Pediatric Hematopoietic Stem Cell Transplantation Patients Research Articles

Treatment outcome at the pediatric stem cell transplantation center in Syria: A single-center experience.

Hematopoietic stem cell transplantation (HSCT) is a therapeutic approach known for its high success rates in treating various hematologic malignancies, hemoglobinopathies, immune deficiencies, and other disorders. Notably, pediatric HSCT commenced in Syria in 2021 amidst the prevailing crisis. This study aims to assess the demographic and clinical profiles of pediatric patients who underwent stem cell transplantation and to analyze treatment outcomes at Syria's inaugural pediatric HSCT center. This study is a single-center retrospective analysis of 25 pediatric patients who underwent HSCT underage of 14 years in the National Stem Cell Center (HAYAT) in Damascus within the period 2021-2023. The databases were created based on data that were collected from patient medical records. In autologous patients, transplant-related mortality (TRM) was 0%, with 4 (57%) experiencing disease relapse, resulting in the death of one patient. Additionally, 3 (42.8%) of patients remain alive under second-line management. The overall survival rate was 6 (85.7%), and the disease-free survival rate was 16 (88%). In allogeneic patients, TRM was 5.5% (1/18). One allogeneic patient experienced disease relapse and subsequently died. The overall survival rate and disease-free survival rate were 16 (88%). The objective of this study was to assess the outcomes of pediatric HSCT patients who have undergone transplantation thus far. Given the recent initiation of pediatric stem cell transplantation in Syria, our dataset provides a basis for comparison with international hematopoietic stem cell transplantation centers regarding treatment complications and outcomes, notwithstanding the challenges and crises faced within our country.

Implementation of a light therapy team to administer photobiomodulation therapy: A standardized protocol to prevent and treat oral mucositis in the pediatric hematopoietic stem cell transplant population.

Oral mucositis (OM) is a painful and common complication of hematopoietic stem cell transplant (HSCT). The Children's Oncology Group recently published guidelines recommending photobiomodulation (PBM) for preventing and treating OM in pediatric HSCT patients. However, this is a rarely used intervention in pediatric hospitals. Patients undergoing allogeneic HSCT, or autologous HSCT for a neuroblastoma diagnosis, had PBM administered from the first day of conditioning to transplant Day +20. We successfully developed a standardized treatment protocol and workflow to ensure consistent and uniform delivery of PBM. In addition, clinical patient data were compared before and after PBM implementation. The administration of PBM at our center was feasible, but required dedicated staff. A registered nurse (RN) was determined to be the best fit to deliver PBM. Sixty-two patients received PBM from October 2022 to September 2023; patients from 2021 before PBM implementation were used for comparison. Patients receiving PBM were more likely (p=.03) to engage in teeth brushing (56/62=90%) compared to baseline (61/81=75%). Mean days of OM decreased from 11.3 to 9days; patients who received PBM were less likely (p<.001) to be discharged on total parental nutrition (TPN) (11/62=18%) compared to baseline (50/82=61%). OM-related supportive care costs (TPN and patient-controlled anesthesia [PCA]) were lower (p=.02) for those who received PBM (median cost=$31,229.87 vs. $37,370.66). PBM, as the standard of care in the pediatric HSCT population, is safe, feasible, and well-tolerated. At our center, a dedicated RN was critical to providing standardized treatment and ensuring sustainability.

Cystatin C Outperforms Creatinine in Predicting Cefepime Clearance in Pediatric Stem Cell Transplant Recipients

