Publications by authors named "Kyung Taek Hong"

39 Publications

Hemophagocytic lymphohistiocytosis associated with parvovirus B19-induced aplastic crisis in a hereditary spherocytosis patient: A case report and literature review.

Pediatr Hematol Oncol 2021 Aug 9:1-8. Epub 2021 Aug 9.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation. It occurs because of severe inflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes, characterized by the production of excessive levels of cytokines. Virus-associated HLH is a well-known entity, and parvovirus B19 is one of the common causes. Parvovirus B19 can also affect blood cell lineages. Therefore, HLH may be accompanied by several diseases such as cytopenia, aplastic anemia, and myelodysplastic syndrome. Herein, we report the case of a patient with hereditary spherocytosis who was diagnosed with parvovirus B19-induced HLH and aplastic crisis. A 7-year-old girl presented to our hospital with fever, pleural effusion, pancytopenia, hepatosplenomegaly, and hypotension. A bone marrow biopsy was performed under the suspicion of HLH, which revealed hemophagocytes. The diagnostic criteria for HLH were met, and prompt chemoimmunotherapy was initiated considering the clinically unstable situation. Her health improved rapidly after initiating treatment. Further study revealed that she had hereditary spherocytosis, and parvovirus B19 had caused aplastic crisis and HLH. The patient's clinical progress was excellent, and chemoimmunotherapy was reduced and discontinued at an early stage. This case shows that aplastic crisis and HLH can coexist with parvovirus B19 infection in patients with hereditary spherocytosis. Although the prognosis was good in this case of HLH caused by parvovirus B19, early detection and active treatment are essential.
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http://dx.doi.org/10.1080/08880018.2021.1949082DOI Listing
August 2021

Open-Label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Pediatric Patients with Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-Host Disease.

Transplant Cell Ther 2021 Jul 24. Epub 2021 Jul 24.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute, Seoul, Republic of Korea; Wide River Institute of Immunology, Seoul National University, Gangwon, Republic of Korea. Electronic address:

Steroid-refractory chronic graft-versus-host disease (cGVHD) is associated with high morbidity. To date, there is no standard therapy for patients who fail to respond to steroids. In this nonrandomized, open-label, single-arm, multicenter prospective phase II study, we evaluated the efficacy and safety of imatinib mesylate and mycophenolate mofetil (MMF) to treat sclerotic/fibrotic type cGVHD. The primary endpoint was the overall response rate (ORR) to imatinib mesylate plus MMF in 1 year, and the secondary endpoints included safety, quality of life, discontinuation of steroids, and overall survival (OS) rate. A total of 13 patients were enrolled, with a median age of 10.4 years (range, 5.0 to 20.1 years). All patients received a myeloablative conditioning regimen. Specifically, 6 of these patients had previously experienced acute GVHD. The most frequently affected organs were the eyes, lungs, skin, and liver. There were 2 premature deaths. One patient died of pulmonary infection and progression of cGVHD, and the other patient died from neuroblastoma progression and septic shock. The ORR was 76.9% (10 of 13 patients), and the median steroid dose was decreased from 1.0 mg/kg/day to 0.21 mg/kg/day. One-year OS was 84.6% (n = 13), and common adverse events included elevated liver enzyme and serum creatinine levels and fever. Although our sample size was limited, treatment of cGVHD with imatinib mesylate plus MMF shows promising results with acceptable toxicity.
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http://dx.doi.org/10.1016/j.jtct.2021.07.019DOI Listing
July 2021

Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: a Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group.

Cancer Res Treat 2021 Apr 20. Epub 2021 Apr 20.

Department of Pediatrics, Kosin University of Medicine, Busan, Korea.

Purpose: Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea.

Materials And Methods: Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively.

Results: Of 801 acute myeloid leukemia(AML) children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3-18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had WBC count greater than 10x109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid (ATRA) and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 (86.8%) patients achieved complete remission (CR) after induction chemotherapy. The causes of death were 3 intracranial hemorrhage (ICH), 1 cerebral infarction, and 1 sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival rate (EFS) and overall survival rates (OS) were 82.1 ± 4.4%, 89.7 ± 5.1% respectively. The 4-yr OS was significantly higher in patients with initial WBC <10x109/L than in those with initial WBC ≥10x109/L (p=0.02).

Conclusion: This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.
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http://dx.doi.org/10.4143/crt.2021.313DOI Listing
April 2021

Stage IV Classical Hodgkin Lymphoma-type Posttransplant Lymphoproliferative Disorder in a Pediatric Liver Transplant Patient: A Case Report and Review of the Literature.

