For decades, an induction chemotherapy combining daunorubicin with cytarabine, the so-called ‘3+7’, has remained the standard of care for younger adult patients with AML.1 Neither adding other drugs to this combination nor using higher doses of cytarabine during induction has been shown to significantly improve outcome.2 However, increasing the daily dose of daunorubicin from 45 to 90 mg/m2 has been associated with higher complete remission (CR) and overall survival (OS) rates, demonstrating that anthracycline intensification could be a critical issue during the induction phase.3 In 2001, because there had been no prospective study comparing idarubicin and daunorubicin at a daily dose higher than 50 mg/m2 for 3 days in patients under the age of 60 years, the Groupe Ouest-Est des Leucémies Aigues et autres Maladies du Sang (GOELAMS) conducted a phase 3 randomized trial comparing 60 mg/m2 daunorubicin for 3 days with 8 mg/m2 idarubicin for 5 days (clinicaltrials.gov, NCT01015196).
From November 2001 to April 2005, a total of 832 AML patients (15–60 years) were enroled in the LAM-2001 study. Details of the treatments and results of the consolidation phase including autologous and allogeneic stem cell transplantation (allo-SCT) have been reported elsewhere.4, 5 Patients were randomly assigned to receive daunorubicin (60 mg/m2/day for 3 days), or idarubicin (8 mg/m2/day for 5 days), with cytarabine (200 mg/m2/day for 7 days). Bone marrow aspiration was performed at day 15 (d15), and if residual leukaemic blasts were observed (cutoff, 5%) a second course was given with 35 mg/m2 daunorubicin or 8 mg/m2 idarubicin, both on days 17 and 18 (to deliver 40% of the total initial dose), and 1000 mg/m2 cytarabine every 12 h on days 17–20. Response criteria, study population, end points and statistical analysis are described in Supplementary Appendix. Of the 832 patients enroled in the study, 14 were excluded (Figure 1). The median follow-up of patients still alive at the date of last contact was 7.22 years (inter-quartile range, 6.4–8.2). Characteristics of the 818 patients are summarized in Supplementary Table S1.
Although the cumulative incidences of CR were not significantly different between the two arms, there were significantly more patients with at least 5% marrow blasts at d15 in the daunorubicin arm than in the idarubicin arm (Supplementary Table S2) and a second induction chemotherapy course was more frequently given to the patients of the daunorubicin arm (28% vs 21%; P=0.02). These findings likely explained why CRs were more rapidly achieved in the idarubicin arm, as depicted on the cumulative incidence curves (Supplementary Figure S1). The incidence of adverse effects during the induction phase was not different between the two groups (Supplementary Table S3).
Univariate analyses showed that patients of the idarubicin arm less frequently relapsed and had an improved 7-year outcome, both in terms of disease-free survival (DFS) and OS (Figure 2a and Supplementary Figures 2A and 2B). However, univariate analyses did not reach significance, although they were associated with borderline P-values. Interaction analyses between the treatment arm and the other covariates that significantly influenced the outcome—age, performance status, cytogenetics and white blood cell count (WBC)—showed that cytogenetics was differently affecting outcome according to the treatment arm (Supplementary Table S4 and Figure 2b). Patients of the idarubicin arm had an improved 7-year OS, unless they had an unfavourable cytogenetics (Figures 2c–e and Supplementary Figure S3). Similar results were observed for a 7-year DFS and relapse incidence (Supplementary Figures S4A–D and S5A–D). To better evaluate the treatment arm effect on the 7-year OS by adjusting it on the other known prognostic factors, different Cox proportional hazards models were performed (Supplementary Table S5). A first standard Cox model, involving all patients, showed that the idarubicin arm was associated with an improved outcome, whether censoring (Cox model #1) or not (Cox model #2) the patients’ outcome at the time they underwent an allo-SCT, if they did. Similar results were observed in subsequent models stratified on cytogenetics, whether censoring outcome at the time of an allo-SCT (Cox model #3) or not (Cox model #4). A last model was considered, which was based on the first one but stratified on the fact that patients could have undergone an allo-SCT. This analysis, which differently took into account the fact that an allo-SCT could have influenced patients’ outcome, also showed that the idarubicin arm was associated with a better outcome (Cox model #5).
Because of the results observed in the interaction analyses, and as the sample size was large enough, a subgroup analysis focused on patients with intermediate-risk cytogenetics. Although the cumulative incidences of CR were not significantly different between the two arms, the effect of idarubicin on early blast clearance was faster and more pronounced in the idarubicin arm (marrow blast by day 15 ⩾5%, 20% in the idarubicin arm vs 36% in the daunorubicin arm; P<0.0001; Supplementary Table S2). As a consequence, more patients in the daunorubicin arm received the second induction course (daunorubicin arm, 35% vs 21% in the idarubicin arm; P<0.001). Patients of the idarubicin arm significantly had a lower 7-year relapse incidence (Supplementary Figure S5B) and higher 7-year DFS (Supplementary Figure S4B) and OS (Figure 2d). These last results were confirmed in the Cox model analysis adjusted on age, WBC and performance status, whether censoring (relative risk (RR), 0.716; 95% confidence interval (CI), 0.547–0.937; P=0.015) or not (RR, 0.701; 95% CI, 0.546–0.90; P=0.0053) outcome at the time of allo-SCT, or stratifying the model on the fact that some patients underwent such a transplantation (RR, 0.734; 95% CI, 0.571–0.943; P=0.015).
