Cancer Research and Treatment

Original Articles

Survival of Children with Acute Lymphoblastic Leukemia with Risk Group-Based Protocol Changes: A Single Center Experience with 460 Patients over a 20-Year Period: Na Hee Lee, Hee Young Ju, Eun Sang Yi, Young Bae Choi, Keon Hee Yoo, Hong Hoe Koo; Received February 6, 2024 Accepted September 21, 2024 Published online September 27, 2024; DOI: https://doi.org/10.4143/crt.2024.127 [Accepted]

Abstract PDF: Purpose
Recent treatments for pediatric acute lymphoblastic leukemia (ALL) are founded on risk stratification. We examined the survival rates and prognostic factors of patients over a 20-year period at a single institution.
Materials and Methods
This study analyzed patients diagnosed with ALL and treated at the Pediatric Department of Samsung Medical Center (SMC). Patients were categorized into standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. The SMC protocol for the HR group underwent two changes during the study period: A modified Children's Cancer Group (CCG)-1882 protocol was used from 2000 to 2005, the Korean multicenter HR ALL-0601 protocol from 2006 to 2014, and the Korean multicenter HR ALL-1501 protocol from 2015 to 2019.
Results
Of the 460 patients, complete remission was achieved in 436 patients (94.8%). The 10-year overall survival rate (OS) was 83.8±1.9% for all patients. OS according to the SMC risk group was as follows: 95.9±1.4% in the SR group, 83.8±3.6% in the HR group, and 66.2±6.9% in the VHR group. The 5-year OS within the HR group varied according to the treatment protocol: 73.9±7.5%, in the modified CCG-1882 protocol, 83.0±3.9%, in the 0601 protocol, and 96.2±2.6%, in the 1501 protocol. For those aged 15 years and older, the OS was only 56.5±13.1%. Relapse occurred in 71 patients (15.4%), and the OS after relapse was 37.7±6.0%.
Conclusion
The treatment outcomes of patients with ALL improved markedly. However, there is a need to further characterize adolescents and young adult patients, as well as those who have experienced relapses.

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The Effect of Hematopoietic Stem Cell Transplantation on Treatment Outcome in Children with Acute Lymphoblastic Leukemia: Hee Young Ju, Na Hee Lee, Eun Sang Yi, Young Bae Choi, So Jin Kim, Ju Kyung Hyun, Hee Won Cho, Jae Kyung Lee, Ji Won Lee, Ki Woong Sung, Hong Hoe Koo, Keon Hee Yoo; Received February 14, 2024 Accepted July 4, 2024 Published online July 5, 2024; DOI: https://doi.org/10.4143/crt.2024.155 [Epub ahead of print]

Abstract PDF PubReader ePub: Purpose
Hematopoietic stem cell transplantation (HSCT) has been an important method of treatment in the advance of pediatric acute lymphoblastic leukemia (ALL). The indications for HSCT are evolving and require updated establishment. In this study, we aimed to investigate the efficacy of HSCT on the treatment outcome of pediatric ALL, considering the indications for HSCT and subgroups.
Materials and Methods
A retrospective analysis was conducted on ALL patients diagnosed and treated at a single center. Risk groups were categorized based on age at diagnosis, initial white blood cell count, disease lineage (B/T), and cytogenetic study results. Data on the patients’ disease status at HSCT and indications of HSCT were collected. Indications for HSCT were categorized as upfront HSCT at 1st complete remission, relapse, and refractory disease.
Results
Among the 549 screened patients, a total of 418 patients were included in the study; B-cell ALL (n=379) and T-cell ALL (T-ALL) (n=39). HSCT was conducted on a total of 106 patients (25.4%), with a higher frequency as upfront HSCT in higher-risk groups and specific cytogenetics. The overall survival (OS) was significantly better when done upfront than in relapsed or refractory state in T-ALL patients (p=0.002). The KMT2A-rearranged ALL patients showed superior event-free survival (p=0.002) and OS (p=0.022) when HSCT was done as upfront treatment.
Conclusion
HSCT had a substantial positive effect in a specific subset of pediatric ALL. In particular, frontline HSCT for T-ALL and KMT2A-rearranged ALL offered a better prognosis than when HSCT was conducted in a relapsed or refractory setting.

