Adrenocortical Function in Children With Brain Tumors and Pediatric Hematopoietic Cell Transplantation Recipients.

Adrenocortical insufficiency (AI) is a clinical condition defined by deficient production of glucocorticoids that can result in life-threatening complications. We examined the prevalence of AI in children with brain tumors and those undergoing hematopoietic cell transplantation. Adrenocorticotropic hormone stimulation (stim) testing was used for the assessment of adrenocortical function. On the basis of 155 stim tests in 117 patients, AI was diagnosed in 27.4% of patients with brain tumors and in 21% of hematopoietic cell transplantation recipients. A number of risk factors associated with AI were identified. Adrenocorticotropic hormone stim testing led to a definitive diagnosis of AI or recovery of adrenal function and unambiguous medical management.

Preventable iatrogenic cause of foot-drop in knee injuries with literature review.

PURPOSE: Common peroneal nerve palsy is quite disabling and every effort should be made to prevent its injury during the treatment. METHODS: We retrospectively reviewed the prospectively collected data of 7 cases of tibial plateau fractures in association with proximal fibula fracture from January 2019 to September 2019 who presented to emergency room of our hospital. RESULTS: In addition to fibular neck fracture, the first case had type 6 tibial plateau displaced fracture and the second case had displaced acetabular fracture with instability of knee with tibial tuberosity avulsion. common peroneal nerve palsy developed following application of distal tibial skeletal traction in both the cases. Other 6 such cases remained neurologically intact as traction was not applied to them. CONCLUSION: Such iatrogenic complication could have been prevented if the injury pattern of "concomitant medial and lateral columns" of the proximal leg is kept in mind by the treating surgeon before applying skeletal traction.

A multicenter report on the safety and efficacy of plerixafor based stem cell mobilization in children with malignant disorders.

BACKGROUND: Pleraxifor for peripheral blood stem cell (PBSC) mobilization in children with malignancies is often given following failure of standard mobilization (SM) rather than as a primary mobilizing agent. STUDY DESIGN AND METHODS: In this retrospective multicenter study, we report the safety of plerixafor-based PBSC mobilization in children with malignancies and compare outcomes between patients who received plerixafor upfront with SM (Group A) with those who received plerixafor following failure of SM (Group B). In the latter pleraxifor was given either following a low peripheral blood (PB) CD34 (<20 cells/cu.mm) (Group B1) or as a second collection process due to an unsuccessful yield (CD34 + < 2 × 106 /kg) (Group B2) following failed SM and first apheresis attempts. RESULTS: The study cohort (n = 47) with a median age of 8 (range 0.6-21) year, comprised 19 (40%) Group A and 28 (60%) Group B patients (B1 = 12 and B2 = 16). Pleraxifor mobilization was successful in 87.2% of patients, similar between Groups A and B (84.2% vs 89.2%) and resulted in a median 4-fold increase in PB CD34. Median number of apheresis attempts was 2 in Groups A and B1 but 4 in Group B2. In Group B2, median total CD34+ yield post-plerixafor was 9-fold higher than after SM (P = .0013). Mild to moderate transient adverse events affected 8.5% of patients. Among patients who proceeded to autologous transplant (n = 39), all but one engrafted. CONCLUSION: Plerixafor-based PBSC collection was safe and effective in our cohort and supports consideration as a primary mobilizing agent in children with malignancies.

Decreased motion with normal strength after Latarjet procedure has minimal impact on return to activity.