Recent randomized phase 3 trials have demonstrated that increasing the daunorubicin dose from 45 to 90 mg/m2 during the induction phase was a major way to improve the outcome in AML patients.3, 6 The long-term results of the LAM-2001 trial presented herein show that a 60 mg dose of daunorubicin is suboptimal compared with idarubicin as delivered in our study. This modality of use of idarubicin allows to give a higher dose of idarubicin (40 mg/m2) compared with most studies dealing with this drug (30–36 mg/m2) without increasing the toxicity.7, 8, 9 In 50-year-old patients and older, similar results favouring idarubicin have also been reported by the Acute Leukaemia French Association (ALFA) study group.10 Eight studies have compared these two anthracyclines as part of the induction chemotherapy. Only three of them enroled patients under 60 years of age. In the Memorial Sloan-Kettering Cancer Center trial, idarubicin (12 mg/m2/day, 3 days) improved CR rate and OS as compared with daunorubicin (50 mg/m2/day, 3 days).11 In the Gruppo Italiano Malattie EMatologiche dell'Adulto and the European Organisation for Research and Treatment of Cancer trial, idarubicin (10 mg/m2 on days 1, 3 and 5) improved OS from CR in patients who did not undergo an allo-SCT as compared with daunorubicin (50 mg/m2 on days 1, 3 and 5).12 In the Japan Adult Leukaemia Study Group (JALSG) trial, idarubicin (12 m/m2/day, 3 days) and daunorubicin (50 mg/m2/day, 5 days) were equally effective.13 Three meta-analyses including both younger and older patients have also been performed.7, 8, 9 Two of them showed that idarubicin significantly improved response rate and OS, especially in younger patients, whereas the third concludes that the superiority of idarubicin for remission induction was restricted to studies with a daunorubicin/idarubicin ratio <5.8 However, there were not enough data available in these meta-analyses to investigate the effects of age and the cytogenetic-risk group.
Idarubicin is a 4-demethoxy-anthracycline analogue of daunorubicin. The absence of the methoxyl group at position 4 of idarubicin’s anthracycline results in an increased lipophility and a better cellular uptake rate compared with daunorubicin. Idarubicin displays a lower susceptibility to multidrug resistance and a stronger binding to DNA resulting in a higher cytotoxic activity compared with daunorubicin. Moreover, its primary metabolite, idarubicinol, which demonstrates similar activity to idarubicin in vitro, is still detectable in plasma at least 72 h following intravenous infusion of idarubicin in contrast to daunorubicin’s lower half-life.14 Besides the dose effect, the duration of exposition to idarubicin given over 5 days in our study could have induced a deeper antileukaemic effect than daunorubicin given over 3 days. The impact of anthracycline exposure duration remains poorly studied, and it is noteworthy that daunorubicin given over 5 days was equally effective as idarubicin given over 3 days in the JALSG trial.
The major impact of idarubicin was observed in patients with intermediate cytogenetic risk. The impact of high-dose daunorubicin was also observed in patients with DNMT3A or NPM1 mutations, which are commonly found in this cytogenetic subgroup.15 It remains to be determined whether idarubicin could also impact outcome in molecularly defined subgroups of patients.
The long-term results of the LAM-2001 trial show that this idarubicin regimen has a better antileukaemic effect than daunorubicin when the latter is used at a 60 mg/m2 daily dose, especially in AML patients with intermediate-risk cytogenetics. In younger patients with AML, this idarubicin schema should be compared with a 3+7 schema with a 90 mg/m2 daily dose of daunorubicin.
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We thank all the GOELAMS investigators. The sponsorship was assumed by the Centre Hospitalier de Nantes, France (Projet Hospitalier de Recherche Clinique, 1998).
BL, AP, J-LH, NI and J-YC wrote the protocol; M-CB and PG performed data collection management, validation and statistical analyses and wrote the manuscript; CR analysed data, recruited patients, provided clinical care, performed bibliographic searches and wrote the manuscript; BL, AP, NV, JD, MH, DG, DB, NF, EJ, SL, ME-J, CB, ER, RG, MO-U, FD, J-LH, NI and JYC recruited patients and provided clinical care; IL validated cytogenetic data. All authors contributed to the gathering of the clinical or biological data and approved the report. Norbert Ifrah is the chairman of the AML scientific council of the GOELAMS.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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