J Pediatr Hematol Oncol 2021 Mar 23. Epub 2021 Mar 23.

Departments of Pediatrics Surgery Pathology Radiology, Seoul National University College of Medicine Seoul National University Cancer Research Institute, Seoul Wide River Institute of Immunology, Hongcheon-gun, Republic of Korea.

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases with abnormal proliferation of lymphoid tissue and classical Hodgkin lymphoma (CHL) type PTLD is a very rare subtype. We describe a successfully diagnosed and treated CHL-PTLD stage IV pediatric patient, 8 years after liver transplantation. The patient was treated with standard CHL (Children's Cancer Group 5942 group 3) chemotherapy, rituximab and reduction of immunosuppressant. The patient remains in complete remission after 3 years with stable graft function. To our best knowledge, this is the first pediatric case report of a successfully treated stage IV CHL-PTLD after a liver transplant.
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http://dx.doi.org/10.1097/MPH.0000000000002121DOI Listing
March 2021

Intracerebral hemorrhage as a rare complication of imatinib in a Philadelphia chromosome positive acute lymphoblastic leukemia pediatric patient.

Pediatr Hematol Oncol 2021 May 3;38(4):378-384. Epub 2021 Mar 3.

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Republic of Korea.

Imatinib is a BCR-ABL tyrosine kinase inhibitor used for the treatment of a variety of diseases including Philadelphia chromosome positive (Ph+) leukemia. We report a 15 year old male patient presenting with symptomatic acute intracerebral hemorrhage (ICH) in midbrain while on imatinib more than three years after completion of therapy for Ph + B-ALL. The patient denied recent trauma history and consumption of other medication. Laboratory findings did not show any signs of relapse, coagulopathy nor thrombocytopenia. Under the impression of imatinib related ICH, imatinib was discontinued and with conservative management the patient recovered without neurologic sequalae. This case demonstrates the first pediatric case of spontaneous ICH as a rare complication of imatinib.
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http://dx.doi.org/10.1080/08880018.2020.1843577DOI Listing
May 2021

Long-Term Outcomes and Sequelae Analysis of Intracranial Germinoma: Need to Reduce the Extended-Field Radiotherapy Volume and Dose to Minimize Late Sequelae.

Cancer Res Treat 2021 Jan 13. Epub 2021 Jan 13.

Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: We aimed to refine the radiotherapy (RT) volume and dose for intracranial germinoma considering recurrences and long-term toxicities.

Materials And Methods: Total 189 patients with intracranial germinoma were treated with RT alone (n=50) and RT with upfront chemotherapy (CRT) (n=139). All cases were confirmed histologically. RT fields comprised the extended-field and involved-field only for primary site. The extended-field, including craniospinal, whole-brain (WB), and whole-ventricle (WV) for cranial field, is followed by involved-field boost. The median follow-up duration was 115 months.

Results: The relapses developed in 13 patients (6.9%). For the extended-field, cranial RT dose down to 18 Gy exhibited no cranial recurrence in 34 patients. In CRT, 74 patients (56.5%) showed complete response to chemotherapy and no involved-field recurrence with low-dose RT of 30 Gy. WV RT with chemotherapy for the basal ganglia or thalamus germinoma showed no recurrence. Secondary malignancy developed in ten patients (5.3 %) with a latency of 20 years (range, 4-26) and caused mortalities in six. WB or craniospinal field rather than WV or involved-field significantly increased the rate of hormone deficiencies, and secondary malignancy. RT dose for extended-field correlated significantly with the rate of hormone deficiencies, secondary malignancy, and neurocognitive dysfunction.

Conclusion: Reduced dose and volume of extended-field rather than total dose or involved-field will be critical to decrease the late toxicities. Upfront chemotherapy could be beneficial for the patients with complete response to minimize the RT dose down to 30 Gy. Prospective trials focused on de-intensification of the extended-field RT are warranted.
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http://dx.doi.org/10.4143/crt.2020.1052DOI Listing
January 2021

Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea.

Cancer Res Treat 2021 Jan 4. Epub 2021 Jan 4.

Department of Pediatrics, Seoul National University Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Effectiveness and safety of clofarabine (one of the treatment mainstays in pediatric patients with relapsed/refractory acute lymphoblastic leukemia [ALL]) was assessed in Korean pediatric patients with ALL to facilitate conditional coverage with evidence development.

