Model-Informed Precision Dosing of Intravenous Busulfan in Thai Pediatrics Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Conditioning bifunctional agent, busulfan, is commonly used on children before hematopoietic stem cell transplantation. Currently, at the Ramathibodi hospital, Bangkok, Thailand, initial dosing is calculated according to age and body surface area, and 7 samples per day are used for therapeutic drug monitoring (TDM). This study aimed to identify the best strategies for individual dosages a priori from patient characteristics and a posteriori based on TDM. METHODS: The pharmacokinetic data set consisted of 2018 plasma concentrations measured in 135 Thai (n = 135) pediatric patients (median age = 8 years) and were analyzed using a population approach. RESULTS: Body weight, presence of malignant disease, and genetic polymorphism of Glutathione S-transferase Alpha-1 (GSTA1) were predictors of clearance. The optimum sampling times for TDM concentration measurements were 0.25, 2, and 5 hours after a 3-hour infusion. This was sufficient to obtain a Bayesian estimate of clearance a posteriori. Simulations showed the poor performance of a priori formula-based dose calculations with 90% of patients demonstrating a 69%-151% exposure interval around the target. This interval shrank to 85%-124% if TDM was carried out only at day 1 and to 90%-116% with TDM at days 1 and 3. CONCLUSIONS: This comprehensive study reinforces the interest of TDM in managing interindividual variability in busulfan exposure. Therapeutic drug monitoring can reliably be implemented from 3 samples using the Bayesian approach, preferably over 2 days. If using the latter is not possible, the formulas developed herein could present an alternative in Thai patients.

Immune reconstitution in children after haploidentical haematopoietic stem cell transplantation.

INTRODUCTION: Immune reconstitution (IR) kinetics of paediatric patients underwent haploidentical haematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCy) have not been extensively studied. We compared IR patterns of children receiving HSCT from haploidentical (n = 92) and HLA-matched donors (n = 36), and analysed risk factors for viral infection in these patients. METHODS: We prospectively measured lymphocyte subset numbers before HSCT and at 1, 3, 6 and 12 months after HSCT. Blood cytomegalovirus (CMV), Epstein-Barr virus, adenovirus, BK virus (BKV) and urine adenovirus and BKV viral loads were measured at designated time points. RESULTS: The median numbers of total T and T helper cells at 1 month were significantly lower in the haploidentical group compared with the HLA-matched group. Haploidentical HSCT recipients had significantly lower median numbers of several T cell subsets and B cells for 1 year after HSCT. The median NK cell count of the haploidentical group was lower at 1 month. BKV haemorrhagic cystitis, blood CMV and urine adenovirus reactivation were more frequently found in the haploidentical group. Post-haploidentical HSCT patients receiving anti-T lymphocyte globulin (ATG) had significantly lower median numbers of total T cells (at 1 month) and T helper cells (at 6 and 12 months) and higher rate of blood BKV reactivation compared with those without ATG. CONCLUSION: Paediatric patients who undergo haploidentical HSCT with PTCy are likely to have delayed IR and an increased risk of viral reactivation/infection compared with HLA-matched HSCT. The addition of ATG to PTCy delayed T cell recovery and increased risk of BKV reactivation.

Assessing the role of mentors in mitigating burnout and enhancing professional development in medical education.

