Paietta, Elisabeth

Abstract Abstract 676 Although maintenance therapy has been shown to be of value in Acute Lymphoid Leukemia, its role in non M3 Acute Myeloid Leukemia (AML) has never been proven. Studies have been limited by issues related to efficacy as well as toxicity. The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(tipifarnib), as maintenance therapy for AML. Patients(pts) with AML in remission after requiring salvage therapy or over age 60 in first remission were eligible. A confirmatory bone marrow exam prior to randomization was required to demonstrate a complete remission (CR) or morphologic remission(MR). Absolute neutrophil count >1000/mm3, platelet count >=50,000/mm3, normal renal, and hepatic function were required. Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of the study was to compare disease free survival (DFS) in the two groups. The study was designed with 84% power to detect a 76% relative increase in the median DFS from 3.4 months to 6 months (mo). The final analysis was to take place when 111 events had taken place. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). The majority of pts enrolled on the study (67%) were in first CR. Seventy three pts were enrolled onto the treatment arm and 71 pts were enrolled onto the observation arm. When the study initially opened, tipifarnib was given at a dose of 400 mg BID with dose reductions and interruptions as per protocol for toxicity. Based on the first interim analysis, toxicity data, the starting dose was decreased to 300 mg BID. Significant hematologic toxicity was seen in patients at both 300 and 400 mg. The majority of patients experienced >=grade 3 neutropenia or thrombocytopenia. There was 1 episode of febrile neutropenia. Non-hematologic toxicities were minimal. At the time of 110 events (90 relapses and 100 deaths), the final analysis of the study was conducted. The relapse rate was 60.3% on tipifarnib vs 64.8% for observation. Median DFS and 10 and 12 mo DFS and overall survival (OS) are documented in Table 1. Kaplan Meier curves for DFS and OS are presented. As the difference in median DFS is not considered significant (9.3 vs 5.8 mo, log rank p value 0.21), in July 2011, pts and physicians were informed of the lack of evidence of benefit so they could decide if they wished to continue drug. However an unplanned analysis of the data demonstrates a statistically significant improvement in OS at 10 months in pts who received tipifarnib. (70% vs 48%, p=0.05). While the benefit is subsequently lost, given a median survival measured in months, an increase in the number of pts alive and/or without disease at 10–12 mo is of value, particularly in the absence of noteworthy toxicity. Future studies are needed to better determine the role of maintenance therapy in pts with AML. Tipifarnib Observation Median DFS (months) 9.3 (95% CI:5.7, 13.3) 5.8 (95% CI: 3.7, 8.8) p=0.21 OS rate at 10 mo 70% (95% CI: 58%, 79%) 48% (95% CI: 36%, 60%) p=0.05 OS rate at 12 mo 59% (95% CI: 47%, 70%) 44% (95% CI: 32%, 55%) p=0.07 DFS rate at 10 mo 47% (95% CI: 36%, 59%) 32% (95% CI: 21%, 43%) p=0.07 DFS rate at 12 mo 39% (95% CI: 28%, 50%) 30% (95% CI: 20%, 41%) p=0.26 Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Abstract Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared to pediatric ALL. Age, as a continuous variable, is negatively correlated with prognosis, in spite of risk-adapted combination chemotherapy. To better understand the etiology of ALL in this age group, we performed the first genome-wide association study (GWAS) to comprehensively examine germline single nucleotide polymorphisms (SNPs) for their association with susceptibility to B-ALL in AYAs. In the discovery GWAS, we compared genotype frequency at 635,297 SNPs between 308 AYA ALL cases (age 16-39 years, treated on the Children’s Oncology Group [COG], the Alliance-Cancer and Leukemia Group B, Eastern Cooperative Oncology Group, MD Anderson Cancer Center, and St. Jude Children’s Research Hospital trials) vs. 6,661 non-ALL controls. The association between genotypes at each SNP and ALL susceptibility was tested by using a logistic regression model after adjusting for genetic ancestries to control for population stratification. SNPs that reached P≤ 5×10-8 in the discovery GWAS were tested in an independent cohort of 82 AYA ALL cases from the COG protocols and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus on 10p14 signified by two SNPs within the GATA3 gene: rs3824662, P=2.8x10-10, odds ratio (OR)=1.77; rs3781093, P=3.2x10-9, OR=1.73, both of which were validated in the replication cohort (P=1.9x10-8 and P=4.3x10-5, respectively). We also examined the association signals in AYAs for susceptibility loci previously identified in pediatric ALL: ARID5B, IKZF1 and PIP4K2A variants were nominally significant in AYAs in the discovery GWAS and/or in the replication analysis, whereas CEBPE or CDKN2A/CDKN2B were not significant. These results imply both similarities and differences in genetic predisposition to ALL between children and AYAs. At the