PURPOSE: The Latarjet procedure can affect the range of motion (ROM) and strength of the shoulder, which determine the time to return to the preinjury level of activity. This study prospectively assessed whether the Latarjet procedure leads to a decrease in range of motion and muscle strength, affecting the time to return to the previous level of activity. METHODS: Fifty-one consecutive patients who underwent the Latarjet procedure for recurrent dislocation of the shoulder were included prospectively. The ROM, strength, Walch-Duplay score, and Rowe score were measured every 3 months for 1 year and then every 6 months for 2 years. Radiological assessments were performed to confirm the graft location, union, and the humeral head position in abduction and external rotation (ER). RESULTS: Out of 51 patients, 49 completed all follow-ups. The median age was 27 years (17-45 years), and the dominant side was involved in 36 patients. The median number of dislocations was 11 (5-50). Twelve patients were sleep dislocators. There was a significant loss (p < 0.0001) of abduction, forward flexion (FF), ER, and internal rotation (IR) in the affected shoulder compared to the contralateral shoulder. Recovery plateaued at 12 months. There was near complete recovery of muscle strength after the Latarjet procedure, and the difference between the affected and contralateral shoulders was not significant (n.s.). The modified Rowe score was excellent in 44 (90%) patients, and the Walch-Duplay score was excellent in 43 patients (88%) at 24 months. Suboptimal results were associated with non-compliance with rehabilitation in two (4%) patients and neglected unreduced dislocation in one (2%) patient. The coracoid graft position was below the equator in 44 patients (90%). Forty-six patients (94%) could return to the previous level of activity. CONCLUSION: The Latarjet procedure results in a restricted ROM of the shoulder, but there is no loss of muscle strength. LEVEL OF EVIDENCE: III.

Giant Cell Tumor of the Ring Finger Distal Phalanx.

Giant cell tumor (GCT) is a benign but locally aggressive neoplasm generally located in the epiphysis and metaphysis of the long bones. Its occurrence in the bones of the hand is rare. Giant cell tumors occurring in the hand account for only 2% of all the GCTs reported. The epimetaphyseal region of short long bones is a common site of GCTs in the hand; however, a phalangeal GCT originating in the distal phalanx is extremely rare. We present the clinical, radiological and histopathological findings of a case of GCT of the distal phalanx of the left ring finger presenting with a fungating mass and treated with en bloc resection by disarticulation of the distal interphalangeal joint.

Anemia in Children With Inflammatory Bowel Disease: A Position Paper by the IBD Committee of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition.

Anemia is one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD). It can be asymptomatic or associated with nonspecific symptoms, such as irritability, headaches, fatigue, dizziness, and anorexia. In IBD patients, the etiology of anemia is often multifactorial. Various causes include iron deficiency, anemia of inflammation and chronic disease, vitamin deficiencies, hemolysis, or myelosuppressive effect of drugs. Anemia and iron deficiency in these patients may be underestimated because of their insidious onset, lack of standardized screening practices, and possibly underappreciation that treatment of anemia is also required when treating IBD. Practitioners may hesitate to use oral preparations because of their intolerance whereas intravenous preparations are underutilized because of fear of adverse events, availability, and cost. Several publications in recent years have documented the safety and comparative efficacy of various intravenous preparations. This article reviews management of anemia in children with IBD, including diagnosis, etiopathogenesis, evaluation of a patient, protocol to screen and monitor patients for early detection and response to therapy, treatment including parenteral iron therapy, and newer approaches in management of anemia of chronic disease. This report has been compiled by a group of pediatric gastroenterologists serving on the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) IBD committee, in collaboration with a pediatric hematologist, pharmacist, and a registered dietician who specializes in pediatric IBD (IBD Anemia Working Group), after an extensive review of the current literature. The purpose of this review is to raise awareness of under-diagnosis of anemia in children with IBD and make recommendations for screening, testing, and treatment in this population.

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.

Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Treatment of pediatric plasma cell myeloma type post-transplant lymphoproliferative disorder with modern risk-directed therapy.

Post-transplant lymphoproliferative disorder (PTLD) related plasma cell neoplasms are rare in pediatric patients. We report a pediatric liver transplant recipient with plasma cell myeloma type PTLD. Cytogenetics included 1q duplication, associated with poor prognosis in adult multiple myeloma, and t(8;14). High-risk cytogenetics has not been reported in pediatric plasma cell myeloma type PTLD. The patient was treated with bortezomib, dexamethasone, and lenalidomide with subsequent autologous stem cell transplant. He achieved a 6-year remission, demonstrating tolerance to and efficacy of this modern myeloma regimen in a pediatric patient. Unfortunately, he subsequently died from complications of repeat liver transplant.

