Effect of the tyrosine kinase inhibitors on the growth in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case-control study

Jiaoyang Cai; Hu Liu; Yumei Chen; Jie Yu; Ju Gao; Hua Jiang; Xiaowen Zhai; Xiuli Ju; Xuedong Wu; Ningling Wang; Xin Tian; Changda Liang; Yongjun Fang; Fen Zhou; Hong Li; Lirong Sun; Liangchun Yang; Jing Guo; Aiguo Liu; Chi-Kong Li; Yiping Zhu; Jingyan Tang; Jun J Yang; Shuhong Shen; Cheng Cheng; Ching-Hon Pui

doi:10.1016/j.lanwpc.2023.100818

Effect of the tyrosine kinase inhibitors on the growth in children with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case-control study

Lancet Reg Health West Pac. 2023 Jun 10:38:100818. doi: 10.1016/j.lanwpc.2023.100818. eCollection 2023 Sep.

Authors

Jiaoyang Cai¹, Hu Liu², Yumei Chen³, Jie Yu⁴, Ju Gao⁵, Hua Jiang⁶, Xiaowen Zhai⁷, Xiuli Ju⁸, Xuedong Wu⁹, Ningling Wang¹⁰, Xin Tian¹¹, Changda Liang¹², Yongjun Fang¹³, Fen Zhou¹⁴, Hong Li¹⁵, Lirong Sun¹⁶, Liangchun Yang¹⁷, Jing Guo¹⁸, Aiguo Liu¹⁹, Chi-Kong Li²⁰, Yiping Zhu⁵, Jingyan Tang¹, Jun J Yang²¹, Shuhong Shen¹, Cheng Cheng²², Ching-Hon Pui²³

Affiliations

¹ Department of Hematology/Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Key Laboratory of Pediatric Hematology & Oncology of China Ministry of Health, and National Children's Medical Center, Shanghai, China.
² Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, China.
³ Department of Pediatrics, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
⁴ Department of Hematology/Oncology, Chongqing Medical University Affiliated Children's Hospital, Chongqing, China.
⁵ Department of Pediatrics, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Disease of Women and Children, Ministry of Education, Chengdu, China.
⁶ Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
⁷ Department of Hematology/Oncology, Children's Hospital of Fudan University, Shanghai, China.
⁸ Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
⁹ Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
¹⁰ Department of Pediatrics, Anhui Medical University Second Affiliated Hospital, Anhui, China.
¹¹ Department of Hematology/Oncology, KunMing Children's Hospital, Kunming, China.
¹² Department of Hematology/Oncology, Jiangxi Provincial Children's Hospital, Nanchang, China.
¹³ Department of Hematology/Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.
¹⁴ Department of Pediatrics, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁵ Department of Hematology/Oncology, Shanghai Children's Hospital, Shanghai, China.
¹⁶ Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China.
¹⁷ Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China.
¹⁸ Department of Hematology/Oncology, Xi 'an Northwest Women's and Children's Hospital, Xi 'an, China.
¹⁹ Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
²⁰ Department of Pediatrics, Hong Kong Children's Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
²¹ Departments of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
²² Departments of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.
²³ Departments of Oncology, Pathology, and Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.

Abstract

Background: First-generation ABL-targeted tyrosine kinase inhibitor (TKI) imatinib is known to retard growth in children but it is not known if the second-generation ABL-targeted TKI dasatinib has the same effect. We aimed to determine the impact of the first- or second-generation TKI on the growth of children treated for Philadelphia chromosome-positive (Ph⁺) childhood acute lymphoblastic leukemia (ALL).

Methods: We evaluated the longitudinal growth changes in 140 children with Ph⁺ ALL treated with imatinib or dasatinib in additional to intensive cytotoxic chemotherapy and 280 matched controls treated with the same intensity of cytotoxic chemotherapy without TKI on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. We retrospectively reviewed the height data obtained during routine clinic visits at 4 time points: at diagnosis, the end of therapy, 1 year and 2 years off therapy. Height z Scores were derived with the aid of WHO Anthro version 3.2.2 and WHO AnthroPlus version 1.0.4, global growth monitoring tool.

Findings: This study consisted only patients who have completed all treatment in continuous complete remission without major events, including 33 patients randomized to receive imatinib, 43 randomized to receive dasatinib, and 64 assigned to receive dasatinib. Similar degree of loss of height z scores from diagnosis to the end of therapy was observed for the 33 imatinib- and the 107 dasatinib-treated patients (median △ = -0.84 vs. -0.88, P = 0.41). Adjusting for height z score at diagnosis, puberty status, and sex, there was no significant difference in the longitudinal mean height z scores between patients treated with imatinib and those with dasatinib (0.08, 95% CI, -0.22 to 0.38, P = 0.60). The degree of loss of height z scores from diagnosis to end of therapy was significantly greater in the 140 TKI-treated patients than the 280 controls (median △ = -0.88 vs. -0.18, P < 0.001). The longitudinal mean height z scores in the TKI-treated patients were significantly lower than those of the controls (-0.84, 95% CI, -0.98 to -0.69; P < 0.001).

Interpretation: These data suggest that dasatinib and imatinib have the similar adverse impact on the growth of children with Ph⁺ ALL.

Funding: This study was supported by the National Natural Science Foundation of China (grant 81670136 [JCai and JT]), the fourth round of Three-Year Public Health Action Plan (2015-2017; GWIV-25 [SS]), Shanghai Health Commission Clinical Research Project (202140161 [JCai]), the US National Cancer institute (CA21765 [C-H Pui]), and the American Lebanese Syrian Associated Charities (CC, JJY, and C-HP). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

Keywords: Acute lymphoblastic leukemia; Dasatinib; Growth; Height; Imatinib; Philadelphia chromosome-positive leukemia; Puberty; Tyrosine kinase inhibitor.