Materials And Methods: In this multicenter, prospective, observational study, patients receiving clofarabine as mono/combination therapy were followed-up every 4-6 weeks for 6-months or until hematopoietic stem cell transplantation (HSCT). Response rates, survival outcomes, and adverse events were assessed.

Results: Sixty patients (2-26 years old; 65% B-cell ALL, received prior ≥2 regimen, 68.3% refractory to previous regimen) were enrolled and treated with at least one dose of clofarabine; of whom 26 (43.3%) completed six months of follow-up after the last dose of clofarabine. Fifty-eight patients (96.7%) received clofarabine combination therapy. Overall remission rate (complete remission [CR] or CR without platelet recovery [CRp]) was 45.0% (27/60; 95% confidence interval [CI] 32.4 to 57.6) and the overall response rate (CR, CRp, or partial remission [PR]) was 46.7% (28/60; 95% CI, 34.0 to 59.3), with 11 (18.3%), 16 (26.7%), and 1 (1.7%) patients achieving CR, CRp, and PR, respectively. The median time to remission was 5.1 weeks (95% CI: 4.7 to 6.1). Median duration of remission was 16.6 weeks (range: 2.0 to 167.6). Sixteen patients (26.7%) proceeded to HSCT. There were 24 deaths; 14 due to treatment-emergent adverse events.

Conclusion: Remission with clofarabine was observed in approximately half of the study patients who had overall expected safety profile; however, there was no favorable long-term survival outcome in this study.
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http://dx.doi.org/10.4143/crt.2020.289DOI Listing
January 2021

Clinical Characteristics and Treatment Outcomes in Children, Adolescents, and Young-adults with Hodgkin's Lymphoma: a KPHOG Lymphoma Working-party, Multicenter, Retrospective Study.

J Korean Med Sci 2020 Nov 30;35(46):e393. Epub 2020 Nov 30.

Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.

Background: Hodgkin's lymphoma (HL) constitutes 10%-20% of all malignant lymphomas and has a high cure rate (5-year survival, around 90%). Recently, interest has increased concerning preventing secondary complications (secondary cancer, endocrine disorders) in long-term survivors. We aimed to study the epidemiologic features and therapeutic outcomes of HL in children, adolescents, and young adults in Korea.

Methods: We performed a multicenter, retrospective study of 224 patients aged < 25 years diagnosed with HL at 22 participating institutes in Korea from January 2007 to August 2016.

Results: A higher percentage of males was diagnosed at a younger age. Nodular sclerosis histopathological HL subtype was most common, followed by mixed cellularity subtype. Eighty-one (36.2%), 101 (45.1%), and 42 (18.8%) patients were classified into low, intermediate, and high-risk groups, respectively. Doxorubicin, bleomycin, vinblastine, dacarbazine was the most common protocol (n = 102, 45.5%). Event-free survival rate was 86.0% ± 2.4%, while five-year overall survival (OS) rate was 96.1% ± 1.4%: 98.7% ± 1.3%, 97.7% ± 1.6%, and 86.5% ± 5.6% in the low, intermediate, and high-risk groups, respectively ( = 0.021). Five-year OS was worse in patients with B-symptoms, stage IV disease, high-risk, splenic involvement, extra-nodal lymphoma, and elevated lactate dehydrogenase level. In multivariate analysis, B-symptoms and extra-nodal involvement were prognostic factors for poor OS. Late complications of endocrine disorders and secondary malignancy were observed in 17 and 6 patients, respectively.

Conclusion: This is the first study on the epidemiology and treatment outcomes of HL in children, adolescents, and young adults in Korea. Future prospective studies are indicated to develop therapies that minimize treatment toxicity while maximizing cure rates in children, adolescents, and young adults with HL.
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http://dx.doi.org/10.3346/jkms.2020.35.e393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707923PMC
November 2020

Outcomes of pediatric acute myeloid leukemia patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era.

Blood Res 2020 Dec;55(4):217-224

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Children's Hospital, Seoul, Korea.

Background: Acute myeloid leukemia (AML) with internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with poor outcomes. This study aimed to analyze the outcomes of pediatric AML patients with FLT3-ITD mutations in the pre-FLT3 inhibitor era.

Methods: We retrospectively reviewed and identified 18 patients diagnosed with non-M3 AML with FLT3-ITD mutations at Seoul National University Children's Hospital between May 2008 and August 2019.

