J Clin Oncol 27: by American Society of Clinical Oncology INTRODUCTION

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1 VOLUME 27 NUMBER 28 OCTOBER 1 2 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Acute Myeloid Leukemia With Translocation (8;21) or Inversion (16) in Elderly Patients Treated With Conventional Chemotherapy: A Collaborative Study of the French CBF-AML Intergroup Thomas Prébet, Nicolas Boissel, Sarah Reutenauer, Xavier Thomas, Jacques Delaunay, Jean-Yves Cahn, Arnaud Pigneux, Bruno Quesnel, Francis Witz, Sylvain Thépot, Valérie Ugo, Christine Terre, Christian Recher, Emmanuelle Tavernier, Mathilde Hunault, Benjamin Esterni, Sylvie Castaigne, François Guilhot, Hervé Dombret, and Norbert Vey From the Institut Paoli Calmettes, Marseille; Hopital Saint Louis, Paris; Centre Hospitalier Universitaire (CHU) Purpan, Toulouse; Hopital Edouard Herriot, Lyon; CHU Nantes, Nantes; Departement Cancerologie et Hematologie CHU Grenoble, Grenoble; Hopital Haut-Leveque, Pessac; Centre Hospitalier Regional Universitaire de Lilles, Lilles; Hopital de Brabois, Nancy; Groupe Francophone des Myélodysplasies, Bobigny; CHU Brest, Brest; Centre Hospitalier de Versailles, Versailles; Institut de Cancérologie de la Loire, Saint Etienne; CHU Angers, Angers; and Clinical Investigation Centre INSERM 82, Poitiers, France. Submitted November 17, 28; accepted March 1, 2; published online ahead of print at on August 31, 2. Written on behalf of the Acute Leukemia French Association, Groupe Ouest- Est des leucémies et autres maladies du sang (GOELAMS), and Core Binding Factor Acute Myeloid Leukemia (CBF AML) intergroup. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. A B S T R A C T Purpose Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly. Patients and Methods Patients with t(8;21) or inv(16) AML who were age 6 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n 72) or intensive consolidation (n 56). Results A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 12 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (1%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS. Conclusion Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted. J Clin Oncol 27: by American Society of Clinical Oncology Corresponding author: Norbert Vey, MD, Département d Onco-Hématologie, Institut Paoli-Calmettes, 232 Blvd Sainte Marguerite, 13 Marseille, France; veyn@marseille.fnclcc.fr. The Acknowledgment and Appendix are included in the full-text version of this article; they are available online at They are not included in the PDF version (via Adobe Reader ). 2 by American Society of Clinical Oncology X// /$2. DOI: 1.12/JCO INTRODUCTION Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16)/t(16;16) are associated with rearrangements of the core binding factor (CBF) genes CBFA and CBFB, and the rearrangements result in impaired transcription of genes involved in myeloid differentiation. 1-3 Patients with AML who harbor t(8;21) or inv(16)/t(16;16) (referred to as patients who have CBF-AML) have a favorable prognosis 4,5 when treated with intensive strategies, including the administration of repeated courses of high-dose cytarabine. 6,7 The incidence of CBF-AML decreases with age, and CBF-AML represents less than 5% of occurrences after people reach the age of 6 years. 8, In the elderly, patients with CBF-AML have higher complete remission (CR) rates and longer survival times 8,1,11 compared with patients who have other types of AML. However, the outcome seems inferior to that of younger patients 5,12,13 : Appelbaum et al 5 reported a 5-year estimated probability of overall survival (OS) of 48% in the whole population compared with 22% for patients older than 65 years. Overall, elderly patients with AML have a poor outcome. This is because of chemotherapy resistance, which is reflected principally by the distribution of cytogenetic categories. 1 Host-related factors, such as comorbidities and poor functional status, also explain this poor outcome In the 2 by American Society of Clinical Oncology 4747

