH, along with elevated levels of tissue factor pathway inhibitors. Activated recombinant factor VII (rFVIIa) activates the tissue factor pathway, successfully overcoming the tissue factor pathway inhibitor (TFPI) inhibition of activation of Factor X. Intrapulmonary administration (IP) of rFVIIa in DAH is described in small case series with successful hemostasis and minimal complications. We completed a single center retrospective descriptive study of treatment with rFVIIa and outcomes in pediatric oncology and HCT patients with pulmonary hemorrhage at a quaternary hematology/oncology hospital between 2011 and 2019. We aimed to assess the safety and survival of patients with pulmonary hemorrhage who received of IP rFVIIa. We identified 31 patients with pulmonary hemorrhage requiring ICU care. Thirteen patients received intrapulmonary rFVIIa, while eighteen patients did not. Overall, 13 of 31 patients (41.9%) survived ICU discharge. ICU survival (n=6) amongst those in the IP rFVIIa group was 46.2% compared to 38.9% (n=7) in those who did not receive IP therapy (p=0.69). Hospital survival was 46.2% in the IP group and 27.8% in the non-IP group (p=0.45). There were no adverse events noted from use of IP FVIIa. Intrapulmonary rFVIIa can be safely administered in pediatric oncology patients with pulmonary hemorrhage and should be considered a viable treatment option for these patients.

Stopping antibacterial prophylaxis in pediatric allogeneic hematopoietic cell transplantation: An internal audit.

Antibacterial prophylaxis in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) is controversial and not recommended by international guidelines. We analyzed relevant posttransplant outcomes following discontinuation of antibacterial prophylaxis at a major European pediatric transplant center. The single-center retrospective audit included all pediatric allogeneic HCT patients (pts) transplanted between 2011 and 2020 before (≤2014) and after (≥2015) stopping routine antibacterial prophylaxis with penicillin, metronidazole, and ciprofloxacin upon start of the conditioning regimen. The primary endpoint was overall survival until the first hospital discharge. Secondary endpoints included the occurrence of fever; bacterial infections; and cumulative days with antibacterial agents until discharge. A total of 257 HCT procedures were performed in 249 pts (median age: 10 years, range, 0.2-22.5) for leukemia/lymphoma (n = 150) and nonmalignant disorders (n = 107). Of these, 104 procedures were performed before (cohort 1) and 153 after (cohort 2) stopping prophylaxis. Overall survival until discharge was 90.4% in cohort 1 and 96.1% in cohort 2 (p = .06). No differences were observed in the occurrence of fever (92.3vs. 94.1%; p = .57) and bacterial infections (34.6vs. 25.5%; p = .11). The median number of days on antibacterial agents was significantly lower in cohort 2 (39vs. 34; p = .002). Detection rates of resistant organisms were overall low. In this single-center audit, the stop of routine antibacterial prophylaxis had no effect on the occurrence of fever, bacterial infections, resistant organisms, and GVHD. Overall antibiotic use was significantly reduced, and survival was noninferior to the historical control cohort.

Reduction of acute kidney injury in pediatric patients after bone marrow transplant: A prospective analysis after quality improvement implementation.