BackgroundPediatric hematopoietic stem cell transplant (HSCT) patients are at risk of developing both sepsis and altered kidney function. Cefepime is used for empiric coverage post-HSCT and requires dose adjustment based on kidney function. Since cefepime's anti-microbial efficacy is determined by the time free concentrations exceed bacterial minimum inhibitory concentration (MIC), it is important to assess kidney function accurately to ensure adequate concentrations. Serum creatinine (SCr) is routinely used to estimate glomerular filtration rate (eGFR) but varies with muscle mass, which can be significantly lower in HSCT patients, making SCr an inaccurate kidney function biomarker. Cystatin C (CysC) eGFR is independent of muscle mass, though steroid use increases CysC. ObjectivesTo describe how eGFR impacts cefepime pharmacokinetic/pharmacodynamic (PK/PD) target attainment in pediatric HSCT patients, to investigate which method of estimating GFR (SCr, CysC, combined) best predicts cefepime clearance, and to explore additional predictors of cefepime clearance. Study DesignPatients admitted to the pediatric HSCT unit who received ≥2 cefepime doses were prospectively enrolled. We measured total cefepime peak/trough concentrations between the 2nd-4th cefepime doses and measured SCr and CysC if not already obtained clinically within 24h of cefepime samples. eGFRs were calculated with Chronic Kidney Disease in Children U25 equations. Bayesian estimates of cefepime clearance were determined with a pediatric cefepime PK model and PK software MwPharm++. Simple linear regression was used to compare cefepime clearance normalized to body surface area (BSA) to BSA-normalized SCr-, CysC-, and SCr-/CysC-eGFRs, while multiple linear regression was used to account for additional predictors of cefepime clearance. For target attainment, we assessed the percentage of time free cefepime concentrations exceeded 1x MIC (%fT>1x MIC) and 4x MIC (%fT>4x MIC) using a susceptibility breakpoint of 8 mg/L for Pseudomonas aeruginosa. ResultsWe enrolled 53 patients (ages 1-30 years, median 8.9 years). SCr- and CysC-eGFRs were lower in patients who attained 100% fT>1xMIC compared to those who did not attain this target: 115 vs 156 mL/min/1.73m2 (p=0.01) for SCr-eGFR and 73.5 vs 107 mL/min/1.73m2 (p<0.001) for CysC-eGFR. SCr-eGFR was weakly positively correlated with cefepime clearance (adjusted [a]r2=0.14), while CysC-eGFR and SCr-/CysC-eGFR had stronger positive correlations (ar2=0.30 CysC, ar2=0.28 combo. There was a weak, significant linear association between increasing CysC-eGFR and decreased %fT>1xMIC (ar2=0.32) and %fT>4xMIC (ar2=0.14). No patients with a CysC-eGFR >120 mL/min/1.73 m2 achieved 100% fT>1xMIC or 50% fT>4x MIC. In multiple regression models, underlying diagnosis of hemoglobinopathy (in all models) and being pre-transplant (in SCr and combined models) were associated with increased cefepime clearance, while concomitant use of calcineurin inhibitors was associated with decreased cefepime clearance in all models. Overall, the combo-eGFR model with timing pre-transplant, hemoglobinopathy, and use of calcineurin inhibitors had the best performance (ar2=0.63). ConclusionsCysC-based eGFRs (CysC alone and combined) predicted cefepime clearance better than SCr-eGFR, even after considering steroid use. Increasing CysC eGFR correlated with decreased probability of PD target attainment, raising concerns for underdosing at high eGFRs. CysC should be included when estimating kidney function to provide adequate dosing of cefepime in pediatric HSCT patients.

Diagnostic performance of a multiplexed gastrointestinal PCR panel for identifying diarrheal pathogens in children undergoing hematopoietic stem cell transplant.

Diarrhea is a common complication of hematopoietic stem cell transplantation (HSCT) and is associated with substantial morbidity, but its etiology is often unknown. Etiologies of diarrhea in this population include infectious causes, chemotherapy- or medication-induced mucosal injury and graft-versus-host disease (GVHD). Distinguishing these potential causes of diarrhea is challenging since diarrheal symptoms are often multifactorial, and the etiologies often overlap in transplant patients. The objectives of this study were to evaluate whether the FilmArray gastrointestinal (GI) panel would increase diagnostic yield and the degree to which pre-transplantation colonization predicts post-transplantation infection. From November 2019 to February 2021, a total of 158 patients undergoing HSCT were prospectively included in the study. Stool specimens were obtained from all HSCT recipients prior to conditioning therapy, 28 ± 7days after transplantation and at any new episode of diarrhea. All stool samples were tested by the FilmArray GI panel and other clinical microbiological assays. The primary cause of post-transplantation diarrhea was infection (57/84, 67.86%), followed by medication (38/84, 45.24%) and GVHD (21/84, 25.00%). Ninety-five of 158 patients were colonized with at least one gastrointestinal pathogen before conditioning therapy, and the incidence of infectious diarrhea was significantly higher in colonized patients (47/95, 49.47%) than in non-colonized patients (10/63, 15.87%) (P < 0.001). Fourteen of 19 (73.68%) patients who were initially colonized with norovirus pre-transplantation developed a post-transplantation norovirus infection. Twenty-four of 62 (38.71%) patients colonized with Clostridium difficile developed a diarrheal infection. In addition, FilmArray GI panel testing improved the diagnostic yield by almost twofold in our study (55/92, 59.78% vs. 30/92, 32.61%). Our data show that more than half of pediatric patients who were admitted for HSCT were colonized with various gastrointestinal pathogens, and more than one-third of these pathogens were associated with post-transplantation diarrhea. In addition, the FilmArray GI panel can increase the detection rate of diarrheal pathogens in pediatric HSCT patients, but the panel needs to be optimized for pathogen species, and further studies assessing its clinical impact and cost-effectiveness in this specific patient population are also needed.

SVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT. ObjectivesTo investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD). MethodsWe prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant. ResultsAll over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1–18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023). ConclusionVEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.

Body Surface Area-Based Dosing of Mycophenolate Mofetil in Pediatric Hematopoietic Stem Cell Transplant Recipients: A Prospective Population Pharmacokinetic Study.

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15-20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m2, 1.0 m2, 1.5 m2) and dosing (400 mg/m2, 600 mg/m2, 900 mg/m2 twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on Vd/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m2 twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice.