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Pediatric cancer

Epidemiology of Acute Leukemia among Children with Down Syndrome in Korea: Young Bae Choi, Keon Hee Yoo; Cancer Res Treat. 2022;54(2):572-578. Published online August 10, 2021; DOI: https://doi.org/10.4143/crt.2021.368

Abstract PDF PubReader ePub

Purpose
Children with Down syndrome (DS) show a higher risk of acute leukemia than those without DS. In this study, we investigated the nationwide incidence of acute leukemia among children with DS and compared their epidemiologic characteristics with those of children with acute leukemia but without DS.
Materials and Methods
Using the National Health Insurance Service database, we selected patients with acute leukemia aged 0–19 years at diagnosis between 2007 and 2016.
Results
Among the 4,697 children with acute leukemia, 54 (1.1%) had DS. The median incidence rate of leukemia with DS by year was 1.3% (range, 0.2%–2.0%). Sixteen patients with acute lymphoblastic leukemia (ALL; 29.6%) and 36 with acute myeloid leukemia (AML; 66.7%) had DS. The DS group showed younger age at diagnosis than the non-DS group, and diagnosis of AML was more frequent in the DS group than in the non-DS group (3 years vs. 9 years, p<0.001; 66.7% vs. 32.4%, P<0.001, respectively). The 5-year overall survival was comparable between the DS and non-DS groups (88.0% vs. 81.9%, p=0.375). Among all the Koreans born between 2007 and 2008, the incidences of acute leukemia, ALL, and AML were 49.25, 20.75, and 163.38 times higher, respectively, in the DS group than in the non-DS group.
Conclusion
Our findings support the fact that the incidence of acute leukemia is higher among patients with DS than among those without DS in Korea. However, the DS and non-DS groups in this study had a comparable overall survival rate.

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Cancer risks related to intellectual disabilities: A systematic review
Amina Banda, Jenneken Naaldenberg, Aura Timen, Agnies van Eeghen, Geraline Leusink, Maarten Cuypers
Cancer Medicine.2024;[Epub] CrossRef

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Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: A Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group: Kyung Mi Park, Keon Hee Yoo, Seong Koo Kim, Jae Wook Lee, Nack-Gyun Chung, Hee Young Ju, Hong Hoe Koo, Chuhl Joo Lyu, Seung Min Han, Jung Woo Han, Jung Yoon Choi, Kyung Taek Hong, Hyoung Jin Kang, Hee Young Shin, Ho Joon Im, Kyung-Nam Koh, Hyery Kim, Hoon Kook, Hee Jo Baek, Bo Ram Kim, Eu Jeen Yang, Jae Young Lim, Eun Sil Park, Eun Jin Choi, Sang Kyu Park, Jae Min Lee, Ye Jee Shim, Ji Yoon Kim, Ji Kyoung Park, Seom Gim Kong, Young Bae Choi, Bin Cho, Young Tak Lim; Cancer Res Treat. 2022;54(1):269-276. Published online April 20, 2021; DOI: https://doi.org/10.4143/crt.2021.313

Abstract PDF PubReader ePub

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 children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×10⁹/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×10⁹/L than in those with initial WBC ≥ 10×10⁹/L (p=0.020).
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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Sabine Kayser, Shannon E. Conneely
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Chi-kong Li, Purna Kurkure, Ramandeep Singh Arora, Bow Wen Chen, Kirill Kirgizov, Yasuhiro Okamoto, Panya Seksarn, Yongmin Tang, Keon Hee Yoo, Bharat Agarwal, Godfrey C.F. Chan, Rashmi Dalvi, Hiroki Hori, Muhammad Saghir Khan, Alice Yu, Akira Nakagawara
JCO Global Oncology.2023;[Epub] CrossRef
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Anna Maria Testi, Mazin Faisal Al-Jadiry, Hasanein Habeeb Ghali, Samaher Abdulrazzaq Fadhil, Amir Fadhil Al-Darraji, Raghad Majid Al-Saeed, Ahmed Hatem Sabhan, Safaa A. Faraj Al-Badri, Wisan Majeed Abed, Najiha Ahmed Ameen, Ruaa Zaki Al-Tameemi, Arabiya I
Leukemia & Lymphoma.2022; 63(12): 2940. CrossRef
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Lila Krebs-Drouot, Georgia Karpathiou, Virginie Scolan, Carolyne Bidat-Callet, Baptiste Boyer, Michel Péoc’h
Forensic Science, Medicine and Pathology.2022; 19(1): 60. CrossRef
Successful Treatment of Isolated Central Nervous System Relapse with Intrathecal Chemotherapy in an Adolescent with Acute Promyelocytic Leukemia
Haerim Song, Eun Sang Yi
Clinical Pediatric Hematology-Oncology.2022; 29(2): 70. CrossRef

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NUDT15 Variants Cause Hematopoietic Toxicity with Low 6-TGN Levels in Children with Acute Lymphoblastic Leukemia: Eun Sang Yi, Young Bae Choi, Rihwa Choi, Na Hee Lee, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Soo-Youn Lee, Hong Hoe Koo; Cancer Res Treat. 2018;50(3):872-882. Published online September 13, 2017; DOI: https://doi.org/10.4143/crt.2017.283

