Randomized Trial of Intermediate-Dose Cytarabine In

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- Whether a higher dose of cytarabine would be more effective is yearDFSswere67%[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; P ¼ investigated. 0.014). Two courses of intermediate-dose cytarabine with dau- Patients and Methods: Subjects with AML age 15–55 years norubicin or mitoxantrone resulted in similar DFS and survival as were randomized to receive daunorubicin, omacetaxine mepe- three courses of high-dose cytarabine when used for post- succinate, and conventional- or intermediate-dose cytarabine. remission therapy. Subjects achieving complete remission were randomized to Conclusions: Induction therapy with intermediate-dose receive 3 courses of high-dose cytarabine or 2 courses of inter- cytarabine with daunorubicin and omacetaxine mepesuccinate mediate-dose cytarabine with daunorubicin in the 1st and mitox- increases DFS and survival in persons with AML ages 15–55 years antrone in the 2nd course. The primary endpoint was disease-free compared with conventional-dose cytarabine. survival (DFS). See related commentary by Watts and Bradley, p. 3073

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, 1State Key Laboratory of Experimental Hematology, Tianjin, China. 2National 59% (95%CI, 46–71; ref. 13). Clinical Research Center for Blood Disease, Tianjin, China. 3Leukemia Center, High-dose cytarabine is commonly used as post-remission (con- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of solidation) therapy (19–23). Intermediate-dose cytarabine alone or 4 Medical Sciences, Tianjin, China. Division of Experimental Medicine, Depart- combined with other drugs are also widely used for post-remission ment of Medicine, Hematology Research Center, Imperial College London, fi 5 therapy (12, 13, 21, 24, 25). In our study, we also compared ef cacy of London, United Kingdom. State Key Laboratory of Cardiovascular Disease, versus Fuwai Hospital, National Center for Cardiovascular Diseases, Peking Union high-dose cytarabine intermediate-dose cytarabine combined Medical College and Chinese Academy of Medical Sciences, Tianjin, China. with daunorubicin and mitoxantrone for post-remission 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, Tianjin 300020, China. Phone/Fax: 8622-2390-9120; E-mail: single-center trial conducted at the Blood Disease Hospital, Chinese [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;26:3154–61 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- 2020 American Association for Cancer Research. jects gave written informed consent.

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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 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 ULN, serum creatinine concentration <2.0 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 was generated with SAS. Treating physicians and G-CSF was given from day 7 after chemotherapy until neutrophils

N Enrolled Excluded ( = 5) N (N = 596) Wrong diagnoses ( = 3) Consent withdrawal (N = 1) Ineligible (N = 1)

Convenonal cytarabine Intermediate cytarabine (CD; N = 296 ) (ID; N = 295)

No remission (N = 61) No remission (N = 29) Died (N = 4); NE (N = 2) Died (N = 7); NE (N = 3) Complete remission Complete remission (N = 229 ) (N = 256)

Not randomized (CD, N = 14; ID N = 15) Subject refusal (N = 16); Infecon (N = 8); Physician refusal (N = 2); Heart failure (N = 1); Kidney failure Transplant Transplant (N = 1); Relapse (N = 1) N (N = 40) ( = 48)

High-dose cytarabine (N = 232) Intermediate-cytarabine (N = 224) CD (N = 112); ID (N = 120) CD (N = 103); ID (N = 121)

Figure 1. CONSORT ﬂow diagram. Abbreviation: NE, not evaluable.

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≥10% bone marrow CD-D blasts d 14

CD-DO ID-D ID-M CD-O CD-O CD-M CD-M

AML R PR CD-DO CR R

ID-DO HD HD HD CD-O CD-O CD-M

Figure 2. Trial design. Abbreviations: AML, acute myelogenous leukemia; R, randomize; CR, complete remission; PR, partial remission; CD, conventional-dose cytarabine; ID, intermediate-dose cytarabine; HD, high-dose cytarabine; D, daunorubicin; O, omacetaxine mepesuccinate; M, mitoxantrone.