Objectives: To assess the correlation between mentor behaviours and medical student burnout and their professional development within medical education. Methods: A cross-sectional study using convenience sampling was conducted among third-, fifth-, and sixth-year medical students (N=307). Participants voluntarily completed anonymous online questionnaires measuring the Mentor Behavior Scale, the Maslach Burnout Inventory-Student Survey, and the Professional Self-Identity Questionnaire. Multivariate regression analysis was performed to analyse relationships between student burnout, mentor behaviours and their impact on professional development. Results: Among participants, 26% (N=80) experienced burnout, which was significantly associated with lower competency support (OR = 2.0, 95% CI: 1.1-3.5, p = 0.016), medication use (OR = 2.1, 95% CI: 1.1-4.0, p = 0.029), and a lower Grade Point Average (OR = 3.3, 95% CI: 1.6-6.9, p = 0.001) compared to non-burnout students. In the development of professional identity, a high level of mentor relationship structure had statistically significant associations with higher scores in key domains of the Professional Self-Identity Questionnaire, including teamwork (OR = 3.9, 95% CI: 1.5-9.9, p < 0.01), communication (OR = 3.4, 95% CI: 1.5-7.7, p < 0.01), ethical awareness (OR = 3.3, 95% CI: 1.4-8.0, p < 0.01), and record use (OR = 2.8, 95% CI: 1.2-6.5, p < 0.05). Conclusions: The impact of mentor behaviours on medical students is evident. Enhancing mentorship by addressing specific mentor behaviours can improve programme quality. Future research should explore the long-term effects and strategies for effectively implementing targeted enhancements in mentor behaviours.

Ambulatory blood pressure monitoring in children and adolescents post-hematopoietic stem cell transplantation.

BACKGROUND: One of the long-term complications after hematopoietic stem cell transplantation (HSCT) is hypertension (HT). Previous studies showed that 10-15% of children post-HSCT had office HT, but only a few studies used ambulatory blood pressure monitoring (ABPM). The present study was aimed at exploring the frequency and factors associated with ABPM HT in children post-HSCT. METHODS: Patients aged ≥ 6 years who survived ≥ 2 years after HSCT were enrolled. Clinical and ABPM data were reviewed. ABPM HT was defined according to the 2022 American Heart Association guidelines. Factors associated with HT were analyzed by logistic regression. RESULTS: Ninety-eight (60 males) patients with a mean age of 15.1 years and a median follow-up time at 4.5 years after HSCT were included. Fifteen patients (15.3%) had ABPM HT (2 ambulatory HT and 13 masked HT). The ABPM HT group had a significantly older age (19 vs. 14 years), a higher proportion of males (87% vs. 57%), a higher office systolic BP index (0.93 vs. 0.85), a higher office diastolic BP index (0.96 vs. 0.82) and a higher proportion of current use of prednisolone and tacrolimus than those in the normal ABPM group. Multivariate analysis revealed that office diastolic BP index was associated with ABPM HT. Left ventricular mass index was significantly correlated with ABPM but not with office BP parameters. CONCLUSIONS: HT in children post-HSCT was not uncommon and most could not be detected with office BP measurement. A diastolic BP index can be used as a screening tool for HT. A higher resolution version of the Graphical abstract is available as Supplementary information.

Screening for ELANE, HAX1 and GFI1 gene mutations in children with neutropenia and clinical characterization of two novel mutations in ELANE gene.

BACKGROUND: Congenital neutropenia is a rare disease. Recurrent infections since young age are the presentation. The most common mutation causing severe congenital neutropenia (SCN) and cyclic neutropenia (CyN) is the ELANE gene. The objectives of this study were to screen the three common genetic mutations of ELANE, HAX1 and GFI1 in children with chronic neutropenia and to describe the clinical characteristics of children who had the mutations. METHODS: Infants having ANC < 1,000/cu mm or children aged > 1 year having ANC < 1,500/cu mm at least 3 times in 3 months were enrolled in the study. Patients who had acquired neutropenia due to infection, immune deficiency, or drugs were excluded. The ELANE gene was first studied; and if mutations were not identified, the HAX1 and GFI1 genes were further examined. RESULTS: A total of 60 patients were enrolled in the study. The median (range) age, ratio of female to male, ANC, and last follow-up age were 9.2 (0.5-45.2) months, 1:1.2, 248 (0-1,101) /cu mm, and 19.9 (3.5-202.3) months, respectively. Infections were noted in 67.3% of all patients. ELANE gene mutation was found in only four patients (6.7%), and the rest (56 patients) showed no mutations in the HAX1 and GFI1 genes. In patients without mutations, 66.0% had normal ANC during the follow-up, with a median (range) age for normal ANC of 19.8 (4.0-60.0) months. Two novel mutations p. Ala79del (c.234_236del) and p. Val197GlufsTer18 (c.589_590insAGGCCGGC) were identified, and they respectively cause SCN and CyN. Patients with the two novel mutations presented with several episodes of infection, including pneumonia, sepsis, abscess, otitis media, and gum infection. CONCLUSION: The genetic screening for ELANE, HAX1, and GFI1 gene mutations in 60 patients with chronic neutropenia could identify four patients (6.7%) with ELANE gene mutation and two novel mutations, p. Ala79del in exon 3 and p. Val197GlufsTer18 in exon 4 causing SCN; and CyN, respectively.