371 Background: Hematopoietic cell transplantation (HCT) is a curative therapy for malignant and non-malignant diseases. Acute kidney injury (AKI) is a common complication after HCT secondary to use of nephrotoxic medications (NTMx) prescribed for conditioning and prophylaxis. A recently published meta-analysis estimates the incidence of AKI after HCT to be 55.1%, with Stage 3 occurring in 8.3% of patients. Nephrotoxic medication–associated AKI (NAKI) affects 19%–31% of children who receive an intravenous aminoglycoside, with NAKI rates doubling with receipt of ≥ 3 nephrotoxic medications on the same day. We hypothesized that reducing NTMx exposure in pediatric HCT patients would be associated with lower all causes AKI incidence in the HCT unit. Methods: Single-center harm-preventing measures have been implemented at our center since 2019 to 2023. A multi-phased approach was used to increase education and recognition surrounding NTMx exposures in the HCT unit and role in subsequent AKI. We identified champions in the Pediatric HCT and Infectious Disease Host Defense teams. Five educational sessions took place from November 2022-June 2023 and an informational handout was created and distributed to HCT providers. Notifications to attending physicians of patients meeting NTMx exposure criteria, with acceptable alternatives to commonly used nephrotoxic drugs, and suggestions for AKI monitoring took place during daily rounds by the clinical pharmacist. Data on exposures and NAKIs’ was collected and reviewed every 3 months. Results: The cohort included 79 unique patients with 3547 patient days admitted to the HCT unit at Nationwide Children’s Hospital between January 1 2022 and March 31 2023. A total of 210 NTMx exposures were identified and resulted in 22 NAKI events. We reduced the rates of nephrotoxic medication exposure by 51% from 14.36 to 7 per month per 1000 patient days and NAKIs by 21% from to 1.27 to 1 per month per 1000 patient days since the start of our interventions. Conclusions: Successful interventions to decrease AKI in patients admitted to the HCT unit require a multi-disciplinary, iterative, and continuous approach, including recurrent education efforts to providers and pharmacy-driven daily physician alerts. Organizational implementation of these interventions is still ongoing.

#17 Gut decontamination, the microbiome, and the risk of bloodstream infections during pediatric allogeneic hematopoietic cell transplantation

Abstract Background Gut decontamination (GD) is the practice of using antibiotics to eradicate intestinal microbes before and during hematopoietic cell transplantation (HCT). Pre-clinical studies suggest that GD may be protective against acute graft-versus-host-disease (aGVHD), although no studies have focused on the potential impact of GD on non-aGVHD treatment related illnesses. Recently, we completed a randomized controlled trial of GD in pediatric patients. We report the results of an exploratory analysis of the impact of gut decontamination on the incidence of bloodstream infections (BSI) in pediatric HCT patients. Method We conducted a randomized phase 2 trial (ClinicalTrials.gov NCT02641236) of GD in pediatric patients undergoing allo-HCT with the primary objective to characterize the gut microbiota at 2-weeks post-HCT. Patients were randomized to receive the GD regimen (Arm A, n=10) (oral vancomycin-polymyxin B from day -5 through neutrophil engraftment) or not receive GD (no-GD; Arm B, n=10). Serial stool samples were collected from patients in both arms and subsequently underwent shotgun metagenomic sequencing to characterize the gut microbiome. In an exploratory, post-hoc analysis, stool metagenomic sequences were compared against the assembled sequence of a BSI isolate for any patient with a BSI in the first 100 days using a population average nucleotide identity (popANI) metric. Assembled BSI contigs and binned contigs from stool metagenomic sequences were profiled for antibiotic resistance genes (ARGs) with the Comprehensive Antibiotic Resistance Database (CARD) and the Resistance Gene Identifier (RGI) using default parameters. Results There was no statistical difference between the two arms in Shannon diversity of the gut microbiota at 2 weeks post-transplant for either genus (p=0.80) or species level (p=0.44). Six patients had a total of nine BSI episodes in the first 100 days post-HCT. We observed fewer BSI (1 vs. 5, Fig. 1A, p=0.048) in the GD vs no-GD arm, respectively. Using strain-specific analysis of BSI-causing bacteria and temporal association with the stool microbiome from patients who developed BSIs, we identified BSI-causing pathogens in 7 of 9 BSI episodes in the gut microbiome in the no-GD arm (Fig. 1B), including the genus Staphylococcus (Fig. 1C) in 2 patients. The 1 BSI in the GD arm was not derived from the gut (Fig. 1B). The number of unique colistin-, polymyxin B-, and vancomycin-ARGs were similar between the two arms (Fig. 1D). Conclusion Shannon diversity was similar in patients with or without GD, possibly due to the prevalent use of systemic antibiotics in the no-GD arm. Staphylococcus was found in the gut suggesting the need for an expanded definition of non-mucosal barrier injury (MBI) pathogens in HCT. All gut-localized BSIs were found in the non-GD arm suggesting that GD may protect against BSI in HCT patients by decreasing the prevalence or abundance of pathogens that can translocate across the mucosal barrier and subsequently cause gut-derived BSIs.

