Acute Leukemia French Association Research Articles

Prognostic Impact of Monoallelic Versus Biallelic TP53 Alterations in Intensively-Treated Adults AML Patients: A Retrospective Study from the ALFA Group

Introduction:TP53 is a key tumor suppressor gene involved in apoptotic pathways, metabolism functions, preservation of genomic balance and DNA repairs. TP53 locus is subject to mutations, deletions and copy-neural loss of heterozygosity. TP53 mutations are associated with a reduced overall survival and are assigned to the ELN 2017 adverse-risk group. Recent studies have suggested a worse prognostic impact of biallelic TP53 alterations compared to monoallelic TP53 mutations in myelodysplastic syndromes (Bernard et al, Nat. Medicine, 2020). Whether TP53 allelic state impairs the prognostic in intensively-treated acute myeloid leukemia (AML) patients and may refine the treatment strategy has not been addressed. Here, we analysed TP53 alterations in newly diagnosed AML patients (pts) from 3 prospective Acute Leukemia French Association (ALFA) trials. Methods: A total of 983 adult AML pts enrolled in ALFA-0701 (NCT00927498), ALFA-0702 (NCT00932412) and ALFA-1200 (NCT01966497) trials were retrospectively screened for TP53 alterations by high throughput sequencing and conventional cytogenetics. Pts displaying at least two TP53 mutations or one TP53 mutation associated with either TP53 locus deletion or TP53 locus copy-neutral loss of heterozygosity (CN-LOH) were assigned as biallelic TP53 alteration patients. TP53 locus CN-LOH were approximated based on variant allele frequencies and copy number analysis. Survival was analysed with multivariate Cox models stratified on the trial. Results: Eighty-three patients had TP53 mutations (8%; ALFA-0701: n=21, ALFA-0702: n=28; ALFA-1200: n=34), including 14 pts with monoallelic and 69 pts with biallelic TP53 alterations respectively. Median age of TP53 mutated patients was 62 years (IQR: 57-68). Leukocytes counts and bone marrow blast counts at diagnosis were lower in TP53 mutated patients (3.0 G/L vs. 8.7 G/L, p<0.0001; 40% vs. 58%, p=0.002, respectively). Median variant allele frequency of TP53 mutations was 43% (IQR: 21-69). As compared to TP53 wildtype AML, TP53 mutated pts more often harbored complex karyotype (n=69 (86%) vs n=51 (6%), p<0.0001) and monosomal karyotype (n=65 (81%) vs n=32 (4%), p<0.0001). The median number of additional mutations was 2 (IQR: 0-3). TP53 mutations were associated with mutations in signalling genes (NF1, NRAS, PTPN11, KRAS, FLT3, KIT and JAK2) in 33 pts (40%). Overall, 43 TP53 mutated AML patients (52%) achieved complete remission (CR)/complete remission without platelet recovery (CRp) after one or two courses of induction whereas 684 TP53-wt patients (76%) were in CR/CRp at that time (p<0.0001). TP53 mutations were associated with a significantly reduced OS and DFS in multivariate analysis including age and WBC count (2-year OS, 11% vs 56%, HR: 3.48, 95% CI: 2.71-4.47, p<0.0001; 2-year DFS, 12% vs 50%, HR: 2.97, 95% CI: 2.12-4.16, p<0.0001, respectively). Among TP53 mutated AML, biallelic TP53 alterations were associated with worse OS compared to monoallelic TP53 alterations (2-year OS, 4% vs 43%, HR: 4.13, 95% CI: 1.87-9.13, p=0.0004 in multivariate analysis accounting for age and WBC count). Interestingly, outcome of the 2017 ELN risk stratification intermediate group was not different to that of monoallelic TP53 pts (2-year OS, 43% for monoallelic TP53 pts vs 53%, HR: 1.07, 95% CI: 0.55-2.07, p=0.84). In pts with biallelic TP53 alterations, presence of signalling mutations was associated with a worse survival in a multivariate analysis accounting for age and WBC (HR: 1.82, 95% CI: 1.06-3.11, p=0.03). Conclusion: Allelic status refines the prognostic value of TP53 mutations in AML. While monoallelic TP53 alterations display similar outcome to that of the ELN 2017 intermediate risk group, biallelic TP53 alterations dramatically impair patient outcome. Patients with biallelic TP53 alterations may be good candidates for new first-line treatment strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic Significance of DDX41 Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Prognostic Significance of DDX41 Germline Mutations in Intensively Treated AML Patients: An ALFA-Filo Study

Early Detection of WT1 minimal Residual Disease Predicts Outcome in Acute Myeloid Leukemia and Identify Patients with High Risk of Relapse Independently of Allogeneic Stem Cell Transplantation