Factors affecting residents' internal motivation, grit, and well-being.

BACKGROUND: Residents completing competency-based medical education for postgraduate training face many challenging situations that may compromise their well-being or result in exhaustion or burnout. Factors described in self-determination theory and grit are important for residents' achievement of learning outcomes and well-being. This study explored the relationships among internal motivation, grit, well-being, and related factors among non-Western Asian residents. METHODS: We conducted an explanatory sequential mixed-methods survey-based study to explore correlations among satisfaction with basic psychological needs, grit, and well-being from September to November 2021 among residents at Ramathibodi Hospital, Mahidol University, Thailand. Data were collected with the Basic Psychological Needs Scale, Short Grit Scale, and World Health Organization-Five Well-Being Index. Next, participants with the highest and lowest scores for each scale were purposively invited to participate in semi-structured interviews. Interview data underwent thematic analysis and data collection continued until saturation was reached. RESULTS: In total, 245 residents (51% major ward, 65% female) completed the survey. There were strong associations between internal motivation, grit, and well-being (r = 0.46-0.90). Female residents had higher autonomy and relatedness scores than males (p = 0.04 and p = 0.01, respectively), and residents with less family responsibility had higher relatedness scores than other residents (p = 0.01). Residents who got more sleep had higher autonomy, relatedness, and well-being scores than those that slept less (p < 0.05). Residents who exercised > 5 times/week had higher well-being scores than other residents (p < 0.01). Thirty residents completed interviews. The thematic analysis revealed internal motivation, grit, and well-being were promoted by a supportive learning environment, a well-designed curriculum, actions and personalities of faculty members, and good personal factors. CONCLUSION: Internal motivation is significantly correlated with residents' grit, well-being, gender, family burdens, exercise, and sleep hours. Priority should be given to promoting internal motivation, grit, and well-being among residents by enhancing a positive learning environment, creating well-designed curricula, fostering good characteristics and actions among faculty members, and supporting residents' personal lives.

Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis.

Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3.

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%-70% of the Asian affected population. METHODS: We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3). RESULTS: Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6-18 months and the age at HSCT was 3.8-15 years in the patients with GD3. The latest age at follow-up was 8-22 years, with a post-HSCT duration of 3-14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment. CONCLUSIONS: ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.

Effective T-cell replete haploidentical stem cell transplantation for pediatric patients with high-risk hematologic disorders.

OBJECTIVES: Patients with high-risk hematologic diseases require intensive modalities, including high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Haploidentical T-cell-replete transplantation is a logical choice because of the limited availability of matched sibling donors and the prolonged time needed to identify matched unrelated donors in Thailand. METHODS: The clinical outcomes data of 43 patients undergoing allo-HSCT were reviewed. All patients had high-risk hematologic malignancies, were younger than 20 years, and were in complete cytological remission at the time of allo-HSCT. We used two different conditioning regimens: total body irradiation (TBI) combined with cyclophosphamide, fludarabine, and melphalan (n = 23) and thiotepa combined with fludarabine and busulfan (n = 20). All patients received a graft-versus-host disease prophylaxis regimen consisting of cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus. RESULTS: There was no difference in engraftment between patients receiving either of the regimens. After a median follow-up of 35.8 (range, 0.6-106.2) months, the overall survival (OS) and event-free survival (EFS) rates were 62.4% and 54.7%, respectively. OS and EFS were comparable between the respective regimens. CONCLUSIONS: We conclude that thiotepa-based conditioning has similar efficacy and tolerability as TBI-based conditioning for haploidentical HSCT with post-transplant cyclophosphamide.