484 - Favorable Outcomes of Pediatric Hematopoietic Cell Transplant Patients Receiving Regen-COV2 for Prophylaxis Against Severe COVID-19 Disease

484 - Favorable Outcomes of Pediatric Hematopoietic Cell Transplant Patients Receiving Regen-COV2 for Prophylaxis Against Severe COVID-19 Disease

Lactobacillus bloodstream infections genetically related to probiotic use in pediatric hematopoietic cell transplant patients.

We describe a cluster of 6 pediatric hematopoietic cell transplant recipients with Lactobacillus bacteremia attributed to probiotic use. Lactobacillus isolates cultured from probiotics and patients' blood were proven to be related using whole-genome sequencing. Clinical studies are needed to evaluate the safety of probiotic use in immunocompromised patients.

Extracorporeal Membrane Oxygenation Candidacy in Pediatric Patients Treated With Hematopoietic Stem Cell Transplant and Chimeric Antigen Receptor T-Cell Therapy: An International Survey.

IntroductionPediatric patients who undergo hematopoietic cell transplant (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at high risk for complications leading to organ failure and the need for critical care resources. Extracorporeal membrane oxygenation (ECMO) is a supportive modality that is used for cardiac and respiratory failure refractory to conventional therapies. While the use of ECMO is increasing for patients who receive HCT, candidacy for these patients remains controversial. We therefore surveyed pediatric critical care and HCT providers across North America and Europe to evaluate current provider opinions and decision-making and institutional practices regarding ECMO use for patients treated with HCT or CAR-T.MethodsAn electronic twenty-eight question survey was distributed to pediatric critical care and HCT providers practicing in North America (United States and Canada) and Europe through the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network and individual emails. Responses to the survey were recorded in a REDCap® database.ResultsTwo-hundred and ten participants completed the survey. Of these, 159 (76%) identified themselves as pediatric critical care physicians and 47 (22%) as pediatric HCT physicians or oncologists. The majority (99.5%) of survey respondents stated that they would consider patients treated with HCT or CAR-T therapy as candidates for ECMO support. However, pediatric critical care physicians identified more absolute and relative contraindications for ECMO than non-pediatric critical care physicians. While only 0.5% of respondents reported that they consider HCT as an absolute contraindication for ECMO, 6% of respondents stated that ECMO is contraindicated in HCT patients within their institution and only 23% have an institutional protocol or policy to guide the evaluation for ECMO candidacy of these patients. Almost half (49.1%) of respondents would accept a survival to hospital discharge of 20-30% for pediatric HCT patients requiring ECMO as adequate.ConclusionsECMO use for pediatric patients treated with HCT and CAR-T therapy is generally acceptable amongst physicians. However, there are differences in the evaluation and decision-making regarding ECMO candidacy amongst providers across medical specialties and institutions. Therefore, multidisciplinary collaboration is an essential component in establishing practice guidelines and advancing ECMO outcomes for these patients.

Candidacy for Extracorporeal Life Support in Children After Hematopoietic Cell Transplantation: A Position Paper From the Pediatric Acute Lung Injury and Sepsis Investigators Network's Hematopoietic Cell Transplant and Cancer Immunotherapy Subgroup.