Background:WT1 overexpression is frequently identified in acute myeloid leukemia (AML) andhas been reported as a potential marker for minimal residual disease (MRD) monitoring. However, the role of WT1 MRD response as prognostic and/or treatment stratifying factor is still under debate.Aims: In this work, we evaluated the prognostic value of post-induction WT1 MRD level, as well as the interaction between post-induction WT1 MRD response and the effect of allogeneic stem cell transplantation (SCT) in first complete remission (CR), in a cohort of AML patients aged 18 to 59 years old treated in the Acute Leukemia French Association (ALFA)-0702 trial.Methods: Among the 713 patients enrolled in ALFA-0702 study (X. Thomas et al, JCO 2017), 539 had an overexpression of WT1 at diagnosis (75.6%) defined as a ratio WT1 transcript/100 ABL transcript above 25% in bone marrow (BM) or 5% in peripheral blood (PB) samples (WT1+). After induction, MRD levels were assessed using cDNA-based real-time quantitative PCR. Occurrence of a WT1 MRD ratio >2.5% in BM or >0.5% in PB was defined here as positive MRD (MRDpos), while ratio under these threshold was defined as negative MRD (MRDneg). The prognostic value of MRD was assessed by comparing cumulative incidence of relapse (CIR) with death in remission as competing event, relapse-free survival (RFS) and overall survival (OS) among patients who achieved first CR. As patients with favorable-risk AML according to European LeukemiaNet (ELN)-2010 classification were not eligible for SCT in first CR, interaction between MRD response and SCT effect was evaluated in patients with intermediate/unfavorable-risk AML by comparing the influence of SCT, considered as a time-dependent covariate, on the outcomes of MRDneg and MRDpos patients.Results: Among the 539 WT1+ patients at diagnosis, 473 achieved CR (87.7%). Post-induction WT1 MRD evaluation was available in 339/473 patients (71.7%), 279 patients were MRDneg and 60 were MRDpos. At this early time point, MRD was predictive of relapse: 4-year CIR was 36.5% in MRDneg patients versus 69.2% in MRDpos patients (Cause-Specific Hazard Ratio, 2.88 [1.93-4.29]; p<0.001). When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRD remained independently associated with relapse incidence (CSHR, 2.15 [1.41-3.29]; p<0.001). This translated into longer survival in MRDneg patients. At 4 years, RFS was 60.9% versus 24.9% (HR, 2.69 [1.89-3.83]; p<0.001) and OS was 71.6% versus 43.3% (HR, 2.34 [1.56-3.51]; p<0.001) in MRDneg and MRDpos patients, respectively. When adjusted on age, cytogenetics, NPM1 mutation status and FLT3-ITD status, MRDneg remained independently associated with longer RFS (HR, 2.12 [1.47-3.07]; p=0.001) and OS (HR, 1.79 [1.18-2.73]; p<0.001).We then analyzed the role of SCT in 254 patients with intermediate/unfavorable-risk AML and available post-induction WT1 MRD evaluation (199 MRDneg, 55 MRDpos). SCT was performed in 155 patients. Overall, both MRD and SCT were independent prognostic factors. Post-induction MRD response remained of strong prognostic value, since MRDpos patients had a higher CIR (CSHR, 2.33 [1.54-3.53]; p<0.001) and a shorter RFS (HR, 2.25 [1.55-3.26]; p<0.001). In this population, SCT was beneficial and significantly improved CIR (CSHR, 0.33 [0.22-0.51]; p<0.001) and RFS (HR, 0.53 [0.37-0.76]; p=0.001). Despite a higher effect of SCT in MRDneg patients (Figure 1), the interaction between MRD status and SCT effect was not statistically significant (p= 0.3).Conclusions: Our study confirms the prognostic value of post-induction WT1 MRD in younger adults with AML treated in the prospective ALFA-0702 study. The observation that early WT1 MRD response retains its prognostic value among patients independently of allogeneic SCT in first CR might help selecting these patients more accurately in the next future. [Display omitted] DisclosuresRenneville:CELGENE: Research Funding. Recher:Novartis, Celgene, Jazz, Sunesis, Amgen: Consultancy; Celgene, Sunesis, Amgen, Novartis: Research Funding. Rousselot:BMS: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy

AbstractTo design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.

Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML: an ALFA study

AbstractIn patients with isocitrate dehydrogenase (IDH)–mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010–eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.

Randomized comparison of double induction and timed-sequential induction to a “3 + 7” induction in adults with AML: long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study

AbstractBetween 1990 and 1996, we conducted a randomized trial in adults with newly diagnosed acute myeloid leukemia (AML) in order to compare relapse-free interval (RFI) after double induction (arm B), timed-sequential induction (arm C), or control “3 + 7” induction (arm A). Patients achieving complete remission (CR) after induction ± salvage received the same consolidation chemotherapy, which included a dosage stratification according to patient's age (younger or older than 50 years). This long-term analysis was performed in 592 patients (arm A/B/C, 197/198/197 patients). Overall CR rate was 76% without differences between the 3 arms, even if a salvage course was less frequently needed in arm B. Treatment-related mortality, either during the induction or the postremission phase, was not significantly higher in arms B and C than in arm A. Among the 449 CR patients, 250 relapsed (arm A/B/C, 90/87/73 patients) without significant differences in RFI in arms B and C versus arm A (P = .39 and .15, by the Gray test). However, when analyzing the 345 patients younger than 50, RFI was significantly improved in younger patients receiving timed-sequential induction (P = .038 by the Gray test), while not in those receiving double induction. Event-free survival and overall survival were similar in the 3 randomization arms.

Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results

AbstractIn this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.

Integrating ELN Criteria and a ‘Knowledge Bank’ Approach to Guide Allogeneic Stem Cell Transplantation (SCT) Indication in Younger Adults with Acute Myeloid Leukemia (AML): An Acute Leukemia French Association Study

Integrating ELN Criteria and a ‘Knowledge Bank’ Approach to Guide Allogeneic Stem Cell Transplantation (SCT) Indication in Younger Adults with Acute Myeloid Leukemia (AML): An Acute Leukemia French Association Study

Characteristics and Outcome of Older Patients with Acute Promyelocytic Leukemia Front-Line Treated with or without Arsenic Trioxide — an International Collaborative Study

Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data.Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy.Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/institutions of the US and Europe (Acute Leukemia French Association, n=228; Programa Espanol de Tratamientos en Hematologia, n=211; Study Alliance Leukemia, n=28; Johns Hopkins School of Medicine, Baltimore, n=8). APL was confirmed either by cytogenetics, fluorescence in situ hybridization and/or polymerase chain reaction. For analysis, pts were grouped according to treatment: i) chemotherapy/all-trans retinoic acid (CTX/ATRA, n=260; consisting of daunorubicin/idarubicin and ATRA for induction and different CTXs+ATRA for consolidation), ii) ATO/ATRA±CTX, n=177 (according to Lo-Coco F, et al. NEJM, 2013, n=23 or CTX/ATO/ATRA, n=154), iii) less intensive therapy, n=26 (reduced CTX, n=2 or ATRA only, n=24) and iv) no treatment/unknown, n=12.Results: Median white blood cell (WBC) and platelet counts at diagnosis were 1.5/nl (range, 0.1-242/nl) and 37/nl (range, 2-261/nl), respectively. Two-hundred twenty-nine pts (48%) were female. Cytogenetic analysis was available in 408 pts and 85 (21%) had additional abnormalities. BCR3 was positive in 138 (44%) of 316 available pts. Only 15 (22%) of 69 tested pts were FLT3-ITD positive. One hundred (22%) of 464 pts had a WBC count >10/nl. Median WBC was significantly lower (P<0.001) in the ATO/ATRA±CTX group (1.2/nl) as compared to the CTX/ATRA (2.05/nl) or less intensive (2.8/nl) group. Median age was comparable in CTX/ATRA (73.5 yrs) and ATO/ATRA±CTX (73.6 yrs) but significantly higher (P<0.001) in the less intensive group (79.6 yrs). Median platelet counts were comparable (P=0.08) in the three groups (CTX/ATRA, 34.5/nl; ATO/ATRA±CTX, 41/nl; less intensive, 39/nl). Response data were available in 459 (97%) pts.Complete remission (CR) after induction therapy was achieved in 75% (194/259) of the CTX/ATRA group, in 93% (162/174) of the ATO/ATRA±CTX group, and in 50% (13/26) of the less intensive group. Two pts of the CTX/ATRA group and one patient after ATRA only were refractory. Early death rates were 24% (n=63) after CTX/ATRA, 7% (n=12) after ATO/ATRA±CTX and 46% (n=12) in the less intensive group. A logistic regression model revealed age above 75 yrs (odds ratio [OR], 0.53; P=0.02) higher WBC (OR, 0.35; P<0.001), less intensive treatment (OR, 0.46; P=0.08) and therapy with ATO/ATRA±CTX (OR, 4.2; P<0.001) as significant factors for achievement of a CR. Median follow-up was 4.7 yrs (95%-CI, 4.2-5.4 yrs) and 5-yrs overall survival (OS) 62% (95%-CI, 57-67%). Treatment with ATO/ATRA±CTX was associated with significantly higher 5-yrs relapse-free (RFS; 96% [95%-CI, 92-99%] vs. 88% [95%-CI, 83-93%]; P=0.007) and OS rates (78% [95%-CI, 72-85] vs. 58% [95%-CI, 52-65%]; P<0.001) as compared to CTX/ATRA. Of note, higher WBC count (>10/nl) was associated with an inferior RFS in CTX/ATRA (P<0.001), but not in ATO/ATRA±CTX (P=0.47). When restricting the analysis according to treatment period after the year 2000, ATO/ATRA±CTX was still associated with a significant better RFS (P=0.05) and OS (P<0.001) as compared to CTX/ATRA. Overall, only five pts relapsed after ATO/ATRA±CTX as compared to 33 after CTX/ATRA. As expected, higher WBC (>10/nl; hazard ratio [HR], 2.36; P<0.001), age >75 yrs (HR, 2.07; P<0.001) and therapy with ATO/ATRA±CTX (HR, 0.48; P<0.001) were significant factors for OS.Conclusions: The ATO-based regimen for first line treatment of elderly APL pts was associated with excellent and sustained response rates. Our data demonstrate the important potential of ATO/ATRA in the primary management of older APL pts. DisclosuresFenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau.

Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group

Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of IDH1/2 mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15–20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify IDH1R132, IDH2R140, and IDH2R172 mutations on genomic DNA in 322 samples from 103 adult patients with primary IDH1/2 mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median IDH1/2 mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 – 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 – 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a NPM1 mutation, and an IDH1/2 mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, IDH1/2 mutations persisted at high levels in complete remission, consistent with the presence of an IDH1/2 mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the IDH1/2 mutation in a pre-leukemic clone may be at high risk of hematologic evolution.

Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy. Prospective Observational Study from the Acute Leukemia French Association (ALFA) Group

▪BACKGROUND:Invasive fungal infections (IFIs) including invasive candidiasis(IC), pulmonary invasive aspergillosis (IA) and other fungal species as mucor mycosis (IM), remain a major clinical problem in neutropenic patients receiving intensive chemotherapy for acute myeloid leukemia (AML) due to their high morbidity and mortality.DESIGN:We performed a prospective observational study on antifungal (AF) prophylaxis used in a prospective clinical trial of intensive chemotherapy within the Acute Leukemia French Association (ALFA 0702 study, ClinicalTrials.gov Identifier: NCT00932412). A total of 677 AML patients from 34 different centers were included, 45% were males, and median age was 46 years (18-60). Prognosis according to cytogenetics was favorable in 23% of patients, intermediate in 53% and unfavorable in 18%. All patients received daunorubicine and aracytine intensive induction chemotherapy. The trial protocol recommended posaconazole suspension as AF prophylaxis at the dose of 200 mg three times a day from day 4 after induction chemotherapy and until neutrophils recovery. Patients were considered evaluable for this study if they received posaconazole for a minimum duration of 7 days and not later than 10 days after the beginning of the induction chemotherapy. IFI were classified by the local investigators and were reviewed later by an independent expert according to the EORTC classification (possible, probable and proven), scanner images were requested for further investigations when needed.The objective of this study was to describe the IFI prophylaxis strategies used in the different centers, to calculate the cumulative incidence of IFI according to different strategies, and to evaluate the overall survival and IFI related mortality.RESULTS:Among the 677 patients, 383 (57%) received posaconazole as AF prophylaxis for a median duration of 25 days (7-253). Posaconazole was introduced after a median time of 3 days after the beginning of the chemotherapy. We distinguished 4 groups, Group 1: patients without any prophylaxis (n = 203, 30%), Group 2: posaconazole alone (n=241, 36%), Group 3: posaconazole plus other prophylaxis (n=142, 21%), and Group 4: patients receiving other prophylaxis (n= 91, 13%). Overall, there were 72 IA [34 (47%) possible, 38 (53%) probable/proven], 17 IC (all probable/proven) and 7 IM [1 possible, 6 probable/proven]. The median delay between posaconazole prophylaxis and IFI occurrence was 22 days (7-50) for IA, 18 days (15-60) for IC and 26 days (13-28) for IM compared to 10 days (3-180), 8 days (3-32) and 21 days (10-32) in case of other prophylaxis. The cumulative incidence of IFI was 2.4% at 10 days (IA: 2.4%, IC : 0%, IM : 0%), 11,2% at 30 days (IA: 8.4%, IC: 2%, IM: 0.7%), 14.2% at 60 days ( IA: 10.6%, IC : 2.5%, IM : 1%), and 14.2% at 100 days (IA:10.6%, IC : 2.5%, IM : 1%). When considering the prophylaxis groups, the cumulative incidence of probable/proven IA at day 60 was 8.37% for Group 1; 4.7% for Groups 2 and 3 combined and 3.3% for Group 4 (Figure 1).After a median follow-up of 27.5 months (0.4- 73.4), 418 patients are alive and 259 (38.3%) died with 5.4% from IFI. Concerning the overall survival, the results were analyzed according to the presence or absence of IFI and AF prophylaxis (Figure 2) we observed a better survival without any IFI whatever the AF prophylaxis was and in case of AF prophylaxis there was an improvement of 2-years survival after chemotherapy induction. Concerning the global mortality and the IFI related mortality, the results were analyzed according to the prophylactic groups and the timing of prophylaxis, the multivariate analysis showed the negative impact of 2 factors on the mortality at day 100: Unfavorable cytogenetics: HR= 3.34 (1-11.20) p=0.05 and presence of IFI: HR = 5.63 (2.62-12.08) p<0.001.CONCLUSION:This study gives 3 important messages: 1) despite the trial protocol recommendations, this study shows that the ECIL recommendations are followed only in 57% of patients with in addition, an early switch in 37% of cases, 2) AF prophylaxis has a significant impact on IFI incidence and when we consider posaconazole alone and IA, this effect is only significant in case of probable/proven IA, 3) a better survival was obtained in patients without IFI whatever the AF prophylaxis was and in case of IFI an improvement of 2 year-survival was observed on AF prophylaxis with an IFI related mortality rate of 5.4%. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group.

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.

Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia Patients in First Complete Remission: Significant Impact of the Interval Between Diagnosis and Transplantation on Different Outcomes

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the main therapeutic option for most patients with high risk acute myeloid leukemia (AML). In order to determine whether time between diagnosis and allo-HSCT could have any impact on transplant outcomes, we screened 700 consecutive adult AML patients diagnosed between January 2007 and June 2014 at the Lyon Sud Hospital transplant center. Inclusion criteria were: (1) newly diagnosed AML in patients with age ≤ 65 years, (2) AML classified in the intermediate-2 and unfavorable risk groups according to the Acute Leukemia French Association (3) patients fit for receiving chemotherapy (4) patients candidates for allo-HSCT and in first complete remission (CR1) at transplantation. Two hundred and one patients met the inclusion criteria and were enrolled in the study. Among them, 137 (68%) received allo-HSCT of whom 83 (41%) only received HSCT in CR1 after a median time of 143 days (range: 69-265) from diagnosis. We collected within this interval different delays for donor search, including patients HLA typing and time to unrelated donor identification when a sibling donor was not available. Patients were split into 2 groups based on their time to transplant. An "early transplant group" included 28 (33%) patients transplanted after a median time of 108 days (range: 69-133) after diagnosis. The other 55 (67%) patients transplanted after a median time of 163 days (range: 134-265) were qualified as "late transplant group". Patients and transplantation characteristics according to the timing of transplantation are shown in table 1. After a median follow-up of 16 months (range: 0-60) the 5-year probability of overall survival (OS) and disease-free survival (DFS) for the whole population were respectively, 63.4% and 48.3%. The cumulative incidences of non-relapse mortality (NRM) at 1 and 5 years were constant at 17.5%. The multivariate analysis using proportional hazards modeling showed that conditioning regimen and sex mismatching were independent prognostic factors for DFS, with no significant impact on OS. To evaluate the long term impact of transplantation timing on OS and DFS, we performed a landmark analysis for patients surviving at 1 year post-allo-HSCT. This analysis showed that patients in the early transplant group had a higher probability of OS at 3 and 5 years with 100% survival respectively compared to the late transplantation group with 85.5% and 79.4% respectively (p=0.09); accordingly, we found a significant difference in terms of DFS with 100% probability at 3 and 5 years for the early transplantation group compared to 80% and 56% respectively in the late transplantation group (p=0.02). This difference in terms of OS and PFS was still valid after stratification on the type of conditioning regimen.These results confirm the important impact of allogeneic HSCT timing in high-risk AML patients, early allo-HSCT for patients transplanted in CR1 is associated with a better OS and a very significant benefit in terms of DFS. Further analyses are ongoing including disease monitoring from diagnosis to the last follow-up to identify the potential of transplantation timing on the graft versus leukemia effect. [Display omitted] DisclosuresNicolini:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association.

Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.

Therapeutic Management of Acute Myeloid Leukemia Patients after Stratification on Age, Prognosis and Allogeneic Hematopoietic Stem Cell Transplantation Eligibility

