Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.,JAMA Oncology

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Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.
JAMA Oncology ( IF 22.5 ) Pub Date : 2020-01-16 , DOI: 10.1001/jamaoncol.2019.5868
Shuhong Shen ₁ , Xiaojuan Chen ₂ , Jiaoyang Cai ₁ , Jie Yu ₃ , Ju Gao ₄ , Shaoyan Hu ₅ , Xiaowen Zhai ₆ , Changda Liang ₇ , Xiuli Ju ₈ , Hua Jiang ₉ , Runming Jin ₁₀ , Xuedong Wu ₁₁ , Ningling Wang ₁₂ , Xin Tian ₁₃ , Kaili Pan ₁₄ , Hui Jiang ₁₅ , Lirong Sun ₁₆ , Yongjun Fang ₁₇ , Chi-Kong Li ₁₈ , Qun Hu ₁₉ , Minghua Yang ₂₀ , Yiping Zhu ₄ , Hui Zhang ₉ , Chunfu Li ₁₁ , Deqing Pei ₂₁ , Sima Jeha ₂₂ , Jun J Yang ₂₃ , Cheng Cheng ₂₁ , Jingyan Tang ₁ , Xiaofan Zhu ₂ , Ching-Hon Pui ₂₂

Affiliation

National Children's Medical Center, Department of Hematology/Oncology, Key Laboratory of Pediatric Hematology and Oncology of China Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
State Key Laboratory of Experimental Hematology and Division of Pediatric Blood Diseases Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Tianjin, China.
Department of Hematology/Oncology, Chongqing Medical University Affiliated Children's Hospital, Chongqing, China.
Department of Pediatrics, Key Laboratory of Birth Defects and Related Disease of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China.
Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, China.
Department of Hematology/Oncology, Children's Hospital of Fudan University, Shanghai, China.
Department of Hematology/Oncology, Jiangxi Provincial Children's Hospital, Nanchang, China.
Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China.
Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
Department of Pediatrics, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Pediatrics, Anhui Medical University Second Affiliated Hospital, Anhui, China.
Department of Hematology/Oncology, Kunming Children's Hospital, Kunming, China.
Department of Hematology/Oncology, Xi'an Northwest Women and Children Hospital, Xi'an, China.
Department of Hematology/Oncology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China.
Department of Hematology/Oncology, Children's Hospital of Nanjing Medical University, Nanjing, China.
Department of Pediatrics, Hong Kong Children's Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.
Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China.
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee.
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.

Importance A randomized clinical trial is needed to determine whether the second-generation Abl-tyrosine kinase inhibitor dasatinib is more effective than the first-generation inhibitor imatinib mesylate for childhood Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Objective To determine whether dasatinib given at a daily dosage of 80 mg/m2 is more effective than imatinib mesylate at a daily dosage of 300 mg/m2 to improve event-free survival of children with Philadelphia chromosome-positive ALL in the context of intensive chemotherapy without prophylactic cranial irradiation. Design, Setting, and Participants This open-label, phase 3 randomized clinical trial was conducted at 20 hospitals in China. Enrollment occurred from January 1, 2015, through September 18, 2018, and randomization was stopped on October 4, 2018, when the early stopping criterion of the trial was met. Patients aged 0 to 18 years were recruited. Of the 225 patients with the diagnosis, 35 declined participation and 1 died before treatment, leaving 189 patients available for analysis. Data were analyzed from January 1 through August 4, 2019. Interventions Patients were randomized to receive daily dasatinib (n = 92) or imatinib (n = 97) continuously for the entire duration of ALL therapy from the time of diagnosis made during remission induction to the end of continuation therapy. Main Outcomes and Measures The primary outcome was event-free survival, analyzed based on intention to treat. The secondary outcomes were relapse, death due to toxic effects, and overall survival. Results Among the 189 participants (136 male [72.0%]; median age, 7.8 [interquartile range (IQR), 5.2-11.3] years) and a median follow-up of 26.4 (IQR, 16.3-34.1) months, the 4-year event-free survival and overall survival rates were 71.0% (95% CI, 56.2%-89.6%) and 88.4% (95% CI, 81.3%-96.1%), respectively, in the dasatinib group and 48.9% (95% CI, 32.0%-74.5%; P = .005, log-rank test) and 69.2% (95% CI, 55.6%-86.2%; P = .04, log-rank test), respectively, in the imatinib group. The 4-year cumulative risk of any relapse was 19.8% (95% CI, 4.2%-35.4%) in the dasatinib group and 34.4% (95% CI, 15.6%-53.2%) in the imatinib group (P = .01, Gray test), whereas the 4-year cumulative risk of an isolated central nervous system relapse was 2.7% (95% CI, 0.0%-8.1%) in the dasatinib group and 8.4% (95% CI, 1.2%-15.6%) in the imatinib group (P = .06, Gray test). There were no significant differences in the frequency of severe toxic effects between the 2 treatment groups. Conclusions and Relevance Intensive chemotherapy including dasatinib at a dosage of 80 mg/m2 per day yielded superior results in the treatment of Philadelphia chromosome-positive ALL compared with imatinib mesylate at a dosage of 300 mg/m2 per day and provided excellent control of central nervous system leukemia without the use of prophylactic cranial irradiation. Trial Registration Chinese Clinical Trial Registry: ChiCTR-IPR-14005706.

更新日期：2020-03-12

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