The last decade has seen improved outcomes for children requiring extracorporeal life support as well as for children undergoing hematopoietic cell transplantation. Thus, given the historically poor survival of hematopoietic cell transplantation patients using extracorporeal life support, the Pediatric Acute Lung Injury and Sepsis Investigators' hematopoietic cell transplantation and cancer immunotherapy subgroup aimed to characterize the utility of extracorporeal life support in facilitating recovery from critical cardiorespiratory illnesses in pediatric hematopoietic cell transplantation patients. All available published data were identified using a set of PubMed search terms for pediatric extracorporeal life support and hematopoietic cell transplantation. All articles that provided original reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support were included. Sixty-four manuscripts met search criteria. Twenty-four were included as primary reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support (11 were single case reports, four single institution case series, two multi-institution case series, and seven registry reports from Extracorporeal Life Support Organization, Pediatric Heath Information System, and Virtual Pediatric Systems). All 24 articles were reviewed by first and last authors and a spread sheet was constructed including sample size, potential biases, and conclusions. Discussions regarding incorporation of available evidence into our clinical practice were held at biannual meetings, as well as through email and virtual meetings. An expert consensus was determined through these discussions and confirmed through a modified Delphi process. Extracorporeal life support in hematopoietic cell transplantation patients is being used with increasing frequency and potentially improving survival. The Pediatric Acute Lung Injury and Sepsis Investigators hematopoietic cell transplantation-cancer immunotherapy subgroup has developed a framework to guide physicians in decision-making surrounding extracorporeal life support candidacy in pediatric hematopoietic cell transplantation patients. In addition to standard extracorporeal life support considerations, candidacy in the hematopoietic cell transplantation population should consider the following six factors in order of consensus agreement: 1) patient comorbidities; 2) underlying disease necessitating hematopoietic cell transplantation; 3) hematopoietic cell transplantation toxicities, 4) family and patient desires for goals of care; 5) hematopoietic cell transplantation preparatory regimen; and 6) graft characteristics. Although risk assessment may be individualized, data are currently insufficient to clearly delineate ideal candidacy. Therefore, we urge the onco-critical care community to collaborate and capture data to provide better evidence to guide physicians' decision-making in the future.

Early stool microbiome and metabolome signatures in pediatric patients undergoing allogeneic hematopoietic cell transplantation.

The contribution of the gastrointestinal tract microbiome to outcomes after allogeneic hematopoietic cell transplantation (HCT) is increasingly recognized. Investigations of larger pediatric cohorts aimed at defining the microbiome state and associated metabolic patterns pretransplant are needed. We sought to describe the pretransplant stool microbiome in pediatric allogenic HCT patients at four centers. We performed shotgun metagenomic sequencing and untargeted metabolic profiling on pretransplant stool samples. Samples were compared with normal age-matched controls and by clinical characteristics. We then explored associations between stool microbiome measurements and metabolite concentrations. We profiled stool samples from 88 pediatric allogeneic HCT patients, a median of 4days before transplant. Pretransplant stool samples differed from healthy controls based on indices of alpha diversity and in the proportional abundance of specific taxa and bacterial genes. Relative to stool from healthy patients, samples from HCT patients had decreased proportion of Bacteroides, Ruminococcaeae, and genes involved in butyrate production, but were enriched for gammaproteobacterial species. No systematic differences in stool microbiome or metabolomic profiles by age, transplant indication, or hospital were noted. Stool metabolites demonstrated strong correlations with microbiome composition. Stool samples from pediatric allogeneic HCT patients demonstrate substantial dysbiosis early in the transplant course. As microbiome disruptions associate with adverse transplant outcomes, pediatric-specific analyses examining longitudinal microbiome and metabolome changes are imperative to identify causal associations and to inform rational design of interventions.

Outcomes of kidney injury including dialysis and kidney transplantation in pediatric oncology and hematopoietic cell transplant patients.