We evaluated in this study the therapeutic management of all newly diagnosed acute myeloid leukemia (AML) patients followed in our center between July 2007 and September 2013, after stratification on age, prognostic factors, whether they were candidate to allogeneic hematopoietic stem cell transplantation (allo-HSCT), transplanted or not with the evaluation of each therapeutic strategy and its impact on overall survival. A total of 572 consecutive newly diagnosed AML patients were included; there were 311 (54%) males and 261 females with a median age of 63 years (range: 20-92), 406 (71%) were de novo AML and 166 (29%) secondary AML. Complete cytogenetic and molecular biology data were collected for all patients and prognosis was differentiated according to the European LeukemiaNet classification (Dohner et al. Blood 2010). Accordingly, 335 (59%) patients were unfavorable, 83 (15%) favorable, 48 (8%) intermediate I and 106 (18%) were in intermediate II category. Following the Acute Leukemia French Association (ALFA) guidelines for allo-HSCT in AML, patients with intermediate II and unfavorable prognosis ≤ 65 years should receive intensive chemotherapy followed by allo-HSCT in the presence of related or unrelated HSCT donors. We divided the population into two sub-populations, the first was considered as “young” with age ≤ 65 years (N=318, 56%) and the second considered as “old” with age > 65 years (N=254, 44%). In the young population, there was 4 groups, group 1: patients with good prognosis (favorable/intermediate1) who received intensive chemotherapy within or according to ALFA protocols (N=105, median age= 47 years); group 2: patients with poor prognosis (intermediate2 /unfavorable) who received intensive chemotherapy within or according to ALFA protocols followed by allo-HSCT (N=126, median age= 50 years), group 3: patients with poor prognosis who received only intensive chemotherapy without allo-HSCT (N=69, median age= 57 years), and group 4: patients with poor prognosis who could not be treated due to early death (N=18). In the old population we distinguished, group 1: patients with good prognosis who received moderate intensity chemotherapy within or according to ALFA protocols (N=25, median age=73 years); group 2: patients with poor prognosis who received azacitidine (N=25, median age=76 years), group 3: patients with poor prognosis who received moderate intensity chemotherapy (N=89, median age=76 years), group 4: patients with poor prognosis who received low dose Ara-C (N=28, median age=76 years), group 5: patients with poor prognosis who received other treatment (N=38, median age=77 years) and finally group 6: patients with poor prognosis considered as palliative or who did not receive any treatment (N=49, median age=77 years). After a median follow-up of 34 months (range: 4-77) for surviving patients, the 2-years probability of overall survival (OS) in the “young” population for groups 1,2,3 and 4 was 84%, 56%, 31% and 0% respectively; and in the “old” group it was 71%, 37%, 31%, 5%, 21% and 0% for groups 1,2,3,4,5 and 6 respectively (figure).We showed that newly diagnosed AML patients with good prognosis all ages included could achieve very good survival rates after intensive chemotherapy; allo-HSCT after induction chemotherapy remains the best therapeutic option for fit patients with poor prognosis while the same fit patients with no donor have significantly lower survival (p<0.001) and for whom allo-HSCT could be proposed by using haploidentical donors in case of cord blood or unrelated donors absence. Interestingly, in the “old” population, we showed that poor prognosis patients receiving azacytidine had a significantly better survival compared to those receiving low dose Ara-C (p=0.015), with a comparable outcome to those receiving induction chemotherapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation for Therapy-Related Acute Myeloid Leukemia

Background:With the expanding pool of cancer survivors, therapy-related AML (t-AML) is increasingly encountered and constitutes approximately 10%-20% of newly diagnosed patients with AML. These patients have a poor prognosis with conventional anti-leukemia therapies with median survival of less than 1 year. This outcome is related to several factors including older age, worse performance score, comorbidities, therapy resistance, and bone marrow failure. Allogeneic hematopoietic stem cell transplantation, when feasible, represents a potential promising treatment for patients with t-AML.Objective:The aim of this study is to evaluate the different treatment options and outcomes of patients with t-AML followed at our center between year 2007 and 2013.Patients and methods:Between July 2007 and September 2013, we evaluated 166 consecutive newly diagnosed t-AML patients among a total of 572 AML diagnosed and followed in our center during this period; there were 95 (57%) males and 71 (43%) females with a median age of 66 years (range: 18-92), 48 (29%) were less than 60 years old, 83 (50%) were between 60 and 75 years, and 35 (21%) were older than 75 years; 128 (77%) were secondary AML after hematological malignancies [66 (56%) myelodysplastic syndrome (MDS) and 44 (34%) myeloproliferative syndromes and 18 (14%) lymphoid malignancies], and 38 (23%) after solid tumors. At diagnosis, the patients were evaluated according to both cytogenetic and molecular biology data as proposed by the European LeukemiaNet (Dohner et al. Blood 2010), accordingly, 160 (96%) patients were unfavorable [having one or more of the following: -5, -7, 5q-, 7q-,11q23 or MLL+ including MLL-PTD (except 9;11), t(6;9) Complex karyotype (≥ 3 abnormalities), 3q26 abnormalities or EVI-1+], and only 6 (4%) had favorable prognosis [t(8;21), in(16) or t(16;16)]. Following the Acute Leukemia French Association (ALFA) guidelines for allo-HSCT in AML, all patients in this study should be candidate for transplantation after induction chemotherapy because of t-AML only if the patient condition is suitable (age, co-morbidities) and hematopoietic stem cell donor is available.Results:Among 166 patients, only 42 (25%) have been treated according to the ALFA recommendations and received induction chemotherapy followed by allo-HSCT, 36 (86%) were in first complete remission (CR1) and 6 were in less than CR1, 18 (43%) received hematopoietic stem cells from identical siblings (15 peripheral blood stem cells, 3 bone marrow) and 24 (57%) from unrelated donors (16 peripheral blood stem cells, 3 bone marrow and 5 cord blood cells); 31 (74%) received reduced intensity conditioning, 6 (14%) myeloablative and 5 (12%) sequential chemotherapy conditioning. For the rest of 124 (75%) patients, they could not benefit from allo-HSCT, they received either induction chemotherapy ± consolidation treatment or chemo/palliative treatment, among them 91 (73%) were ineligible to allo-HSCT due to age > 65 years and 33 (27%) could not be transplanted due to either non-availability of stem cells donor (N=12), early death before donor search (N=6), early death despite availability of stem cells donor (N=8), other comorbidities (N=7).The probability of overall survival (OS) at 2 years was 55% (range: 47-63) for patients who received allo-HSCT and it was 18% (range: 14-22) for those who received induction or palliative treatment without allo-HSCT with a median OS of 33 and 7 months respectively. The probability of progression-free survival for patients who received allo-HSCT was 68% (range: 60-76) at two years with a median not reached, and the cumulative incidence of transplant-related mortality was 24% (range: 17-31) at two years.Conclusion:Therapy-related acute myeloid leukemia remains having a poor prognosis with conventional therapy. Allogeneic HCT represents the only curative approach. We obtained encouraging results in eligible patients who received allogeneic transplantation especially that the majority of patients had unfavorable prognosis factors according to molecular biology and cytogenetics. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Serum 2-Hydroxyglutarate Production in IDH1- and IDH2-Mutated De Novo Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association Group