Pediatric hemophagocytic lymphohistiocytosis in a tropical country: Results of a multicenter study in Thailand.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition caused by genetic mutation or various triggers disturbing the immune system. METHODS: A multicenter retrospective study of pediatric patients with HLH receiving a diagnosis between January 2005 and December 2019 from three pediatric oncology centers was conducted to explore the clinical characteristics and determine prognostic factors associated with outcomes among Thai children. RESULTS: In all, 78 patients with HLH with a median age at diagnosis of 3.17 (range, .08-17.83) years were enrolled. The male to female ratio was 1.2:1. The most common type of HLH was infection-associated hemophagocytic syndrome (IAHS) (n = 59, 75%) of which Epstein-Barr virus was the most common pathogen. Thrombocytopenia, hyperbilirubinemia, and treatment response at weeks 2 and 8 after initiating treatment were associated with mortality. Platelet count <50,000 cells/mm3 was the only independent prognostic factor to define survival outcome (p-value .035). Two-year overall survival rate was 71.3% (95% confidence interval, 59.2%-80.3%). Survival rates between IAHS, malignant associated HLH, macrophage activation syndrome, and unspecific HLH did not significantly differ (p-value .571). CONCLUSION: IAHS was the most common cause among pediatric HLH in Thailand. The outcomes of Thai children with HLH were comparable to those of developed countries. Platelet count <50,000 cells/mm3 was the only independent prognostic factor to define survival outcome.

Association of zinc deficiency with infectious complications in pediatric hematopoietic stem cell transplantation patients.

BACKGROUND: Zinc plays essential roles in immune function and epithelial integrity. Patients undergoing hematopoietic stem cell transplantation (HSCT) often have low plasma zinc levels because of poor intake and diarrhea. We hypothesized that patients with zinc deficiency before HSCT had worse infectious complications after HSCT compared with patients with normal zinc levels. Citrulline, a marker of intestinal integrity, was also hypothesized to be lower in patients with zinc deficiency. PATIENTS AND METHODS: Thirty patients undergoing HSCT at Ramathibodi Hospital during March 2020-September 2021 were enrolled. Blood samples for plasma zinc and citrulline were collected during the HSCT period. The 14- and 90-day outcomes after HSCT were prospectively recorded. RESULTS: Twelve of 30 (40%) patients had zinc deficiency before HSCT. Zinc-deficient patients were younger (median (interquartile range): 6 (8.8) vs 13 (5.8) years old; p = 0.017). Zinc levels tended to increase after admission in both groups. Patients with zinc deficiency had lower citrulline levels than those with normal zinc levels. Citrulline levels decreased in both groups after stem cell infusion, and the level was not significantly different between the two groups. Zinc-deficient patients had a higher rate of bacterial infection within 90 days after HSCT than those with normal zinc levels (6 in 12 patients (50.0%) vs 1 in 18 patients (5.6%); odds ratio [OR]: 17.0; 95% confidence interval [CI]: 1.68-171.70; p = 0.016). This remained significant after adjustments for age (adjusted OR: 12.31; 95% CI: 1.084-139.92; p = 0.043). CONCLUSION: The prevalence of zinc deficiency in pediatric patients undergoing HSCT was high. Zinc-deficient patients had lower citrulline levels and higher incidence of bacterial infection after HSCT. However, citrulline level was not different between patients with and without bacterial infections. It is worth to investigate whether zinc supplementation before HSCT can reduce bacterial infection after HSCT.

Central nervous system involvement and thrombocytopenia as predictors of mortality in children with hemophagocytic lymphohistiocytosis.