Influence and Role of the Body Mass Index and Its Development on the Course of Pediatric HSCT - a Retrospective Analysis

T Stetter and M Döring contributed equally to this work. Background Children and adolescents are at increased risk of malnutrition during the course of hematopoietic stem cell transplantation (HSCT). Increased endocrine activity, a catabolic metabolic state and inflammatory processes increase the energy metabolism and therapy-associated side effects impair nutritional intake. Studies have shown that the nutritional status before HSCT in adults has a decisive influence on the time afterwards. The role of nutritional status in children and adolescents before, during, and after HSCT remains poorly understood. Patients and Methods In this monocentric, retrospective study, data from patients who underwent autologous or allogeneic HSCT at the University Children's Hospital Tübingen between November 2012 and November 2021, were analyzed. Exclusion criteria were known gastrointestinal malformations, permanent enteral/parenteral nutrition, and known chronic inflammatory bowel disease before HSCT. On three observation days (baseline: day of in-patient admission, day +30, and day +200 after HSCT) data on age-adjusted BMI percentiles, incidence of transplant-associated adverse events (TRAE; e.g., graft-versus-host disease (GvHD), veno-occlusive disease (VOD), mucositis, infection), and survival (up to 10 years after HSCT; last note in file). were collected. Patients were categorized into alloHSCT and autoHSCT Patients as well as BMI-percentile groups depending on baseline BMI percentile: &amp;lt;3rd percentile, 3rd-&amp;lt;10th percentile, 10th-&amp;lt;25th percentile, 25th-&amp;lt;50th percentile, 50th-&amp;lt;75th percentile, 75th-97th percentile, and &amp;gt;97th percentile. Results A total of 365 patients with a median age of 9 years (0-23 years), 56% of whom were female, were studied. Of these, 307 (84%) underwent allogeneic and 58 (16%) autologous HSCT. The underlying disease was malignant in 262 cases (72%) and non-malignant in 103 cases (28%). The proportions of patients fell into the corresponding BMI percentile groups at the respective observation days (see Table). During the course of time until day +200 after HSCT, the BMI percentile category remained the same in 28% of the cases, in 17%, 10%, and 3% of cases, respectively, patients moved up one, two, and &amp;gt;2 categories, respectively; in 20%, 12%, and 9% of cases, patients dropped one, two, and &amp;gt;2 categories, respectively, compared to baseline. However, comparing the alloHSCT and autoHSCT patients, a different distribution in the development until day +200 is noticeable. Overall, 27% of the alloHSCT and 44% of autoHSCT patients ascend one or more percentile groups, whereas 46% of the alloHSCT and 22% of the autoHSCT patients descend one or more BMI percentile categories. Higher-grade intestinal GvHD stage 3-4 occurred statistically more frequently in the percentile group &amp;gt;75th-97th ( p=0.0028), but when all grades were considered together, no significant clustering in any group was observed. A significant accumulation ( p=0.0413) of VOD, BKV cystitis ( p=0.0021), and Viremia ( p=0.0081) was found in the group &amp;gt;75th-97th percentile. A total of 115 patients (32%) died during the observation period. In the alloHSCT group, 35 deaths (12% of alloHSCT patients) fell under TRM. Here, of the 35 deceased, 12 (34% of deceased, 4% of total alloHSCT patients) were ascribed to the &amp;gt;75th-97th percentile group; the median proportion of deceased patients was 9% (1% of alloHSCT group) in the other percentile groups. In the autoHSCT group, a total of 23 patients (41%) died; of these, all were due to progression or recurrence of the underlying disease. The &amp;lt;3rd percentile and &amp;gt;25th-50th percentile groups each recorded the most deaths, with 26% of those who died and 11% of patients in the autoHSCT group, respectively. Conclusions Contrary to the expectation that particularly underweight pediatric HSCT patients might be more affected by complications, this data collection showed statistically clustered complications and TRM in the group of patients between the 75th-97th BMI percentiles. Although this is only a status description of body weight and length during follow-up, and not a specific survey of nutritional status, the data analysis suggests that HSCT patients in the overweight range should be focused on more closely. A prospective survey of differential nutritional status in pediatric HSCT patients is currently being conducted at our study center.

High Incidence of Vitamin D Deficiency Among Patients Undergoing Hematopoietic Stem Cell Transplant and a Single Ultra-High Dose Vitamin D Replacement