2 Prébet et al case of CBF-AML, the role of host-related factors may be predominant, because they prevent the use of high-dose cytarabine. 7 To study the clinical and biologic characteristics of CBF in the elderly, and to evaluate the outcome and response to treatment in this group, we constituted a large database that included patients treated in centers from both the Acute Leukemia French Association (ALFA) and Groupe Ouest-Est des leucémies et autres maladies du sang (GOELAMS) groups. The results of treatment for 147 elderly patients with CBF-AML who received conventional chemotherapy are presented here. PATIENTS AND METHODS Patients We selected patients according to the following criteria: previously untreated AML diagnosed according to the French-American-British (FAB) criteria 17 with t(8;21), inv(16)/t(16;16), and/or their molecular equivalents; age 6 years or older; treatment with at least one course of anthracycline plus cytarabine based induction chemotherapy. Mutations t(8;21), t(16;16), and inv(16) were diagnosed by using conventional cytogenetic methods. Complex karyotype was defined as at least two other additional abnormalities. A predefined set of data, including demography, Eastern Cooperative Oncology Group (ECOG) performance status (PS), FAB categories, antecedent of hematologic disorder, de novo or secondary AML, karyotype, WBC count (hyperleukocytosis defined as WBC 3 G/L), platelet count, postremission therapy, and outcome were analyzed. All patients gave written informed consent according to institutional guidelines. Treatment Patients were treated according to the following protocols: BGMT 5, 18 GOELAMS SA3, 1 GOELAMS SA4, 2 ALFA 81, 21 ALFA 83, 22 EORTC AML 11, and EORTC AML Briefly, all patients underwent induction chemotherapy with an anthracycline plus cytarabine based regimen. Once in CR, patients received either maintenance chemotherapy or intensive postremission therapy. Maintenance consisted of low-dose cytarabine, methotrexate, and mercaptopurine. Intensive therapy consisted of an intermediate- to high-dose cytarabine regimen (IHDAra-C), defined as intravenous bolus of cytarabine 5 mg/m 2 /d or greater for at least 2 days, or high-dose melphalan followed by autologous stem-cell transplantation (Appendix Fig A1, online only). Response Criteria CR was defined by normalization of bone-marrow morphology to 5% or fewer blast cells and by normalization of peripheral counts to granulocytes greater than 1 G/L and platelets greater than 1 G/L without transfusion according to standard criteria. 24 Induction death, including early death and hypoplastic death, were evaluated as previously described. 15 Statistical Analyses Data were summarized by frequency and percentage for categoric variables. For continuous variables, the median and range were computed. All results are presented with their 5% CIs. Statistical tests were two sided at the 5% level of significance. To investigate the association between continuous variables and categoric variables, univariate analyses were performed with the nonparametric Wilcoxon rank sum test or Kruskal-Wallis rank sum test when appropriate. Survival rates were estimated by the Kaplan-Meier method. OS was defined by the time interval from the date of the AML diagnosis until death as a result of any cause, and observation ended at the date of last contact for patients last known to be alive. The leukemia-free survival (LFS) was defined as the time from the date of CR to relapse or death as a result of any cause. Patients without an event were censored at the date of the last follow-up. Multivariate analyses were performed with a Cox method or logistic regression method when appropriate. All variables with P less than.15 in univariate analysis were included in the Cox model by using a stepwise procedure selection. Multivariate analyses of OS and LFS were stratified on the period of treatment; three periods were defined: before 15, between 15 and 2, and after 2. Age was tested as a continuous variable and as categoric variable by using decades for cutoff. Statistical analysis was performed with the R software (R Development Core Team, Vienna, Austria; RESULTS Demographics The characteristics of the 147 patients are listed in Table 1. The median age of the population was 67 years, and 41 patients (28%) were 7 years or older. Inv(16)/t(16;16) was the more frequent finding (5%), especially in the oldest patients (56% in patients younger than 7 years and 65% in patients older than 7 years). In 25 patients (17%), AML was diagnosed after a prior cancer therapy (breast cancers, n 12; other solid tumors, n 7; hematologic malignancies, n 6) or exposure to environmental toxics (n 2). Hyperleukocytosis (ie, WBC 3 G/L) was more frequent in patients with inv(16)/ t(16;16) than in patients with t(8;21) (P.7). Ninety-four percents of patients with inv(16)/t(16;16) had FAB AML-M4. Patients with t(8;21) had a mix of FAB AML-M2 (83%) and AML-M1 (17%). Bone marrow blast counts were similar between the two subgroups. Table 1. Patient Demographic and Clinical Characteristics Patients by Mutation Group Characteristic Global T(8;21) Inv(16) P No. of patients Age, years Median NS Range Sex Male NS Female NS ECOG PS 2 No NS % NS WBC, g/l Median NS Range Platelets, g/l Median NS Range WBC 3 g/l No % PB blast, % Median Range BM blast, % Median NS Range Extramedullary disease No NS % Secondary AML No NS % Abbreviations: T, translocation; Inv, inversion; NS, not significant; ECOG, Eastern Cooperative Oncology Group; PS, performance status; PB, peripheral blood; BM, bone marrow; AML, acute myeloid leukemia by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