Pediatric oncology and hematopoietic cell transplant (HCT) patients are susceptible to both acute kidney injury (AKI) and chronic kidney disease (CKD). The etiologies of AKI vary but include tumor infiltration, radiation, drug-induced toxicity, and fluid and electrolyte abnormalities including tumor lysis syndrome. HCT patients can also have additional complications such as sinusoidal obstructive syndrome, graft-versus-host disease, or thrombotic microangiopathy. For patients with severe AKI requiring dialysis, multiple modalities can be used successfully, although continuous kidney replacement therapy (CKRT) is often the principal modality for critically ill patients. While increasing numbers of pediatric cancer and HCT patients are now surviving long term, they remain at risk for a number of chronic medical conditions, including CKD. Certain high-risk patients, due to underlying risk factors or treatment-related complications, eventually develop kidney failure and may require kidney replacement therapies. Management of co-morbidities and complications associated with kidney failure, including use of erythropoietin for anemia and potential need for ongoing cancer-related treatment while on dialysis, is an additional consideration in this patient population. Kidney transplantation can be successfully performed in pediatric cancer survivors, although additional features such as specific cancer diagnosis and duration of remission should be considered.

A Randomized Trial of Caspofungin vs Triazoles Prophylaxis for Invasive Fungal Disease in Pediatric Allogeneic Hematopoietic Cell Transplant.

Children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) are at high risk for invasive fungal disease (IFD). This multicenter, randomized, open-label trial planned to enroll 560 children and adolescents (3 months to <21 years) undergoing allogeneic HCT between April 2013 and September 2016. Eligible patients were randomly assigned to antifungal prophylaxis with caspofungin or a center-specific comparator triazole (fluconazole or voriconazole). Prophylaxis was administered from day 0 of HCT to day 42 or discharge. The primary outcome was proven or probable IFD at day 42 as adjudicated by blinded central review. Exploratory analysis stratified this evaluation by comparator triazole. A planned futility analysis demonstrated a low rate of IFD in the comparator triazole arm, so the trial was closed early. A total of 290 eligible patients, with a median age of 9.5 years (range 0.3-20.7), were randomized to caspofungin (n = 144) or a triazole (n = 146; fluconazole, n = 100; voriconazole, n = 46). The day 42 cumulative incidence of proven or probable IFD was 1.4% (95% confidence interval [CI], 0.3%-5.4%) in the caspofungin group vs 1.4% (95% CI, 0.4%-5.5%) in the triazole group (P = .99, log-rank test). When stratified by specific triazole, there was no significant difference in proven or probable IFD at day 42 between caspofungin vs fluconazole (1.0%, 95% CI, 0.1%-6.9%, P = .78) or caspofungin vs voriconazole (2.3%, 95% CI, 0.3%-15.1%, P = .69). In pediatric HCT patients, prophylaxis with caspofungin did not significantly reduce the cumulative incidence of early proven or probable IFD compared with triazoles. Future efforts to decrease IFD-related morbidity and mortality should focus on later periods of risk. NCT01503515.

How We Treat Fever and Hypotension in Pediatric Hematopoietic Cell Transplant Patients

Pediatric allogeneic hematopoietic cell transplant (HCT) survival is limited by the development of post-transplant infections. In this overview, we discuss a clinical approach to the prompt recognition and treatment of fever and hypotension in pediatric HCT patients. Special attention is paid to individualized hemodynamic resuscitation, thorough diagnostic testing, novel anti-pathogen therapies, and the multimodal support required for recovery. We present three case vignettes that illustrate the complexities of post-HCT sepsis and highlight best practices that contribute to optimal transplant survival in children.

Clinical spectrum and outcome of invasive mucormycosis in children and adults: Polish experience of the decade 2010–2019

