Diagnosing and Grading of Sinusoidal Obstructive Syndrome after Hematopoietic Stem Cell Transplant of Children, Adolescent and Young Adults treated in a Pediatric Institution with Pediatric Protocols.

Sinusoidal obstructive syndrome (SOS), or veno-occlusive disease, of the liver has been recognized as a complex, life-threatening complication in the posthematopoietic stem cell transplant (HSCT) setting. The diagnostic criteria for SOS have evolved over the last several decades with a greater understanding of the underlying pathophysiology, with 2 recent diagnostic criteria introduced in 2018 (European Society of Bone Marrow Transplant [EBMT] criteria) and 2020 (Cairo criteria). We sought out to evaluate the performance characteristics in diagnosing and grading SOS in pediatric patients of the 4 different diagnostic criteria (Baltimore, Modified Seattle, EBMT, and Cairo) and severity grading systems (defined by the EBMT and Cairo criteria). Retrospective chart review of children, adolescent, and young adults who underwent conditioned autologous and allogeneic HSCT between 2017 and 2021 at a single pediatric institution. A total of 250 consecutive patients underwent at least 1 HSCT at UCSF Benioff Children's Hospital San Francisco for a total of 307 HSCT. The day 100 cumulative incidence of SOS was 12.1%, 21.1%, 28.4%, and 28.4% per the Baltimore, Modified Seattle, EBMT, and Cairo criteria, respectively (P < .001). We found that patients diagnosed with grade ≥4 SOS per the Cairo criteria were more likely to be admitted to the Pediatric Intensive Care Unit (92% versus 58%, P = .035) and intubated (85% versus 32%, P = .002) than those diagnosed with grade ≥4 per EBMT criteria. Age <3 years-old (HR 1.76, 95% [1.04 to 2.98], P = .036), an abnormal body mass index (HR 1.69, 95% [1.06 to 2.68], P = .027), and high-risk patients per our institutional guidelines (HR 1.68, 95% [1.02 to 2.76], P = .041) were significantly associated with SOS per the Cairo criteria. We demonstrate that age <3 years, abnormal body mass index, and other high-risk criteria associate strongly with subsequent SOS development. Patients with moderate to severe SOS based on Cairo severity grading criteria may correlate better with clinical course based on ICU admissions and intubations when compared to the EBMT severity grading system.

Alpha-mannosidosis: a case with novel ultrastructural and light microscopy findings.

OBJECTIVES: Alpha-mannosidosis is a rare genetic lysosomal storage condition leading to the systemic buildup of oligomannoside. Clinical presentation and associated conditions, as well as the full extent of histopathologic changes associated with this disease process, are not fully understood. CASE PRESENTATION: We present the case of an 8-year-1-month old patient with persistent anemia and who was initially diagnosed with Celiac disease before ultimately being diagnosed with alpha-mannosidosis. As part of his diagnostic work-up, duodenal and bone marrow biopsies were examined by pathology. Duodenal biopsies showed foamy plasma cells expanding the lamina propria which triggered a workup for a genetic storage disease; features suggestive of Celiac disease which resolved on gluten-free diet were also noted by pathology. Bone marrow analysis via electron microscopy showed cytoplasmic granules and inclusions in multiple immune cell lines. CONCLUSIONS: Alpha-mannosidosis can occur with Celiac disease and milder forms may only be suspected from incidental pathology findings. The ultrastructural bone marrow findings from this case, the first to be reported from human, show numerous disease-associated changes in multiple immune cell lines whose contribution to disease-associated immunodeficiency is unclear.

Oral complications in a paediatric graft versus host disease (GVHD) clinic: A retrospective study.

OBJECTIVE: The aim of this study was to investigate the oral health status among allogeneic transplant recipients who were seen in a multidisciplinary graft-versus-host disease paediatric clinic at the University of California, San Francisco (UCSF). METHODS: This was a retrospective cohort study of patients who underwent allogeneic transplants and were seen in the graft-versus-host disease paediatric clinic between January 2010 and September 2021. Demographic, medical and oral health data were recorded and analysed using descriptive statistics. RESULTS: A total of 25 patients were seen in the paediatric graft-versus-host disease clinic (68% males) with a median age of 12 years at the time of transplant were included. Among them, 12 patients (48%) were diagnosed with oral chronic GVHD, 11 (44%) with dry mouth, four (16%) with oral pseudomembranous candidiasis, one (4%) with recrudescent Herpes Simplex Virus (HSV) infection and one (4%) with mammalian target of rapamycin-inhibitor stomatitis and were managed by the oral medicine team, accordingly with medications, such as topical steroids (44%) and anti-fungal (20%). CONCLUSIONS: HSCT recipients may present with a variety of oral complications. Patients may benefit by a multi-disciplinary approach including a dental specialist as part of the cancer care team.