Results: The median age was 13 years (range, 6?19 yr). The median follow-up time was 43 months (range, 6?157 mo). Fourteen patients received BH-AC-based (N4-Behenoy1-1-b-D-arabinofuranosy1cytosine) and 4 received cytarabine-based induction chemotherapy. Complete remission (CR) was achieved in 72.2% of the patients after the first induction chemotherapy and 80% of the patients achieved CR after salvage therapy. The overall CR rate was 94% (17/18 patients). These 17 patients underwent hematopoietic stem cell transplantation (9 matched unrelated donors, 5 matched related donors, and 3 haploidentical donors). Relapse occurred in 22% of the patients. Event free survival and overall survival rates were 53.8±12.1% and 53.6±12.1%, respectively, and they were not significantly different according to the type of induction chemotherapy (P=0.690) or the type of donor (P=0.102).

Conclusion: This study outlines the outcomes of pediatric AML patients with FLT3-ITD-mutations in one institution over a decade. Outcomes were significantly improved in this study compared to our previous report in 2004, where RFS and EFS were 0%. This study can provide baseline data for pediatric patients in the pre-FLT3 inhibitor era.
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http://dx.doi.org/10.5045/br.2020.2020127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784129PMC
December 2020

Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years.

Cancer Res Treat 2021 Apr 28;53(2):378-388. Epub 2020 Oct 28.

Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Purpose: Atypical teratoid/rhabdoid tumor (ATRT) is a highly aggressive malignancy with peak incidence in children aged less than 3 years. Standard treatment for central nervous system ATRT in children under the age of 3 years have not been established yet. The objective of this study was to analyze characteristics and clinical outcomes of ATRT in children aged less than 3 years.

Materials And Methods: A search of medical records from seven centers was performed between January 2005 and December 2016.

Results: Forty-three patients were enrolled. With a median follow-up of 90 months, 27 patients (64.3%) showed at least one episode of disease progression (PD). The first date of PD was at 160 days after diagnosis. The 1- and 3-year progression-free survivals (PFS) were 51.2% and 28.5%, respectively. The 1- and 3-year overall survivals were 61.9% and 38.1%, respectively. The 3-year PFS was improved from 0% in pre-2011 to 47.4% in post-2011. Excluding one patient who did not receive any further therapy after surgery, 27 patients died due to PD (n=21), treatment-related toxicity (n=5), or unknown cause (n=1). In univariate analysis, factors associated with higher 3-year PFS were no metastases, diagnosis after 2011, early adjuvant radiotherapy, and high-dose chemotherapy (HDCT). In multivariate analysis, the use of HDCT and adjuvant radiotherapy remained significant prognostic factors for PFS (both p < 0.01).

Conclusion: Aggressive therapy including early adjuvant radiotherapy and HDCT could be considered to improve outcomes of ATRT in children under the age of 3 years.
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http://dx.doi.org/10.4143/crt.2020.756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053862PMC
April 2021

Treatment outcome and long-term follow-up of central nervous system germ cell tumor using upfront chemotherapy with subsequent photon or proton radiation therapy: a single tertiary center experience of 127 patients.

BMC Cancer 2020 Oct 9;20(1):979. Epub 2020 Oct 9.

Departments of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: Central nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy.

Methods: We retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children's Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients' choice.

Results: The median age at diagnosis was 11.9 (range, 3.8-25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy.

Conclusion: The strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.
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http://dx.doi.org/10.1186/s12885-020-07484-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547441PMC
October 2020

A Case of Consumptive Hypothyroidism in a 1-Month-Old Boy with Diffuse Infantile Hepatic Hemangiomas.

J Korean Med Sci 2020 Jun 8;35(22):e180. Epub 2020 Jun 8.

Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Korea.

Consumptive hypothyroidism is a rare paraneoplastic syndrome characterized by excessive inactivation of the thyroid hormones due to increased type 3 iodothyronine deiodinase activity of tumors. We report the case of severe consumptive hypothyroidism in a 1-month-old boy with infantile hepatic hemangiomas who presented with cardiac failure and cholestasis. Diffuse infiltration of hepatic hemangiomas was detected on abdominal imaging studies, and thyroid function screening test revealed severe hypothyroidism, which necessitated the administration of higher-than-usual doses of levothyroxine for the normalization of thyroid function. The patient was successfully treated with propranolol, prednisolone, and levothyroxine, and he showed normal thyroid function at 3 months of age and normal neurodevelopment at 9 months of age. This case highlights the importance of early recognition and prompt management of consumptive hypothyroidism in patients with infantile hepatic hemangiomas.
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http://dx.doi.org/10.3346/jkms.2020.35.e180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279942PMC
June 2020

Immunosenescent characteristics of T cells in young patients following haploidentical haematopoietic stem cell transplantation from parental donors.

