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Abstract: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment strategy for patients with inborn errors of immunities (IEIs). The objective of this study was to assess the optimal busulfan exposure before allogeneic HCT for patients with an IEI who received an IV busulfan-based conditioning regimen. Patients from 17 international centers were included. The main outcome of interest was event-free survival (EFS). Patients were categorized into 4 IEI subgroups: combined immunodeficiency (CID), severe combined immunodeficiency (SCID), neutrophil disorders, and hemophagocytic lymphohistiocytosis (HLH)-related disorders. Busulfan exposure was calculated by individual centers (area under the curve [AUC]CENTER) and re-estimated using a nonlinear mixed-effects model (NONMEM; exposure defined as AUCNONMEM). Overall, 562 patients were included: 173 (30.8%) with CID, 154 (27.4%) with SCID, 101 (18.0%) with HLH-related disorders, and 134 (23.8%) with neutrophil disorders. The median busulfan AUCNONMEM was 69.0 mg × h/L and correlated poorly with the AUCCENTER (r2 = 0.54). In patients with SCID, HLH-related, and neutrophil disorders with a busulfan AUCNONMEM of 70 to 90 mg × h/L, 2-year EFS was superior to <70 mg × h/L, and >90 mg ×h/L. Full donor chimerism increased with higher busulfan AUCNONMEM, plateauing at 90 mg × h/L. For patients with CID, the optimal AUCNONMEM for donor chimerism was found to be >70 mg × h/L. Improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUCNONMEM of 80 mg × h/L (range, 70-90). Our study stresses the importance of uniformly using a validated population pharmacokinetic model to estimate AUCNONMEM., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Access to hematopoietic stem cell transplantation (HSCT) in pediatric acute lymphoblastic leukemia (ALL) primarily depends on disease-related factors but may be influenced by social and economic determinants. We included all children aged < 15 years with newly diagnosed ALL in Canada between 2001 and 2018 using the Cancer in Young People in Canada national registry. We examined factors potentially associated with the likelihood of receiving HSCT using univariate and multivariable logistic regression models. A total of 3992 patients with newly diagnosed ALL were included. Three hundred twenty-five (8.1%) received an HSCT and formed the transplant cohort. In multivariable analysis factors independently associated with an increased odds of receiving HSCT were male sex (odds ratio [OR], 1.42; 95% confidence interval [CI], 1.05 to 1.93), initial WBC ≥ 50,000 × 10 9 /L (OR, 1.58; 95% CI, 1.09 to 2.28), mixed phenotype acute leukemia relative to B-precursor ALL (OR, 34.32; 95% CI, 16.64 to 70.79), T cell relative to B-precursor ALL (OR, 1.77; 95% CI, 1.07 to 2.91), unfavorable relative to standard cytogenetics (OR, 3.96; 95% CI, 2.56 to 6.12), and relapse before HSCT (OR, 32.77; 95%, 23.89 to 44.96). No association was found between race, neighborhood income quintile or region at diagnosis, and receipt of HSCT. Diagnosis at an HSCT treating center (OR, 1.51; 95% CI, 1.09 to 2.09) and residential distance from the ALL treating center (OR, 1.84 for ≥300 km compared with <100 km; 95% CI, 1.17 to 2.91) were associated with higher odds of receiving HSCT. In a publically funded healthcare system, children with ALL had equitable access to HSCT, which was largely governed by biologic disease-related factors. Patients diagnosed at an HSCT performing center and patients who live farthest away from their treatment center had higher odds of receiving HSCT, although the effect was small, possibly suggesting preferential referral to HSCT for some patients., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT.