Prospective Validation and Refinement of a Population Pharmacokinetic Model of Fludarabine in Children and Young Adults Undergoing Hematopoietic Cell Transplantation.

Fludarabine is a nucleoside analog with antileukemic and immunosuppressive activity commonly used in allogeneic hematopoietic cell transplantation (HCT). Several fludarabine population pharmacokinetic (popPK) and pharmacodynamic models have been published enabling the movement towards precision dosing of fludarabine in pediatric HCT; however, developed models have not been validated in a prospective cohort of patients. In this multicenter pharmacokinetic study, fludarabine plasma concentrations were collected via a sparse-sampling strategy. A fludarabine popPK model was evaluated and refined using standard nonlinear mixed effects modelling techniques. The previously described fludarabine popPK model well-predicted the prospective fludarabine plasma concentrations. Individuals who received model-based dosing (MBD) of fludarabine achieved significantly more precise overall exposure of fludarabine. The fludarabine popPK model was further improved by both the inclusion of fat-free mass instead of total body weight and a maturation function on fludarabine clearance. The refined popPK model is expected to improve dosing recommendations for children younger than 2 years and patients with higher body mass index. Given the consistency of fludarabine clearance and exposure across its multiple days of administration, therapeutic drug monitoring is not likely to improve targeted exposure attainment.

A pilot trial of prophylactic defibrotide to prevent serious thrombotic microangiopathy in high-risk pediatric patients.

BACKGROUND: Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury complication of hematopoietic stem cell transplant (HSCT) leading to end-organ damage and high morbidity and mortality. Defibrotide is an anti-inflammatory and antithrombotic agent that may protect the endothelium during conditioning. PROCEDURE: We hypothesized that prophylactic use of defibrotide during HSCT conditioning and acute recovery could prevent TA-TMA. A pilot single-arm phase II trial (NCT#03384693) evaluated the safety and feasibility of administering prophylactic defibrotide to high-risk pediatric patients during HSCT and assessed if prophylactic defibrotide prevented TA-TMA compared to historic controls. Patients received defibrotide 6.25 mg/kg IV q6h the day prior to the start of conditioning through day +21. Patients were prospectively monitored for TA-TMA from admission through week 24 post transplant. Potential biomarkers of endothelial injury (suppression of tumorigenicity 2 [ST2], angiopoietin-2 [ANG-2], plasminogen activator inhibitor-1 [PAI-1], and free hemoglobin) were analyzed. RESULTS: Twenty-five patients were enrolled, 14 undergoing tandem autologous HSCT for neuroblastoma and 11 undergoing allogeneic HSCT. Defibrotide was discontinued early due to possibly related clinically significant bleeding in 12% (3/25) of patients; no other severe adverse events occurred due to the study intervention. The other 22 patients missed a median of 0.7% of doses (0%-5.2%). One patient developed nonsevere TA-TMA 12 days post HSCT. This observed TA-TMA incidence of 4% was below the historic rate of 18%-40% in a similar population of allogeneic and autologous patients. CONCLUSIONS: Our study provides evidence that defibrotide prophylaxis is feasible in pediatric patients undergoing HSCT at high risk for TA-TMA and preliminary data indicating that defibrotide may reduce the risk of TA-TMA.

Pulmonary microbiome and gene expression signatures differentiate lung function in pediatric hematopoietic cell transplant candidates.

Impaired baseline lung function is associated with mortality after pediatric allogeneic hematopoietic cell transplantation (HCT), yet limited knowledge of the molecular pathways that characterize pretransplant lung function has hindered the development of lung-targeted interventions. In this study, we quantified the association between bronchoalveolar lavage (BAL) metatranscriptomes and paired pulmonary function tests performed a median of 1 to 2 weeks before allogeneic HCT in 104 children in The Netherlands. Abnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung injury-related mortality after HCT. Depletion of commensal supraglottic taxa, such as Haemophilus, and enrichment of nasal and skin taxa, such as Staphylococcus, in the BAL microbiome were associated with worse measures of lung capacity and gas diffusion. In addition, BAL gene expression signatures of alveolar epithelial activation, epithelial-mesenchymal transition, and down-regulated immunity were associated with impaired lung capacity and diffusion, suggesting a postinjury profibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT pulmonary function tests for the outcome of post-HCT mortality. These findings suggest a potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.

Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Hematopoietic Cell Transplantation-Comorbidity Index Score Is Correlated with Treatment-Related Mortality and Overall Survival following Second Allogeneic Hematopoietic Cell Transplantation in Children.

Allogeneic hematopoietic cell transplantation (HCT) can lead to considerable complications and treatment-related mortality (TRM); therefore, a detailed assessment of risks is essential. The Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) can predict both TRM and overall survival (OS). Although the HCT-CI has been validated as a useful tool for first HCT, its potential utility for second HCT has not yet been investigated. Here we aimed to evaluate the utility of the HCT-CI score in assessing the risk of TRM and OS in the setting of a second allogeneic HCT. This was a retrospective analysis of all pediatric patients (age <21 years) who underwent a second allogeneic HCT at UCSF Benioff Children's Hospital San Francisco between 2008 and 2019. According to their HCT-CI, patients were classified as "low risk" with an HCT-CI of 0 or "intermediate-high risk" with an HCT-CI ≥1. A total of 59 patients were included in the study. Our primary endpoint was TRM, observed at 100 days, 180 days, 1 year, and last follow-up following HCT, and our secondary endpoint was OS at 1 year and at 5 years or last follow-up. We also evaluated outcomes of patients admitted to the pediatric intensive care unit based on the HCT-CI score. Seventy-six percent of patients had an HCT-CI of 0. The most frequent comorbidities were pulmonary, seen in 7 patients (12%; 95% CI, 5% to 23%), including 5 (71%) with moderate and 2 (29%) with severe comorbidities. The OS and the cumulative incidence of TRM at 1 year for the entire cohort were 81% (95% CI, 69% to 90%) and 12% (95% CI, 5% to 22%), respectively. The cumulative incidence of TRM and OS at 1 year showed a significant correlation with HCT-CI score; TRM was 4% (95% CI, 1% to 13%) for an HCT-CI of 0 versus 36% (95% CI, 13% to 60%) for an HCT-CI ≥1 (P < .001), and OS was 89% (95% CI, 75% to 99%) for an HCT-CI of 0 versus 57% (95% CI, 28% to 78%) for an HCT-CI ≥1 (P = .003). After adjusting for covariates, HCT-CI continued to be associated with both TRM (P = .004) and OS (P = .003). In addition, comparing patients with malignancies and nonmalignant disorders, disease-free-survival at last follow-up was higher in the nonmalignant disorder group and also was influenced by the HCT-CI score in each group (P = .0035). There also was a significant difference in outcomes of patients admitted to the pediatric intensive care unit; 15 patients (68%) with an HCT-CI of 0 were alive at last follow-up, compared with only two (22%) with an HCT-CI ≥1 (P = .016). HCT-CI has an impact on TRM and OS and may serve as a predictor of outcomes of second allogeneic transplantation. Although this study was conducted in a relatively small sample, it is the first to investigate the utility of the HCT-CI score in predicting outcomes after a second allogeneic HCT in pediatric recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Advances in the management of α-thalassemia major: reasons to be optimistic.

α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with ß-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.

Population Pharmacokinetic Model Development of Tacrolimus in Pediatric and Young Adult Patients Undergoing Hematopoietic Cell Transplantation.

Background: With a notably narrow therapeutic window and wide intra- and interindividual pharmacokinetic (PK) variability, initial weight-based dosing along with routine therapeutic drug monitoring of tacrolimus are employed to optimize its clinical utilization. Both supratherapeutic and subtherapeutic tacrolimus concentrations can result in poor outcomes, thus tacrolimus PK variability is particularly important to consider in the pediatric population given the differences in absorption, distribution, metabolism, and excretion among children of various sizes and at different stages of development. The primary goals of the current study were to develop a population PK (PopPK) model for tacrolimus IV continuous infusion in the pediatric and young adult hematopoietic cell transplant (HCT) population and implement the PopPK model in a clinically available Bayesian forecasting tool. Methods: A retrospective chart review was conducted of 111 pediatric and young adult patients who received IV tacrolimus by continuous infusion early in the post-transplant period during HCT from February 2016 to July 2020 at our institution. PopPK model building was performed in NONMEM. The PopPK model building process included identifying structural and random effects models that best fit the data and then identifying which patient-specific covariates (if any) further improved model fit. Results: A total of 1,648 tacrolimus plasma steady-state trough concentrations were included in the PopPK modeling process. A 2-compartment structural model best fit the data. Allometrically-scaled weight was a covariate that improved estimation of both clearance and volume of distribution. Overall, model predictions only showed moderate bias, with minor under-prediction at lower concentrations and minor over-prediction at higher predicted concentrations. The model was implemented in a Bayesian dosing tool and made available at the point-of-care. Discussion: Novel therapeutic drug monitoring strategies for tacrolimus within the pediatric and young adult HCT population are necessary to reduce toxicity and improve efficacy in clinical practice. The model developed presents clinical utility in optimizing the use of tacrolimus by enabling model-guided, individualized dosing of IV, continuous tacrolimus via a Bayesian forecasting platform.