Introduction: Vitamin D involves in several important human physiologic pathways from bone metabolism to inflammation and immune regulation. Patients who undergo hematopoietic stem cell transplant (HSCT) are at risk of developing vitamin D deficiency from various mechanisms and replacement of vitamin D in these patients can be challenging according to several reasons. In addition, vitamin D may potentially affect outcomes, overall health and quality of life after HSCT. An ultra-high dose vitamin D replacement was previously explored in pediatric HSCT patients but has never been investigated in adult patient population. In this study, we explored the incidence of vitamin D deficiency, the safety and efficacy of a single ultra-high dose vitamin D replacement including its effect on bone health among adult patients with hematologic malignancy undergoing HSCT. Patients and Methods: First, we looked at the retrospective cohort of patients who underwent HSCT between January 2017 and August 2022 to explore the incidence of vitamin D deficiency (25-hydroxy vitamin D level &amp;lt;20 ng/mL) in Thailand. Subsequently, we prospectively included adult patients with hematologic malignancy undergoing both autologous (ASCT) and allogeneic HSCT (alloHSCT) from September 2022 to June 2023. All patients received a single ultra-high dose vitamin D on the day of admission prior to the initiation of conditioning regimens. We reported the safety and efficacy of a single ultra-high dose vitamin D (Ergocalciferol; Vitamin D2) replacement as calculated by weight and pre-transplantation vitamin D level among these patients using the Stoss protocol previously described. The effect of an ultra-high dose vitamin D on bone turnover was also monitored. Results: In the retrospective cohort, 229 patients underwent HSCT (146 ASCT and 83 alloHSCT). Vitamin D deficiency was observed in 147 patients (64.6%) including 91 (62.3%) ASCT and 56 (67.5%) alloHSCT. The median 25-hydroxy (25-OH) vitamin D level was 17.6 (4.0-86.3) ng/mL comparable between autologous and allogeneic patients. In the prospective cohort, 45 patients underwent HSCT (27 ASCT and 18 alloHSCT). The median age of patients at the time of HSCT was 49 (23-67) years with 18 patients (40%) being male. The median pre-transplant 25-OH vitamin D level was 20.2 ng/mL with 22 patients (48.9%) (13 ASCT, 9 alloHSCT) meeting the criteria of vitamin D deficiency. The median dose of vitamin D2 used was 500,000 (300,000-600,000) IU. At day +28 post-HSCT, 40% of patients were able to attain 25-OH vitamin D level above 30 ng/mL comparable between ASCT and alloHSCT but significantly higher compared to the retrospective cohort. The time to neutrophil and platelet engraftment were 13 (9-26) days and 14 (9-33) days, comparable between the controlled retrospective cohort and high dose replacement prospective cohort. The median levels of parathyroid hormone (PTH) and bone turnover markers including osteocalcin, β-CrossLaps (β-CTx), and procollagen type I N-propeptide (PINP) at day+28 was 45.4 (19.4-152.2) pg/mL, 11.3 (6.0-16.8) ng/mL, 0.79 (0.1-13.0) ng/ml and 43.7 (19.7-133.7) mcg/L, respectively. Among patients who underwent alloHSCT, the incidence of cytomegalovirus reactivation and acute graft versus host disease was 72.2% and 11.1% (no grade 3-4), respectively. Figure 1 shows the kinetic of serum 25-OH vitamin D, Calcium, β-CTx and PINP of patients in the prospective cohort from baseline to day +28 post-HSCT. At all timepoints (day 0, +7, +14, +21, +28), the median level of vitamin D level was significantly higher whereas the median serum PINP level was significantly lower compared to the baseline level. There was no occurrence of hypercalcemia or bony events during the time of the study. Conclusion: Our study highlights a high incidence of vitamin D deficiency in HSCT patients. Utilizing a single ultra-high dose vitamin D is an effective and safe approach to replace vitamin D in adult patients undergoing HSCT. A high percentage of patients could maintain adequate vitamin D level during post-transplant period. PINP level was sustainably decreased after vitamin D replacement indicating a lower bone resorption. Whether this approach will translate into improved immune function, long-term bone health and outcomes compared to the conventional replacement strategy warrants further exploration in prospective randomized clinical trials.

Exploring the Efficacy and Feasibility of Outpatient Blinatumomab Short Cycles in Pediatric Patients with Relapsed/Refractory B-ALL in LMIC: Preliminary Results