3 CBF Leukemia in Elderly Patients Cytogenetics Cytogenetic variants were found in two patients with t(8;21): One patient had t(8;12;21), and the other had insertion (5;8) and addition (21). Diagnosis was confirmed by fluorescent in situ hybridization and polymerase chain reaction for both patients. Additional chromosomal abnormalities were found in 71 patients (48%); these abnormalities are listed in Table 2. As previously described, the frequency of additional abnormalities was significantly higher in patients with t(8;21) (P.7). Trisomy (22) was specifically associated with inv(16)/t(16;16) (P.1) and was the sole additional abnormality in 1 (63%) of 16 patients. There was no correlation between trisomy (22) incidence and other pretreatment variables. Deletion (del) (q) was specifically associated with t(8;21) (P.1) and was associated with other abnormalities in three of the eight patients. There was no correlation between the presence of del(q) and other pretreatment variables. The mutation t(8;21) also was significantly associated with loss of a sex chromosome (1 of 21 patients; P.1) and included six patients with deletion X (only in women; P.7) and 15 patients with deletion Y (P.1). Complex karyotypes were found in 23 patients and included five patients with monosomy 7 (P.1; only one patient had an isolated monosomy 7). Complex karyotypes were more frequent in patients with t(8;21) (P.3) and were not correlated with other pretreatment variables. Other abnormalities included monosomy 5/del(5q) (n 4, all associated with complex karyotype), chromosome 11 abnormalities (n 3, including one amplification of MLL) and trisomy (21) (n 2). Response to Induction After the first induction course, 118 patients (8%) achieved CR (5% CI, 74% to 87%). Twelve patients who failed the first course received a second course, and 11 finally achieved CR. The CR rate was 88% (5% CI, 82% to 3%). Fifteen patients died during induction (induction death rate, 1%; 5% CI, 5% to 15%), including one patient who died during the second induction course. Causes of death were infection (n 8), acute respiratory distress syndrome (n 5), congestive heart failure (n 1), and hemorrhage (n 1). A total of 17 patients (12%) became critically Table 2. Additional Cytogenetic Findings Global (n 147) Patients by Mutation Group T(8;21) (n 6) Inv(16) (n 87) Cytogenetic Variable No. % No. % No. % P No other abnormality Trisomy LOS Trisomy NS Del(q) ,7q NS Chr NS Chr NS Complex karyotype Abbreviations: T, translocation; Inv, inversion; LOS, loss of sex chromosome; NS, not significant; Del, deletion; Chr, chromosome. Complex karyotype was defined as three or more independent cytogenetic abnormalities, and it potentially included one or more of the other abnormalities listed in this table. ill and required intensive care during induction, and eight (47%) of these patients died. Only three patients survived induction and did not achieve CR. There was no pretreatment variable in common for these patients. Interestingly, none of them were offered a second cycle of induction chemotherapy. Univariate analysis of factors influencing CR showed a negative impact of high WBC (77% v 2%; P.24), de novo AML versus secondary AML (85% v 1%; P.35), and inv(16)/t(16;16) (84% v 3%; P.8). Additional cytogenetic abnormalities had no significant influence on CR rate. By multivariate analysis, only high WBC counts remained of significant prognostic value (odds ratio, 67; 5% CI,. to.82; P.18). A Overall Survival (probability) Estimation CI5 Censoring Time Since Diagnosis (months) B Leukemia-Free Survival (probability) Estimation CI5 Censoring Time Since CR (months) Fig 1. (A) Overall survival of the whole population. (B) Leukemia-free survival of the whole population. CI5, 5% CI; CR, complete response. 2 by American Society of Clinical Oncology 474

