Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1069-1076 ◽  
Author(s):  
Veronika Rockova ◽  
Saman Abbas ◽  
Bas J. Wouters ◽  
Claudia A. J. Erpelinck ◽  
H. Berna Beverloo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Survival Analysis ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Free Survival ◽  
Intermediate Group ◽  
Prognostic Importance ◽  
Survival Tree ◽  
Acute Myeloid

Abstract Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients (age < 60 years) to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, that is, FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2, and CEBPADM/SM (double/single). Univariable survival analysis shows that (1) patients with FLT3ITD mutations have inferior overall survival (OS) and event-free survival (EFS), whereas CEBPADM and NPM1 mutations indicate favorable OS and EFS in intermediate-risk AML, and (2) high transcript levels of BAALC, CD34, MN1, EVl1, and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG, and CEBPADM remain significant. Using survival tree and regression methodologies, we show that CEBPADM, CD34, and IDH2 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% vs 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML.

Low Platelet Counts at Diagnosis Predict Better Survival for Patients with Intermediate-Risk Acute Myeloid Leukemia

2019 ◽  
Vol 143 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Yimin Zhang ◽  
Haihui Gu ◽  
Qi Chen ◽  
Ying Zhang ◽  
Hui Cheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Negative Impact ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Risk Patients ◽  
Immature Cells ◽  
Acute Myeloid

Background: Aggressive growth of primitive and immature cells in the bone marrow results in reductions in megakaryocyte and platelet (PLT) counts, leading to thrombocytopenia in acute myeloid leukemia (AML). However, not all AML patients show thrombocytopenia at the time of diagnosis, and the association of PLT count with patient survival is largely unknown. Methods: A retrospective study was performed to determine PLT counts at diagnosis in the peripheral blood in 291 newly diagnosed AML patients and assess the association of PLT counts with the overall survival (OS) and disease-free survival (DFS) of these patients. Results: Low PLT counts (≤40 × 109/L) were associated with better outcomes for the whole cohort (5-year OS, 55.1 ± 3.8 vs. 35.3 ± 3.5%, p < 0.001; 5-year DFS, 49.1 ± 3.8 vs. 25.7 ± 4.0%, p < 0.001) and intermediate-risk patients (5-year OS, 64.5 ± 5.4 vs. 41.0 ± 4.8%, p < 0.001; 5-year DFS, 60.8 ± 5.6 vs. 28.6 ± 5.6%, p < 0.001). Moreover, low PLT counts were related to deeper molecular remission. Low PLT counts correlated with better survival of intermediate-risk AML patients treated with chemotherapy only. Allogeneic hematopoietic stem cell transplantation attenuated the negative impact of high PLT counts on the survival of intermediate-risk patients. Furthermore, univariate and multivariate analyses demonstrated that PLT count at diagnosis was an independent prognostic factor for intermediate-risk AML. Conclusion: PLT count at diagnosis predicts survival for patients with intermediate-risk AML.

Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3747-3754 ◽  
Author(s):  
Roel G. W. Verhaak ◽  
Chantal S. Goudswaard ◽  
Wim van Putten ◽  
Maarten A. Bijl ◽  
Mathijs A. Sanders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Molecular Abnormalities ◽  
Cell Counts ◽  
Gene Expression Signatures ◽  
Acute Myeloid

Mutations in nucleophosmin NPM1 are the most frequent acquired molecular abnormalities in acute myeloid leukemia (AML). We determined the NPM1 mutation status in a clinically and molecularly well-characterized patient cohort of 275 patients with newly diagnosed AML by denaturing high-performance liquid chromatography (dHPLC). We show that NPM1 mutations are significantly underrepresented in patients younger than 35 years. NPM1 mutations positively correlate with AML with high white blood cell counts, normal karyotypes, and fms-like tyrosine kinase-3 gene (FLT3) internal tandem duplication (ITD) mutations. NPM1 mutations associate inversely with the occurrence of CCAAT/enhancer-binding protein-α (CEBPA) and NRAS mutations. With respect to gene expression profiling, we show that AML cases with an NPM1 mutation cluster in specific subtypes of AML with previously established gene expression signatures, are highly associated with a homeobox gene–specific expression signature, and can be predicted with high accuracy. We demonstrate that patients with intermediate cytogenetic risk AML without FLT3 ITD mutations but with NPM1 mutations have a significantly better overall survival (OS) and event-free survival (EFS) than those without NPM1 mutations. Finally, in multivariable analysis NPM1 mutations express independent favorable prognostic value with regard to OS, EFS, and disease-free survival (DFS).