CONCLUSIONS In low- and middle-income countries (LMIC) like Mexico, the treatment of patients with refractory or relapsed acute lymphoblastic leukemia (r/r ALL) represents a significant challenge due to limited access to immunotherapy and hematopoietic stem cell transplantation (HSCT). As a result, the one-year survival rate is reported to be less than 20%. The use of intensive chemotherapy has not improved survival in this group due to its high toxicity. Blinatumomab uses the patient's own cytotoxic T-cells to induce lysis of the leukemia cells expressing CD19 and has been established as a bridge therapy for transplant in patients with r/r B-ALL. The usual pattern of administration is a dose scaled up to complete a total of 28 days of infusion. According to various studies, it is considered appropriate to use repeated cycles of this antibody to achieve the desired response. However, there are also reports of patients achieving complete responses within the first 15 days of the cycle. The high costs of Blinatumomab's administration present a significant barrier to its use in LMIC. As a consequence, the application of prolonged or multiple cycles of the drug becomes unaffordable for a substantial portion of the global population. Demonstrate the safety and efficacy of utilizing short cycles of Blinatumomab (21 days) as a bridge therapy to HSCT in pediatric patients with r/r ALL to explore the potential cost-reduction benefits and increased access to this therapy in resource-limited settings. A pilot clinical trial was conducted. Pediatric patients (&amp;lt;16 y) diagnosed with r/r B- ALL between the years 2020-2022 were included. The usual Blinatumomab dosing regimen was adopted, but the total duration of the cycle was reduced. Continuous infusion was initiated at a dose of 5 mcg/m2/day for the first 7 days, followed by an increase to 15 mcg/m2/day for 14 days (21-day total treatment duration). To mitigate cytokine release syndrome (CRS) a single dose of dexamethasone was administered at the start of the infusion and after the dose escalation. The entire regimen was administered on an outpatient basis, with an infusion pump at home. Caregivers were instructed on the operation of the pump and detection of any signs of toxicity, with 24/7 contact with the medical team and the option to hospitalize if necessary. A total of 7 patients were included, and all of them received Blinatumomab in a single 21-day cycle. The median age was 5 years (15 mo- 13 y). The majority of patients were stratified as high-risk at the time of diagnosis (85.7%). Among the patients, 4 had relapsed ALL, while 3 had refractory disease. The median time from the initial diagnosis to the use of Blinatumomab was 16 months (ranging 7-29 mo), and the median number of treatment lines before Blinatumomab administration was 3 (ranging 2-4). The highest level of minimal residual disease (MRD) detected before the Blinatumomab treatment was 4.2% (by flow cytometry). Remarkably, all patients (100%, n=7) achieved a complete response, with MRD being negative for flow cytometry after the 21-day cycle of Blinatumomab. In 5 out of 7 patients, the administration of the drug was completely ambulatory. Only 2 patients experienced grade I CRS which was successfully managed with steroids. No adverse effects greater than grade 2 were reported, and no patient required support with transfusion therapy during or after the infusion. There were no reports of profound neutropenia, and no treatment-related deaths occurred. HSCT was conducted in all patients to consolidate the response, with 6 patients undergoing haploidentical and 1 patient undergoing identical allogeneic HSCT. At present, 5 out of 7 patients are alive and in complete remission. One patient died on day +51 post-HSCT due to pulmonary thromboembolism, and the second patient experienced relapse on day +395 post-HSCT and subsequently died on day +640 due to disease progression. The median overall survival at 3 years was 66.7%, with a median follow-up period of 21 months (4 -30mo). An alternative outpatient, low-toxicity and cost-effective treatment approach was implemented. The findings from this study could shed light on a promising strategy to improve the outcomes for patients with ALL patients with limited therapeutic options, particularly in the context of resource-constrained settings.

Financial burden and recommended multilevel solutions among caregivers of pediatric hematopoietic stem cell transplant recipients.

The healthcare costs of patients who receive hematopoietic stem cell transplantation (HSCT) are substantial. At the same time, the increasing use of pediatric HSCT leaves more caregivers of pediatric HSCT recipients at risk for financial burden-an understudied area of research. Financial burden experienced by caregivers of recipients who received autologous or allogeneic transplants was assessed using an explanatory mixed-methods design including a one-time survey and semi-structured interviews. Financial burden was assessed through an adapted COmprehensive Score for financial Toxicity (COST) as well as questions about the types of out-of-pocket costs and cost-coping behaviors. Chi-squared or Fisher's exact tests were used to assess differences in costs incurred and coping behaviors by financial toxicity and financial toxicity by demographic factors. Interviews were audio recorded, transcribed, and analyzed using directed content analysis. Of 99 survey participants, 64% experienced high financial toxicity (COST 22). Caregivers with high financial toxicity were more likely to report costs related to transportation and diet. High financial toxicity was associated with nearly all cost-coping behaviors (e.g., borrowed money). High financial toxicity was also associated with increased use of hospital financial support and transportation assistance. Qualitative analysis resulted in four categories that were integrated with quantitative findings: (1) care-related out-of-pocket costs incurred, (2) cost-coping behaviors, (3) financial support resources used, and (4) multilevel recommendations for reducing financial burden. Considering the substantial, long-term financial burden among pediatric HSCT patients and their caregivers, this population would benefit from adapted and tailored financial burden interventions.

Prognostic factors and predictive scores for 6-months mortality of hematopoietic stem cell transplantation recipients admitted to the pediatric intensive care unit.

Despite advances in hematopoietic stem cell transplantation (HSCT), a considerable number of pediatric HSCT patients develops post-transplant complications requiring admission to the pediatric intensive care unit (PICU). The objective of this study was to evaluate clinical findings, PICU supportive therapy and outcome as well as predictive factors for 6-months survival after discharge of HSCT patients from PICU. This retrospective single-center analysis investigated patient characteristics, microbiological findings, reasons for admission and death of 54 cases accounting for 94 admissions to the PICU of the University Children's Hospital Tuebingen from 2002 to 2017. We compared clinical characteristics between children with and without 6-months survival after discharge from PICU following HSCT. Finally, we assessed the potential prognostic value of the oncological Pediatric Risk of Mortality Score (O-PRISM), the Pediatric Sequential Organ Failure Assessment Score (pSOFA) and the pRIFLE Criteria for Acute Kidney Injury for 6-months survival using Generalized Estimating Equations (GEE) and Receiver Operating Characteristic curves. Respiratory insufficiency, gastroenterological problems and sepsis were the most common reasons for PICU admission. Out of 54 patients, 38 (70%) died during or after their last PICU admission, 30% survived for at least six months. When considering only first PICU admissions, we could not determine prognostic factors for 6-months mortality. In contrast, under consideration of all PICU admissions in the GEE model, ventilation (p=0.03) and dialysis (p=0.007) were prognostic factors for 6-months mortality. Furthermore, pSOFA (p=0.04) and O-PRISM (p=0.02) were independent risk factors for 6-months mortality considering all PICU admissions. Admission of HSCT patients to PICU is still associated with poor outcome and 69% of patients died within 6 months. Need for respiratory support and dialysis are associated with poor outcome. Prediction of 6-months survival is difficult, especially during a first PICU admission. However, on subsequent PICU admissions pSOFA and O-PRISM scores might be useful to predict mortality. These scores should be prospectively evaluated in further studies to verify whether they can identify pediatric HSCT recipients profiting most from transferal to the PICU.