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening condition. This study aimed to evaluate treatment outcomes and identify prognostic-related factors in Thai children with HLH. Materials and methods: We retrospectively reviewed the medical records of 76 pediatric patients with HLH who were treated at Ramathibodi Hospital between January 2004 and December 2019. Treatment outcomes were defined as early mortality (death within 30 days after diagnosis) and early treatment response (resolution of all clinical features and normalization of at least one HLH-related laboratory parameter within 4 weeks). Results: The overall mortality rate was 38% (29/76), with an early mortality rate of 45% (13/29). Malignancy-associated HLH had the highest mortality rate (88%), followed by primary HLH (56%). The predictors of early mortality were central nervous system (CNS) involvement [OR 13 (95%CI 2-83), p = 0.007] and platelet counts <44 × 106/mm3 [OR 8 (95%CI 1.3-49), p = 0.024]. The predictors of early treatment response were no CNS involvement [OR 6.6 (95%CI 1.5-28.8), p = 0.011], platelet counts more than 44 × 106/mm3 [OR 8 (95%CI 2.1-30.9), p = 0.003], and total bilirubin levels <1.8 mg/dL [OR 4 (95%CI 1.1-14.8), p = 0.036]. In the mixed-model analysis, platelet counts in non-survivors increased significantly less than those in survivors, with a mean difference in platelet changes between the two groups of 94.6 × 106/mm3 (p = 0.003). Conclusion: The independent predictors of early mortality in children with HLH were CNS involvement and low baseline platelet counts. A slow rate of platelet increases during the first week after diagnosis was also associated with mortality.

Haploidentical Hematopoietic Stem Cell Transplantation in Thalassemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pre transplant immune suppression phase (PTIS) and two courses of dexamethasone (DXM) and fludarabine (FLU) followed by pre transplant conditioning with intravenous FLU busulfan (BU) and post transplant graft-vs.-host disease (GvHD) prophylaxis with cyclophosphamide (CPM), tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia; the 3-year projected overall and event-free survival is over 96.0%, and there have been no secondary graft failures. Of the first 31 patients, we had two graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific human leukocyte antigen (HLA) antibodies [anti-donor specific antibodies (DSAs)], but after adjusting the PTIS to include bortezomib (BORT) and rituximab (RIX) for patients with high titers of anti-DSAs and using pharmacologic dose guidance for BU, we had no graft failures in the last 52 patients. Six (7.0%) of 83 patients developed severe GvHD. We conclude that this is a safe and efficacious approach to allogeneic HSCT in thalassemia.

Ruxolitinib Treatment in an Adolescent With Chronic Graft-Versus-Host Disease Mimicking Eosinophilic Gastrointestinal Disorders: A Case Report.

BACKGROUND: Eosinophilic gastrointestinal disorders (EGIDs) are well-documented entities in pediatric solid organ transplantation. However, the diseases are rare after bone marrow transplantation (BMT). CASE PRESENTATION: We present an adolescent male with hemoglobin E-ß-thalassemia who underwent BMT and developed chronic graft-versus-host disease (GVHD) mimicking EGIDs. Initially, the patient presented with a presumed diagnosis of eosinophilic gastroenteritis (subserosal type) and received corticosteroids for 12 weeks. Six months after corticosteroids cessation, he again developed abdominal pain, treated with corticosteroids, azathioprine, and a six-food elimination diet. Still, he later had similar symptoms with persistent hypereosinophilia. The patient was subsequently diagnosed with chronic GVHD after excluding various potential causes. Ruxolitinib also led to significant clinical improvement and the disappearance of eosinophilia. CONCLUSION: The differential diagnosis of chronic GVHD should be a concern in BMT recipients with persistent gastrointestinal symptoms and eosinophilia. Ruxolitinib may be a treatment option in children with a steroid-refractory disease.

Target Enrichment Metagenomics Reveals Human Pegivirus-1 in Pediatric Hematopoietic Stem Cell Transplantation Recipients.

Human pegivirus-1 (HPgV-1) is a lymphotropic human virus, typically considered nonpathogenic, but its infection can sometimes cause persistent viremia both in immunocompetent and immunosuppressed individuals. In a viral discovery research program in hematopoietic stem cell transplant (HSCT) pediatric patients, HPgV-1 was detected in 3 out of 14 patients (21.4%) using a target enrichment next-generation sequencing method, and the presence of the viruses was confirmed by agent-specific qRT-PCR assays. For the first time in this patient cohort, complete genomes of HPgV-1 were acquired and characterized. Phylogenetic analyses indicated that two patients had HPgV-1 genotype 2 and one had HPgV-1 genotype 3. Intra-host genomic variations were described and discussed. Our results highlight the necessity to screen HSCT patients and blood and stem cell donors to reduce the potential risk of HPgV-1 transmission.