4 Prébet et al OS After a median follow-up of 48 months (range, 4 to 114 months), 6 patients were alive, which included 55 patients in continuous first CR. Eighty-seven patients died: 68 patients (78%) died as a result of relapse; 15 patients (17%) died as a result of induction death; and four patients (5%) died in CR from other causes (metastatic melanoma, n 1; breast cancer, n 1; congestive heart failure, n 1; infection, n 1). Seventy-three patients (57%) experienced relapse with a median of 1 months from CR (range, 3 to 53 months). Median OS was 24 months (5% CI, 1 to 35 months; Fig 1A), and the 5-year OS was 31% (5% CI, 23% to 41%). Univariate analysis of the factors that influenced OS showed that high WBC (P.2), PS 2(P.1), and del(q) (P.2) had negative impacts on OS (Appendix Tables A1 and A2, online only). Presence of trisomy (22) was associated with a favorable outcome (P.5). Cytogenetic group, such as t(8;21) or inv(16), and age had no significant impacts on survival. By multivariate analysis, WBC, PS, and del(q) retained a significant impact on OS (Table 3). We then conducted the same analysis separately in both t(8;21) and inv(16) groups. Additional del(q) was associated with a lower OS in the t(8;21) group (median OS, 13 months v 24 months; P.2; Fig 2A). Additional trisomy (22) was associated with longer OS in patients with inv(16) in univariate analysis (median OS, not reached v 22 months; P.5; Fig 2B). The multivariate model in the t(8;21) group retained del(q) (hazard ratio [HR], 3.11; 5% CI, 1.24 to 7.82; P.16) and PS 2 (HR,7.64; 5% CI, 2.4 to 32.48, P.1) as significantly associated with a worse OS. In patients with inv(16)/t(16; 16), multivariate analysis retained PS 2 (HR, 8.87; 5% CI, 3.67 to 21.43; P.1) and high bone marrow blast count (HR,2.78; 5% CI, 1.33 to 5.84; P.7) as significantly associated with a worse OS. LFS Median LFS was 18 months (5% CI, 14 to 24 months; Fig 1B), and 5-year LFS was 26% (5% CI,18% to 36%), with no plateau (Fig 1B ). The univariate analysis of the factors affecting LFS in the whole population showed that PS greater than 2 (P.2), being critically ill during induction (P.3), high WBC (P.58), and del(q) (P.4) were significantly associated with a shorter LFS (Appendix Tables A1 and A2). Conversely, trisomy (22) (P.5) and use of intensive consolidation (P.5) were significantly associated with a longer LFS. There was a trend to a longer LFS for patients who received IHDAra-C (median LFS, 26 months v 14 months; P.8) compared with maintenance therapy. This effect of IHDAra-C reached statistical significance in patients with t(8; 21) (median, not reached v 1 months; HR,.163; 5% CI,.4 to.62; P.7) but not in patients with inv(16)/t(16;16) (median LFS, 23 months in both groups; P.78; Fig 3). Of the 48 patients Table 3. Multivariate Analysis of Overall Survival Analysis Variable HR 5% CI P WBC 3 g/l to Impaired PS to Deletion q to Abbreviations: HR, hazard ratio; PS, performance status. A Delq Delq + B Overall Survival (probability) Overall Survival (probability) Tri22 Tri Time Since Diagnosis (months) t(8;21) treated with IHDAra-C, 25 (52%) received at least two cycles (range: two to four cycles), and their LFS rates did not differ statistically from the patients who received only one cycle (22 months v 18 months; P.76). Multivariate analysis (Table 4) showed that high WBC count, poor PS, need for critical care, and del(q) were independently associated with a shorter LFS. Outcome After Relapse Of the 73 patients who experienced relapse, 36 (4%) received a salvage regimen with intensive chemotherapy (cytarabine alone, n 8; cytarabine in combination with anthracyclines, n 17; or gemtuzumab ozogamycin, n 4; and, others regimens, n 7). Two 14 1 Inversion Time Since Diagnosis (months) 11 3 Delq + Delq Log-rank P =.18 Tri22 + Tri22 Log-rank P =.4 Fig 2. (A) Overall survival in the translocation (t) (8;21) subgroup is influenced by the additional deletion (del) (q). (B) Overall survival in the inversion (inv) (16) subgroup is influenced by an additional trisomy (tri) (22) by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