Results of Acute Myeloid Leukemia Treated with Triple-Drug Regimen Based on HA as Induction Chemotherapy and Its Relationship with Karyotype.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4595-4595
Author(s):  
Jianxiang Wang ◽  
Yingchang Mi ◽  
Yangping Xue ◽  
Wenjuan Yu ◽  
Shougeng Bian
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Risk Groups ◽  
Drug Regimen ◽  
Free Survival ◽  
Intermediate Group ◽  
Favorable Group ◽  
Acute Myeloid

Abstract 243 untreated de novo acute myeloid leukemia (AML) patients were treated with (homoharringtonine+AraC, HA) based induction therapy which composing of three chemotherapeutic drugs (HAD, HAM, HAA, HAE) in our hospital for recent 12 years. Complete remission (CR) rate, disease free survival (DFS) and overall survival (OS) of the patients were calculated. 184 patients who had karyotype results were divided into four groups according to SWOG (Southwestern Oncology Group) criteria. Differences of CR rate, DFS and OS of different groups were evaluated. The CR rate of all 243 cases was 77.4%, and 94.6% out of them were for 1~2 courses. Median DFS of the 188 CR patients was 28.5 (range from 1.0 to 153) months. DFS rates at 3 years and 5 years were 45.4%, 40.2% respectively. The median OS of 243 patients was 18.4 (range from 0.5 to 154) months. OS rates at 3 years and 5 years were 36.9%, 31.4% respectively. CR rate, DFS and OS of the different cytogenetic risk groups were also be analyzed. According to SWOG criteria, patients were classified into favorable, intermediate, adverse and unknown groups. CR rate, median DFS and OS were 97.8%, 87.4 months and 89.0 months in favorable group; 81.9%, 17.6 months and 22.3 months in intermediate group; 61.5%, 9 months and 11.5 months in the adverse group; 79.3%, 29.0 months, 19.9 months in the unknown group, respectively. The differences among the four groups were statistically significant. Multivariates analyses confirmed contribution of cytogenetics and courses of post-remission chemotherapy to DFS and OS. If we incorporated unknown group into the intermediate group, the CR rate is 80.6%. DFS rates at 3 years and 5 years were 40.5%, 38.1% respectively. OS rates at 3 years and 5 years were 40.3%, 37.4% respectively. We conclude triple-drugs induction regimens based on HA are highly effective in adult AML in China. Cytogenetics is the important prognostic factor. SWOG karyotype subtyping criteria is appropriate to our patients and unknown group can be incorporated into the intermediate group.

Molecular Markers Predicting Clinical Outcome in Patients with Intermediate-Risk Acute Myeloid Leukemia Receiving Autologous Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 604-604
Author(s):  
Jordi Esteve ◽  
Susana Kalko ◽  
Montserrat Torrebadell ◽  
Mireia Camos ◽  
Pedro Jares ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Post-remission therapy in patients with acute myeloid leukemia (AML) is assigned according to the predictable biological risk of the disease, mainly based on cytogenetics. Nonetheless, optimal post-remission strategy for the intermediate-risk subtype, given the prognostic heterogeneity of this category, is currently undefined. Analysis of potentially relevant molecular features within this subgroup might contribute to clarify the role of autologous stem cell transplantation (autoHSCT) in these patients. Thirty seven patients (age: 53, 15–66; 51% female) diagnosed with intermediate-risk de novo AML during the period 1994–2006 who received an autoHSCT in first complete response were included in the study. Pre-transplant therapy was similar in all patients, consisting of standard induction chemotherapy (ICE, n=8, IDICE, n=29) and one cycle of high-dose ara-C-based consolidation chemotherapy. Internal tandem duplication of flt-3 (flt-3 ITD) and exon 12 NPM1 mutations were studied by either PCR or RT-PCR following standard methods. Gene expression profiling was examined in 28 patients with oligonucleotide HGU133 Plus 2.0 arrays (Affymetrix). Gene expression measures were normalized using RMA methodology (Affy package), and dChip v1.3 and Limma software (Bioconductor) were used for unsupervised and supervised analyses. In order to identify genes with prognostic value, a supervised analysis based on patients’ outcome (relapsed patients vs. long-term responders, i.e. >2-year duration) was performed. The combined results of NPM mutation and flt-3 ITD defined three subgroups of patients with different outcome: group 1 (n=12), constituted by patients with mutated NPM1 without flt-3 ITD; group 2 (n=20), which included patients with neither NPM1 mutation or flt-3 ITD; and group 3 (n=5), defined by flt-3 ITD regardless NPM1 mutational status. Thus, 5-year survival of these 3 subgroups of patients was 91%±9%, 52%±12%, and 20%±18%, respectively (p=0.02; see figure). Preliminary results of multiple gene profile comparisons between subgroups of patients with different outcome disclosed a cluster of genes with differential expression. Thus, in the most significant balanced comparison, 1238 genes were found to vary significantly in the unsupervised analysis, and 109 differentially expressed genes were identified in the supervised analysis. Interestingly, overexpression of genes such as TNF, RETN, CFLAR, SLC16A7, ENG, CD48, PLCR1, and SULTB1 correlated with a high relapse risk, whereas increased expression of YY1, FBXL12 and EXOSC6 were associated with a favorable outcome. In conclusion, presence of NPM1 mutation and flt-3 ITD are strong predictors of the outcome after autoHSCT in patients with intermediate-risk AML. Furthermore, genome-wide analysis may contribute to further define gene clusters with prognostic significance in patients with cytogenetically intermediate-risk AML receiving autoHSCT as consolidation therapy. Figure Figure