Abstract PDF PubReader ePub

Purpose
We aimed to identify the impact of NUDT15 variants on thiopurine intolerance and 6-thioguanine nucleotide (6-TGN) levels in Korean children with acute lymphoblastic leukemia (ALL).
Materials and Methods
Genotyping of NUDT15 was tested in 258 patients with ALL registered at Samsung Medical Center. Patients were classified into normal-activity (wild-type), intermediate-activity (heterozygous variant), and low-activity groups (homozygous or compound heterozygous variant). Clinical and laboratory features during the first year of maintenance therapy were investigated.
Results
A total of 182 patients were included in the final analysis. There were five (2.7%), 46 (25.3%), and 131 (72.0%) patients in low-, intermediate-, and normal-activity groups, respectively. The lowest 6-mercaptopurine (6-MP) dose (mg/m2/day) was administered to the low-activity group (low-activity group 7.5 vs. intermediate-activity group 24.4 vs. normalactivity group 31.1, p < 0.01) from three months to a year after beginning maintenance therapy. The low-activity group experienced the longest duration of therapy interruption during the first year (low-activity group 169 days vs. intermediate-activity group 30 days vs. normal-activity group 16 days, p < 0.01). They also showed the lowest blood cell counts and had a longer duration of leukopenia (low-activity group 131 days vs. intermediate-activity group 92 days vs. normal-activity group 59 days, p < 0.01). 6-TGN level and its ratio to 6-MP dose were lowest in the low-activity group.
Conclusion
NUDT15 variants cause hematopoietic toxicity with low 6-TGN levels. NUDT15 genotyping should be conducted before administering thiopurine, and dose adjustments require caution regardless of 6-TGN levels.

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XiaoXia Wei, Jing Zhuang, Na Li, Bin Zheng, Hong Sun, JiaQin Cai, Xuhui Huang, Guifeng Zhang, Jie Zhuang
International Journal of Hematology.2022; 115(2): 278. CrossRef
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Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Atypical Teratoid/Rhabdoid Tumor: Ki Woong Sung, Do Hoon Lim, Eun Sang Yi, Young Bae Choi, Ji Won Lee, Keon Hee Yoo, Hong Hoe Koo, Ji Hye Kim, Yeon-Lim Suh, Yoo Sook Joung, Hyung Jin Shin; Cancer Res Treat. 2016;48(4):1408-1419. Published online April 1, 2016; DOI: https://doi.org/10.4143/crt.2015.347

Abstract PDF PubReader ePub

Purpose
We prospectively evaluated the effectiveness of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in improving the survival of patients with atypical teratoid/rhabdoid tumors while reducing the risks of late adverse effects from radiotherapy (RT).
Materials and Methods
For young children (< 3 years old), tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy. RT was deferred until after 3 years of age unless the tumor showed relapse or progression. For older patients (> 3 years old), RT including reduced-dose craniospinal RT (23.4 or 30.6 Gy) was administered either after two cycles of induction chemotherapy or after surgery, and tandem HDCT/auto-SCT was administered after six cycles of induction chemotherapy.
Results
A total of 13 patients (five young and eight older) were enrolled from November 2004 to June 2012. Eight patients, including all five young patients, had metastatic disease at diagnosis. Six patients (four young and two older) experienced progression before initiation of RT, and seven were able to proceed to HDCT/auto-SCT without progression during induction treatment. Three of six patients who experienced progression during induction treatment underwent HDCT/auto-SCT as salvage treatment. All five young patients died from disease progression. However, four of the eight older patients remain progression-freewith a median follow-up period of 64 months (range, 39 to 108 months). Treatment-related late toxicities were acceptable.
Conclusion
The required dose of craniospinal RT might be reduced in older patients if the intensity of chemotherapy is increased. However, early administration of RT should be considered to prevent early progression in young patients.