5 CBF Leukemia in Elderly Patients A No B Leukemia-Free Survival (probability) Leukemia-Free Survival (probability) No Time Since CR (months) t(8;21) patients were treated with allogeneic stem-cell transplantation in second CR (CR2) by using reduced-intensity regimens, and both remained in CR at last follow-up. Median OS after relapse was 6 months (5% CI, 4 to 8 months; range, 3 to 54 months; Appendix Fig A2, online only). At last follow-up, six (17%) of the 36 patients are still alive in second CR. By univariate analysis, administration of intensive salvage (17 v 3 months; P.1), First CR duration was more than 12 months (4 v 18 months; P.1), achievement of CR2 (14 versus 4 months, P.1; Fig A2B) and inv(16)/t(16;16) (7 v 4 months, P.2) predicted a better survival after relapse. The multivariate model retained only CR2 as being significantly associated with a longer survival from relapse (HR, 4; 5% CI,.18 to.64; P.1). 8 6 Inversion Time Since CR (months) 1 No Log-rank P = No Log-rank P = Fig 3. Leukemia-free survival is influenced by the use of intermediate- to high-dose cytarabine regimen (IHDAra-C) in the (A) translocation (t) (8;21) subgroup but not in the (B) inversion (16) subgroup. CR, complete response. Table 4. Multivariate Analysis of Leukemia-Free Survival Variable HR 5% CI P WBC 3 g/l to Impaired PS to 4..3 Deletion q to Critically ill patient to DISCUSSION Analysis Abbreviations: HR, hazard ratio; PS, performance status. This study represents the largest reported cohort of elderly CBF-AML to date. After conventional induction, elderly patients with CBF-AML had a high rate of CR comparable to younger patients. However, this did not translate into a substantial cure rate, because 5-year estimated probability of LFS was only 26%, and no plateau was seen on the LFS curve. The frequency of CBF-AML among patients older than 6 years ranges from 3% to 7% in the literature, 5,12 and this explains the absence of large series. In addition to reduced incidence, we found substantial differences in clinicobiologic features of CBF-AML in the elderly compared with younger patients. First, there is a reverse CBF to CBF ratio. This observation is consistent with a previous report. 5 It has been speculated that this might reflect the increase of therapyrelated CBFs (which are preferentially of the CBF subtype) in the elderly. However, this was not true in our series. Second, we observed a higher median WBC count in the t(8;21) subgroup and a lower frequency of extramedullary disease than reported in younger patients. 5,12,25 Conversely, the distribution of the most frequent additional abnormalities was not different from younger patients. These abnormalities were seen in 48% of patients and were more frequent in the t(8;21) group than in the inv(16)/t(16;16) group (62% v 41%), which confirms previous observations. 5,12 The prognostic value of these additional abnormalities is still controversial. In our series, there was a negative impact of del(q) on OS and LFS. This has been already reported in a cohort of younger patients 26 but has not been confirmed by others. 5,12 We also observed a positive impact of trisomy (22) on OS and LFS in patients with inv(16)/t(16;16), as already reported in larger series, 5,27 but this was not confirmed by multivariate analysis. The rare complex karyotypes (16%) did not appear to affect the outcome. Recent studies have highlighted the importance of other biologic factors, such c-kit mutations, that are observed in approximately 3% of patients with CBF-AML 28 and that are associated with a poor prognosis both in t(8;21) 2 and inv(16)/t(16;16) 3 in younger patients. The impact of c-kit mutation in elderly patients with CBF-AML has not been studied yet. Due to the lack of available blast samples, we were unable to evaluate this parameter in our study. Our study has shown that disease-related parameters (eg, WBC count, del(q)) or host-related parameters (eg, PS) identify a group of patients with a high risk of relapse and death. In addition to the above-mentioned molecular markers, which might be important, the evaluation of comorbidities or functional status must be considered in this elderly population. In particular, the presence of comorbidities that could not be assessed in the retrospective study presented here 2 by American Society of Clinical Oncology 4751