Effect of GSTA1 Variants on Busulfan-Based Conditioning Regimen Prior to Allogenic Hematopoietic Stem-Cell Transplantation in Pediatric Asians.

Busulfan is widely used as a chemotherapy treatment before hematopoietic stem-cell transplantation (HSCT). However, the response of busulfan is highly variable and unpredictable, whereby the pharmacogenetic interference of glutathione S-transferase (GST) has strong evidence in Caucasians and some adult Asians but not in pediatric Asian patients. This study was aimed at investigating the associations of GST genetic polymorphisms with variations in the pharmacokinetic (PK) properties of busulfan in pediatric Asian patients. This retrospective cohort study recruited 92 pediatric patients. The polymorphism of GSTA1 was genotyped by Sanger sequencing, and GSTM1 and GSTP1 were genotyped by real-time PCR. Drug concentration and PK estimation were identified using an LC-MS/MS method and a noncompartmental model. Statistical analysis was performed by R software. Out of 92 patients, 48 (53%) were males, the mean age was 8.4 ± 5.12 years old, and the average weight was 26.52 ± 14.75 kg. The allele frequencies of GSTA1*B and of GSTM1 and GSTP1* deletions were 16.9%, 68.5%, and 21.2%, respectively. Patients with GSTA1*B had a statistically significant impact on the PK of busulfan, whereas those with GSTM1 and GSTP1 did not (p > 0.05). The carriers of GSTA1*B showed a significant difference compared to noncarriers in terms of t1/2 (for first dose: 161.9 vs. 134.3 min, p = 0.0016; for second dose: 156.1 vs. 129.8, p = 0.012), CL (88.74 vs. 124.23 mL/min, p = 0.0089), Cmax (4232.6 vs. 3675.5 ng/mL, p = 0.0021), and AUC (5310.6 vs. 4177.1 µM/min, p = 0.00033). The augmentation of AUC was around 27.1% in patients carrying the GSTA1*B variant. The GSTA1 polymorphism was significantly associated with variations of the pharmacokinetic properties of busulfan treatment in pediatric Asian patients.

Clinical outcomes and screening for organ involvement in pediatric Langerhans cell histiocytosis in Thailand: multicenter study on behalf of the Thai Pediatric Oncology Group.

Langerhans cell histiocytosis (LCH) is a rare disease across all age groups and is characterized by various degrees of severity and organ system involvement. A multi-institutional retrospective study of pediatric patients with LCH treated between 1999 and 2018 at five pediatric oncology centers was conducted to describe the clinical characteristics, prognostic factors, and outcomes of LCH and to validate screening tools for organ system involvement in pediatric LCH in Thailand. A total of 127 patients with a median age of 2.7 years were studied. The single-to-multisystem (MS) LCH ratio was 1:1. Forty-seven patients (71%) with MS-LCH had risk-organ involvement (RO +), whereas 19 (29%) patients had no risk-organ involvement (RO -). The 5-year overall and event-free survival rates were 91.3% and 73.6%, respectively, which were comparable to those in developed countries. Prognostic factors included age < 2 years, RO + MS-LCH, and number of RO + . Abnormal complete blood count was a highly sensitive indicator of bone marrow involvement. Plain radiography is an appropriate screening tool to detect bone involvement.

Successful haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide in a child with X-linked chronic granulomatous disease: A first report in Asia.