GATA3 locus, rs3824662 risk variant was over-represented in Philadelphia chromosome (Ph)-like ALL in AYAs (P=0.02), confirming our previous report of Ph-like ALL susceptibility variants in GATA3 (Nat Genet 45:1494). Importantly, even after excluding Ph-like cases, rs3824662 remained associated with the risk of developing ALL in AYAs, suggesting that the influence of the GATA3risk variant on ALL susceptibility in AYAs extends beyond the predisposition to Ph-like subtype. We next examined the relationship between GATA3 risk allele frequency and age at diagnosis in a cohort of unselected childhood and adolescent ALL cases enrolled in the COG P9900 protocols (N=1,827). Dividing patients into four consecutives age groups (<5, 5-10, 10-15 and >15 years), we observed a clear progressive increase in the risk allele frequency at rs3824662 (P=6.29×10-11) with increasing allelic odds ratio (i.e. relative risk of ALL conferred by each copy of the risk allele). This correlation between genotype and age was evident regardless of genetic ancestry, although the risk variant was more common among individuals with higher Native American ancestry. In contrast, the frequency of ALL susceptibility variant in ARID5B decreased progressively with increasing age at diagnosis (P=0.006), whereas PIP4K2A, CDKN2A/CDKN2B, IKZF1 and CEBPE variants were not related to age. Finally, we compared rs3824662 risk variant frequency by age in the COG P9900 protocols after stratifying the ALL cases into TCF3-PBX1, ETV6-RUNX1, hyperdiploid, MLL-rearranged and B-other. There was a trend that the risk allele was more frequent in cases older than 16 years compared to those below 16 in the five subtypes examined. In conclusion, we have identified inherited GATA3 genetic variants that strongly influence ALL susceptibility in adolescent and young adults, indicating potential age-related differences in ALL biology. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 663 Introduction: The biology and outcome of adult t(4;11) ALL are poorly understood. We report here 85 patients treated uniformly on the prospective trial (UKALL XII/ECOG 2993) with the aim of describing outcome and identifying prognostic factors and optimal therapy. Patients and methods: 1914 adult patients (≥15 years) with ALL were registered on the UKALL XII/ECOG 2993 study in the UK or United States from 1993–2006. Cell lineage was classified by local institutions (UK) or central immunophenotyping (ECOG). Cytogenetic, FISH and RT-PCR analyses of pre-treatment samples were either performed locally and reviewed centrally or performed centrally. Results: The 85 patients with t(4;11) were predominantly female (68%). Median age was 38 years (vs 32 years in the non-t(4;11) group) and 42% were >40 years. They had high white cell counts with 87% >30 and 66% >100 × 109/l (vs 7% in the non-t(4;11) group). Among the 27 ECOG patients, 22 (81%) had the typical pro-B (CD10NEG) immunophenotype, compared to 12% in t(4;11)NEG patients. Aside from expression of myeloid antigens, CD65 and CD15, which is part of the pro-B immunophenotype, t(4;11)POS lymphoblasts showed a unique combination of stem cell antigens: lower expression of CD34 and CD105, but higher expression of CD133 and CD135 compared to t(4;11)NEG blasts (p<0.0001). Additional cytogenetic abnormalities (ACAs) were present in 31/75 (41%) evaluable cases. Most common ACAs were gain of chromosome X (n=13), i(7)(q10) (n=7) and abnormalities of 1p (n=4). Deletion of IKZF1 or CDKN2A/B was present in 18% of patients tested; neither affected outcome. Seventy seven evaluable patients attained complete remission (CR1, 93%). Treatment received in CR1 was either chemotherapy (n=46, 59%) or a myeloablative allograft (N=31, 16 matched sibling, 1 mismatched related and 15 unrelated donors UD). CR1 treatment received strongly correlated with age with the number of allografts decreasing with age: <25 years 12/17 patients; 24–39 years 13/29 and 40+ years 6/31 (p=0.001). At median follow up of 5.4 years, five year EFS was 34% (24–44%, 95% CI) and OS 35% (25–45%). Five year relapse rate was 45% (33–58%); only 1 relapsed patient survived, nearly all events had occurred by 2 years. The 46 patients who received chemotherapy had 24% survival and 69% relapsed but 5 year OS of patients who had sibling or UD allografts was 56% and 67% respectively (p=0.013) and only 3/31 relapsed. An allograft improved OS, EFS and relapse in the <40 year group. Age was also strongly associated with outcome (figure). Conclusions: This is the largest series of adult t(4;11) ALL patients treated uniformly. Allograft in CR1 from sibling or unrelated donors is an effective strategy. Current prospective trials of intensive pediatric-type regimens in younger patients will determine if CR1 allografts are necessary. Older patients have a poor outcome and different strategies such as reduced intensity allografting should be explored. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1038 The relationships of inherent disease-related characteristics and of treatment to the nature of APL cell clones that emerge at disease relapse are poorly understood. We studied these relationships in 45 patients who relapsed after ATRA/chemotherapy treatment on the non-arsenic trixoxide arm of intergroup phase III trial C9710 (Powell, et al. Blood, Epub). Four variably-expressed APL cell clonal markers were assessed: PML-RARA ligand binding domain mutations (LBD-M), FLT3 internal tandem duplication mutations (ITD), FLT3 receptor tyrosine kinase mutations (D835; RTK-M) and additional chromosome abnormalities (ACA), i.e., in addition to the hallmark t(15;17). The methods for mutation analysis of PML-RARA and FLT3 have been reported and were RNA transcript-initiated supplemented by selected quantitative FLT3 mutation analyses initiated from DNA. Karyotype data were derived by standard cytogenetic methods. Four patients were excluded from analysis because the sample level of PML-RARA, as determined by quantitative RT-PCR, was insufficient to exclude possible false-negative mutation results. In 41 evaluable patients, the marker incidences were: LBD-M, 44%; ITD, 37%; RTK-M, 12%; ACA (22 tested), 59%. At presentation, the corresponding incidences were: LBD-M, 0% (by high-sensitivity testing a minor subclone of the relapse mutation was found in 2/7 patients tested); ITD, 43% (37 tested); RTK-M, 22% (37 tested); ACA, 24% (34 tested). The low frequency of RTK-M impeded further analysis. The other markers, using relapse determinations, were assessed for potential associations between the markers and with the following parameters: age, sex, presenting WBC count, PML-RARA type, time to relapse, relapse on or off ATRA treatment (on = taking or within 30 days of discontinuing) and post-relapse survival. The most essential positive findings are summarized below:Association of Marker with Parameter or Other MarkerCases with ParameterCases without Parameterp-valuePretreatment parameters: LBD-M with WBC count < 5,000/uL12/18 (67%)7/23 (30%)0.030 ITD with WBC count >10,000/uL10/15 (67%)5/26 (19%)0.006 ITD with S-form PML-RARA15/15 (100%)10/26 (38%)<0.0001Relapse parameters: ITD with lack of ACA1/7 (14%)12/15 (80%)0.007 LBD with relapse On-ATRA11/18 (61%)7/23 (30%)0.064 Off-ATRA only: LBD with lack of ITD0/7 (0%)9/16 (56%)0.019 The results confirm reports, which tested pretreatment samples, of a strong association between FLT3ITD mutations present at relapse and high WBC count and S-form PML-RARA. At relapse, there was, also, divergent selection of ITD-harboring vs ACA-harboring clones. LBD-M occurred more frequently in patients with low presenting WBC counts. They, also, occurred in patients who relapsed while on ATRA, consistent with an ATRA selective role for clones harboring LBD mutations. A significant segregation of patients with LBD-M or ITD was observed after relapse off ATRA treatment (p = 0.019), while no segregation was observed in overall relapse patients (p = 0.346) or after relapse on ATRA (p = 0.316). In 2 patients who relapsed on ATRA, quantitative analysis indicated that LBD-M and ITD mutations must be present in the same APL cell clone. There were no significant survival differences related to any clonal marker (post-relapse survival = 66%). Although the small number of cases is cautionary, the overall data suggest that LBD-M may have an overriding, dominant APL clone selection role in relapse that occurs on ATRA therapy. Other inherent clinicopathologic characteristics of APL may predispose to divergent molecular pathways of disease progression and relapse in patients alternatively harboring clones with LBD-M or ITD after the termination of ATRA selection pressure. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 169 The Philadelphia positive (Ph+) arm of the international adult acute lymphoblastic leukaemia (ALL) trial UKALL12/ECOG2993 opened in 1993 and is the largest single study of patients with Ph+ ALL, with a total of 441 participants. The first cohort of study patients was treated prior to Imatinib (N=266 “Pre Imatinib“) with 2 phases of induction therapy given over 2 months followed by matched sibling or unrelated donor myeloablative allogeneic haematopoietic stem cell transplant (alloHSCT) whenever possible. The treatment protocol and outcome for these patients has been published (Fielding et al, Blood 2009). Beginning March 2003, a second cohort of study patients had Imatinib 600mg daily added, as a consolidation block after the second induction chemotherapy, (N=86, “Late Imatinib”). From late 2005, a final cohort within the trial were given Imatinib earlier, in conjunction with the second phase of induction (N=89, “Early Imatinib”). Patients in both Imatinib cohorts resumed the drug for a further 2 years following alloHSCT, if tolerated. If alloHSCT was not possible, Imatinib was permitted for 2 years, with maintenance. The trial closed to recruitment in December 2006 (USA) and October 2008 (UK). All except 8 patients have now completed therapy. An earlier analysis of these data did not indicate a clear long-term advantage to receiving Imatinib. We now report 3-year