Transplant-associated thrombotic microangiopathy in pediatric patients: pre-HSCT risk stratification and prophylaxis.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome that complicates hematopoietic stem cell transplant (HSCT). Morbidity and mortality from TA-TMA remain high, making prevention critical. We describe our retrospective single-center experience of TA-TMA after pediatric allogeneic HSCT and present a novel pre-HSCT risk-stratification system and prophylaxis regimen. From January 2012 through October 2019, 257 patients underwent 292 allogeneic HSCTs. Prospective risk stratification was introduced in December 2016. High-risk (HR) patients were treated with combination prophylaxis with eicosapentaenoic acid and N-acetylcysteine. The 1-year cumulative incidence of TA-TMA was 6.3% (95% confidence interval [CI], 3.2-9.4). Age ≥10 years, myeloablative conditioning with total body irradiation, HLA mismatch, diagnosis of severe aplastic anemia or malignancy, prior calcineurin inhibitor exposure, and recipient cytomegalovirus seropositivity were found to be pre-HSCT risk factors for development of TA-TMA. Before routine prophylaxis, TA-TMA rates were significantly different between the HR and standard-risk groups, at 28.2% (95% CI, 0-12.7) vs 3.2% (0.1-6.3), respectively (P < .001). After introduction of prophylaxis, the 1-year cumulative incidence of TA-TMA in the HR group decreased to 4.5% (95% CI, 0-13.1; P = .062, compared with the incidence before prophylaxis). Multicenter pediatric studies are needed to validate these risk criteria and to confirm the efficacy of the prophylactic regimen.

The Relationship Between Busulfan Exposure and Achievement of Sustained Donor Myeloid Chimerism in Patients with Non-Malignant Disorders.

The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell or gene product for disease correction. It is unclear whether lower busulfan exposure may be sufficient in this population to facilitate durable myeloid engraftment and limit toxicity. Given that neither the ideal level of mixed myeloid chimerism for specific non-malignant diseases nor how to condition a patient to achieve stable mixed myeloid chimerism is fully known, we sought to analyze the relationships among busulfan exposure, myeloid chimerism, and outcomes in patients with non-malignant conditions receiving busulfan as a part of combination pretransplant conditioning at our institution. This was a single-center, retrospective study including pediatric patients with a variety of non-malignant disorders who underwent allogeneic HCT at the University of California San Francisco Benioff Children's Hospital from March 2007 to June 2018. The busulfan cumulative area under the curve (cAUC) was estimated using a validated population pharmacokinetic model and nonlinear mixed effects modeling. Median busulfan cAUC for all patients was 70 mg·h/L (range, 53 to 108). All of the 29 patients with a busulfan cAUC of ≥70 mg·h/L achieved long-term disease correction with full or stable mixed (>20%) myeloid chimerism, compared to 78.5% (22/28) of patients with a cAUC of <70 mg·h/L (P = .01). Overall ksurvival was evaluated up to 3 years and was identical in patients with busulfan cAUC < 70 mg·h/L and patients with busulfan cAUC ≥70 mg·h/L (96% versus 93%; P = .92). Only three patients died, at days 65, 164 and 980 days post-HCT. Severe busulfan-related toxicities and graft-versus-host-disease (GVHD) were rare, with veno-occlusive disease occurring in four patients (7%), acute respiratory distress syndrome in three patients (5%), and GVHD in five patients (9%). These results demonstrate excellent outcomes and extremely low rates of toxicity across our entire cohort. Based on the results of this study, we recommend a busulfan exposure target of 75 mg·h/L (range, 70 to 80) in all non-malignant patients receiving allogeneic HCT to ensure optimal exposure for achievement of high-level stable myeloid chimerism.

The pulmonary metatranscriptome prior to pediatric HCT identifies post-HCT lung injury.