Health-Related Quality-of-Life Profile of Pediatric Patients with β Thalassemia after Hematopoietic Stem Cell Transplantation.

Matched hematopoietic stem cell transplantation (HSCT) is a feasible and curative treatment in pediatric patients with beta thalassemia major (β-TM). However, little data are available regarding patients and their parents' health-related quality of life (HRQoL) after the procedure. As such, we investigated the HRQoL of pediatric patients with β-TM after HSCT compared to that of patients treated with blood transfusions and iron chelation. The health-related quality of life of 43 β-TM pediatric patients and 43 parents were evaluated using the Pediatric Quality of Life Inventory (PedsQL). A total of 25 patients underwent HSCT: 15 from a sibling and 10 from an HLA-matched donor. The median follow-up time from HSCT was 5 years (range 1-13 years). The mean ages at the survey were 10.1 years (range 5-15) and 9.6 years (range 5-15) for transfused and transplanted patients, respectively. A significant reduction in HRQoL was reported in the group of transfused patients compared with that of patients transplanted in the following PedsQL domains: children's and parents' physical functions, Δ = -15.4, p = 0.009 and Δ = -11.3, p = 0.002, respectively; children's and parents' emotional functioning, Δ = -15.2, p = 0.026 and Δ = -15.2, p = 0.045, respectively; child's and parents' school functioning, Δ = -25, p = 0.005 and Δ = -22.5, p = 0.011, respectively; total child and parents scores, Δ = -14.5, p = 0.004 and Δ = -13.2, p = 0.005, respectively. The results of a multivariable analysis showed that the HSCT procedure was significantly associated with a higher total child PedsQL score (adjusted mean difference = 15.3, p = 0.001) and a higher total parent PedsQL score (adjusted mean difference = 14.1, p = 0.006). We found no significant difference in the HRQoL measured after sibling or unrelated human leukocyte antigen (HLA)-matched HSCT. Finally, a significant positive correlation across all the PedsQL domains was found between the scores reported by the children and those reported by their parents. In conclusion, our study shows that HSCT in pediatric patients with β-TM is associated with a good overall HRQoL profile. This information further supports physicians when counseling patients and their parents before the HSCT procedure.

Monitoring vascular endothelial growth factor-a levels during follow-up after hematopoietic stem cell transplantation in pediatric patients at a Mexican hospital: A pilot study

Vascular endothelial growth factors are proteins that participate in processes related to normal physiology, solid tumors and hematologic malignancies; however, their role in hematopoietic stem cell transplantation (HSCT) requires further investigation. To better define the role and changes in vascular endothelial growth factor-A (VEGF-A) in the context of HSCT, we conducted an observational prospective analysis of VEGF-A expression during the early period after HSCT in pediatric patients. Thirty-seven pediatric patients who underwent hematopoietic stem cell transplantation at the Federico Gómez Children's Hospital in Mexico between June 2016 and July 2018 were prospectively enrolled in this study. Ribonucleic acid was isolated from the venous blood of these patents on Days 0, +7, +14, +21, +28, and +35 after transplantation, and TaqMan reverse transcription-polymerase chain reaction was performed using specific primers and a probe for VEGF-A. The concentration of VEGF-A was determined using a complementary deoxyribonucleic acid control. Data were analyzed using one-way ANOVA and Dunnett post hoc tests. Statistical analysis was performed using SPSS version 25. There were significant differences in the concentrations of VEGF-A between Day 0 vs. Day +28 (p = 0.009 95% CI=0.02–0.24), Day 0 vs. Day +35 (p = 0.006; 95% CI=0.03–0.28) and Day 7 vs. Day + 35 (p = 0.006; 95% CI=0.03–0.24) after allogeneic HSCT. We observed significant increases in the VEGF-A concentration during the early period after stem cell transplantation in pediatric patients. Our results provide important insights that should be considered a basis for future clinical trials of pediatric HSCT, including the monitoring of VEGF-A concentrations, proteins and in vitro analysis.

