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Original Investigation
January 16, 2020

Effect of Dasatinib vs Imatinib in the Treatment of Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial

Author Affiliations
  • 1National 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
  • 2State 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
  • 3Department of Hematology/Oncology, Chongqing Medical University Affiliated Children’s Hospital, Chongqing, China
  • 4Department 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
  • 5Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, China
  • 6Department of Hematology/Oncology, Children’s Hospital of Fudan University, Shanghai, China
  • 7Department of Hematology/Oncology, Jiangxi Provincial Children’s Hospital, Nanchang, China
  • 8Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, China
  • 9Department of Hematology/Oncology, Guangzhou Women and Children’s Medical Center, Guangzhou, China
  • 10Department of Pediatrics, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 11Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 12Department of Pediatrics, Anhui Medical University Second Affiliated Hospital, Anhui, China
  • 13Department of Hematology/Oncology, Kunming Children’s Hospital, Kunming, China
  • 14Department of Hematology/Oncology, Xi’an Northwest Women and Children Hospital, Xi’an, China
  • 15Department of Hematology/Oncology, Shanghai Children’s Hospital, Shanghai Jiao Tong University, Shanghai, China
  • 16Department of Pediatrics, Affiliated Hospital of Qingdao University, Qingdao, China
  • 17Department of Hematology/Oncology, Children’s Hospital of Nanjing Medical University, Nanjing, China
  • 18Department of Pediatrics, Hong Kong Children’s Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
  • 19Department of Pediatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  • 20Department of Pediatrics, Xiangya Hospital Central South University, Changsha, China
  • 21Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 22Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 23Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee
JAMA Oncol. Published online January 16, 2020. doi:10.1001/jamaoncol.2019.5868
Key Points

Question  Is dasatinib more effective than imatinib mesylate for childhood Philadelphia chromosome–positive acute lymphoblastic leukemia?

Findings  In this randomized clinical trial of 189 children with Philadelphia chromosome–positive acute lymphoblastic leukemia, the 92 patients treated with dasatinib at 80 mg/m2 per day had significantly higher rates of 4-year event-free survival (71.0% vs 48.9%) and overall survival (88.4% vs 69.2%) and lower relapse rates (19.8% vs 34.4%) than the 97 treated with imatinib mesylate at 300 mg/m2 per day. There were no significant differences in severe toxic effects between the 2 groups.

Meaning  These findings support the use of dasatinib at a dosage of 80 mg/m2 per day in children with Philadelphia chromosome–positive acute lymphoblastic leukemia.

Abstract

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

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