6 Prébet et al were recently shown to have an impact on the outcome of elderly patients treated for AML. 31,32 Prospective evaluation by using scores like the hematopoietic cell transplantation comorbidity index must be envisaged for additional studies. In previous studies, elderly patients were shown to have lower CR rates and higher early death rates than younger patients. 5 The patients presented here had received a conventional induction regimen that proved successful by the 88% CR rate, which is comparable to the CR rate of young patients and confirms the high chemotherapy sensitivity of CBF-AML. In the different protocols used here, doses of anthracyclines and cytarabine were similar to the doses used for younger patients. This may explain why comparable CR rates were achieved. Although the 1% mortality rate observed here was low compared with other series of elderly patients, 33,34 morbidity was high, and 17% of the patients became critically ill and required transfer to an intensive care unit. Half of them survived and achieved CR, but that half had a poor long-term outcome, which suggests that the consequences and sequellae of this initial event prevented the administration of an appropriate postremission therapy. Altogether, this suggests that induction chemotherapy should be refined to limit initial toxicity. Replacement of anthracyclines by gemtuzumab ozogamicin 35 represents a promising approach in this setting. The results of this study raise the issue of the optimal postremission therapy for elderly patients with CBF-AML. Elderly patients are often not offered intensive treatments that are associated with toxicity and that have been recently identified as inferior to lower-dose maintenance. 22 Nevertheless, studies in younger patients with CBF-AML have shown that the favorable prognosis is supported by the particular sensitivity of this form of AML to IHDAra-C. 7,13 This high sensitivity to IHDAra-C regimens seems also to be found in elderly patients, because we report here that intensive postremission therapy was associated with a trend to a better LFS. This effect was marked in patients with t(8;21), as demonstrated by multivariate analysis. The number of IHDAra-C courses was shown to impact the outcome of young patients with CBF-AML. 7 This impact was not observed in our study, but the number of patients who received more than one cycle (n 25) was probably too low to provide such a conclusion. We also analyzed the outcome of patients who experienced and received intensive salvage chemotherapy. Generally, elderly patients with relapsed AML are offered palliative treatment. Our results suggest that, forcbf-aml, intensivesalvageshouldbeconsideredinparticularin patients with inv(16) and a first-cr duration greater than 12 months. In conclusion, new postremission strategies need to be evaluated in elderly patients with CBF-AML. With modern supportive care and improved selection criteria, the use of more intensive approaches, such as repeated courses of IHDAra-C, or synergistic associations of cytarabine with fludarabine 36 or clofarabine 37 could be feasible and might improve the patient outcomes. The role of allogeneic transplantation with reduced-intensity conditioning has to be considered, given the high relapse rate seen in elderly patients with CBF-AML. On the basis of data from this study, the benefit-to-risk ratio should favor reduced-intensity conditioning hematopoietic stem-cell transplantation in patients with del(q) and high WBC counts. 38,3 Nevertheless, it is clear that there is a subset of elderly patients (especially among those patients older than 7 years) who cannot tolerate IHDAra-C and for whom the maintenance of remission remains a challenge. Maintenance therapies with multi-hit tyrosine kinase inhibitors that target Kit, Ras, and Flt3 all of which play a role in the pathogenesis of the disease 2,4 or with epigenetic drugs 41 like demethylating agents or histone deacetylase inhibitors have to be investigated. Given the small number of elderly patients with CBF- AML, only large multicenter studies could evaluate any of these strategies. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Thomas Prébet, Norbert Vey Provision of study materials or patients: Thomas Prébet, Nicolas Boissel, Sarah Reutenauer, Xavier Thomas, Jacques Delaunay, Jean-Yves Cahn, Arnaud Pigneux, Bruno Quesnel, Francis Witz, Sylvain Thépot, Valérie Ugo, Christine Terre, Emmanuelle Tavernier, Mathilde Hunault, Sylvie Castaigne, François Guilhot, Christian Recher Collection and assembly of data: Thomas Prébet, Nicolas Boissel, Sarah Reutenauer, Xavier Thomas, Jacques Delaunay, Jean-Yves Cahn, Arnaud Pigneux, Bruno Quesnel, Francis Witz, Sylvain Thépot, Valérie Ugo, Christine Terre, Christian Recher, Emmanuelle Tavernier, Mathilde Hunault, Sylvie Castaigne, François Guilhot Data analysis and interpretation: Thomas Prébet, Nicolas Boissel, Benjamin Esterni, Hervé Dombret, Norbert Vey Manuscript writing: Thomas Prébet, Norbert Vey Final approval of manuscript: Thomas Prébet, Nicolas Boissel, Hervé Dombret, Norbert Vey REFERENCES 1. 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