follow-up, which shows large outcome differences between the 3 groups. There were no pre-existing differences between the 3 cohorts in terms of gender, presenting white blood cell counts and presence of central nervous system disease at diagnosis. However, the Pre-Imatinib cohort was younger than the two Imatinib cohorts, due to an increase in the upper age limit for study entry. Percentage complete remission (CR) rates and survival of induction therapy are shown in table 1. The total CR rate for the imatinib cohorts was significantly higher than for the pre-imatinib cohort (p=0.004). Table 1 Pre-Imatinib With Imatinib N=266 Total With Imatinib N=175 Part 1 Late Imatinib N=86 Part 2 Early Imatinib N=89 Died in induction<d56 5 5 3 7 Survived induction but never achieved remission 13 3 5 1 Total not achieving CR 18 8 8 8 CR on protocol induction 67 77 73 80 Total CR rate (includes those achieving remission later than post induction) 82 92 92 92 Pre- Imatinib, only 28% of patients went on to receive alloHSCT as per protocol. With any Imatinib, 44% of patients received alloHSCT as per protocol. Survival outcomes of patients in the 3 cohorts are shown in the table 2. Overall survival (OS), event free survival (EFS) and relapse free survival (RFS) are all at 3 years with 95% confidence intervals (CI) shown in brackets. The P values are for two comparisons - ** denotes the comparison between patients receiving any Imatinib and patients receiving none and ^ denotes the comparison between the Early and Late Imatinib cohorts. Table 2 Pre-Imatinib With Imatinib Total With Imatinib Part 1 Late Imatinib Part 2 Early Imatinib % OS (95% CI) (see also Figure 1) 25 (20–30) 42 (34–49) 34 (24–44) 48 (36–60) p=0.0001** p=0.05^ % EFS (95% CI) 19 (14–24) 36 (29–44) 29 (19–38) 45 (34–56) p=0.0001** p=0.04^ % RFS (95% CI) 36 (28–43) 54 (45–63) 45 (33–57) 62 (50–75) p=0.0001** p=0.02^ Figure 1 Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. Figure 1. Three-year OS for patients who received per protocol alloHSCT was 59% vs. 28% (with no plateau on the curve) for those who did not receive alloHSCT as per protocol. By comparison, pre-imatinib, 5 year OS was 40% for transplanted- and 19% for non-transplanted patients. Hence, the extent to which Imatinib without subsequent alloHSCT can improve the outcome for adult Ph+ ALL is not yet clear. In conclusion, receiving any Imatinib during induction for Ph+ ALL significantly enhances CR rate and increase alloHSCT rate. This translates into a highly significant EFS, OS and RFS advantage to receiving Imatinib during therapy. An earlier start to Imatinib is significantly better than a later start. Though comparisons between study cohorts are not randomised, the large differences seen are unlikely to be explained by factors other than treatment. There can be no basis for omitting Imatinib from the initial therapy of adult patients with Ph+ ALL. However, our data show that the best outcome is seen when patients receive Imatinib followed by myeloablative alloHSCT, where nearly 60% of such patients survive 3 years from diagnosis. Disclosures: Goldstone: Roche: Honoraria, Speakers Bureau.

Abstract Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Abstract The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL. Significance: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL. This article is highlighted in the In This Issue feature, p. 305

To improve the outcome of relapsed/refractory acute myeloid leukemia (AML), a randomized phase II trial of three novel regimens was conducted. Ninety patients were enrolled and were in first relapse or were refractory to induction/re‐induction chemotherapy. They were randomized to the following regimens: carboplatin‐topotecan (CT), each by continuous infusion for 5 days; alvocidib (formerly flavopiridol), cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen; or sirolimus combined with mitoxantrone, etoposide, and cytarabine (S‐MEC). The primary objective was attainment of a complete remission (CR). A Simon two‐stage design was used for each of the three arms. The median age of the patients in the FLAM arm was older at 62 years compared with 55 years for the CT arm and the S‐MEC arm. The overall response was 14% in the CT arm (5/35, 90% CI 7%‐35%), 28% in the FLAM arm (10/36, 90% CI, 16%‐43%), and 16% in the S‐MEC arm (3/19, 90% CI, 4%‐36%). There were nine treatment‐related deaths, seven of which occurred in the FLAM arm with four of these in elderly patients. We conclude that the FLAM regimen had an encouraging response rate and should be considered for further clinical development but should be used with caution in elderly patients.

AbstractThis study examines the long‐term OS of relapsed AML patients who were enrolled to 9 successive ECOG‐ACRIN trials for newly diagnosed AML, during 1984‐2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long‐term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow‐up was 9.7 years. The median OS from relapse was 0.5 years and the 5‐year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.