Lung injury after pediatric allogeneic hematopoietic cell transplantation (HCT) is a common and disastrous complication that threatens long-term survival. To develop strategies to prevent lung injury, novel tools are needed to comprehensively assess lung health in HCT candidates. Therefore, this study analyzed biospecimens from 181 pediatric HCT candidates who underwent routine pre-HCT bronchoalveolar lavage (BAL) at the University Medical Center Utrecht between 2005 and 2016. BAL fluid underwent metatranscriptomic sequencing of microbial and human RNA, and unsupervised clustering and generalized linear models were used to associate microbiome gene expression data with the development of post-HCT lung injury. Microbe-gene correlations were validated using a geographically distinct cohort of 18 pediatric HCT candidates. The cumulative incidence of post-HCT lung injury varied significantly according to 4 pre-HCT pulmonary metatranscriptome clusters, with the highest incidence observed in children with pre-HCT viral enrichment and innate immune activation, as well as in children with profound microbial depletion and concomitant natural killer/T-cell activation (P < .001). In contrast, children with pre-HCT pulmonary metatranscriptomes containing diverse oropharyngeal taxa and lacking inflammation rarely developed post-HCT lung injury. In addition, activation of epithelial-epidermal differentiation, mucus production, and cellular adhesion were associated with fatal post-HCT lung injury. In a separate validation cohort, associations among pulmonary respiratory viral load, oropharyngeal taxa, and pulmonary gene expression were recapitulated; the association with post-HCT lung injury needs to be validated in an independent cohort. This analysis suggests that assessment of the pre-HCT BAL fluid may identify high-risk pediatric HCT candidates who may benefit from pathobiology-targeted interventions.

Lower Exposure to Busulfan Allows for Stable Engraftment of Donor Hematopoietic Stem Cells in Children with Mucopolysaccharidosis Type I: A Case Report of Four Patients.

Busulfan is an alkylating agent routinely used in conditioning regimens prior to allogeneic hematopoietic cell transplantation (HCT) for various nonmalignant disorders, including inborn errors of metabolism. The combination of model-based dosing and therapeutic drug monitoring (TDM) of busulfan pharmacokinetics (PK) to a lower exposure target has the potential to reduce the regimen-related toxicity while opening marrow niches sufficient for engraftment in diseases such as mucopolysaccharidosis type I (MPS I). We present four cases of the severe form of MPS I or Hurler syndrome, demonstrating successful and stable CD14/15 donor chimerism following the prospective application of model-based dosing and TDM aimed to achieve lower busulfan exposure. All patients received a busulfan-based conditioning regimen with a median cumulative area-under-the-curve (cAUC) target of 63.7 mg h/L (range, 62.4 to 65.0) in protocol-specific combination of chemotherapeutic regimen. The donor source was unrelated umbilical cord blood for three patients and matched sibling donor bone marrow for one patient. The observed median busulfan cAUC was 66.1 mg h/L (range, 65.2 to 70.6) and was within 10% of the intended target. Stable, full donor myeloid chimerism was achieved for three patients, while one patient achieved a stable mixed chimerism (76% donor CD14/15 at 53 months) without a recurring need for enzyme replacement. The normalization of α-L-iduronidase enzyme levels followed the attainment of successful donor myeloid chimerism in all patients. Regimen-related toxicity remained low with no evidence of acute graft-versus-host disease (GVHD) grades II to IV and chronic GVHD.

Assessment of a Model-Informed Precision Dosing Platform Use in Routine Clinical Care for Personalized Busulfan Therapy in the Pediatric Hematopoietic Cell Transplantation (HCT) Population.