were >0.5 109/L. Subjects with intermediate- or adverse-risk calculated by the Kaplan–Meier method. Log-rank test was used for leukemia could receive an allogeneic hematopoietic cell transplant univariable analyses and the proportional hazard model of Cox for based on criteria of the National Comprehensive Cancer Network multivariable analyses of DFS, EFS, and survival. CIR was calculated by (NCCN; ref. 28). using the competing-risk analysis considering of death as a competing event (29). Data were analyzed with and without censoring of trans- Outcomes plant recipients at the time of transplant. Age and WBC were analyzed The primary endpoint was DFS. Co-secondary endpoints included as continuous variables in multivariable analyses. To test factors rates of complete remission, event-free survival (EFS), cumulative associated with complete remission, c2 and Fisher exact tests were incidence of relapse (CIR), survival and deaths within <30 days. used in univariable analyses and in a multiple logistic regression model Subgroup analyses were exploratory. DFS in subjects achieving com- for multivariable analyses. We also performed sensitivity analyses of plete remission was defined as the interval from complete remission to the remission induction cohorts excluding subjects in the conven- relapse or death from any cause and censored at last follow-up visit or tional-dose cytarabine cohort receiving a 2nd induction cycle for DFS, contact. EFS was defined as the interval from randomization to EFS, and survival. Statistical tests were two-sided with a significance assessment of response after the induction cycle if the subject failed level set at 0.05. Analyses were done with SAS (version 9.4). to achieve a complete remission, the date of relapse in subjects achieving a complete remission or the date of death, whichever occurred first. Survival was defined as the interval from 1st random- Results ization to death. CIR was measured from the date of complete Between September 1, 2010 and January 13, 2016, 596 subjects age remission to relapse. Death without relapse was defined as a competing 15–≤55 years with de novo newly diagnosed AML were enrolled. Five event in calculating the CIR. Deaths within <30 days were measured subjects were subsequently excluded because of incorrect diagnoses from day of 1st randomization. Follow-up of living subjects was (N ¼ 3), withdrawal of consent (N ¼ 1) and ineligibility (N ¼ 1). 320 censored at last visit or contact. Durations of neutrophils <0.5 (54%) were male. Median age was 36 years (range, 15–55 years). 109/L and platelets <25 109/L were analyzed in subjects achieving 296 subjects were randomly assigned to receive conventional- and 295 complete remission after only one course defined as the interval to receive intermediate-dose cytarabine. The cohorts were balanced from beginning induction therapy to neutrophils ≥0.5 109/L and for baseline variables, including sex, age, baseline WBC and cyto- platelets ≥25 109/L. genetic risk group (Table 1). Six subjects in the conventional-dose cohort did not complete the 1st induction cycle because of severe Statistical analyses infection (N ¼ 4), tumor lysis syndrome (N ¼ 1) and acute myocardial We assumed a remission rate of 60%. We then used the Lakatos infarction (N ¼ 1). The same was so for 2 subjects in the intermediate- method to calculate sample size of 533 subjects equally divided dose cytarabine cohort because of severe infection. These 8 subjects are between the cohorts and 171 events to detect a hazard ratio of 0.65 included in the intent-to-treat analyses. Median follow-up of survivors assuming the 3-year DFSs were 41% in the conventional-dose cytar- is 49 months (range, 5–94 months). abine induction regimen group and 56% in the intermediate-dose cytarabine induction regimen group with 80% power at a 0.05 signif- Induction response icance level in a two-sided log-rank test. Study duration was estimated 485 subjects (82%; 95% CI, 79–85) achieved a complete remission. at 4 years. 208 subjects (70%; 95%CI, 65–76) in the conventional-dose cohort All randomized subjects were included in analyses of complete achieved a complete remission after the 1st induction cycle. Nine remission, EFS, survival and death <30 days by intent-to-treat. All subjects achieved a partial remission after 1st induction cycle. Eight randomized subjects achieving complete remission were included in received a 2nd cycle four of whom subsequently achieved a complete DFS and CIR analyses by intent-to-treat. DFS, EFS, and survival were remission. One subject did not receive a 2nd induction course because

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Table 1. Baseline clinical and laboratory variables.

