Kyung Taek Hong

Peri-engraftment syndrome in allogeneic hematopoietic SCT.

Engraftment syndrome (ES) and pre-engraftment syndrome (pre-ES) are both inflammatory conditions that occur after hematopoietic SCT (HSCT) and are characterized by non-infectious fever and skin rash. Although the pathogenesis is not fully understood, both syndromes are similar, and could be defined as a new clinical syndrome, named as peri-engraftment syndrome (peri-ES). We retrospectively analyzed the clinical records in 176 pediatric patients, following allogeneic HSCT. We utilized the definition of ES by Spitzer as the diagnostic criteria, excluding ‘within 96 h of engraftment’ criteria. Thirty cases developed peri-ES with a cumulative incidence of 17.0%. High cumulative incidence (50%) was seen in patients who underwent a double-unit cord blood transplantation (DUCBT; P<0.01). Clinical findings of peri-ES are similar, regardless of the onset day, and encephalopathy was the most severe complication. In the DUCBT cohort, the use of TBI and early complete chimerism (⩽day 21) were identified as risk factors that predispose the development of peri-ES. We determined that both, ES and pre-ES, might have similar causes, which could be included in peri-ES. Particularly, it occurred more in DUCBT patients, which means that not only neutrophil engraftment but also immune reactions within the two units might contribute to peri-ES.

Successful mobilization using a combination of plerixafor and G-CSF in pediatric patients who failed previous chemomobilization with G-CSF alone and possible complications of the treatment

Peripheral blood stem cell (PBSC) mobilization, which uses plerixafor (AMD 3100), a newly developed specific inhibitor of the CXCR4 receptor, in combination with granulocyte-colony stimulating factor(G-CSF), has been shown to enhance the stem cell mobilization in adult patients, but pediatric data are scarce. We documented our experience with this drug in 6 Korean pediatric patients who had failed in chemomobilization, using G-CSF, alone. All patients were mobilized CD34+ cells (median, 11.08 × 106/kg: range, 6.34-28.97 × 106/kg) successfully within 2 to 3 cycles of apheresis, without complications. A total of 7 autologous transplantations were performed, including 1 tandem transplantation. However, 2 patients with brain tumors showed severe pulmonary complications, including spontaneous pneumomediastinum. This is the first study of PBSC mobilization with plerixafor in Asian pediatric patients. Furthermore our study suggests that mobilization with plerixafor may be effective in Korean pediatric patients, who have previously been heavily treated and have failed PBSC mobilization with classical chemomobilization, using G-CSF. However, further studies are needed to examine the possible complications of autologous transplantation, using a mobilized plerixafor product in children.

A Significant Influence of Metronidazole on Busulfan Pharmacokinetics: A Case Report of Therapeutic Drug Monitoring.

Busulfan is a cytotoxic agent used in preconditioning for hematopoietic stem cell transplantation. Therapeutic drug monitoring of busulfan is necessary owing to its narrow therapeutic range. Patients undergoing preconditioning are susceptible to infection and might require coadministration of antibiotics. We present a case study of a 3-year-old girl with precursor T-cell acute lymphoblastic leukemia who received intravenous busulfan before hematopoietic stem cell transplantation. Metronidazole was coadministered before the third dose of busulfan because of Clostridium difficile infection. The daily pharmacokinetic analysis revealed that the clearance reduced to 57% of that before the coadministration. Although the underlying mechanism is unclear, a significant pharmacokinetic interaction was observed between busulfan and metronidazole, underscoring the importance of therapeutic drug monitoring.

