Asparaginase (ASP) is a critical treatment component of acute lymphoblastic leukemia (ALL), yet associated with potentially severe complications. We assessed whether serum asparaginase activity (SAA) is associated with development of venous thrombosis, acute pancreatitis, bleeding and/or hypersensitivity events. We included 84 patients (median age 6.4 years, 66% male) with newly diagnosed ALL/lymphoblastic lymphoma who received ≥1 dose of ASP and with ≥1 available SAA level(s). Median peak and trough SAA levels were 2.36 IU/mL and 0.77 IU/mL. High peak SAA levels were associated with a trend toward increased venous thrombosis risk (HR: 1.51, p = 0.058). No association between SAA peak and/or trough levels and acute pancreatitis nor hypersensitivity was observed. SAA do not appear to predict the risk of ASP-related toxicities. Our data do not support individualized dosing to prevent toxicities such as thrombosis or pancreatitis. Larger prospective studies are required to help identify children at high risk of ASP-related toxicities.

BACKGROUND:Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). While HLA compatibility is a key determinant, increasing evidence suggests that non-HLA immune gene polymorphisms, particularly those in cytokine genes, contribute to GVHD risk. OBJECTIVE:This study seeks to validate in a pediatric population, cytokine-related single nucleotide polymorphisms (SNPs) associated with acute GVHD (aGVHD) and analyze them in combination with the previously identified HLA risk alleles. METHODS:Pediatric HSCT recipients were recruited from the CHU Sainte-Justine biobank and a prior European Society for Blood and Marrow Transplantation (EBMT) multicenter study. Twenty-five SNPs in 12 cytokine genes were selected based on published associations with aGVHD. Genotypes were obtained for discovery (n = 87) and replication (n = 154) cohorts and association analyses were conducted in each cohort and in the combined dataset. RESULTS:Two SNPs, IL1B rs1143627 and IL17A rs8193036, were significantly associated with increased risk of aGVHD II-IV (p = 0.019 and p < 0.001, respectively). These associations were strongest in HLA-matched unrelated-donor-recipient pairs for IL1B rs1143627 (p = 0.015) and in all HLA-matched pairs for IL17A rs8193036 (p = 0.004). Notably, carriers of one or both risk alleles combined with HLA-B*15:01 had a markedly elevated risk (HR: 2.14 CI:1.41-3.25, p = 6 ×10⁻⁶). CONCLUSION:These findings highlight the relevance of non-HLA genetic variants in aGVHD pathogenesis. Incorporating cytokine SNP profiles, especially IL1B rs1143627 and IL17A rs8193036, alongside HLA typing may improve donor selection and guide individualized aGVHD prophylaxis.

Over the past decades, survival outcomes for childhood acute lymphoblastic leukaemia (ALL) have significantly improved. However, adverse drug reactions (ADRs), particularly those related to 6-mercaptopurine (6-MP), remain a major concern. Myelosuppression associated with 6-MP administration can lead to infections or treatment interruptions. Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. This study investigates genetic variants influencing 6-MP response in children with ALL. Seventeen tagSNPs in key enzymes involved in 6-MP metabolism, GMPS, IMPDH1, XO, and ITPA, were analysed. Genetic data were correlated with clinical and pharmacological parameters in 280 ALL patients treated under DFCI ALL 05-001, 11-001, and 16-001 protocols at CHU Sainte-Justine. Outcomes included 6-MP dose intensity, 6-TGN and 6-MMP metabolite levels, and hematologic and hepatic toxicities during consolidation II and maintenance phases. Results revealed that the rs6710015 variant allele in the XO gene is linked to lower 6-TGN and higher 6-MMP levels, while rs1884725 variant allele in the same gene is correlated with reduced neutropenia and higher cumulative 6-MP doses. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients.

Background: Therapeutic drug monitoring (TDM) is crucial in optimizing the outcomes of hematopoietic stem cell transplantation by guiding busulfan (Bu) dosing. Limited sampling strategies show promise for efficiently adjusting drug doses. However, comprehensive assessments and optimization of sampling schedules for Bu TDM in pediatric patients are limited. We aimed to establish optimal sampling designs for model-informed precision dosing (MIPD) of once-daily (q24h) and 4-times-daily (q6h) Bu administration in pediatric patients. Methods: Simulated data sets were used to evaluate the population pharmacokinetic model-based Bayesian estimation of the area under the concentration–time curve (AUC) for different limited sampling strategy designs. The evaluation was based on the mean prediction error for accuracy and root mean square error for precision. These findings were validated using patient-observed data. In addition, the MIPD protocol was implemented in the Tucuxi software, and its performance was assessed. Results: Our Bayesian estimation approach allowed for flexible sampling times while maintaining mean prediction error within ±5% and root mean square error below 10%. Accurate and precise AUC0–24h and cumulative AUC estimations were obtained using 2-sample and single-sample schedules for q6h and q24h dosing, respectively. TDM on 2 separate days was necessary to accurately estimate cumulative exposure, especially in patients receiving q6h Bu. Validation with observed patient data confirmed the precision of the proposed limited sampling scenarios. Implementing the MIPD protocol in Tucuxi software yielded reliable AUC estimations. Conclusions: Our study successfully established precise limited sampling protocols for MIPD of Bu in pediatric patients. Our findings underscore the importance of TDM on at least 2 occasions to accurately achieve desired Bu exposures. The developed MIPD protocol and its implementation in Tucuxi software provide a valuable tool for routine TDM in pediatric hematopoietic stem cell transplantation.

Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at −52 or −69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at −52 (rs3957356) and −69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.