Busulfan (Bu) is a key component of conditioning regimens used before hematopoietic stem cell transplantation (SCT) in children. Different predictive methods have been used to calculate the first dose of Bu. To evaluate the necessity of further improvements, we retrospectively analyzed the currently available weight- and age-based guidelines to calculate the first doses in 101 children who underwent allogenic SCT in CHU Sainte-Justine, Montreal, after an intravenous Bu-containing conditioning regimen according to genetic and clinical factors. The measured areas under the curve (AUCs) were within target (900 to 1500 µM/min) in 38.7% of patients after the administration of the first dose calculated based on age and weight, as locally recommended. GSTA1 diplotypes linked to poor Bu metabolism (G3) and fludarabine-containing regimens were the only factors associated with AUC within target (OR, 4.7 [95% CI, 1.1 to 19.8, P = .04]; and OR, 9.9 [95% CI, 1.6 to 61.7, P = .01], respectively). From the 11 methods selected for dose calculation, the percentage of AUCs within the target varied between 16% and 74%. In some models G3 was associated with AUCs within the therapeutic and the toxic range, whereas rapid metabolizers (G1) were correlated with subtherapeutic AUCs when different methods were used. These associations were confirmed by clearance-prediction analysis, in which GSTA1 diplotypes consistently influenced the prediction errors of the methods. These findings suggest that these factors should be considered in Bu dose prediction in addition to the anthropometric data from patients. Furthermore, our data indicated that GSTA1 diplotypes was a factor that should be included in future population pharmacokinetic models, including similar conditioning regiments, to improve the prediction of Bu exposure after its initial dose., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared with other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GVHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (<18 years) with ALL in first complete remission (CR1; n = 257, 40%) or second complete remission (CR2; n = 383, 60%) who received myeloablative conditioning followed by a single-unit UCBT from 2000 to 2012. Most received antithymocyte globulin (88%) or total body irradiation (TBI; 69%), and cord blood grafts were primarily mismatched at 1 (50%) or 2 + (34%) HLA loci. Considering patients in CR1, the rates of 5-year overall survival (OS), leukemia-free survival (LFS), and relapse were 59%, 52%, and 23%, respectively. In multivariate analysis (MVA), acute GVHD (grades II to IV) and TBI protected against relapse. In patients in CR2, rates of 5-year OS, LFS, and the cumulative incidence of relapse were 46%, 44%, and 28%, respectively. In MVA, longer duration from diagnosis to UCBT (≥30 months) and TBI were associated with decreased relapse risk. Importantly, receiving a fully HLA matched graft was a strong risk factor for increased relapse in MVA. An exploratory analysis of all 640 patients supported the important association between the presence of acute GVHD and less relapse but also demonstrated an increased risk of nonrelapse mortality. In conclusion, the impact of GVHD as a graft-versus-leukemia marker is evident in pediatric ALL after UCBT. Strategies that promote graft-versus-leukemia while harnessing GVHD should be further investigated., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT., Methods: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUC NONMEM ), non-compartmental analysis (AUC from 0 to infinity [AUC 0-∞ ] and to the next dose [AUC 0-τ ]), and by individual centres using various approaches (AUC centre ). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses., Findings: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUC NONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC 0-∞ (r 2 =0·74), but the latter correlated poorly with AUC centre (r 2 =0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37)., Interpretation: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications., Funding: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Previous studies have shown that maintaining high hemoglobin levels in patients after chemotherapy reduced the length of neutropenia. Thus, we undertook a randomized, controlled, clinical trial in children undergoing allogeneic bone marrow transplantation after receiving a myeloablative conditioning regimen to compare 2 hemoglobin thresholds as triggers for red blood cell transfusion: 120 g/L in the experimental arm and 70 g/L in the control arm. The Data and Safety Monitoring Board closed the study after enrollment of the sixth patient because 3 patients in the experimental arm contracted veno-occlusive disease, but none in the control arm did (P = .05). Ascites was present in all 3 patients, pleura effusion in 2, and portal vein thrombosis in 2. One patient experienced hepatic failure and required treatment with the molecular adsorbent recycling system. Another patient required hemodialysis for renal failure. No major imbalance between groups was seen with regard to risk factors for veno-occlusive disease. Therefore, maintaining the hemoglobin at higher levels should be avoided after hematopoietic stem cell transplantation., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to evaluate the effect of salivary stimulation therapies on the salivary flow, oral mucositis, and salivary cytokine levels in patients receiving allogeneic hematopoietic stem cell transplantation., Study Design: Thirty-five eligible patients were randomized into 4 groups: control, mechanical sialogogue, transcutaneous electrical nerve stimulation (TENS) sialogogue, and combined mechanical/electrical sialogogue. Saliva was collected from patients before transplantation and at days 3, 7, and 14 after transplantation. The volume was measured and salivary cytokines were assessed using enzyme-linked immunosorbent assay., Results: By day 14, resting and stimulated salivary flow levels were diminished. Resting salivary flow rates decreased the most in the control and mechanical groups. In contrast, TENS alone or in combination with mechanical stimulatory therapy benefited the patients. TENS-treated patients showed increase in resting salivary flow. Also, the groups treated with TENS had fewer patients affected by grades 3 and 4 mucositis, and less mucositis was associated with better patient survival (P = .027)., Conclusions: TENS-associated salivary stimulation therapies minimized the reduction of salivary flow and prevented severe chemotherapy-induced oral mucositis., (Copyright © 2012 Elsevier Inc. All rights reserved.)