Pharmacometabolomics for predicting variable busulfan exposure in paediatric haematopoietic stem cell transplantation patients

Owing to its narrow therapeutic range and high pharmacokinetic variability, optimal dosing for busulfan is important to minimise overexposure-related systemic toxicity and underexposure-related graft failure. Using global metabolomics, we investigated biomarkers for predicting busulfan exposure. We analysed urine samples obtained before busulfan administration from 59 paediatric patients divided into 3 groups classified by area under the busulfan concentration-time curve (AUC), i.e., low-, medium-, and high-AUC groups. In the high-AUC group, deferoxamine metabolites were detected. Phenylacetylglutamine and two acylcarnitines were significantly lower in the high-AUC group than in the low-AUC group. Deferoxamine, an iron-chelating agent that lowers serum ferritin levels, was detected in the high-AUC group, indicating that those patients had high ferritin levels. Therefore, in a retrospective study of 130 paediatric patients, we confirmed our hypothesis that busulfan clearance (dose/AUC) and serum ferritin level has a negative correlation (r = −0.205, P = 0.019). Ferritin, acylcarnitine, and phenylacetylglutamine are associated with liver damage, including free radical formation, deregulation of hepatic mitochondrial β-oxidation, and hyperammonaemia. Our findings reveal potential biomarkers predictive of busulfan exposure and suggest that liver function may affect busulfan exposure.

Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant

&NA; STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post‐hematopoietic stem cell transplantation (post‐HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post‐HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno‐occlusive disease, acute graft‐vs‐host disease, chronic graft‐vs‐host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P = 0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P = 0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post‐transplant outcomes. HighlightsAssociation of rs7574865 polymorphism in donors with outcomes after HSCTPresence of TT genotype increases susceptibility to CMV infection.Possible association of rs7574865 with a weaker immune response in recipients

Pediatric patients undergoing hematopoietic stem cell transplantation can greatly benefit from a novel once‐daily intravenous busulfan dosing nomogram

Busulfan, a bifunctional alkylating agent, has been used as a conditioning regimen prior to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to derive a novel once‐daily intravenous (IV) busulfan dosing nomogram for pediatric patients undergoing HSCT using a population pharmacokinetic (PK) model. A population PK analysis was performed using 2183 busulfan concentrations in 137 pediatric patients (age: 0.6‐22.2 years), who received IV busulfan once‐daily for 4 days before undergoing HSCT. Based on the final population PK model, an optimal once‐daily IV busulfan dosing nomogram was derived. The percentage of simulated patients achieving the daily target area under the concentration‐time curve (AUC) by the new nomogram was compared with that by other busulfan dosing regimens including the FDA regimen, the EMA regimen, and the empirical once‐daily regimen without therapeutic drug monitoring (TDM). A one‐compartment open linear PK model incorporating patients body surface area, age, dosing day, and aspartate aminotransferase as a significant covariate adequately described the concentration–time profiles of busulfan. An optimal dosing nomogram based on the PK model performed significantly better than the other dosing regimens, resulting in >60% of patients achieving the target AUC while the percentage of patients exceeding the toxic AUC level was kept <25% during the entire treatment period. A novel once‐daily busulfan dosing nomogram for pediatric patients undergoing HSCT is useful for clinicians, particularly in a setting where TDM service is not readily available or to optimize the dose on day 1.

Pharmacokinetics of fludarabine and its association with clinical outcomes in paediatric haematopoietic stem cell transplantation patients

Fludarabine is used as a common component of conditioning regimens for haematopoietic stem cell transplantation (HSCT). However, knowledge regarding the pharmacokinetic characteristics of once-daily fludarabine dosing in children is limited. This study investigated the pharmacokinetics of fludarabine and evaluated its associations with clinical outcomes in paediatric patients. A total of 802 blood samples obtained from 43 paediatric patients who underwent HSCT were included in a population pharmacokinetic analysis using non-linear mixed-effects modelling. The relationships between systemic 9-β-d-arabinofuranosyl-2-fluoroadenine (F-ara-A) exposure derived from the model and the clinical outcome variables were explored. A two-compartment model with proportional residual error adequately described the pharmacokinetics of F-ara-A. The body surface area and glomerular filtration rate were significant covariates for the clearance of F-ara-A. After the first dose of fludarabine at 40 mg/m2, the median (min—max) values for the area under the concentration-time curve (AUC) from dosing to infinity and the elimination half-life were 4696 (3056–10,477) ng·h/mL and 7.95 (4.78–10.88) h, respectively. No significant associations were found between systemic exposure and graft-vs.-host disease, neurologic and pulmonary complications, relapse or survival. Systemic exposure was comparable to that of previous reports from different populations and had no association with clinical outcomes.