Clin Transl Immunology 2020 Apr 8;9(4):e1124. Epub 2020 Apr 8.

Department of Pediatrics Seoul National University College of Medicine Seoul South Korea.

Objectives: Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients.

Methods: In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy).

Results: Senescent T cells, CD28 or CD57 cells, were significantly expanded in patients. Further, not only CD4CD28 T cells, but also CD4CD28 T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4 and CD8 T cells in patients were influenced by donor age and the frequency of CD28 cells, respectively.

Conclusion: Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.
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http://dx.doi.org/10.1002/cti2.1124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142179PMC
April 2020

Combination Therapy With Chemotherapy, Donor Lymphocyte Infusion With Concurrent Blinatumomab in Relapsed/Refractory Acute Precursor B-Lymphoblastic Leukemia.

J Pediatr Hematol Oncol 2021 03;43(2):e280-e283

Department of Pediatrics, Seoul National University College of Medicine.

The therapeutic approach for relapsed/refractory acute lymphoblastic leukemia (ALL) remains to be a challenge. The patient was diagnosed as B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic hematopoietic stem cell transplantation (one after first complete remission [CR1] and the other after CR2). During blinatumomab monotherapy, he developed an extramedullary relapse. Finally, the combined therapy with clofarabine, donor lymphocyte infusion, and blinatumomab induced CR of the bone marrow and extramedullary relapse. Unfortunately, the patient developed central nervous system relapse, however, this case showed a promising potential for combination therapy with clofarabine, donor lymphocyte infusion, and blinatumomab in relapsed/refractory B-cell ALL.
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http://dx.doi.org/10.1097/MPH.0000000000001789DOI Listing
March 2021

Nitrosourea, etoposide and cyclophosphamide followed by autologous stem cell transplantation for pediatric lymphoma patients.

Int J Hematol 2020 Jun 26;111(6):877-887. Epub 2020 Mar 26.

Department of Pediatrics, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.

Treatment outcomes in pediatric lymphoma have improved substantially over the past 2 decades; however, the prognosis for patients with high risk or relapsed disease remains poor. We evaluated outcomes of high-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) in 56 pediatric lymphoma patients. Patients received nitrosourea (51 BCNU; 5 ACNU), etoposide, and cyclophosphamide (BEC; AEC). Median age at HDC/auto-SCT was 12 years (range 2-17 years). Forty-four patients underwent HDC/auto-SCT because they did not achieve complete remission after induction chemotherapy. Eight patients showed relapse and four NK/T-cell lymphoma patients also underwent HDC/auto-SCT. BCNU pneumonitis was diagnosed in nine (16.0%) patients. Eight (14.3%) relapsed after HDC/auto-SCT. Treatment-related mortality occurred in three cases. Five-year event-free survival and overall survival rates were 74.8% [72.7% non-Hodgkin's lymphoma (NHL); 83.3% Hodgkin's disease (HD); 72.7%] and 83.6% (81.6% NHL; 91.7% HD), respectively. HDC/auto-SCT with BEC or AEC regimen for pediatric high-risk lymphoma patients showed feasible outcomes. However, treatment modifications are warranted to reduce relapse and toxicity.
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http://dx.doi.org/10.1007/s12185-020-02863-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222091PMC
June 2020

Cytomegalovirus disease in a retinoblastoma cohort: The role of preemptive screening.

Pediatr Blood Cancer 2020 03 2;67(3):e28101. Epub 2019 Dec 2.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Background: Cytomegalovirus (CMV) disease is underrecognized in children with retinoblastoma. This study investigated rates of CMV infection and disease in this specific population receiving chemotherapy.

Methods: From a cohort of 164 patients with retinoblastoma diagnosed from 2011 to 2018, 107 patients were evaluated for CMV infection determined by antigenemia assay or real-time PCR. Preemptive CMV screening was implemented in 2013. CMV disease was diagnosed by tissue biopsy, culture, or ophthalmic examination.

Results: Thirty-seven and 70 patients before and after the screening strategy, respectively, were included. Before screening, 10/37 (27%) were diagnosed with CMV infection during chemotherapy. Among them, 5 (50%) developed CMV disease (hepatitis, pneumonia, and retinitis) and one patient died of CMV pneumonia. During screening, 18/70 (26%) were documented with 36 episodes of CMV infection and 9 patients received 25 preemptive antiviral therapies. Age at chemotherapy tended to be younger in patients with CMV infection, and fewer were seronegative prior to chemotherapy. Patients who started chemotherapy at <12 months of age received preemptive therapies significantly more often than those started at ≥12 months. Two (11%) out of 18 patients with CMV infection developed CMV retinitis and colitis, and there were no fatal cases. Preemptive therapy along with active CMV screening significantly reduced the risk of developing CMV disease, from 14% to 2.9% (P = 0.047).

