Letters to the Editor 440 Long-term results of a randomized phase 3 trial comparing idarubicin and in younger patients with acute myeloid leukaemia

Leukemia (2014) 28, 440–443; doi:10.1038/leu.2013.290 years, the Groupe Ouest-Est des Leuce´mies 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). For decades, an induction combining daunorubicin From November 2001 to April 2005, a total of 832 AML with , the so-called ‘3 þ 7’, has remained the standard of patients (15–60 years) were enroled in the LAM-2001 study. care for younger adult patients with AML.1 Neither adding other Details of the treatments and results of the consolidation phase drugs to this combination nor using higher doses of cytarabine including autologous and allogeneic stem cell transplantation during induction has been shown to significantly improve (allo-SCT) have been reported elsewhere.4,5 Patients were outcome.2 However, increasing the daily dose of daunorubicin randomly assigned to receive daunorubicin (60 mg/m2/day for from 45 to 90 mg/m2 has been associated with higher complete 3 days), or idarubicin (8 mg/m2/day for 5 days), with cytarabine remission (CR) and overall survival (OS) rates, demonstrating that (200 mg/m2/day for 7 days). Bone marrow aspiration was intensification could be a critical issue during the performed at day 15 (d15), and if residual leukaemic blasts induction phase.3 In 2001, because there had been no prospective were observed (cutoff, 5%) a second course was given with study comparing idarubicin and daunorubicin at a daily dose 35 mg/m2 daunorubicin or 8 mg/m2 idarubicin, both on days 17 higher than 50 mg/m2 for 3 days in patients under the age of 60 and 18 (to deliver 40% of the total initial dose), and 1000 mg/m2

832 patients randomly assigned

411 assigned to daunorubicin 421 assigned to idarubicin

5 received idarubicin 8 patients with wrong diagnosis 1 death before induction

406 induction therapy with daunorubicin 412 induction therapy with idarubicin

19 deaths during induction 20 deaths during induction 49 resistant leukaemia 46 resistant leukaemia

338 CR 346 CR

14 chemotherapy only 15 chemotherapy only 5 infection 3 infection 5 early relapse 3 early relapse 4 refusal 9 investigator decision 14 investigator decision 7 toxicity 3 toxicity 1 sudden death 3 unknown

290 post-remission treatment 308 post-remission treatment Intend-to-treat: 92 allo-SCT, 198 auto-SCT Intend-to-treat: 98 allo-SCT, 210 auto-SCT Per Protocol: 76 allo-SCT, 132 auto-SCT Per Protocol: 87 allo-SCT, 110 auto-SCT

Figure 1. Trial profile. CR, complete response; SCT, stem cell transplantation.

Accepted article preview online 9 October 2013; advance online publication, 29 October 2013

Leukemia (2014) 404 – 463 & 2014 Macmillan Publishers Limited Letters to the Editor 441 cytarabine every 12 h on days 17–20. Response criteria, study themodelonthefactthatsomepatientsunderwent population, end points and statistical analysis are described in such a transplantation (RR, 0.734; 95% CI, 0.571–0.943; Supplementary Appendix. Of the 832 patients enroled in the P ¼ 0.015). study, 14 were excluded (Figure 1). The median follow-up of Recent randomized phase 3 trials have demonstrated that patients still alive at the date of last contact was 7.22 years (inter- increasing the daunorubicin dose from 45 to 90 mg/m2 during quartile range, 6.4–8.2). Characteristics of the 818 patients are the induction phase was a major way to improve the outcome in summarized in Supplementary Table S1. AML patients.3,6 The long-term results of the LAM-2001 trial AlthoughthecumulativeincidencesofCRwerenotsig- presented herein show that a 60 mg dose of daunorubicin is nificantly different between the two arms, there were signifi- suboptimal compared with idarubicin as delivered in our study. cantly more patients with at least 5% marrow blasts at d15 in This modality of use of idarubicin allows to give a higher dose of the daunorubicin arm than in the idarubicin arm idarubicin (40 mg/m2) compared with most studies dealing with (Supplementary Table S2) and a second induction chemother- this drug (30–36 mg/m2) without increasing the toxicity.7–9 In 50- apy course was more frequently given to the patients of the year-old patients and older, similar results favouring idarubicin daunorubicin arm (28% vs 21%; P ¼ 0.02). These findings likely have also been reported by the Acute Leukaemia French explained why CRs were more rapidly achieved in the idarubicin Association (ALFA) study group.10 Eight studies have compared arm, as depicted on the cumulative incidence curves these two as part of the induction chemotherapy. (Supplementary Figure S1). The incidence of adverse effects Only three of them enroled patients under 60 years of age. during the induction phase was not different between the two In the Memorial Sloan-Kettering Cancer Center trial, idarubicin groups (Supplementary Table S3). (12 mg/m2/day, 3 days) improved CR rate and OS as compared Univariate analyses showed that patients of the idarubicin arm with daunorubicin (50 mg/m2/day, 3 days).11 In the Gruppo less frequently relapsed and had an improved 7-year outcome, Italiano Malattie EMatologiche dell’Adulto and the European both in terms of disease-free survival (DFS) and OS (Figure 2a and Organisation for Research and Treatment of Cancer trial, Supplementary Figures 2A and 2B). However, univariate analyses idarubicin (10 mg/m2 on days 1, 3 and 5) improved OS from CR did not reach significance, although they were associated with in patients who did not undergo an allo-SCT as compared with borderline P-values. Interaction analyses between the treatment daunorubicin (50 mg/m2 on days 1, 3 and 5).12 In the Japan Adult arm and the other covariates that significantly influenced the Leukaemia Study Group (JALSG) trial, idarubicin (12 m/m2/day, 3 outcome—age, performance status, cytogenetics and white days) and daunorubicin (50 mg/m2/day, 5 days) were equally blood cell count (WBC)—showed that cytogenetics was effective.13 Three meta-analyses including both younger and differently affecting outcome according to the treatment arm older patients have also been performed.7–9 Two of them (Supplementary Table S4 and Figure 2b). Patients of the idarubicin showed that idarubicin significantly improved response rate arm had an improved 7-year OS, unless they had an unfavourable and OS, especially in younger patients, whereas the third cytogenetics (Figures 2c–e and Supplementary Figure S3). Similar concludes that the superiority of idarubicin for remission results were observed for a 7-year DFS and relapse incidence induction was restricted to studies with a daunorubicin/ (Supplementary Figures S4A–D and S5A–D). To better evaluate the idarubicin ratio o5.8 However, there were not enough data treatment arm effect on the 7-year OS by adjusting it on the other available in these meta-analyses to investigate the effects of age known prognostic factors, different Cox proportional hazards and the cytogenetic-risk group. models were performed (Supplementary Table S5). A first standard Idarubicin is a 4-demethoxy-anthracycline analogue of Cox model, involving all patients, showed that the idarubicin arm daunorubicin. The absence of the methoxyl group at position was associated with an improved outcome, whether censoring 4 of idarubicin’s anthracycline results in an increased (Cox model #1) or not (Cox model #2) the patients’ outcome at the lipophility and a better cellular uptake rate compared with time they underwent an allo-SCT, if they did. Similar results were daunorubicin. Idarubicin displays a lower susceptibility to observed in subsequent models stratified on cytogenetics, multidrug resistance and a stronger binding to DNA resulting whether censoring outcome at the time of an allo-SCT (Cox in a higher cytotoxic activity compared with daunorubicin. model #3) or not (Cox model #4). A last model was considered, Moreover, its primary metabolite, idarubicinol, which demon- which was based on the first one but stratified on the fact that strates similar activity to idarubicin in vitro, is still detectable in patients could have undergone an allo-SCT. This analysis, which plasma at least 72 h following intravenous infusion of differently took into account the fact that an allo-SCT could have idarubicin in contrast to daunorubicin’s lower half-life.14 influenced patients’ outcome, also showed that the idarubicin arm Besides the dose effect, the duration of exposition to was associated with a better outcome (Cox model #5). idarubicin given over 5 days in our study could have Because of the results observed in the interaction analyses, induced a deeper antileukaemic effect than daunorubicin and as the sample size was large enough, a subgroup analysis given over 3 days. The impact of anthracycline exposure focused on patients with intermediate-risk cytogenetics. duration remains poorly studied, and it is noteworthy that Although the cumulative incidences of CR were not significantly daunorubicin given over 5 days was equally effective as different between the two arms, the effect of idarubicin on early idarubicin given over 3 days in the JALSG trial. blast clearance was faster and more pronounced in the The major impact of idarubicin was observed in patients with idarubicin arm (marrow blast by day 15 X5%, 20% in the intermediate cytogenetic risk. The impact of high-dose daunor- idarubicin arm vs 36% in the daunorubicin arm; Po0.0001; ubicin was also observed in patients with DNMT3A or NPM1 Supplementary Table S2). As a consequence, more patients in the mutations, which are commonly found in this cytogenetic daunorubicin arm received the second induction course subgroup.15 It remains to be determined whether idarubicin (daunorubicin arm, 35% vs 21% in the idarubicin arm; could also impact outcome in molecularly defined subgroups of Po0.001). Patients of the idarubicin arm significantly had a patients. lower 7-year relapse incidence (Supplementary Figure S5B) and The long-term results of the LAM-2001 trial show that this higher 7-year DFS (Supplementary Figure S4B) and OS idarubicin regimen has a better antileukaemic effect than (Figure 2d). These last results were confirmed in the Cox model daunorubicin when the latter is used at a 60 mg/m2 daily dose, analysis adjusted on age, WBC and performance status, whether especially in AML patients with intermediate-risk cytogenetics. In censoring (relative risk (RR), 0.716; 95% confidence interval (CI), younger patients with AML, this idarubicin schema should be 0.547–0.937; P ¼ 0.015) or not (RR, 0.701; 95% CI, 0.546–0.90; compared with a 3 þ 7 schema with a 90 mg/m2 daily dose of P ¼ 0.0053) outcome at the time of allo-SCT, or stratifying daunorubicin.

& 2014 Macmillan Publishers Limited Leukemia (2014) 404 – 463 Letters to the Editor 442 1.0

0.8

0.6

0.4

Daunorubicin (Patients, n=406 - Events, n=234) 0.2 Idarubicin (Patients, n=412 - Events, n=212) Probability of Overall Survival Log-rank test p-value=0.094 0.0 Cox-adjusted p-value=0.017 0 1234567 Treatment arms Patients at risk Time (years) Daunorubicin 406 299 237 194 181 163 149 134 Idarubicin 412 316 255 220 207 198 181 145

Overall Survival Random Effect Model Percent Directional Deaths per treatment arm Percent per treatment arm 95.00% Random Zero-Effect Idarubicin Daunorubicin Idarubicin Daunorubicin Odds confidence Effects Test Cytogenetics arm arm arm arm Ratio Interval Weight Chi-2 p-value Favourable risk 9 / 56 20 / 67 16.07 29.85 0.463 0.195 - 1.104 17.40 3.016 0.083

Intermediate risk 114 / 238 139 / 230 47.90 60.43 0.603 0.418 - 0.870 48.71 7.328 0.007

Failures 10 / 22 13 / 31 45.45 41.94 1.151 0.391 -3.389 12.19 0.065 0.798

Unfavourable 79 / 96 62 / 78 82.29 79.49 1.199 0.567 - 2.538 21.71 0.226 0.635

Average (Random Effect Model) 0.724 0.481 - 1.090 6.361 0.012 Average (Fixed Effect Model) 0.683 0.509 - 0.919

0.1 1 10 Odds Ratio

1.0 1.0

0.8 0.8

0.6 0.6

0.4 0.4 Daunorubicin (Patients, n=67 - Events, n=20) Idarubicin (Patients, n=56 - Events, n=9) Daunorubicin (Patients, n=230 - Events, n=139) 0.2 0.2 Idarubicin (Patients, n=238 - Events, n=114) Log-rank test p-value=0.096 Probability of Overall Survival Log-rank test p-value=0.0045 Probability of Overall Survival Cox-adjusted p-value=0.17 Cox-adjusted p-value=0.0053 0.0 0.0 01234567 01234567 Treatment arms Patients at riskTime (years) Treatment arms Patients at risk Time (years) Daunorubicin 67 63 59 53 51 48 48 40 Daunorubicin 230 166 129 102 96 85 78 71 Idarubicin 56 52 50 48 48 48 48 48 Idarubicin 238 194 158 135 128 122 110 90

1.0

0.8

0.6

0.4

0.2 Daunorubicin (patients, n=78 - events, n=62)

Probability of Overall Survival Idarubicin (patients, n=96 - events, n=79) Log-rank test p-value=0.72 0.0 Cox-adjusted p-value=0.76 01234567 Treatment arms Patients at risk Time (years) Daunorubicin 78 46 29 19 16 15 15 15 Idarubicin 96 53 33 24 21 18 15 11 Figure 2. Estimates of survival end points. (a) 7-year overall survival according to the treatment arm. The 7-year overall survival was 41% in the daunorubicin arm (95% CI, 37–46) versus 48% in the idarubicin arm (95% CI, 43–53). The Cox-adjusted P-value corresponds to the one obtained with Cox model #2 (Supplementary Table S5). (b) A Forest plot summarizing the influence of cytogenetics on treatment arm effect with respect to the 7-year overall survival. (c) 7-year overall survival of the patients with favourable-risk cytogenetics according to the treatment arm. The 7-year overall survival was 68% in the daunorubicin arm (95% CI, 57–81) versus 84% in the idarubicin arm (95% CI, 75–94). The Cox-adjusted P-value corresponds to the one obtained in a Cox proportional hazards model including age, performance status as well as white blood cell count at diagnosis (RR for idarubicin as treatment arm, 0.559; 95% CI, 0.242–1.290). (d) 7-year overall survival of the patients with intermediate-risk cytogenetics according to the treatment arm. The 7-year overall survival was 39% in the daunorubicin arm (95% CI, 33– 46) versus 52% in the idarubicin arm (95% CI, 46–58). The Cox-adjusted P-value corresponds to the one obtained in a Cox proportional hazards model including age, performance status as well as white blood cell count at diagnosis (RR for idarubicin as treatment arm, 0.701; 95% CI, 0.546–0.900). (e) 7-year overall survival of the patients with unfavourable-risk cytogenetics according to the treatment arm. The 7-year overall survival was 19% in the daunorubicin arm (95% CI, 12–30) versus 16% in the idarubicin arm (95% CI, 10 to 26). The Cox-adjusted P-value corresponds to the one obtained in a Cox proportional hazards model including age, performance status as well as white blood cell count at diagnosis (RR for idarubicin as treatment arm, 1.053; 95% CI, 0.752–1.474).

Leukemia (2014) 404 – 463 & 2014 Macmillan Publishers Limited Letters to the Editor 443 CONFLICT OF INTEREST 17Service d’He´matologie, Centre Hospitalier Universitaire de The authors declare no conflict of interest. Clermont-Ferrand, Universite´ Clermont 1, EA7283, Inserm CIC-501, Clermont-Ferrand, France; 18Service d’He´matologie, Hoˆpital E. Muller, Mulhouse, France; ACKNOWLEDGEMENTS 19Institut de Cance´rologiedel’Ouest,CentreRene´ Gauducheau, Nantes We thank all the GOELAMS investigators. The sponsorship was assumed St Herblain, Nantes, France and by the Centre Hospitalier de Nantes, France (Projet Hospitalier de Recherche 20Service d’He´matologie, Centre Hospitalier Universitaire de Grenoble, Clinique, 1998). UMR 5525 CNRS, Universite´ Joseph Fournier, Grenoble, France. 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Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu)

& 2014 Macmillan Publishers Limited Leukemia (2014) 404 – 463