Favorable Outcome of Post-Transplantation Cyclophosphamide Haploidentical Peripheral Blood Stem Cell Transplantation with Targeted Busulfan-Based Myeloablative Conditioning Using Intensive Pharmacokinetic Monitoring in Pediatric Patients

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PTCy) was performed previously in adults using a nonmyeloablative conditioning regimen and bone marrow as a graft source. In an effort to reduce relapse rates, myeloablative conditioning regimens with higher intensities are now used. We used an intensive daily pharmacokinetic monitoring method for busulfan dosing in children for effective myeloablation and to reduce toxicity. Here, we report the retrospective results of 34 patients (median age 11.1 years) who underwent haplo-HSCT with PTCy using a targeted busulfan-based myeloablative conditioning regimen and peripheral blood as a stem cell source. The donor-type neutrophil engraftment rate was 97.1%, and the cumulative incidence rates of grade II to IV and grade III to IV acute and extensive chronic graft-versus-host disease were 38.2%, 5.9%, and 9.1%, respectively. The overall survival and event-free survival rates, and treatment-related mortality were 85.0%, 79.4%, and 2.9%, respectively. Based on the subgroup analysis of patients with malignancies (n = 23), the relapse incidence rate was 21.7%. Haplo-HSCT using PTCy with targeted busulfan-based myeloablative conditioning and peripheral blood as a stem cell source was a safe and promising therapeutic option for children.

WHIM Syndrome With a Novel CXCR4 Variant in a Korean Child

Dong Woo Shin, M.D., Si Nae Park, M.S., Sung-Min Kim, B.S., Kyongok Im, M.T., Jung-Ah Kim, M.D., Kyung Taek Hong, M.D. , Jung Yoon Choi, M.D. , Che Ry Hong, M.D. , Kyung Duk Park, M.D. , Hee Young Shin, M.D. , Hyoung Jin Kang, M.D. , Hyun Kyung Kim, M.D., and Dong Soon Lee, M.D. Department of Laboratory Medicine, Seoul National University College of Medicine; Cancer Research Institute, Seoul National University College of Medicine; Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea

Therapy-related Acute Myeloid Leukemia After the Treatment of Primary Solid Cancer in Children: A Single-center Experience

Therapy-related acute myeloid leukemia (t-AML) has a dismal prognosis and is one of the most frequent second malignant neoplasms which could be encountered by pediatric oncologists. Between October 2000 and September 2016, 16 patients who had primary solid tumors were diagnosed with t-AML at the Seoul National University Children’s Hospital. The median patient age at the time of diagnosis of their primary solid tumors was 9.6 years (range, 0.1 to 15.4 y), and that of t-AML was 14.0 years (range, 4.7 to 23.9 y). The median latency period from the end of the primary tumor treatment to the initial diagnosis of t-AML was 29 months (range, 6 to 130 mo). Twelve patients achieved complete remission. Of them, only 7 patients underwent hematopoietic stem cell transplantation (HSCT). The 3-year overall survival (OS) rates and event-free survival rates were 33.7±12.2% and 26.9±11.5% respectively. The patients who underwent HSCT showed favorable 5-year OS rates (57.1±18.7%), whereas the 5-year OS rates of those who did not undergo HSCT was 0%. This study demonstrates that an achievement of complete remission and a subsequent HSCT can be the optimal solution for the treatment of t-AML, and this strategy showed acceptable outcomes.