INTRODUCTION: Population pharmacokinetic (PK) studies demonstrate model-based dosing for busulfan that incorporates body size and age improve clinical target attainment as compared to weight-based regimens. Recently, for clinical dosing of busulfan and TDM, our institution transitioned to a cloud-based clinical decision support tool (www.insight-rx.com). The goal of this study was to assess the dose decision tool for the achievement of target exposure of busulfan in children undergoing hematopoietic cell transplantation (HCT). PATIENTS AND METHODS: Patients (N = 188) were grouped into cohorts A, B, or C based on the method for initial dose calculation and estimation of AUC: Cohort A: Initial doses were based on the conventional dosing algorithm (as outlined in the manufacturers' package insert) and non-compartmental analysis (NCA) estimation using the trapezoidal rule for estimation of AUC following TDM. Cohort B: Initial doses for busulfan were estimated by a first-generation PK model and NCA estimation of AUC following TDM. Cohort C: Initial doses were calculated by an updated, second-generation PK model available in the dose decision tool with an estimation of AUC following TDM. RESULTS: The percent of individuals achieving the exposure target at the time of first PK collection was higher in subjects receiving initial doses provided by the model-informed precision dosing platform (cohort C, 75%) versus subjects receiving initial doses based on either of the two other approaches (conventional guidelines/cohort A, 25%; previous population PK model and NCA parameter estimation, cohort B, 50%). Similarly, the percent of subjects achieving the targeted cumulative busulfan exposure (cAUC) in cohort C was 100% vs. 66% and 88% for cohort A and B, respectively. For cAUC, the variability in the spread of target attainment (%CV) was low at 4.1% for cohort C as compared to cohort A (14.8%) and cohort B (17.1%). CONCLUSION: Achievement of goal exposure early on in treatment was improved with the updated model for busulfan and the Bayesian platform. Model-informed dosing and TDM utilizing a Bayesian-based platform provides a significant advantage over conventional guidelines for the achievement of goal cAUC exposure.

Reduced Toxicity Conditioning for Nonmalignant Hematopoietic Cell Transplants.

Allogeneic hematopoietic cell transplantation (HCT) for children with nonmalignant disorders is challenged by potential drug-related toxicities and poor engraftment. This retrospective analysis expands on our single pediatric medical center experience with targeted busulfan, fludarabine, and intravenous (IV) alemtuzumab as a low-toxicity regimen to achieve sustained donor engraftment. Sixty-two patients received this regimen for their first HCT for a nonmalignant disorder between 2004 and 2018. Donors were matched sibling in 27%, 8/8 HLA allele-matched unrelated in 50%, and 7/8 HLA allele-mismatched in 23% (some of whom received additional immunoablation with thiotepa or clofarabine). Five patients experienced graft failure for a cumulative incidence of 8.4% (95% CI, 1 to 16%). In engrafted patients, the median donor chimerism in whole blood and CD3, CD14/15, and CD19 subsets at 1-year were 96%, 90%, 99%, and 99%, respectively. Only one patient received donor lymphocyte infusions (DLIs) for poor chimerism. Two patients died following disease progression despite 100% donor chimerism. The 3-year cumulative incidence of treatment-related mortality was 10% (95% CI, 2 to 17%). Overall survival and event-free-survival at 3-years were 87% (95% CI, 78 to 95%) and 80% (95% CI, 70 to 90%), respectively. The 6-month cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 7% (95% CI, 3 to 13%), while the 3-year cumulative incidence of chronic GVHD was 5% (95% CI, 0 to 11%). These results suggest that use of targeted busulfan, fludarabine and IV alemtuzumab offers a well-tolerated option for children with nonmalignant disorders to achieve sustained engraftment with a low incidence of GVHD.

The impact of total body irradiation-based regimens on outcomes in children and young adults with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Total body irradiation (TBI)-based conditioning is the standard of care in the treatment of acute lymphoblastic leukemia (ALL) that requires allogeneic hematopoietic stem cell transplantation (HSCT). However, TBI is known to be associated with an increased risk of late effects, and therefore, non-TBI regimens have also been utilized successfully. A recent study showed that patients that were next-generation sequencing-minimal residual disease (NGS-MRD) negative prior to allogeneic HSCT had a very low risk of relapse, and perhaps could avoid exposure to TBI without compromising disease control. We examined outcomes at our institution in patients that received a TBI or non-TBI regimen, as well as explored the impact of NGS-MRD status in predicting risk of relapse post transplant. PROCEDURES: This retrospective analysis included 57 children and young adults with ALL that received their first myeloablative allogeneic HSCT from 2012 to 2017 at the University of California San Francisco. Our primary endpoint was the cumulative incidence of relapse at 3 years post transplant. RESULTS: We demonstrated similar cumulative incidence of relapse for patients treated with either a TBI or non-TBI conditioning regimen, while NGS-MRD positivity prior to transplant was highly predictive of relapse. The presence of acute graft-versus-host disease was associated with decreased relapse rates, particularly among patients that received a TBI conditioning regimen and patients that were NGS-MRD positive prior to HSCT. CONCLUSIONS: Our data suggest that the decision to use either a TBI or non-TBI regimens in ALL should depend on NGS-MRD status, with conditioning regimens based on TBI reserved for patients that cannot achieve NGS-MRD negativity prior to allogeneic HSCT.