The effects of correction of vitamin D deficiency in children undergoing hematopoietic stem cell transplantation

Literature data suggest that vitamin D (VD) deficiency may adversely affect many systems of the body, not only skeletal system, as believed earlier, but also central nervous system, cardiovascular system, urinary system, and immune system, which is particularly important for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Two consecutive studies of VD deficiency after allogeneic HSCT in pediatric patients showed that VD deficiency was associated with decreased overall survival. The correction of VD deficiency was also reported to be a challenge, and in some cases higher doses of VD were needed (200 IU/kg/day or more), but even with this more aggressive approach VD deficiency could persist. In this article, we present a literature review on this topic as well as our data on the management of VD deficiency and monitoring of serum 25-hydroxycholecalciferol (25-HVD) levels in 18 children undergoing allogeneic HSCT at our hospital. This study was approved by the Independent Ethics Committee of the Regional Children's Clinical Hospital (Yekaterinburg). Unfortunately, because of the small size of the patient group we were not able to obtain reliable scientific data. However, here we present our approach to the clinical management of VD deficiency, personalized dosing of VD, and safe therapeutic ranges of VD metabolites in blood. The majority of HSCT recipients in our study achieved therapeutic levels of 25-hydroxycholecalciferol. Treatment of VD deficiency in children undergoing allogeneic HSCT is a promising way to improve overall survival, but further studies are needed to develop optimal clinical strategies.

Assessment of micafungin dosage regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

The objective of this study was to evaluate the efficacy of various micafungin dosing regimens against Candida spp. in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration targets of micafungin. Current standard clinical micafungin dosing regimens of 1 and 2 mg/kg/day were appropriate for the prevention and treatment of Candida glabrata infection in pediatric patients undergoing HSCT, respectively. Moreover, the high-dose prophylactic dosage (2 mg/kg/day) and therapeutic dosage (4 mg/kg/day) should be the preferred option to optimize efficacy against Candida albicans. However, none of the simulated regimens was effective against Candida parapsilosis in pediatric HSCT patients. These PK/PD-based simulations rationalize and optimize the micafungin dosing regimens against Candida spp. in pediatric patients undergoing HSCT.

BK Polyomavirus Diversity After Hematopoietic Stem Cell Transplantation.

BK polyomavirus (BKPyV) infection is common after hematopoietic stem cell transplantation (HSCT) and is associated with the development of hemorrhagic cystitis (HC). The role that BKPyV plays in the pathogenesis of HC is not well characterized. We investigated the impact of BKPyV diversity on the development of HC using a previously established cohort of pediatric HSCT patients. There were 147 urine samples with quantifiable BKPyV at month 1 after HSCT; 137 (93.2%) were amplified using our in-house polymerase chain reaction approach and sent for next-generation sequencing. Subtype Ia was most frequent (61.3%), followed by subtype Ib1 (31.4%). The median viral load of subtype Ia samples was higher than for subtype Ib1 at month 1. Across the protein coding regions, APOBEC-induced mutations and signature patterns associated with HC were identified. This is the largest sequencing study of a single cohort of HSCT patients, providing a vast resource of sequence data for future analyses.

Efficacy of Azacitidine and Prophylactic Donor Lymphocyte Infusion after HSCT in Pediatric Patients with Acute Myelogenous Leukemia: A Retrospective Pre-Post Study

Pediatric patients with acute myeloid leukemia (AML) who undergo allogeneic hematopoietic stem cell transplantation (HSCT) continue to have high rates of relapse. In 2018, Phoenix Children's Hospital started using post-HSCT maintenance therapy in patients with AML in attempt to decrease the number of relapses after HSCT. This therapy consisted of the hypomethylating agent azacitidine (AZA; 6 cycles starting on day +60) and prophylactic donor lymphocyte infusion (DLI; 3 escalating doses beginning after day +120). We aimed to compare 2-year leukemia-free survival (LFS) post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI and historical control patients who did not receive post-HSCT therapy. This retrospective pre-post study was conducted at Phoenix Children's Hospital and included patients with AML who underwent HSCT between January 1, 2008, and May 31, 2022. We compared LFS, overall survival (OS), and immune reconstitution patterns post-HSCT between patients with AML who received post-HSCT maintenance therapy with AZA and prophylactic DLI (postintervention group) and historical control patients who did not receive this post-HSCT maintenance therapy (preintervention group). Sixty-three patients were evaluable. After excluding 7 patients who died or relapsed prior to day +60, 56 patients remained, including 39 in the preintervention group and 17 in the postintervention group. The median age at transplantation was 9.1 years in the preintervention group and 11 years in the postintervention group (P=.33). The 2-year LFS was 61.5% in the preintervention group, compared to 88.2% in the postintervention group (P=.06). The 2-year OS was 69.2% in the preintervention group and 88.2% in the postintervention group (P=.15). The rates of CD3+CD4+ T cell and CD19+ B cell recovery were faster in the preintervention group compared to the postintervention group (P = .004 and .0006, respectively). In this limited retrospective study, post-HSCT maintenance therapy using AZA and prophylactic DLI was well tolerated; however, its efficacy is yet to be fully determined.