Citations

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Beate Timmermann, Claire Alapetite, Karin Dieckmann, Rolf-Dieter Kortmann, Yasmin Lassen-Ramshad, John H. Maduro, Monica Ramos Albiac, Umberto Ricardi, Damien C. Weber
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Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors
Hana Lim, Minji Im, Eun Seop Seo, Hee Won Cho, Hee Young Ju, Keon Hee Yoo, Sung Yoon Cho, Jong-Won Kim, Do Hoon Lim, Ki Woong Sung, Ji Won Lee
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Pediatric Blood & Cancer.2023;[Epub] CrossRef
Comparative treatment results of children with atypical teratoid/rhabdoid tumor of the central nervous system in the younger age group
L. V. Olkhova, O. G. Zheludkova, L. S. Zubarovskaya, A. S. Levashov, A. Yu. Smirnova, Yu. V. Dinikina, Yu. V. Kushel, A. G. Melikyan, S. K. Gorelyshev, M. V. Ryzhova, Yu. Yu. Trunin, A. G. Gevorgyan, O. B. Polushkina, V. E. Popov, L. P. Privalova, N. B. Y
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Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children: Case Reports and Literature Review
Gengyin Guo, Jianfeng Zhuang, Keke Zhang, Zhizhen Zhou, Yanjun Wang, Zhen Zhang
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Atypical Teratoid/Rhabdoid Tumor of the Central Nervous System in Children under the Age of 3 Years
Meerim Park, Jung Woo Han, Seung Min Hahn, Jun Ah Lee, Joo-Young Kim, Sang Hoon Shin, Dong-Seok Kim, Hong In Yoon, Kyung Taek Hong, Jung Yoon Choi, Hyoung Jin Kang, Hee Young Shin, Ji Hoon Phi, Seung-Ki Kim, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Hong H
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L. V. Olkhova, O. G. Zheludkova, L. S. Zubarovskaya, A. Yu. Smirnova, Yu. V. Dinikina, Yu. V. Kushel, A. G. Melikyan, S. K. Gorelyshev, M. V. Ryzhova, Yu. Yu. Trunin, E. I. Shults, A. G. Gevorgyan, S. V. Gorbatykh, A. N. Kislyakov, V. E. Popov, L. P. Priv
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Wan-Chin Yang, Hsiu-Ju Yen, Muh-Lii Liang, Hsin-Hung Chen, Yi-Yen Lee, Feng-Chi Chang, Shih-Chieh Lin, Tai-Tong Wong, Yu-Wen Hu, Yi-Wei Chen
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Lindsey M Hoffman, Elizabeth Anne Richardson, Ben Ho, Ashley Margol, Alyssa Reddy, Lucie Lafay-Cousin, Susan Chi, Irene Slavc, Alexander Judkins, Martin Hasselblatt, Franck Bourdeaut, Michael C Frühwald, Rajeev Vibhakar, Eric Bouffet, Annie Huang
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Reena M. Underiner, Mostafa Eltobgy, Joseph R. Stanek, Jonathan L. Finlay, Mohamed S. AbdelBaki
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Safety and feasibility of outpatient autologous stem cell transplantation in pediatric patients with primary central nervous system tumors
Jane Koo, Stacy Silverman, Brandon Nuechterlein, Amy K. Keating, Michael R. Verneris, Nicholas K. Foreman, Jean M. Mulcahy Levy
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Wan-Chin Yang, Hsiu-Ju Yen, Muh-Lii Liang, Hsin-Hung Chen, Yi-Yen Lee, Tai-Tong Wong, Yu-Wen Hu, Yi-Wei Chen
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Jung Yoon Choi, Hyoung Jin Kang, Kyung Taek Hong, Che Ry Hong, Yun Jeong Lee, June Dong Park, Ji Hoon Phi, Seung-Ki Kim, Kyu-Chang Wang, Il Han Kim, Sung-Hye Park, Young Hun Choi, Jung-Eun Cheon, Kyung Duk Park, Hee Young Shin
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Clinical Significance of Tyrosine Hydroxylase mRNA Transcripts in Peripheral Blood at Diagnosis in Patients with Neuroblastoma: Na Hee Lee, Meong Hi Son, Young Bae Choi, Eunsang Yi, Ji Won Lee, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo; Cancer Res Treat. 2016;48(4):1399-1407. Published online March 24, 2016; DOI: https://doi.org/10.4143/crt.2015.481

Abstract PDF PubReader ePub

Purpose
The purpose of this study is to investigate the clinical significance of tyrosine hydroxylase (TH) expression in peripheral blood (PB) at diagnosis in patients with neuroblastoma.
Materials and Methods
TH mRNA expression in PB was measured by reverse transcription quantitative real-time polymerase chain reaction in 210 patients who were newly diagnosed with neuroblastoma from July 2005 to June 2015 and the clinical significance of TH expression in PB at diagnosis was evaluated.
Results
TH expression was positive in 60 patients (28.6%). Fifty of 60 TH-positive patients had metastatic tumors and the remaining 10 had localized tumors. TH expression was associated with high-risk features (i.e., advanced stage, older age, unfavorable pathology, and MYCN amplification) at diagnosis. Among TH-positive patients, higher TH expression level was observed in high-risk patients than in low- or intermediate-risk patients (p=0.035). The probability of 5-year progression-free survival (PFS) was lower in TH-positive patients than in TH-negative patients (63.8±6.9% vs. 94.7±2.1%, p < 0.001). In analysis confined to high-risk patients, the 5-year probability of PFS remained lower in TH-positive patients (55.7±8.2% vs. 89.6±5.8%, p < 0.001). Among TH-positive patients, a higher expression level of TH was associated with a worse outcome. In multivariate analyses, positive TH expression in PB at diagnosis was an independent poor prognostic factor for PFS.
Conclusion
The treatment intensity should be tailored according to TH expression in PB at diagnosis.

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