Randomization of induction Randomization of consolidation Conventional (N ¼ 296) Intermediate (N ¼ 295) High-dose (N ¼ 232) Intermediate-dose (N ¼ 224)

Age <45 y 218 231 180 170 ≥45 y 78 64 52 54 Median (y; range) 36 (15–54) 35 (15–54) 34.5(15–54) 36 (15–54) Male 161 159 120 128 WBC (109/L; median; range) 12.3 (0.6–247) 12.8 (0.7–371) 12.9 (0.7–247) 12.9 (0.8–371) <10 136 131 104 95 ≥10 160 164 128 129 Hemoglobin (g/L; median; range) 82 (45–163) 81 (41–153) 82 (41–158) 82 (41–163) <100 222 231 175 169 ≥100 74 64 57 55 Platelets (x109/L; median; range) 43 (3–317) 42 (8–356) 39 (7–356) 45 (7–317) <50 163 170 138 122 ≥50 133 125 94 102 Cytogenetic riska Favorable 80 83 78 72 Intermediate 179 182 135 131 Adverse 19 15 7 11 Unknown 18 15 12 10 NPM1 Mutated 51 38 42 35 Wild-type 228 243 183 173 Unknown 17 14 7 16 FLT3-ITD Positive 35 31 19 25 Negative 259 263 212 198 Unknown 2 1 1 1 CEBPA bi-allelic Yes 32 43 32 34 No 247 236 189 175 Unknown 17 16 11 15 Induction regimen Conventional-dose cytarabine NA NA 112 103 Intermediate-dose cytarabine NA NA 120 121 Consolidation regimen High-dose cytarabine NA NA Intermediate-dose cytarabine NA NA Transplant CR1 No 243 239 192 176 Yes 53 56 40 48

Abbreviation: NA, not available. aCytogenetic risk was classified according to the Refined Medical Research Council criteria (33). of bleeding. Before the protocol amendment on March 1, 2013, 15 of course indicated a significant improvement in complete remission rate 113 subjects randomized to conventional induction cohort had bone (78%; 95%CI, 74–83 for conventional-dose vs. 87%; 95%CI, 83–91 for marrow blasts ≥10% on day 14. Thirteen in the conventional arm did intermediate-dose; P ¼ 0.0094). not achieve complete remission; 2 did. After March 1, 2013, 32 of 183 In multi-variable analyses intermediate-dose cytarabine was inde- randomized to conventional induction cohort had bone marrow pendently associated with a higher complete remission rate (odds blasts ≥10% on day 14. Twenty-three received a 2nd induction course ratio, 2.09; 95%CI, 1.29–3.39; P ¼ 0.003; Supplementary Table S3). on day 14, 17 of whom achieved a complete remission. Nine similar Other variables significantly correlated with complete remission subjects did not receive the 2nd induction course because of infection included cytogenetic risk cohort, NPM1 mutation, bi-allelic CEBPA (N ¼ 7), tumor lysis syndrome (N ¼ 1) and refusal (N ¼ 1). A mutation and FLT3-ITD mutation (Supplementary Table S3). CONSORT diagram of subjects in the induction therapy phase is displayed in Supplementary Fig. S1. 256 subjects (87%; 95%CI, 83–91) Consolidation therapy in the intermediate-dose cytarabine cohort obtained a complete 456 of 485 subjects (94%) achieving a complete remission were remission after the 1st induction course compared with 229 (77%; randomly assigned to receive post-remission therapy with high-dose 95%CI, 72–82; P ¼ 0.004) in the conventional-dose cohort after the 1st cytarabine (N ¼ 232) or intermediate-dose cytarabine with daunoru- and 2nd induction courses. Sensitivity analyses of the cohorts exclud- bicin for the 1st cycle and mitoxantrone for the 2nd (N ¼ 224). Baseline ing subjects in the conventional-dose cohort receiving a 2nd induction variables at randomization are displayed in Table 1. 109 (18%) of

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Figure 3. Outcomes after induction cytarabine dose randomization. (A) DFS; (B) EFS; (C) survival.