Mutated isocitrate dehydrogenases (IDHs) 1 and 2 produce high levels of 2-hydroxyglutarate (2-HG). We investigated whether, in acute myeloid leukemia (AML), serum 2-HG would predict the presence of IDH1/2 mutations at diagnosis and provide a marker of minimal residual disease (MRD). Serum samples from 82 patients at diagnosis of de novo AML (IDH1/2 mutated, n = 53) and 68 patients without AML were analyzed for total 2-HG and its ratio of D to L stereoisomers by mass spectrometry. We measured 2-HG levels and molecular markers of MRD (WT1 and NPM1) in serial samples of 36 patients with IDH1/2 mutations after induction therapy. In patients with AML with IDH1/2 mutations, 2-HG serum levels were significantly higher than in patients with IDH1/2 wild type (P < .001). Area under the receiver operating characteristic curve was 99%. The optimum diagnostic cutoff between IDH1/2 mutated and normal was 2 μmol/L (sensitivity, 100%; specificity, 79%). Quantification of the D/L stereoisomers increased specificity (100%; 95% CI, 83% to 100%) compared with total 2-HG (P = .031). In patients with IDH2 R172 mutations, 2-HG levels were higher relative to those with other IDH1/2 mutations (P < .05). During follow-up, serum 2-HG levels showed strong positive correlation with WT1 and NPM1 (P < .001). After induction therapy, total 2-HG serum levels < 2 μmol/L were associated with better overall (P = .008) and disease-free survival (P = .005). Serum 2-HG is a predictor of the presence of IDH1/2 mutations and outcome in these patients. Discrimination between D/L stereoisomers improved specificity.

Heterogeneity Of Patients With Cytogenetically Normal Acute Myeloid Leukemia (CN-AML) and Nucleophosmin-1 (NPM1) Gene Mutation: An Acute Leukemia French Association (ALFA) Study