AbstractNo epidemiological data exist so far on invasive mucormycosis (IM) in Polish hematopoietic cell transplantation (HCT) and pediatric hemato-oncology (PHO) centers. The objective of this study was to analyze the incidence, clinical course, therapy, and outcome of IM in pediatric and adult patients undergoing HCT and children with hemato-oncological diseases in Poland. A total number of 12425 at-risk patients were retrospectively analyzed, and the period between 2010 and 2019 was included. Patients were analyzed in three groups: nontransplant children with malignancies, children undergoing HCT, and adults after HCT. Twenty-one patients were diagnosed with IM, including 15 children (10 non-HCT, 5 HCT) and 6 HCT adults. Proven IM was confirmed in 18 patients, probable in 2 patients, and possible in 1 patient. Proven IM was diagnosed in 7.1% of all patients with invasive fungal diseases (IFDs), including 8.1% among PHO patients, 5.4% among pediatric HCT patients, and 7.0% among adult HCT patients. Clinically, pneumonia was diagnosed in 10 (47.6%) patients, involvement of the paranasal sinuses was found in 3 (14.3%) patients, gastrointestinal disease was noted in 2 (9.5%) patients, and disseminated mucormycosis was found in 6 (28.6%) patients. The probability of overall survival in IM patients was 0.50 ± 0.11. Infection-related mortality (IRM) was 10% for pediatric nontransplant IM patients and 82% for transplant IM (pediatric + adult) patients (p = 0.004). Among the transplant patients, all adults died within 120 days. IRM for pediatric HCT patients was 60% (p = 0.038). The only prognostic factor was HCT, which adversely influenced survival in IM patients.

Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort

AbstractTransplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT). Diagnosis is challenging and in the absence of a tissue biopsy, TA-TMA is provisionally diagnosed by meeting clinical criteria. In this study, we describe the prevalence, outcomes, and risk factors for meeting 2 different diagnostic criteria for TA-TMA and for increased transplant-related mortality (TRM). In this retrospective study of 307 pediatric HCT patients, records were reviewed for the first 100 days after HCT. Patients who were diagnosed with TA-TMA by a provider during this time were included. In addition, the Cho et al criteria (2010) and Jodele et al (2014) TA-TMA criteria were applied retrospectively. Eight patients (2.6%) were diagnosed with TA-TMA by their provider. However, on retrospective review, 20% and 36% met the Cho and Jodele criteria for TA-TMA, respectively. Overall survival was significantly worse (P < .0001) and TRM was significantly higher in patients who met criteria for TA-TMA (MC-TA-TMA) (P < .0001). After controlling for comorbid conditions, MC-TA-TMA (hazard ratio [HR], 10.9; P = .0001) and grade 3/4 acute graft-versus-host-disease (aGVHD) (HR 3.5; P = .01) remained independently associated with increased TRM. Among allogeneic HCT recipients, features associated with an increased risk for MC-TA-TMA included ≥2 HCT, concurrent grade 3/4 aGVHD and concurrent infections. Among patients who MC-TA-TMA, LDH ≥2 times the upper limit of normal (P = .001), the need for ≥2 antihypertensive medications (P < .0001), and acute kidney injury (P = .003) were associated with significantly increased TRM.

Thoughts from the threshold: patient and family hopes, fears, values, and goals at the onset of pediatric hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) affords curative potential for high-risk patients but also carries risk of morbidity and mortality. Early palliative care (PC) integration can aid in supporting patients and families, fostering goal-directed care, and maximizing quality-of-life throughout. However, little is known about patient and family hopes, worries, goals, or values in pediatric HCT. Through retrospective review of pretransplant PC consultations, this study sought to provide insights from this unique patient population. Across 100 initial PC encounters conducted between December 2015 and March 2018, patient and caregiver responses to five targeted questions were extracted and analyzed. Data analysis revealed themes related to patient quality-of-life, caregiver/parent role, hopes, and worries. The most commonly identified thematic responses within each topic area were patient quality-of-life "electronics/entertainment" (49%), caregiver/parent role "doing right by my child" (58%), hopes "cure" (83%), worries "potential side effects" (43%), other spirituality (34%), and resiliency (29%). These findings provide an understanding of the values, goals, priorities, hopes, and fears experienced by pediatric HCT patients and their families, which may help inform a targeted approach to improve communication and overall care throughout transplantation. Variability was noted, underscoring the importance of fostering flexible, patient/family-centered communication beginning in the pretransplant period.