BACKGROUND: HLA-matched hematopoietic stem cell transplantation (HSCT) is the curative treatment for chronic granulomatous disease (CGD). OBJECTIVE: To report a case of X-linked CGD with active infection successfully treated by haploidentical HSCT with post-transplant high dose cyclophosphamide (PTCY). METHODS: A 5-year-old Thai boy with CGD was undergone for haploidentical HSCT using PTCY with correction of the phagocytic function. He presented with Chromobacterium violaceum liver abscess at the age of 9 months and experienced recurrent perianal abscess and invasive pulmonary aspergillosis even receiving antimicrobial prophylaxis. PTCY was given on day 3 and 4, after CD34+ cells infusion. RESULTS: The peripheral blood-nucleated cell chimerism showed 100% on day 16 and remained 100%. Dihydrorhodamine (DHR) assay on day 108 and day 214 showed normal results. Currently at 22 months post HSCT, he does not receive antibiotic and anti-fungal prophylaxis. CONCLUSIONS: Haploidentical HSCT with PTCY could be an effective treatment option for children with CGD.

Production and characterization of haploidentical CD19 CAR T cells: Validated to induce a continuous complete remission in a patient with relapsed refractory B-cell ALL.

AIMS: The purpose of this study was to design and manufacture CD19 chimeric antigen receptor (CAR)-modified T cells for clinical use in Thailand, as a model for how this technology can be directly applied at individual institutions treating high-risk leukemia patients. METHODS: We constructed second-generation CAR T cells expressing CD19 scFV-CD28-CD3ζ with different lengths of the spacer region: full, intermediate, and short length, by using a lentiviral vector. We wanted to determine whether the difference in length of the spacer would affect the cytotoxic potential of the CD19 CAR T cells against the leukemic cells. RESULTS: We found that all constructs of CD19 CAR T cells exhibited a similar level of cytotoxicity against several human lymphoma and leukemia cell lines. For the clinical application, we chose the intermediate length spacer construct CD19 CAR T cells, hypothesizing that the highest transduction efficiency coupled with a slower initial proliferation in vitro might lead to effective leukemic cell kill, yet a lower probability for serious clinical side effects. We then tested the clinical efficacy of our CD19 CAR T cells in one patient with refractory/relapsed acute B-cell lymphoblastic leukemia. This patient indeed had minimal clinical side effects after the CAR T-cell infusion, and he remains in an unmaintained, ongoing complete remission 10+ months after his T-cell treatment. CONCLUSION: Our CD19 CAR T cells demonstrated efficacies in acute lymphoblastic B-cell leukemia, and will be used to establish an immunotherapeutic program for high-risk B-cell acute lymphoblastic leukemia in Thailand. We propose that this approach can be used as a model for how this new exciting technology can be applied directly at individual institutions that treat (a large number of) patients with high-risk leukemia.

Bloodstream bacterial infections in thalassemic pediatric and adolescent patients after hematopoietic stem cell transplantation.

BACKGROUND: Thalassemic patients usually require regular blood transfusions; however, HSCT can provide a cure. Incidence of IBI in pediatric patients post-HSCT is still scant. OBJECTIVES: This study aimed to explore whether thalassemic patients had a different incidence of post-HSCT IBI compared with patients with other underlying diseases. Factors associated with IBI in the pediatric population undergoing HSCT were also investigated. METHODS: In this retrospective cohort study, clinical data of pediatric patients who underwent HSCT during the period from 2011 to 2016 were reviewed and analyzed. The primary outcome was incidence of IBI within 1-year post-HSCT. RESULTS: Of 123 patients, 53 were thalassemic. IBI was diagnosed in 23 patients within 1 year after HSCT (incidence: 19.5 episodes/1000 patients/month). The IBI incidence was lower in thalassemic patients than in patients with other underlying diseases (6.9 vs. 31.6 episodes/1000 patients/month). Having thalassemia as an underlying disease was the only factor associated with lower IBI in pediatric post-HSCT patients (hazard ratio: 0.245; 95% confidence interval, 0.080-0.748). In post-HSCT thalassemic patients, IBI mostly occurred within 100 days after HSCT, and most of these cases had catheter-related blood stream infection. The risk of IBI tended higher for haploidentical HSCT, but this difference was not statistically significantly different. CONCLUSION: The IBI incidence after HSCT was lower in thalassemic patients than in those with other underlying diseases. Catheter-related blood stream infection was the major IBI in these patients. IBI was not a major complication in thalassemic pediatric patients undergoing HSCT.