Conclusions: Children with retinoblastoma can experience significant morbidity and even mortality from CMV infection during chemotherapy in Korea. Preemptive screening and appropriate antiviral therapy can reduce the development of CMV disease and subsequent mortality.
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http://dx.doi.org/10.1002/pbc.28101DOI Listing
March 2020

Stress Induced Cardiomyopathy Requiring Ventricular Assist Device Support in an 8-Year-Old Girl with Acute Leukemia.

Chonnam Med J 2019 Sep 24;55(3):179-180. Epub 2019 Sep 24.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Children's Hospital, Seoul, Korea.

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http://dx.doi.org/10.4068/cmj.2019.55.3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769250PMC
September 2019

Successful preemptive therapy with single-dose rituximab for Epstein-Barr virus infection to prevent post-transplant lymphoproliferative disease after pediatric hematopoietic stem cell transplantation.

Transpl Infect Dis 2019 Dec 15;21(6):e13182. Epub 2019 Oct 15.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.

Background: The efficacy of preemptive treatment containing rituximab to prevent post-transplant lymphoproliferative disease (PTLD) in children has not yet been fully elucidated.

Methods: We analyzed 19 pediatric patients who developed high Epstein-Barr virus (EBV) DNAemia (EBV viral load of greater than 40 000 copies/mL) after allogeneic hematopoietic stem cell transplantation (HSCT) and were preemptively administered rituximab. Rituximab was intravenously injected at a dose of 375 mg/m once the EBV viral load was greater than 40 000 copies/mL.

Results: In all 19 patients, EBV DNAemia was eradicated after a median of 9 days (range, 3-20 days), and PTLD did not occur. One patient had transient fever, and four patients did not fully recover B cell counts after transplantation. We suggested that delayed B cell recovery was caused by chronic graft-versus-host disease (GVHD) related drugs, not rituximab administration. And there were no other infection-related side effects.

Conclusions: In conclusion, preemptive therapy containing rituximab is expected to reduce the incidence of PTLD after HSCT and improve post-transplantation outcomes in children.
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http://dx.doi.org/10.1111/tid.13182DOI Listing
December 2019

Successful treatment of refractory CMV colitis after haploidentical HSCT with post-transplant cyclophosphamide using CD45RA depleted donor lymphocyte infusion.

Bone Marrow Transplant 2020 08 16;55(8):1674-1676. Epub 2019 Sep 16.

Department of Pediatrics, Seoul National University College of Medicine and Seoul National University Cancer Research Institute, Seoul, Republic of Korea.

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http://dx.doi.org/10.1038/s41409-019-0685-zDOI Listing
August 2020

Pharmacokinetics of high-dose carboplatin in children undergoing high-dose chemotherapy and autologous stem cell transplantation with BSA-based dosing.

Bone Marrow Transplant 2020 01 28;55(1):137-146. Epub 2019 Aug 28.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Body surface area (BSA)-based carboplatin dosing is used in various centers due to practical issues of renal function-based dosing with area under the curve (AUC) measurement. Pharmacokinetic (PK) analysis of high-dose carboplatin was performed in pediatric solid tumor patients undergoing high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) with BSA-based dosing to calculate the AUCs achieved with this dosing method and to find the correlation between the PK and the renal functions and the adverse events. Carboplatin was administered as once daily intravenous doses at 300, 400, or 500 mg/m/day over 1 h for 3 or 4 days. On the first and the last day of carboplatin administration, PK samplings were done at 0, 1, 2, and 5 h and only at 0 h on any other days. Mean AUC on the first and the last day were 4.85 ± 0.95 min × mg/mL and 5.27 ± 1.04 min × mg/mL, respectively (n = 23). Overall, negative correlations between the renal functions and the AUCs were mild to moderate, but they were stronger in nephrectomized patients. Cr-EDTA clearance decreased with statistical significance with each additional dose of carboplatin (P = 0.020). Optimal high-dose carboplatin dosing method and optimal target AUCs for the different tumors need further analysis.
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http://dx.doi.org/10.1038/s41409-019-0655-5DOI Listing
January 2020

Tandem high-dose chemotherapy with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin regimens for pediatric high-risk brain tumors.