Incidence of Breakthrough Invasive Fungal Infections While on Micafungin for Antifungal Prophylaxis in Pediatric Hematopoietic Cell Transplant Patients

Introduction Pediatric hematopoietic cell transplant (HCT) patients are at significant risk for invasive fungal infections (IFIs). IFIs are life threatening for HCT patients. Due to its tolerability and lack of drug interactions, micafungin is utilized as primary antifungal prophylaxis (PAP) in the peri-transplant period. In 2012, we created a micafungin dosing protocol for pediatric patients based on the most current literature at that time. Objectives Our primary endpoint was to determine the prevalence of breakthrough IFIs in pediatric HCT patients after initiating PAP according to this institutional micafungin dosing protocol. The secondary endpoint was to evaluate the incidence of adverse effects (AEs). Methods Retrospective analyses of our institution's electronic records were performed to quantify the incidence of breakthrough IFIs in pediatric HCT patients who received micafungin for PAP according to institutional protocol between July 2012 and Dec 2017. Micafungin Pediatric Dosing Guidelines. PAP for HCT Results A total of 300 pediatric HCT patients were included in the analysis. All patients were neutrophil engrafted by Day +30. All patients started micafungin PAP prior to conditioning and continued through Day +100. Of the 300 patients, 50% converted to voriconazole, 30% remained on micafungin, 20% converted to fluconazole and 10% received amphotericin B. Per the European Organization for Research and Treatment of Cancer (EORTC) IFI Criteria Classification, 10 patients (3.1%) developed an IFI. Eight cases (2.6%) were classified as proven and 2 cases (0.7%) were probable. Pathogens identified were Candida parapsilosis (5/8 cases), Rhizopus (1 case), Candida krusei (1 case) and one case had both Mucormycosis and Rhizopus. The infection source was blood in 6/8 cases, wound (1 case) and sinuses/brain (1 case). Seven of eight patients with ‘proven' IFI died. Two deaths were directly associated with IFI (C. parapsilosis and mucormycosis); other deaths were attributed to bacterial infection (3), pulmonary hemorrhage or underlying disease. For the entire study group, approximately 8%, 5.7% and 1.7% had Grade 2, 3 and 4 hepatotoxicity, respectively (CTCAE grading criteria). Most patients with Grade 3 or 4 were noted to have moderate to severe Veno-Occlusive Disease or other primary disease processes so the events were likely not related to micafungin. Conclusions The micafungin dosing protocol for pediatric HCT patients has shown to be efficacious with very few documented breakthrough IFI over a five year study period. Additionally, micafungin was well tolerated at these doses with few treatment-related and/or low grade AEs.

Evaluation of Mucositis in Pediatric Hematopoietic Cell Transplant Patients Receiving Palifermin

Background Oral mucositis (OM) occurs in up to 70-80% of children undergoing myeloablative conditioning during hematopoietic cell transplant (HCT). OM has various negative clinical sequelae; therefore, efforts to prevent this common transplant complication have important potential clinical benefits. The keratinocyte growth factor, palifermin, stimulates the proliferation of mucosal cells and may be protective against the development of OM when administered to patients receiving regimens containing total body irradiation (TBI) or alkylating agents. Methods We performed a retrospective review of children (up to age 21 years) undergoing autologous or allogeneic HCT who received palifermin in the peri-transplant period over a 5-year period (2014-2018) at our institution. Subjects were included if they received TBI (≥12 Gy) or multiple alkylating agents (including melphalan) as part of their conditioning regimen. The recommended dosing is 60 mcg/kg/day intravenously 3 days before conditioning and 3 doses post-HCT on days 0, +1, +2. We excluded children who completed the pre-transplant palifermin doses greater than 48 hours prior to initiation of the conditioning regimen and those who did not receive all 6 planned doses. The primary outcome was the incidence, severity, and duration of mucositis. Secondary outcomes included the need for supportive care measures such as parenteral nutrition (PN) and patient controlled analgesia (PCA) use. We also examined the cost associated with palifermin use. Results A total of 44 children were evaluated. Ten children were excluded due to inappropriate palifermin dosing, two were excluded for infectious complications that resulted in aborting the preparative regimen, and two had incomplete data during chart review. Thirty remaining evaluable subjects were included in the full analysis. The most common chemotherapy-only conditioning regimens were carboplatin/etoposide/melphalan (n=8) and fludarabine/melphalan/thiotepa (n=7); 12 patients received TBI. Twenty-two patients (73.3%) developed Grade 3 or 4 mucositis (Grade 3, n=17; Grade 4, n=5). The median duration of mucositis, PN use, and PCA were 15 days (IQR 10-20), 18 days (IQR 13-25), and 10.5 days (IQR 7-16), respectively. The median hospital length of stay was 33 days (IQR 27-45). When subjects who were excluded due to inappropriate dosing were included in the analysis, there were no significant changes in the primary and secondary outcome measures. The average cost of palifermin per patient is approximately $15,350, translating to $135,080 of additional overall charges annually. Conclusion Despite the use of palifermin, the incidence of severe OM was high in our pediatric population. Given concerns regarding cost and questionable efficacy, the role of palifermin in HCT supportive care remains uncertain.