Tandem thiotepa with autologous hematopoietic cell rescue in patients with recurrent, refractory, or poor prognosis solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE: Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS: Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS: Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.

Outcome of children with rhinovirus detection prior to allogeneic hematopoietic cell transplant.

Rhinoviruses are commonly detected in symptomatic and asymptomatic children prior to HCT. Unlike pre-HCT detection of other respiratory viruses, it is not known whether RV detection, with or without clinical symptoms, is associated with worse outcomes in children post-HCT. In a retrospective study of children undergoing allogeneic HCT from January 2009 to February 2015, 91 children underwent allogeneic HCT, and 62 children had RPP testing within 30 days pre-HCT. Fifty-six (90%) children had either no pathogen (n = 34, 55%) or single RV detection (n = 22, 35%), which was the most common pathogen identified. Compared with virus negative children, children with pre-HCT RV detection were not more likely to require ventilated support and did not have longer length of stay, higher mortality, or less days alive and out of the hospital within the first 100 days post-HCT. In a secondary analysis of all 56 patients with RPP testing and no pathogen or RV alone detected, the seven children with LRTI had less days alive and out of the hospital within the first 100 days post-HCT compared with the 49 children who were either asymptomatic or had URTI (10 vs 60 days, P = 0.002). In a bootstrapped regression model, presence of LRTI, not RV detection, was significantly associated with decreased days alive and out of the hospital within the first 100 days post-HCT. Thus, pre-HCT detection of RV, without associated LRTI, does not always warrant HCT delay.

Forced deflation pulmonary function test: a novel method to evaluate lung function in infants and young children.

We describe the safety and feasibility of a forced deflation pulmonary function test (dPFT) in infants and young children. Fifty-two dPFT studies were performed in 26 patients (median age, 1.4 years). Forced vital capacity (FVC) and forced expiratory flow (FEF75 ) were normal in all except one case, but respiratory system compliance (Crs) was reduced in 24% patients. There were no significant differences in pre-blood and marrow transplantation FVC, FEF75 , and Crs between those patients who did and those who did not have posttransplant pulmonary complications. A larger study is needed to determine the prevalence and significance of PFT abnormalities in this age group.

A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients.

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 µg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 µg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 µg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 µg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.

The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial.

Sirolimus has activity against acute lymphoblastic leukemia (ALL) in xenograft models and efficacy in preventing acute graft-versus-host disease (aGVHD). We tested whether addition of sirolimus to GVHD prophylaxis of children with ALL would decrease aGVHD and relapse. Patients were randomized to tacrolimus/methotrexate (standard) or tacrolimus/methotrexate/sirolimus (experimental). The study met futility rules for survival after enrolling 146 of 259 patients. Rate of Grade 2-4 aGVHD was 31% vs 18% (standard vs experimental, P = .04), however, grade 3-4 aGVHD was not different (13% vs 10%, P = .28). Rates of veno-occlusive disease (VOD) and thrombotic microangiopathy (TMA) were lower in the nonsirolimus arm (9% vs 21% VOD, P = .05; 1% vs 10% TMA, P = .06). At 2 years, event free survival (EFS) and overall survival (OS) were 56% vs 46%, and 65% vs 55% (standard vs experimental), respectively (P = .28 and .23). Multivariate analysis showed increased relapse risk in children with ≥0.1% minimal residual disease (MRD) pretransplant, and decreased risk in patients with grades 1-3 aGVHD (P = .04). Grades 1-3 aGVHD were associated with improved EFS (P = .02), whereas grade 4 aGVHD and extramedullary disease at diagnosis led to inferior OS. Although addition of sirolimus decreased aGVHD, survival was not improved. This study is registered with ClinicalTrials.gov as #NCT00382109.

TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children's Oncology Group Study (ASCT0521).

Idiopathic pneumonia syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were < 18 years old, within 120 days after transplantation, and with radiographic evidence of a diffuse pneumonitis. All patients underwent a pretherapy broncho-alveolor lavage (BAL) to establish the diagnosis of IPS. Systemic corticosteroids (2.0 mg/kg/day) plus etanercept (.4 mg/kg twice weekly × 8 doses) were administered. Response was defined as survival and discontinuation of supplemental oxygen support by day 28 of study. Thirty-nine patients (median age, 11 years; range, 1 to 17) were enrolled, with 11 of 39 patients nonevaluable because of identification of pathogens from their pretherapy BAL. In the remaining 28 patients, the median fraction of inspired oxygen at study entry was 45%, with 17 of 28 requiring mechanical ventilation. Complete responses were seen in 20 (71%) patients, with a median time to response of 10 days (range, 1 to 24). Response rates were higher for patients not requiring mechanical ventilation at study entry (100% versus 53%, P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.

Sirolimus-induced interstitial lung disease following pediatric stem cell transplantation.

Sirolimus-induced ILD is a known but rare complication in adults who have undergone SOT. However, little is known about this adverse effect in children. Diagnosis of sirolimus-induced ILD can be challenging, especially in patients who have difficulty participating in lung function testing. We present a case of presumed sirolimus-induced ILD in a pediatric stem cell transplant patient who developed polycythemia and hypoxemia. To our knowledge, no other cases of sirolimus-induced pulmonary toxicity in children after HCT have been reported.

Grading acute graft-versus-host disease: time to reconsider.

Acute graft-versus-host disease (GVHD) is a common and serious complication of allogeneic blood and marrow transplantation. Acute GVHD is commonly graded according to modified Glucksberg criteria. There is considerable within-grade heterogeneity with different patterns of skin, liver, or gut involvement. In this commentary, we provide an analytical review of ambiguities in acute GVHD severity scoring and offer specific proposals meant to generate discussion in the BMT community for adoption, refinement, and where appropriate, validation studies.

Phototoxic dermatoses in pediatric BMT patients receiving voriconazole.

We investigated the incidence of phototoxic skin reactions in pediatric BMT recipients treated with voriconazole. Nine out of 40 patients (22.5%), all Caucasian, developed skin lesions in sun-exposed distributions. Dermatologic findings included sunburn-like erythema, pseudo-porphyria, linear papulovesicular lesions, severe erosive cheilitis, dermatoheliosis and lentigines. Patients were treated with sun avoidance, high-potency sunscreens, and topical steroids with significant improvement in all cases. Prolonged voriconazole use requires close monitoring for chronic skin toxicities. Long-term risks including the risk of skin cancer need to be investigated.

Valproate, risperidone, and paliperidone: A case of valproate-induced hyperammonemic encephalopathy.

Hyperammonemia is a well-known adverse effect of valproate that can progress to a potentially fatal condition known as valproate-induced hyperammonemic encephalopathy (VHE). VHE is more common when valproate is used in combination therapy with other antiepileptic medications. A growing number of case reports have pointed to a possible interaction with the antipsychotic risperidone leading to an increased risk of VHE. We present a case of VHE in which a 20-year-old male patient with bipolar affective disorder developed VHE when on concomitant valproate, risperidone, and paliperidone palmitate. On the seventh day of treatment with oral risperidone, oral divalproex sodium was added. Intramuscular paliperidone palmitate was initiated on day 13, and oral risperidone was discontinued after the second loading dose on day 16. The following day, the patient displayed worsening psychomotor retardation, swaying gait, drowsiness, and vomiting. The patient was found to have hyperammonemia and transferred to the emergency department for treatment of suspected VHE.

Sirolimus pharmacokinetics in early postmyeloablative pediatric blood and marrow transplantation.

This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R(2) = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.