Int J Clin Oncol 2019 Dec 27;24(12):1515-1525. Epub 2019 Jul 27.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.

Background: High-dose chemotherapy (HDC) and autologous stem-cell transplantation (auto-SCT) are used to improve the survival of children with high-risk brain tumors who have a poor outcome with the standard treatment. This study aims to evaluate the outcome of HDC/auto-SCT with topotecan-thiotepa-carboplatin and melphalan-etoposide-carboplatin (TTC/MEC) regimens in pediatric brain tumors.

Methods: We retrospectively analyzed the data of 33 children (median age 6 years) who underwent HDC/auto-SCT (18 tandem and 15 single) with uniform conditioning regimens.

Results: Eleven patients aged < 3 years at diagnosis were eligible for HDC/auto-SCT to avoid or defer radiotherapy. In addition, nine patients with high-risk medulloblastoma (presence of metastasis and/or postoperative residual tumor ≥ 1.5 cm), eight with other high-risk brain tumor (six CNS primitive neuroectodermal tumor, one CNS atypical teratoid/rhabdoid tumor, and one pineoblastoma), and five with relapsed brain tumors were enrolled. There were three toxic deaths, and two of which were due to pulmonary complications. The main reason for not performing tandem auto-SCT was due to toxicities and patient refusal. The event-free survival (EFS) and overall survival (OS) rates of all patients were 59.4% and 80.0% at a median follow-up with 49.1 months from the first HDC/auto-SCT, respectively. The EFS/OS rates of patients aged < 3 years at diagnosis, high-risk medulloblastoma, other high-risk brain tumor, and relapsed tumors were 50.0/81.8%, 87.5/85.7%, 66.7/88.9%, and 20.0/60.0%, respectively.

Conclusions: Although tandem HDC/auto-SCT with TTC/MEC regimens showed promising survival rates, treatment modifications are warranted to reduce toxicities. The survival rates with relapsed brain tumors were unsatisfactory despite HDC/auto-SCT, and further study is needed.
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http://dx.doi.org/10.1007/s10147-019-01517-8DOI Listing
December 2019

Late Recurrence of Wilms Tumor After 17 Years: A Case Report.

J Pediatr Hematol Oncol 2020 08;42(6):e488-e490

Departments of Pediatrics.

Wilms tumor is the most common renal malignancy in children. Most of Wilms tumor recurrences occur within 2 years of the first diagnosis. Relapse after 5 years after the first diagnosis is called "late recurrence" and is rare in Wilms tumor. There are few case reports or small series of late recurrence of Wilms tumor. Because of the rarity of late recurrence of Wilms tumor, there is no clear guideline for its management. We describe a case of late recurrence of Wilms tumor as a remote metastasis in the lung at 18 years after the first diagnosis and 17 years after the second remission, which was achieved by radiotherapy and high-dose chemotherapy with autologous stem cell rescue. After late recurrence, the patient was treated by surgery and adjuvant chemotherapy, and remained disease-free for 11 months. Several very late recurrences of Wilms tumor in the literature are reviewed.
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http://dx.doi.org/10.1097/MPH.0000000000001473DOI Listing
August 2020

Application of Fluorescence In Situ Hybridization on Cerebrospinal Fluid Cytospins for the Detection of Residual Leukemic Cells in Patients With Childhood Acute Lymphoblastic Leukemia.

Am J Clin Pathol 2019 03;151(4):416-423

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.

Objectives: Diagnosis of central nervous system involvement in acute lymphoblastic leukemia (ALL) requires morphologic expertise; therefore, we evaluated interphase fluorescence in situ hybridization (iFISH) of cerebrospinal fluid (CSF) cytospin preparations as a potential complementary test.

Methods: Twenty-three CSF cytospin specimens from 13 pediatric patients with ALL were included. iFISH probes detecting BCR-ABL1, ETV6-RUNX1, and KMT2A rearrangement and CDKN2A deletion, which were present at initial diagnosis, were used on follow-up CSF cytospin specimens and were compared with cytology.

Results: Seventeen (73.9%) follow-up specimens showed concordant results between iFISH and cytology. Two (8.7%) samples with discordant results were positive by iFISH but not by cytology; one (4.3%) was positive only by cytology. In the remaining three (13.0%) specimens, too few cells were available for cytology, whereas iFISH interpretation was possible.

