Published OnlineFirst February 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3433 CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia Hui Wei1,2,3, Ying Wang2,3, Robert Peter Gale4, Dong Lin3, Chunlin Zhou3, Bingcheng Liu3, Shaowei Qiu3, Runxia Gu3, Yan Li3, Xingli Zhao3, Shuning Wei3, Benfa Gong3, Kaiqi Liu3, Xiaoyuan Gong3, Yuntao Liu3, Guangji Zhang3, Zhen Song2, Yang Wang5, Wei Li5, Yingchang Mi1,2,3, and Jianxiang Wang1,2,3 ABSTRACT ◥ Purpose: Cytarabine, 100–200 mg/mEþ2/day, is commonly Results: 591 subjects were randomized to intermediate- (N ¼ used in induction therapy of acute myelogenous leukemia (AML). 295) or conventional-dose (N ¼ 296) cytarabine group. Three-year Whether a higher dose of cytarabine would be more effective is DFSs were 67% [95% confidence interval (CI), 61–73] in the unknown. Also, there is controversy whether high-dose cytarabine intermediate-dose cohort compared with 54% (95% CI, 48–61) in is better than an intermediate-dose combined with other drugs for the conventional-dose cohort [Hazard Ratio (HR), 0.67; 95%CI, post-remission therapy. In this open-label, randomized controlled, 0.51–0.89; P ¼ 0.005). Three-year survivals were 68% (95%CI, parallel group study, roles of intermediate-dose cytarabine were 63–74) and 59% (95%CI, 53–65; HR, 0.720; 95%CI, 0.56–0.94; investigated. P ¼ 0.014). Two courses of intermediate-dose cytarabine with Patients and Methods: Subjects with AML age 15–55 years daunorubicin or mitoxantrone resulted in similar DFS and survival were randomized to receive daunorubicin, omacetaxine mepesuc- as three courses of high-dose cytarabine when used for post- cinate, and conventional- or intermediate-dose cytarabine. Subjects remission therapy. achieving complete remission were randomized to receive 3 courses Conclusions: Induction therapy with intermediate-dose cytar- of high-dose cytarabine or 2 courses of intermediate-dose cytar- abine with daunorubicin and omacetaxine mepesuccinate increases abine with daunorubicin in the 1st and mitoxantrone in the 2nd DFS and survival in persons with AML ages 15–55 years compared course. The primary endpoint was disease-free survival (DFS). with conventional-dose cytarabine. Introduction included subjects of diverse ages that might explain some discordances as might center effects. Cytarabine is a common component of induction therapy of acute The standard remission induction regimen in China is cytarabine myelogenous leukemia (AML). Cytarabine, 100–200 mg/mEþ2/day and daunorubicin combined with omacetaxine mepesuccinate (homo- for 5–10 days, typically 7 days, is typically combined with daunoru- harringtonine). Because of the bone marrow suppression associated bicin, 60–90 mg/mEþ2/day for 3 days (1–3). Higher doses of cytar- with homoharringtonine the dose of daunorubicin is typically reduced abine, namely intermediate-dose (1–2 g/mEþ2/day) and high-dose to 40 mg/mEþ2/day for 3 days rather than the 60 mg/mEþ2/day used (2–3 g/mEþ2/day) were tested in several clinical trials with contra- when homoharringtonine is not given (reviewed in Supplementary dictory results (4–10). Some studies reported no survival benefit(4–6) Table S2; refs. 11–18). In the pilot study for this trial, we used whereas others reported better relapse-free survival (reviewed in intermediate-dose cytarabine combined with daunorubicin and Supplementary Table S1; refs, 4–8, 10). These multicenter studies homoharringtonine. Three-year disease-free survival (DFS) was 63% [95% confidence interval (CI), 51–76] and three-year survival, 59% (95%CI, 46–71; ref. 13). 1State Key Laboratory of Experimental Hematology, Tianjin, China. 2National High-dose cytarabine is commonly used as post-remission (con- Clinical Research Center for Blood Disease, Tianjin, China. 3Leukemia Center, solidation) therapy (19–23). Intermediate-dose cytarabine alone or Institute of Hematology and Blood Diseases Hospital, Chinese Academy of combined with other drugs are also widely used for post-remission 4 Medical Sciences, Tianjin, China. Division of Experimental Medicine, Depart- therapy (12, 13, 21, 24, 25). In our study, we also compared efficacy ment of Medicine, Hematology Research Center, Imperial College London, of high-dose cytarabine versus intermediate-dose cytarabine com- London, United Kingdom. 5State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union bined with daunorubicin and mitoxantrone for post-remission Medical College and Chinese Academy of Medical Sciences, Tianjin, China. therapy. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Patients and Methods H. Wei and Y. Wang contributed equally to the article. Study design and participants Corresponding Authors: Jianxiang Wang, Institute of Hematology and Blood This study was an open-label, randomized controlled, parallel group Diseases Hospital, Chinese Academy of Medical Sciences, Nanjing Road 288, single-center trial conducted at the Blood Disease Hospital, Chinese Tianjin 300020, China. Phone/Fax: 8622-2390-9120; E-mail: [email protected]; and Yingchang Mi, [email protected] Academy of Medical Science from September 1, 2010 to January 13, 2016 registered at www.chictr.org.cn (identifier: ChiCTR-TRC- Clin Cancer Res 2020;XX:XX–XX 10001202). The study was approved by the Hospital Ethics Committee doi: 10.1158/1078-0432.CCR-19-3433 and conducted in accordance with the Declaration of Helsinki. Sub- Ó2020 American Association for Cancer Research. jects gave written informed consent. AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 6, 2020; DOI: 10.1158/1078-0432.CCR-19-3433 Wei et al. subjects were not blinded to therapy-assignment but investigators Translational Relevance assessing outcomes and statisticians were. Cytarabine is commonly used in acute myelogenous leukemia (AML). Whether an induction regimen with intermediate-dose Treatment cytarabine would be more effective than one with conventional Eligible subjects were randomly assigned to conventional- dose is unknown. Also, there is controversy whether high-dose (100 mg/mEþ2/day days 1–7 as a 12-hour intravenous infusion) or cytarabine is better than an intermediate-dose combined with other intermediate-dose cytarabine (100 mg/mEþ2/day days 1–4asa drugs for post-remission therapy. In this open-label, randomized 12-hour intravenous infusion and 1 g/mEþ2 every 12 hours as a controlled, parallel group trial, we show that intermediate-dose 3-hour intravenous infusion on days 5–7). Subjects also received dau- cytarabine induction combined daunorubicin and omacetaxine norubicin (40 mg/mEþ2/day on days 1–3) and omacetaxine mepe- mepesuccinate produced a higher rate of complete remissions, succinate (2 mg/mEþ2/day on days 1–7). A CONSORT flow diagram better event- and disease-free survival (EFS and DFS) and survival and treatment scheme are displayed in Figs. 1 and 2. Criteria for compared with conventional-dose cytarabine with no increase in response and relapse followed the Report of the National Cancer early deaths in young adults with new-diagnosed de novo AML. In Institute-Sponsored Workshop (27). For subjects randomized to contrast, there was no difference in cumulative incidence of relapse conventional-dose cytarabine, a 2nd induction course, identical to the (CIR), DFS or survival between intermediate- and high-dose 1st, could be given if a partial remission was achieved after 1st induction cytarabine given for post-remission consolidation. cycle and when blood cell counts recovered. From March 1, 2013 subjects randomized to receive conventional-dose cytarabine with bone marrow blasts ≥10% on day 14 could receive a 2nd induction course of cytarabine (100 mg/mEþ2/day on days 1–5 as a 12-hour Newly diagnosed persons with de novo AML excluding acute intravenous infusion) and daunorubicin (45 mg/mEþ2/day days 1–3). promyelocytic leukemia age 15 ≤ 55 years were eligible. Main Subjects randomized to receive intermediate-dose cytarabine did not inclusion criteria were: (i) AML according to WHO classification receive a 2nd induction course because of hematopoietic toxicity. (2008; ref. 26); (ii) ECOG performance score ≤2; (iii) cardiac Subjects achieving a complete remission were randomized to receive ejection-fraction determined by echocardiography ≥50%; (iv) three courses of high-dose cytarabine (3 g/mEþ2 days 1–3 every serum total bilirubin concentration <1.5 Â upper limit normal 12 hours as a 3-hour intravenous infusion) or two courses of (ULN), aspartate aminotransferase and alanine aminotransferase intermediate-dose cytarabine (1.5 g/mEþ2 at the same schedule) with concentrations <2.5 Â ULN, serum creatinine concentration <2.0 Â daunorubicin (40 mg/mEþ2/day on days 1–3) in the first and mitox- ULN and cardiac enzymes <2.0 ULN. antrone (6 mg/mEþ2/day on days 1–3) in the second courses. The There were two 1:1 randomization that were computer-generated second randomization was not stratified for induction regimen. with allocation concealment in an unreadable computer system that Subjects could receive 4 cycles of intrathecal methotrexate, cytarabine, investigators could access only after a subject was enrolled. Random- and dexamethasone to prevent CNS leukemia if they agreed. ization sequence