Autoimmune Cytopenias Following Allogeneic Hematopoietic Stem Cell Transplant in Pediatric Patients: A Case-Control Cohort Study

Introduction Autoimmune cytopenia (AIC) is a rare, but serious complication of allogeneic hematopoietic cell transplantation (HCT), and treatment for post-HCT AIC can have severe short- and long-term consequences. We sought to identify AIC risk factors and evaluate treatment-related late effects, in order to better guide management. Methods We performed a retrospective case-control study of pediatric patients who underwent HCT at Children's Hospital Colorado from June 2005 to March 2019. We compared clinical and transplant-related characteristics, chimerism, immune reconstitution, outcomes and late effects between patients who developed AICs (n=20) and a control group (n=40) matched by primary disease category and donor source. Results The incidence of AIC was 5.6% amongst all patients who received allogeneic HCT in the study timeframe (n=354). Of these, 75% had non-malignant disease (n=15). Thirteen developed autoimmune hemolytic anemia (65%), 5 had immune thrombocytopenia (25%), 1 had Evans syndrome (5%) and 1 had autoimmune neutropenia (5%). Median time to AIC was 219 days (range 97-1205 days). There was no difference between AIC patients and controls in gender, age at HCT, conditioning regimen, serotherapy, total body irradiation (TBI), GVHD prophylaxis, chronic GVHD, or time to neutrophil and platelet recovery. Compared to controls, more AIC patients had ABO mismatch (50% vs. 40%, p=0.07), and a higher proportion of grade I-II acute GVHD (93.9% vs. 50%, p=0.06), but was not statistically significant. Seventeen patients (85%), had >95% donor chimerism immediately prior to development of AIC. Fifteen patients (75%) received steroids as part of first-line therapy for AIC and 17 patients (85%) received rituximab as part of all therapy. Eleven patients (64.7%) received rituximab as part of first-line therapy. Only 25% of patients (n=5) responded to initial therapy. Median time to resolution of AIC was 12.0 months (range 10 days to 90 months). Strikingly, 12 patients (70.6%) are still receiving intravenous immune globulin (IVIG) replacement for hypogammaglobulinemia at least 1-year after HCT at a median time of 597.5 days (range 83-3715 days) from last rituximab dose. Iron overload was more prevalent in AIC patients compared to controls (n=8 vs n=1, p=0.0004, median of 2.3 years after HCT). The overall survival (OS) of the AIC cohort was similar to the control group (85% vs 82.5%). No patients in the AIC cohort died from AIC-related complications. In the AIC cohort, 2 patients died from sepsis and 1 patient died from relapsed disease. Conclusions In this case-control study of pediatric HCT patients, AIC was not associated with mixed chimerism or GVHD. The majority of AIC cases did not respond to first-line therapy and required multiple treatment modalities to achieve a complete response. Late effects from AIC-directed therapies include prolonged hypogammaglobulinemia and iron overload.