591 randomized subjects, 53 in the conventional-dose and 56 in (95%CI, 53–64) versus 42% (95%CI, 37–48; P <0.0001; Fig. 3B) intermediate-dose cytarabine induction cohorts received an allotrans- and 68% (95%CI, 63–74) versus 59% (95%CI, 53–65; P ¼ plant in 1st complete remission. Median intervals to transplant were 0.014; Fig. 3C), respectively. In multivariable analyses the inter- 6 months in both cohorts (ranges, 4–35 months and 4–25 months for mediate-dose cytarabine induction regimen was independently the conventional-dose and intermediate-dose cytarabine induction associated with a better EFS and survival with HR, 0.63 (95%CI, cohorts, respectively). 0.46–0.85; P < 0.0001; Supplementary Table S4) and HR, 0.70 (95%CI, 0.50–0.97; P ¼ 0.03; Supplementary Table S4). Other Survival variables significantly associated with EFS and survival were similar, In subjects achieving complete remission, three-year DFS was 61% including WBC at diagnosis, cytogenetic risk cohort, transplant (95%CI, 56–65), including 67% (95%CI, 61–73) in the intermediate- in the 1st complete remission and NPM1 and bi-allelic CEBPA and 54% (95%CI, 48–61; P ¼ 0.005; Fig. 3A) in the conventional-dose mutations (Supplementary Tables S4). cytarabine induction cohort. In multi-variable analyses intermediate- In sensitivity analyses of the cohorts excluding subjects in dose cytarabine induction regimen was independently associated with the conventional-dose cohort receiving a 2nd induction course, better DFS than conventional-dose cytarabine with an HR, 0.64 intermediate-dose induction therapy was also associated with (95%CI, 0.48–0.85; P ¼ 0.002). Other significant variables for DFS improved DFS, EFS, and survival compared with conventional- were WBC at diagnosis, cytogenetic risk cohort, transplant in 1st dose cytarabine (Supplementary Fig. S2). The advantage of inter- complete remission and NPM1 and bi-allelic CEBPA mutations mediate- versus conventional-dose cytarabine remained significant (Supplementary Table S4). for DFS (HR, 0.62; 95%CI, 0.46–0.84; P ¼ 0.004; Supplementary In all subjects, 3-year EFSs and survivals for the intermediate- Fig. S3A), EFS (HR, 0.53; 95%CI, 0.41–0.70; P ¼ 0.0003; Supple- and conventional-dose cytarabine induction cohorts were 58% mentary Fig. S3B) and survival (HR, 0.67; 95%CI, 0.51–0.88;

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Figure 4. Outcomes after consolidation cytarabine dose randomization. (A) DFS; (B)CIR;(C) survival.

P ¼ 0.006; Supplementary Fig. S3C) after censoring subjects at the transplant at the date of transplant (Supplementary Fig. S5). Inter- date of transplant. mediate-dose cytarabine induction improved DFS in both consolida- In sub-group analysis, subjects in the cytogenetic intermediate- and tion cohorts but survival only in the high-dose cytarabine consolida- adverse-risk cohorts had significantly a higher complete remission rate tion cohort compared with the conventional-dose cytarabine induc- with intermediate- compared with conventional-dose cytarabine tion (Supplementary Table S5). [(84%; 95%CI, 78–89) vs. (73%; (95%CI, 66–79); P ¼ 0.011; and 73%; 95%CI, 47–90) vs. 37% (95%CI, 19–60); P ¼ 0.032]. In contrast, Safety and toxicity there was no significant difference in complete remission rate in Deaths <30 days were similar in the intermediate- and conventional- favorable-risk group [98% (95%CI, 92–100) vs. 95% (95%CI, dose cytarabine induction cohorts, 1% (95%CI, 0.4–3.4) vs.2% 88–99); P ¼ 0.44, for the intermediate-dose and conventional-dose (95%CI, 1–5; P ¼ 0.36). Durations of neutrophils <0.5 109/L cytarabine induction cohort, respectively). Intermediate-dose cytar- and platelets <25 109/L were longer for the intermediate-dose abine was only found to be associated with better DFS, EFS, and cytarabine cohort compared with the conventional-dose cohort (20 survival in subjects with intermediate-risk cytogenetics. (Supplemen- vs. 21 days; P < 0.0001; 20 vs. 22 days; P < 0.0001; Table 2). There tary Fig. S4). We were unable to determine whether there was a benefit was a trend toward more RBC transfusions in the intermediate- vs. of intermediate-dose cytarabine in the favorable and adverse cyto- the conventional-dose cohorts [(U; median), 12 (range, 12–35 U) vs. genetic cohorts because of small sample sizes. 11 (range, 0–40 U); P ¼ 0.05]. Platelet transfusions were similar There were no significant differences in DFS, CIR, or survival [(U; median), 60 U (range, 24–402 U) vs.60U(range,9–392 U); between the consolidation cohorts in the exploratory analysis (Fig. 4). P ¼ 0.11]. There was also a trend toward more bacteremia in This was confirmed in sensitivity analyses that excluded subjects in the the intermediate- vs. conventional-dose induction cohorts [16%, conventional-dose cohort receiving a 2nd induction course (data not (12%–21%) vs. 12% (8%–15%); P ¼ 0.092). There were no shown) and in sensitivity analyses censoring subjects receiving a significant differences in cumulative incidence of death in