BACKGROUND:Genotype-phenotype analyses of rare diseases often suffer from a lack of power, due to small sample size, which makes identifying significant associations difficult. Sinusoidal obstruction syndrome (SOS) of the liver is a rare but life-threatening complication of hematopoietic stem cell transplantation (HSCT). The alkylating agent busulfan is commonly used in HSCT and known to trigger SOS. We developed a novel pipeline to identify genetic determinants in rare diseases by combining in vitro information with clinical whole-exome sequencing (WES) data and applied it in SOS patients and controls.METHODS:First, we analysed differential gene expression in six lymphoblastoid cell lines (LCLs) before and after incubation with busulfan. Second, we used WES data from 87 HSCT patients and estimated the association with SOS at the SNP and the gene levels. We then combined the results of the expression and the association analyses into an association statistic at the gene level. We used an over-representation analysis to functionally characterize the genes that were associated with a significant combined test statistic.RESULTS:After treatment of LCLs with busulfan, 1708 genes were significantly up-, and 1385 down-regulated. The combination of the expression experiment and the association analysis of WES data into a single test statistic revealed 35 genes associated with the outcome. These genes are involved in various biological functions and processes, such as "Cell growth and death", "Signalling molecules and interaction", "Cancer", and "Infectious disease".CONCLUSIONS:This novel data analysis pipeline integrates two independent omics datasets and increases statistical power for identifying genotype-phenotype associations. The analysis of the transcriptomics profile of cell lines treated with busulfan and WES data from HSCT patients allowed us to identify potential genetic contributors to SOS. Our pipeline could be useful for identifying genetic contributors to other rare diseases where limited power renders genome-wide analyses unpromising.TRIAL REGISTRATION:For the clinical dataset: Clinicaltrials.gov: NCT01257854. https://clinicaltrials.gov/ct2/history/NCT01257854.

Introduction Childhood cancer and its treatment may lead to various health complications. Related impairment in quality of life, excess in deaths and accumulated healthcare costs are relevant. Genetic variations are suggested to contribute to the wide inter-individual variability of complications but have been used only rarely to risk-stratify treatment and follow-up care. This study aims to identify germline genetic variants associated with acute and late complications of childhood cancer. Methods and analysis The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. Eligible are patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Paediatric Biobank for Research in Haematology and Oncology, Geneva, host of the national Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS). GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study. Clinical outcome data consists of organ function testing, health conditions diagnosed by physicians, second primary neoplasms and self-reported information from participants. Germline genetic samples and sequencing data are collected in BISKIDS. We will perform association analyses using primarily whole-exome or whole-genome sequencing to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. Discussion GECCOS will improve knowledge of germline genetic variants associated with childhood cancer-associated health conditions and help to further individualise cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects. Ethics and dissemination The Geneva Cantonal Commission for Research Ethics has approved the GECCOS study. Research findings will be disseminated through national and international conferences, publications in peer-reviewed journals and in lay language online. Trial registration number NCT04702321.

Background Childhood cancer and its treatment may lead to many acute and chronic health complications. Related impairment in quality of life, excess in deaths, and accumulated health care costs are relevant. There is a wide inter-individual variability in the type and severity of health complications. Genetic variations are suggested to contribute to individual susceptibility. So far, only few genetic variants have been used to risk-stratify treatment and follow-up care. This study platform aims to identify germline genetic variants associated with acute and late complications of childhood cancer. Methods The Genetic Risks for Childhood Cancer Complications Switzerland (GECCOS) study is a nationwide cohort study. It includes patients and survivors who were diagnosed with childhood cancers or Langerhans cell histiocytosis before age 21 years, were registered in the Swiss Childhood Cancer Registry (SCCR) since 1976 and have consented to the Pediatric Biobank for Research in Hematology and Oncology (BaHOP), Geneva, host of the Germline DNA Biobank Switzerland for Childhood Cancer and Blood Disorders (BISKIDS). BISKIDS is a national biobank for the collection of germline DNA in childhood cancer patients and survivors. GECCOS uses demographic and clinical data from the SCCR and the associated Swiss Childhood Cancer Survivor Study (SCCSS), which contains health-related data of survivors. Phenotypic data consist of objective measurements, health conditions diagnosed by physicians, second primary neoplasms, self-reported and health-related information from participants. Germline genetic samples and sequencing data have been collected in BISKIDS. We will perform gene panel sequencing, whole-exome sequencing, or whole-genome sequencing depending on the research questions. We will perform association analyses to identify genetic variants associated with specified health conditions. We will use clustering and machine-learning techniques and assess multiple health conditions in different models. Discussion GECCOS will serve as an overarching platform to enable genotype-phenotype association analyses on complications associated with childhood cancer and its treatments. Knowledge of germline genetic variants associated with childhood cancer-associated health conditions will help to further individualize cancer treatment and follow-up care, potentially resulting in improved efficacy and reduced side effects, for personalized cancer care. Trial registration Clinicaltrials.gov: NCT04702321

In busulfan-based conditioning regimen for hematopoietic stem cell transplantation in children, accurate a priori determination of the first dose is important because of its narrow therapeutic window. Sickle cell disease (SCD) influences pharmacokinetics of the commonly used drugs by affecting organs responsible for drug metabolism and elimination. This pharmacokinetics study assesses the influence of SCD on the metabolic pathway of busulfan that is mainly metabolized in the liver. In this retrospective cross-sectional case-control study, 16 patients with SCD were matched to 50 patients without SCD on known busulfan clearance's covariates (glutathione-S-transferase alpha1 polymorphisms, age, weight). Clearance of the first dose of busulfan was not significantly different independently of genetic or anthropometric factors in patients with or without SCD.