▪ BackgroundCN-AML with NPM1 mutation accounts for 25% of AML cases and is individualized as a provisional entity in the WHO classification. In this large AML subset, additional gene mutations could influence patient outcome, like it has been shown for bad-prognosis FLT3 internal tandem duplication (FLT3-ITD). We thus reviewed the characteristics and outcome of 409 patients with de novo NPM1-mutated CN-AML treated in sequential ALFA studies. MethodsPatients were treated between 1990 and 2012 (median follow-up, 31 months) according to ALFA-9000 (#16), 9801 (#91), 9802 (#89), 9803 (#19) and 0701 (#84) published protocols or in the ongoing 0702 study (#110). In addition to NPM1, the following mutations were centrally assessed using standard-PCR methods and Sanger sequencing: FLT3-ITD, mutations of FLT3 tyrosine kinase domain (FLT3-TKD, i.e. FLT3D835/I836), IDH1R132, IDH2R140, IDH2R172, TET2 (exons 3-11), and DNMT3A (exons 8-9, 11-23). Primary endpoint was cumulative incidence of relapse (CIR) after censoring the 73 patients who received allogeneic stem cell transplantation (SCT) in first CR at SCT time. Analyses were performed with multiple imputations of missing values, followed by multivariable logistic regression or Cox model. ResultsMedian age was 52 years (17-79). Median white blood cell count (WBC) was 23.5 x 109/L (0.8-377). Gene mutations are indicated in Table 1. Multivariable analyses showed that: 1) FLT3-ITD was associated with higher median WBC (60 versus 18 x 109/L, P<0.001) and less frequent FLT3-TKD, IDH1R132 and IDH2R140 mutations (P=0.003, 0.037 and <0.001, respectively); 2) IDH2R140 mutations were associated with higher median WBC (42 versus 24 x 109/L, P<0.001) and less frequent IDH1R132 and DNMT3AR882 mutations (P<0.001 and 0.001, respectively); 3) TET2 mutations were associated with higher median WBC (37 versus 22 x 109/L, P=0.003) and less frequent FLT3-ITD, FLT3-TKD, and IDH1R132 mutations (P=0.007, 0.028 and 0.022, respectively); and 4) non-R882 DNMT3A mutations, but not R882 mutations, were markedly associated with advanced age (22% in patients ≥ 50 years versus 9% in younger patients; P<0.001). Overall, 372 patients (91%) reached complete remission (CR). In multivariable models, advanced age and higher WBC negatively influenced CR achievement (P=0.044 and 0.037, respectively), but none of the additional mutations. In CR patients, 3-year CIR was 51% (45-58). In a first multivariable model not considering TET2 mutational status (analyzed in 232 patients only), advanced age was associated with a higher specific hazard of relapse (SHR) (P<0.001). At 3 years, CIR was 63% in patients ≥ 50 years versus 35% in younger patients. The other factors associated with a higher CIR were FLT3-ITD (SHR, 2.04 [1.35-3.09]; P=0.001) and non-R882 DNMT3A mutations (SHR, 1.94 [1.10-3.42]; P=0.023), while FLT3-TKD was associated with a lower CIR (SHR, 0.38 [0.16-0.94]; P=0.036). Conversely, WBC, IDH1/2 mutations and R882 DNMT3A mutations did not influence CIR. Advanced age, FLT3-ITD and non-R882 DNMT3A mutations were also identified as independent risk factors in a second multivariable model performed in the subset of patients tested for TET2 mutations. Here, TET2 mutations had no impact on CIR. Overall 3-year CIR estimates were 41%, 61%, 68% and 94% in the FLT3-ITD-/non-R882 DNMT3A-, FLT3-ITD+/non-R882 DNMT3A-, FLT3-ITD-/non-R882 DNMT3A+, and FLT3-ITD+/non-R882 DNMT3A+ subsets, respectively.Table 1Gene mutations.PatientsIncidencePositive/Tested (N)OverallFLT3-ITD+no FLT3-ITDNPM1409/409---FLT3, all186/40746%--FLT3-ITD150/40737%--FLT3-TKD36/4049%3%12%IDH1/2, all101/37227%18%32%IDH1R13252/37414%11%15%IDH2R14049/37113%7%17%IDH2R1720/3710%0%0%DNMT3A, all148/31048%47%48%DNMT3AR882100/31032%30%34%DNMT3A other48/31016%17%15%TET233/23214%11%18% ConclusionsThis study confirms the heterogeneity of patients with NPM1-mutated CN-AML, independently of the known poor prognosis of FLT3-ITD. Higher WBC was associated with FLT3-ITD, IDH2R140 and TET2 mutations, but did not represent per se an independent risk factor for relapse. Higher incidence of unfavorable non-R882 DNMT3A mutations in older patients may explain, at least in part, why older patients do worse than younger patients in this peculiar AML subset. A potential favorable prognostic role of FLT3-TKD mutations in these patients needs to be confirmed. Disclosures:No relevant conflicts of interest to declare.

Acute myeloid leukemia with translocation t(3;5): new molecular insights

Acute myeloid leukemia with translocation t(3;5): new molecular insights

Superior Long-Term Outcome With Idarubicin Compared With High-Dose Daunorubicin in Patients With Acute Myeloid Leukemia Age 50 Years and Older

Although standard chemotherapy remains associated with a poor outcome in older patients with acute myeloid leukemia (AML), it is unclear which patients can survive long enough to be considered as cured. This study aimed to identify factors influencing the long-term outcome in these patients. The study included 727 older patients with AML (median age, 67 years) treated in two idarubicin (IDA) versus daunorubicin (DNR) Acute Leukemia French Association trials. Prognostic analysis was based on standard univariate and multivariate models and also included a cure fraction model to focus on long-term outcome. Age, WBC count, secondary AML, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adverse-risk and favorable-risk AML subsets (European LeukemiaNet classification) all influenced complete remission (CR) rate and overall survival (OS). IDA random assignment was associated with higher CR rate, but not with longer OS (P = .13). The overall cure rate was 13.3%. Older age and ECOG-PS more than 1 negatively influenced cure rate, which was higher in patients with favorable-risk AML (39.1% v 8.0% in adverse-risk AML; P < .001) and those treated with IDA (16.6% v 9.8% with DNR; P = .018). The long-term impact of IDA was still observed in patients younger than age 65 years, although all of the younger patients in the DNR control arm received high DNR doses (cure rate, 27.4% for IDA v 15.9% for DNR; P = .049). In multivariate analysis, IDA random assignment remained associated with a higher cure rate (P = .04), together with younger age and favorable-risk AML, despite not influencing OS (P = .11). In older patients with AML, younger age, favorable-risk AML, and IDA treatment predict a better long-term outcome.