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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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.

Citations

Citations to this article as recorded by

The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia
Muhammad Muhammad, Maher Saifo, Majd Aljamali, Mousa Alali, Khaled M. Ghanem
Frontiers in Oncology.2024;[Epub] CrossRef
Editorial Response to the Letter Relating to our Article “Predicting Adverse Events to Thiopurines in IBD: Are We a Step Closer?”
Mohmmed Tauseef Sharip, Miles Parkes, Sreedhar Subramanian
Inflammatory Bowel Diseases.2024;[Epub] CrossRef
Mercaptopurine induced myelosuppression in a child with a NUDT15 rs116855232 homozygous variant
Navya Gupta, Latha Sneha Magatha, Dhaarani Jayaraman, Julius Xavier Scott, Sharon Benita Antony, Teena Koshy
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Density functional study of transition metal (Fe,Co,Ni)‐doped C60 fullerenes as 6‐thioguanine delivery system
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Applied Organometallic Chemistry.2023;[Epub] CrossRef
The influence of NUDT15 variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia
Mai-Lan Nguyen, Anh Vu Hoang, Bich Tram Duong, Nguyen The Nguyen Phung
Human Genetics and Genomics Advances.2023; 4(2): 100183. CrossRef
NUDT15 genetic testing-guided 6-mercaptopurine dosing in children with ALL likely to be cost-saving in China
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
NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine
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The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia
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DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes
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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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