Conclusions: iFISH of CSF cytospin preparations improves malignant cell detection in pediatric ALL.
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http://dx.doi.org/10.1093/ajcp/aqy160DOI Listing
March 2019

Quantification of Thiopurine Nucleotides in Erythrocytes and Clinical Application to Pediatric Acute Lymphoblastic Leukemia.

Ther Drug Monit 2019 02;41(1):75-85

Department of Laboratory Medicine, Seoul National University College of Medicine.

Background: Concentrations of 6-thioguanine (6TG) nucleotides and 6-methylmercaptopurine (6MMP) nucleotides in RBCs were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This assay was validated for clinical use and was applied to blood samples from patients taking mercaptopurine (6MP).

Methods: RBCs were hemolyzed and deproteinized using perchloric acid, followed by heating for the hydrolysis of nucleotides, and the resultant base was measured using LC-MS/MS. Precision, recovery, linearity, matrix effect, and limit of quantification was validated for clinical application. Our results were compared with another institution's established LC-MS/MS assay. We measured the concentrations of 6TG and 6MMP in RBCs of pediatric patients with acute lymphoblastic leukemia (ALL), and the clinical impact of those metabolites was investigated.

Results: The imprecision coefficient of variations of 6TG and 6MMP were 5.7%-8.1%, and the bias was within 5%. Lower limits of quantification were set at 54 ng/mL for 6TG and 1036 ng/mL for 6MMP. Correlation coefficients for 6TG and 6MMP were 0.997 and 1.0 in a comparison study. For clinical proof-of-concept, 74 blood samples were collected from 37 pediatric ALL patients receiving maintenance therapy. Concentration of 6TG ranged from 16.1 to 880 pmol/8 × 10 RBCs and that of 6MMP from 55 to 20,937 pmol/8 × 10 RBCs. The 6MP metabolites were not correlated with WBC or absolute neutrophil count. On the other hand, the higher 6MMP level was associated with elevated alanine aminotransferase and aspartate aminotransferase.

Conclusions: In this study, an assay for the quantification of 6TG and 6MMP in RBCs was established and applied to pediatric ALL patients. Interindividual variability in 6MP metabolite concentrations was considerable and associated with elevation of liver enzymes, which may be useful in the clinical monitoring of 6MP maintenance therapy in pediatric ALL patients.
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http://dx.doi.org/10.1097/FTD.0000000000000575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358190PMC
February 2019

The First Case of Congenital Prekallikrein Deficiency in Korea With a Novel Pathogenic Variant (c.1198G>T).

Ann Lab Med 2019 Mar;39(2):229-231

Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.

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http://dx.doi.org/10.3343/alm.2019.39.2.229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240513PMC
March 2019

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.

Biol Blood Marrow Transplant 2018 11 6;24(11):2239-2244. Epub 2018 Jul 6.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea; Seoul National University Cancer Research Institute, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1016/j.bbmt.2018.06.034DOI Listing
November 2018

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

Bone Marrow Transplant 2019 02 18;54(2):284-292. Epub 2018 Jun 18.

Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

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/m, 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.
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http://dx.doi.org/10.1038/s41409-018-0260-zDOI Listing
February 2019

Successful haploidentical transplantation with post-transplant cyclophosphamide for activated phosphoinositide 3-kinase δ syndrome.

J Allergy Clin Immunol Pract 2019 03 8;7(3):1034-1037.e1. Epub 2018 Jun 8.

Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea; Seoul National University Cancer Research Institute, Seoul, Korea. Electronic address:

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http://dx.doi.org/10.1016/j.jaip.2018.05.029DOI Listing
March 2019

Successful Treatment of Pediatric Epstein-Barr Virus-positive Aggressive Natural Killer-Cell Leukemia.

J Pediatr Hematol Oncol 2019 07;41(5):e336-e337

Department of Pediatrics, Seoul National University College of Medicine, Seoul National University Cancer Research Institute.

Epstein-Barr virus (EBV)-positive aggressive natural killer-cell leukemia (ANKL) is a rare malignancy of mature natural killer cells, with a very poor survival rate. Patients have a rapidly declining clinical course and a poor prognosis, with a median survival of only a few months. Herein, we describe a 16-year-old boy who was diagnosed with EBV-positive ANKL and successfully treated using combination chemotherapy and a subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT). The patient is disease free 4 years and 9 months after alloHSCT. Thus, combination chemotherapy followed by alloHSCT seems to be a promising therapeutic option for EBV-positive ANKL.
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http://dx.doi.org/10.1097/MPH.0000000000001237DOI Listing
July 2019
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