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Table 2. Toxicities during induction therapy. receiving a transplant in first remission or after relapse. The reason(s) for this discordance is unclear. Conventional Intermediate P There are several important limitations to our study. Some are Deaths <30 d (n) 4 7 0.36 generic to large randomized trials in AML such as selection biases, loss Neutrophils (d; median, range)a 20 (12–34) 21 (12–31) <0.0001 of subjects, and withdrawals of consent. We tried to overcome some by Platelets (d; median; range)a 20 (12–40) 22 (14–44) <0.0001 our intent-to-treat and sensitivity analyses. Another limitation is Sepsis (n) 40 53 0.14 withdrawal of subjects to receive transplant, a selection bias difficult Bacteria (n) 34 48 0.09 or impossible to control. However, we analyzed our data with and Fungi (n) 6 5 0.77 without censoring at transplant with similar conclusions. There was also an imbalance in numbers of induction courses, 1 for the inter- a Defined in text. mediate-dose cytarabine cohort and up to two in the conventional dose cytarabine cohort. We addressed this issue by excluding subjects in the complete remission between two consolidation cohorts (Supple- conventional-dose cohort receiving a 2nd induction course. There are mentary Fig. S6). other limitations to generalizing our conclusions to other settings such as our use of a lower dose of daunorubicin (40 mg/mEþ2) compared with other countries (60–90 mg/mEþ2) and adding omacetaxine Discussion mepesuccinate. Our data indicate that intermediate-dose cytarabine induction In summary, we show a benefit of intermediate-dose cytar- combined daunorubicin and omacetaxine mepesuccinate is associated abine in induction therapy in person 15–≤55 years with newly with a higher rate of complete remissions, better DFS, EFS, and survival diagnosed de novo AML when combined with daunorubicin and compared with conventional-dose cytarabine with no increase in omacetaxine mepesuccinate. We also found 2 consolidation deaths within <30 days in persons 15–≤55 years with new- courses of intermediate-dose cytarabine combined with dauno- diagnosed de novo AML meeting our study-entry criteria. In contrast, rubicin and mitoxantrone was as effective as 3 courses high-dose there was no difference in DFS, CIR or survival between intermediate- cytarabine. Our conclusions require confirmation but could and high-dose cytarabine given for post-remission consolidation. improve therapy-outcomes if validated. These data are like other reports (14, 16, 18). In sub-group analyses, the benefit of intermediate-dose cytarabine induction on DFS, EFS, Disclosure of Potential Conflicts of Interest and survival was limited to subjects with intermediate-risk No potential conflicts of interest were disclosed. cytogenetics. Disclaimer Studies from HOVON-SAKK, SWOG, ALSG and German AMLCG The funder had no role in the study-design, data collection, analyses, interpre- reported no improvement in survival with high-dose cytarabine in tation, developing the article or the decision to publish the article. Authors had access AML induction therapy (4–6, 30). There are, however, important to all study data. differences between these studies and ours outlined in Supplementary Table S1. First, we studied intermediate- not high-dose cytarabine. Authors’ Contributions Second, our study included a lower dose of daunorubicin but added Conception and design: Y. Mi, J. Wang omacetaxine mepesuccinate. Third, median age of our study subjects Development of methodology: J. Wang Acquisition of data (provided animals, acquired and managed patients, provided was 36 years compared with 49 and 43 years in the HOVON-SAKK