Impact of ALK fusion variants and genetic profiles on prognosis in Chinese pediatric patients with ALK-positive anaplastic large cell lymphoma
Year: 2025
Type: conference-abstract
Abstract: Introduction: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is a major subtype of pediatric non-Hodgkin lymphoma. NPM1::ALK is the most common fusion in Chinese pediatric ALK-positive ALCL patients. However, the prognostic implications of variant ALK fusions and genetic profiles in Chinese pediatric patients with ALK-positive ALCL has not been fully characterized, hindering risk-adapted treatment strategies. Amis: This study aimed to explore the molecular variation characteristics of Chinese pediatric ALK-positive ALCL patients, including the distribution of fusion partner genes and mutation genes, as well as their relationship with prognosis. The findings will provide a basis for clinical prognosis assessment and personalized treatment. Methods: We analyzed 323 pediatric patients with ALK-positive ALCL (≤16 years) from the China Network of Childhood Lymphoma (CNCL). ALK-fusion status was determined by quantitative RT-PCR in 323 patients, and targeted next-generation sequencing of 262 lymphoma-related genes was performed in 50 patients. Molecular-clinical correlations were evaluated for survival and relapse outcomes. The median follow-up time was 36.8 months (95% CI: 31.6-40.8). Results: Of 323 pediatric ALK-positive ALCL patients with fusion data, 275 (85.1%) had ALK fusions. The majority (n=247, 89.8%) carried NPM1::ALK fusions, while 28 (10.2%) had non-NPM1::ALK fusions. Among the variant ALK-partner genes, we detected TPM3 (n = 7; 25% of variant fusions), TPM4, TRAF1, ATIC and CLTC (each n = 3; 11%), EEF1G, KIF5B and MYH9 (each n = 2; 7%), and EVI1, SATB1 and TXLNA (each n = 1; 4%). Univariate-Cox regression analysis revealed significantly poor event-free survival (EFS) in patients with non-NPM1::ALK fusions (log-rank p<0.001; median EFS: 30.5 months, 95% CI: 17.5–NA). The 3-year EFS rate was 28.9% in the non-NPM1::ALK group compared with 70.7% in the NPM1::ALK group. No significant difference in overall survival (OS) was observed. Among 50 patients with mutation data, 36 (72%) carried somatic mutations. A total of 39 mutated genes were identified, with TP53 (26%), STAG2 (12%), KMT2A (6%), PRDM1 (6%), and TET2 (6%) being most frequent. Other recurrently mutated genes included KIT, KMT2D, NF1, PCLO, USH2A, and VCAN. Univariate-Cox regression analysis showed that compared with those without TP53 mutations, the patients with TP53 mutationshad significantly poorer EFS and OS (EFS: log-rank p=0.03, median EFS=11.1 months [95%CI: 7.17-NA], 3-year EFS: 27.0% [95%CI: 8.43-86.5%], OS: log-rank p=0.0025, 3-year OS: 66.7% [95%CI: 37.9-100%]). Further analysis revealed that among patients with NPM1::ALK fusions, TP53 mutations were significantly associated with inferior outcomes, whereas no TP53-mutated cases were identified in the non-NPM1::ALK fusion subgroup. No significant co-occurrence or mutual exclusivity was observed between fusion types and mutations. Conclusions: In Chinese pediatric patients with ALK-positive ALCL, the NPM1::ALK fusion represents the most common genetic alteration, while variant ALK-partners account for approximately 10% of cases. Non-NPM1::ALK fusion correlated with unfavorable outcomes in this cohort. Additionally, TP53 mutations, which were observed in 26% of patients, were associated with poor prognosis. The mechanistic interplay between these molecular aberrations and clinical outcomes warrants further investigation. (Yang Li & Jing Yang; Qinlong Zheng & Yonghong Zhang contributed equally).
Source: Blood
Authors: Yang Li, Jing Yang, Yanlong Duan, Keyan Yang, Ying Liu, Xiaomei Yang, Jian Jiang, Pan Wu, Yunpeng Dai, Yueping Jia, Ansheng Liu, Jian Wang, Jianwen Zhou, Xiaojun Yuan, Zhujun Wang, Baoxi Zhang, Xige Wang, Hui Gao, Shuquan Zhuang, Qinlong Zheng, Yongh Zhang
Institutions: Capital Medical University, Beijing Children’s Hospital, Shandong University, Qingdao University, Affiliated Hospital of Qingdao University, Hunan Children's Hospital, Shandong Provincial Hospital, Peking University, Peking University People's Hospital, Xi’an Children’s Hospital, Anhui Provincial Children's Hospital, Zhengzhou Children's Hospital, Shanghai Jiao Tong University, XinHua Hospital, Huazhong University of Science and Technology, Hebei Medical University, Second Hospital of Hebei Medical University, Third Affiliated Hospital of Zhengzhou University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4417016496
Cites:
Cited by:
Related to: