Comparison of 60 or 90 mg/m<sup>2</sup> of daunorubicin in induction therapy for acute myeloid leukemia with intermediate or unfavorable cytogenetics
Authors: Raynier Devillier, Sarah Bertoli, Thomas Prébet, Françoise Huguet, Anne Etienne, Aude Charbonnier, Jérôme Rey, Eric Delabesse, Evelyne D'Incan, Anne Huynh, Didier Blaise, Christian Récher, Norbert Vey
Journal: American Journal of Hematology (2014)

To the Editor: Induction therapy for acute myeloid leukemia (AML) based on 3 days of anthracycline and 7 days of cytarabine has been a standard of care since many years but the optimal regimen is still a matter of debate. Recently, the use of high dose 90 mg/m2 daunorubicin (DNR) was reported in several phase III clinical trials to improve both complete remission (CR) rate and overall survival (OS) as compared with low dose DNR (45 mg/m2) and is now considered as a standard of care 1, 2. However, the dose of 45 mg/m2 is not used worldwide and several groups use intermediate dose of 60 mg/m2 and reported OS of approximately 40%–45% at 5 years in younger AML patients 3, 4. A formal comparison between daunorubicin 60 and 90 mg/m2 has yet to be published. In 2010 following Fernandez reports and in the absence of active protocol, GOELAMS switched the DNR induction dose from 60 to 90 mg/m2 for all newly diagnosed patients. Both reports of Fernandez and Löwenberg suggest that patients with favorable cytogenetics benefit the most from high dose DNR while outcome of unfavorable cytogenetic patients was not improved using 90 versus 45 mg/m2 of DNR. To deal with this possible interaction between cytogenetics and DNR dose, we previously compared 60 with 90 mg/m2 in the specific setting of core binding factor AML (CBF-AML) in a separate report and showed that 90 mg improved outcome compared with 60 mg 5. However, it was not certain that the same comparison would be beneficial in patients with intermediate or unfavorable cytogenetic features. In this present study, we compared the outcome of AML patients with intermediate or unfavorable cytogenetics treated with 90 mg/m2 daunorubicin to historical controls treated with 60 mg/m2. We retrospectively analyzed 300 consecutive patients with previously untreated AML who received induction therapy in Marseille and Toulouse. Selection criteria were: (1) adult patients younger than 61 years; (2) diagnosis of AML according to the WHO classification 6; (3) induction therapy with DNR (60 or 90 mg/m2/d, 3 days) and cytarabine (200 mg/m2/d, 7 days); and (4) patients with favorable cytogenetics [t(8;21), inv(16), t(16;16), t(15;17)] were not included in this study and have been reported elsewhere 5. This study was approved by our institutional review board and is in accordance with the Helsinki declaration. We performed univariate comparisons according to DNR dose in subgroups of age (≤ and >50 years), white blood cells (WBC) (≤ and >50 G/L), AML occurrence (de novo and secondary), cytogenetics (intermediate and unfavorable), and genotype (favorable [NPM1-mutated/FLT3-wild-type or CEBPA-mutated/FLT3-wild-type] and other [other combinations of these three genes]). The impact of DNR dose was adjusted using a multivariate Cox model including age (≤ vs. >50 years), WBC (≤ vs. >50 G/L), occurrence of AML (de novo vs. secondary), and cytogenetics (intermediate vs. unfavorable). Seventy-five patients treated from 2010 to 2012 received 90 mg/m2 daunorubicin (DNR90 group), and 225 patients treated from 2006 to 2010 received 60 mg/m2 daunorubicin (DNR60 group) (Table 1). There was no difference between the two dose groups except a trend for higher median WBC at diagnosis in the DNR90 group (9 vs. 15 G/L, P = 0.056). As the treatment periods were different between the two groups, the median follow up was longer in the DNR60 group (58 vs. 31 months, P < 0.001). No differences in terms of CR, CR + CRi, or induction death rates were seen (Table 1). Once in CR or CRi (IWG2003 criteria7), 116/238 (49%) patients underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT), without significant difference between the two dose groups [DNR60: 88/177 (50%) vs. DNR90: 28/61 (46%), P = 0.891]. Two-year cumulative incidence of relapse was 36% and 33% in the DNR60 and DNR90, respectively, (P = 0.836), while the 2-year cumulative incidence of death in CR was 12% and 10% in the DNR60 and DNR90 groups, respectively (P = 0.645). Interestingly, in the specific setting of patients who underwent Allo-HSCT in CR1, the cumulative incidence of death in CR was not increased in the DNR90 group (14%) compared with the DNR60 group (16%) (P = 0.873). We found similar 2-year probability of RFS (52% vs. 57% in the DNR60 vs. DNR90 groups, respectively, P=0.688) and 2-year probability of OS (54% vs. 59% in the DNR60 vs. DNR90 groups, respectively, P = 0.352; Table 2). There was no difference according to DNR dose in all the subgroups of age, WBC, cytogenetics, and genotypes (Table 2). After adjustment with multivariate Cox model, daunorubicin dose did not significantly influence either RFS [Hazard ratio, 95% confidence interval (HR, 95CI): 0.91, 0.58–1.43; P = 0.692] or OS (HR, 95CI: 0.84, 0.57–1.26; P = 0.404) while age ≥50 years (RFS: HR, 95CI: 1.48, 1.01–2.15; P = 0.040; OS: HR, 95CI: 1.53, 1.11–2.10; P = 0.010), WBC ≥50 G/L (RFS: HR, 95CI: 1.68, 1.09–2.61; P = 0.020; OS: HR, 95CI: 1.48, 1.02–2.15, P = 0.040) and unfavorable cytogenetics (RFS: HR, 95CI: 1.48, 0.94–2.33; P = 0.090; OS: HR, 95CI: 1.52, 1.05–2.19; P = 0.026) were associated with poor outcome. Our results suggest that a dose of 90 mg/m2 of DNR did not confer further benefit as compared with an "intermediate" dose of 60 mg/m2 in the setting of patients without favorable cytogenetics. The 2-year OS of the DNR90 arm in the Fernandez study was 49% (59% in our study) although they included also patients with favorable cytogenetics 2. The better results in our series that excluded favorable cytogenetics are likely due to the higher proportion of patients who underwent allogeneic transplantation in first CR (49%) compared with 10% in the Fernandez report. We could suggest that this major difference in transplantation rates in our study compared with the Fernandez study explains in part the different conclusions regarding DNR doses. We failed to identify subgroups which could benefit from high dose DNR. No difference was found according to DNR dose in all "conventional" subgroups as shown by ECOG and HOVON studies 1, 2. It stresses the need to identify new predictive markers of chemosensitive disease to select patients for intensified induction therapy. Molecular findings could be a promising approach to solve in part this issue. The dose issue in the specific setting of AML with favorable genotype is of particular interest when intensified chemotherapy appears as a promising way to improve outcome in this situation 8, 9. In this setting, we did not find any difference between the DNR90 and DNR60 groups. However, the low number of patients with favorable genotype does not allow us drawing clear conclusions. It was reported that patients with some somatic mutations such as DNMT3A mutant could specifically benefit from intensive anthracycline dose regimens 10, 11. Of note, we showed that DNR90 mg/m2 was not associated to an increased treatment-related mortality as compared with DNR60 and had no deleterious impact on post-transplant outcome. Our study has limitations due to this retrospective nature. One could argue that the low number of patients in the DNR90 group leads to low statistical power hiding a potential difference between the two groups. However, hazard ratio in the multivariate model (0.91 for RFS and 0.84 for OS) do not support a dramatic influence of DNR dose in our series. Moreover, improvements of AML therapy results over time might confound the results of historical control comparison as previously shown 12, 13, but in our analysis, this would have favor the DNR90 group. Although these limitations, our results are important to give the basis of a potential prospective comparison of these regimens with the objectives of confirming our retrospective data but more importantly to try to define subgroups of patients for which dose intensification may be beneficial. Designed the study and supervised research: N Vey, C Recher, T Prebet Data collection: R Devillier, S Bertoli, T Prebet Wrote the manuscript: R Devillier, N Vey Statistical analyses: R Devillier Recruited patients, contributed data and commented on the manuscript: R Devillier, S Bertoli, F Huguet, A Huynh, T Prebet, A Etienne, A Charbonnier, J Rey, E Delabesse, E D'Incan, D Blaise, C Recher, N Vey All authors approved submission of the manuscript for publication purposes. The authors would like to thank Audrey Sarry for data management, the GAEL Association (Gael Adolescent Espoir Leucémie) for their support to patients. Raynier Devillier,1,2 Sarah Bertoli,3 Thomas Prébet,1 Françoise Huguet,3 Anne Etienne,1 Aude Charbonnier,1 Jérôme Rey,1 Eric Delabesse,3,4 Evelyne D'Incan,1 Anne Huynh,3 Didier Blaise,1,4 Christian Récher,3,4* and Norbert Vey1,2* 1Hematology Department, Institut Paoli Calmettes, Marseille, France 2Aix-Marseille University, Medecine Faculty, Marseille, France 3Département D'hématologie, Institut Universitaire du Cancer Toulouse – Oncopole, Toulouse, France 4Toulouse University, Medecine Faculty, Toulouse, France