Levofloxacin prophylaxis and parenteral nutrition have a detrimental effect on intestinal microbial networks in pediatric patients undergoing HSCT

The gut microbiome (GM) has shown to influence hematopoietic stem cell transplantation (HSCT) outcome. Evidence on levofloxacin (LVX) prophylaxis usefulness before HSCT in pediatric patients is controversial and its impact on GM is poorly characterized. Post-HSCT parenteral nutrition (PN) is oftentimes the first-line nutritional support in the neutropenic phase, despite the emerging benefits of enteral nutrition (EN). In this exploratory work, we used a global-to-local networking approach to obtain a high-resolution longitudinal characterization of the GM in 30 pediatric HSCT patients receiving PN combined with LVX prophylaxis or PN alone or EN alone. By evaluating the network topology, we found that PN, especially preceded by LVX prophylaxis, resulted in a detrimental effect over the GM, with low modularity, poor cohesion, a shift in keystone species and the emergence of modules comprising several pathobionts, such as Klebsiella spp., [Ruminococcus] gnavus, Flavonifractor plautii and Enterococcus faecium. Our pilot findings on LVX prophylaxis and PN-related disruption of GM networks should be considered in patient management, to possibly facilitate prompt recovery/maintenance of a healthy and well-wired GM. However, the impact of LVX prophylaxis and nutritional support on short- to long-term post-HSCT clinical outcomes has yet to be elucidated.

Mortality in pediatric oncology and stem cell transplant patients with bloodstream infections.

Bloodstream infections (BSI) continue to represent a significant source of morbidity for pediatric oncology patients, however less is known regarding this population's risk of death. We sought to evaluate the risk of BSI and death at a large pediatric cancer center. We retrospectively collected inpatient data from pediatric oncology and hematopoietic stem cell transplant (HSCT) patients over a 9-year period. We performed univariate and multivariable modeling to assess risk of BSI and mortality examining the following variables: demographics, underlying malignancy, history of HSCT, central line type, and febrile neutropenia (FN). During the study period, 6763 admissions from 952 patients met inclusion criteria. BSI occurred in 367 admissions (5.4%) from 231 unique individuals. Risk factors for BSI include younger age, diagnoses of hemophagocytic lymphohistiocytosis or acute myeloid leukemia, ethnicity, and history of HSCT. Mortality for those with BSI was 6.5%, compared to 0.7% without (OR 7.2, CI 4.1 - 12.7, p<0.0001). In patients with BSI, admissions with FN were associated with reduced mortality compared to admissions without FN (OR 0.21, CI 0.05 - 0.94, p=0.04). In both univariate and multivariable analysis, no other risk factor was significantly associated with mortality in patients with BSI. BSI is a significant source of mortality in pediatric oncology and HSCT patients. While demographic variables contribute to the risk of BSI, they did not influence mortality. These findings highlight the importance of BSI prevention to reduce the risk of death in pediatric oncology patients. Future studies should focus on comprehensive BSI prevention.

959: TRACHEOSTOMY IN PEDIATRIC ONCOLOGY AND HEMATOPOIETIC STEM CELL TRANSPLANT POPULATIONS

Introduction: Children with oncologic diagnoses and those who undergo hematopoietic stem cell transplantation (HSCT) have infrequent but high intensity utilization of critical care services, including need for prolonged mechanical ventilation (MV). While tracheostomy has been shown to be a safe procedure with increasing incidence in other pediatric populations, there is no overall consensus on optimal timing, patient selection, or relative contraindications. This study describes the HSCT and oncology cohorts from multiple pediatric centers who underwent tracheostomy. Methods: The Pediatric Health information System database (2009-2020) was used for a retrospective, descriptive cohort study of all patients with an oncologic diagnosis and/or SCT code and underwent tracheotomy. Results: 1,061 patients were included, 217 (20%) of whom had undergone HSCT. The annual incidence in tracheostomy did not change significantly over the study period. The majority (62%) underwent tracheostomy early (< 30 days) in the admission. Complications reported included tracheostomy site bleeding (< 1%) and infection (24%). The overall rate of MV at discharge was 26% and was significantly associated with preexisting chronic lung disease (adjusted odds ratio [OR] 2.1; 95% CI 1.19- 3.7), and acute lung disease ([OR] 1.63; 95% CI 1.12-2.35). Those who underwent the procedure late (>90 days) had a significant increase in MV at discharge (52% vs 25%, p< 0.001) and in hospital mortality (53% vs 18%, p< 0.001) compared to the early subgroup. The overall rate of mortality was 28% within the cohort and significantly associated with HSCT ([OR] 2.04; 95% CI 1.17- 3.56), diagnosis of sepsis ([OR] 2.09; 95% CI 1.36- 3.19), and requirement for renal replacement therapy ([OR] 2.86; 95% CI 1.71- 4.79). Conclusions: This is the first study describing pediatric oncology and HSCT patients who undergo tracheostomy. Despite implicit concerns for immunocompromised or thrombocytopenic status, complication rates are not disproportionate. Significantly higher need for MV at discharge and mortality, however, is seen in patients who undergo the procedure late in a hospitalization, with certain chronic conditions. and other ICU specific comorbidities. Further understanding of this vulnerable cohort, however, is needed to inform timing and patient selection.