facilities, etc.): H. Wei, D. Lin, C. Zhou, B. Liu, S. Qiu, R. Gu, Y. Li, X. Zhao, S. Wei, and ALSG trials (4, 6). Fourth, there may be differences in cytogenetics B. Gong, K. Liu, X. Gong, Y. Liu, G. Zhang, J. Wang and/or mutation topography of AML between Chinese and persons of Analysis and interpretation of data (e.g., statistical analysis, biostatistics, predominately European descent (31, 32). Eighty-nine percent subjects computational analysis): H. Wei, R.P. Gale, Z. Song, Y. Wang, W. Li in our trial were in favorable and intermediate risk group, which was Writing, review, and/or revision of the manuscript: H. Wei, Y. Wang, higher than other randomized clinical trials. R.P.Gale,D.Lin,S.Qiu,R.Gu,Y.Li,X.Zhao,B.Gong,X.Gong,Y.Liu, fi G. Zhang, J. Wang Our data indicate that the bene t of intermediate-dose cytarabine Administrative, technical, or material support (i.e., reporting or organizing data, operated predominately in subjects with intermediate-risk cytogenet- constructing databases): H. Wei, Y. Wang, S. Qiu, R. Gu, Y. Li, X. Zhao, B. Gong, ics. Because our subjects were of age <55 years we cannot know if this Y. Liu, G. Zhang, J. Wang benefit would occur in older persons. Other studies reported better Study supervision: Y. Mi, J. Wang survival with high-dose cytarabine in young subjects (7, 10). We also Acknowledgments cannot comment on whether intermediate-dose cytarabine would fi Supported in part by the National Key Research and Development Program for have the same bene t in persons receiving a higher dose of dauno- Precision Medicine (2017YFC0909800), CAMS Innovation Fund for Medical rubicin with or without omacetaxine mepesuccinate. Sciences (2016-I2M-1-001), Foundation for Innovative Research Groups of the Natural There were two consolidation cohorts in our study: (i) three course Science Foundation of China (81421002), State Key Program of National Natural of high-dose cytarabine; or (ii) two courses of intermediate-dose Science of China (81770181, 81430004; to J. Wang), and National Institute of cytarabine, the first with daunorubicin and the second with mitox- Health Research (NIHR) Biomedical Research Centre funding scheme (to R.P. Gale). antrone. We used only two courses of intermediate-dose cytarabine Profs. Elihu H. Estey (Fred Hutchinson Cancer Research Centre), Charles A. Schiffer (Karmanos Cancer Centre) and Mei-Jie Zhang (Medical College Wisconsin) kindly because of concern over bone marrow toxicity from the combination reviewed the typescript and provided helpful comments. with daunorubicin or mitoxantrone. Using a Cox proportional hazards model in the post hoc analysis, we found that intermediate-dose The costs of publication of this article were defrayed in part by the payment of page advertisement cytarabine induction improved DFS in both consolidation cohorts charges. This article must therefore be hereby marked in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. but survival only in the high-dose cytarabine consolidation cohort compared with conventional-dose cytarabine induction (Supplemen- Received October 21, 2019; revised January 10, 2020; accepted February 3, 2020; tary Table S5). This discordance persisted even after excluding subjects published first February 6, 2020.

3160 Clin Cancer Res; 26(13) July 1, 2020 CLINICAL CANCER RESEARCH

Intermediate-dose Cytarabine in Adult AML

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AACRJournals.org Clin Cancer Res; 26(13) July 1, 2020 3161

Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia

Hui Wei, Ying Wang, Robert Peter Gale, et al.

Clin Cancer Res 2020;26:3154-3161. Published OnlineFirst February 6, 2020.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-19-3433

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