scholarly journals Identification of Prognostic Signature Based on the Copy Number Variation (CNV) and Expression in Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Changchun Niu ◽  
Di Wu ◽  
Alexander J. Li ◽  
Kevin H. Qin ◽  
Daniel A. Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Survival Analysis ◽  
Copy Number Variation ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Risk Groups ◽  
Number Variation ◽  
Acute Myeloid ◽  
Cancer Panel

Abstract Purpose Acute myeloid leukemia (AML) is caused by multiple genetic alterations in the hematopoietic progenitors, and molecular genetic analysis has provided useful information for AML diagnosis and prognosis. However, an integrative understanding about the prognosis value of specific copy number variation (CNV) and CNV-modulated gene expression has been limited. Methods We conducted an integrative analysis of CNV profiling and gene expression using data from the TARGET and TCGA AML cohorts. The CNV data from TCGA were analyzed using the GISTIC. CNV survival analysis and mRNA survival analysis were conducted with the Multivariate Cox proportional hazards regression model using R software with “survminer” and “survival” packages. KEGG cancer panel genes were extracted from the cancer related pathways from Kyoto Encyclopedia of Genes and Genomes (KEGG). The R package “circlize” was used for mapping the CNV genes to chromosomes. Results From this investigation, we observed distinct CNV patterns in the AML risk groups as well as the expression of 251 genes significantly modulated by CNV in both cohorts. There were 102 CNV genes (located at 7q31-34, 16q24) associated with clinical outcomes in AML, which were identified in the TARGET cohort and validated in the TCGA cohort, three of which being miRNA genes (MIR29A, MIR183, MIR335) that overlapped with a KEGG cancer panel. Five genes were identified whose expressions were modulated by CNV and significantly associated with clinical outcomes, and among them, the deletion of SEMA4D and CBFB were found to potentially have protective effects against AML. Moreover, the distribution of CNV in these five CNV-modulated genes was independent of the risk groups, which suggests that they are independent prognosis factors. Conclusion Overall, this study identified 102 CNV genes and five CNV-modulated gene expressions that are crucial for developing new modes of prognosis evaluation and target therapy for AML.

scholarly journals An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4193-4201 ◽  
Author(s):  
Klaus H. Metzeler ◽  
Manuela Hummel ◽  
Clara D. Bloomfield ◽  
Karsten Spiekermann ◽  
Jan Braess ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Score ◽  
Gene Expression Signature ◽  
Event Free Survival ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Expression Signature ◽  
Acute Myeloid

Abstract Patients with cytogenetically normal acute myeloid leukemia (CN-AML) show heterogeneous treatment outcomes. We used gene-expression profiling to develop a gene signature that predicts overall survival (OS) in CN-AML. Based on data from 163 patients treated in the German AMLCG 1999 trial and analyzed on oligonucleotide microarrays, we used supervised principal component analysis to identify 86 probe sets (representing 66 different genes), which correlated with OS, and defined a prognostic score based on this signature. When applied to an independent cohort of 79 CN-AML patients, this continuous score remained a significant predictor for OS (hazard ratio [HR], 1.85; P = .002), event-free survival (HR = 1.73; P = .001), and relapse-free survival (HR = 1.76; P = .025). It kept its prognostic value in multivariate analyses adjusting for age, FLT3 ITD, and NPM1 status. In a validation cohort of 64 CN-AML patients treated on CALGB study 9621, the score also predicted OS (HR = 4.11; P < .001), event-free survival (HR = 2.90; P < .001), and relapse-free survival (HR = 3.14, P < .001) and retained its significance in a multivariate model for OS. In summary, we present a novel gene-expression signature that offers additional prognostic information for patients with CN-AML.

ASXL1 Mutations Identify a High-Risk Subgroup of Older Patients with Primary Cytogenetically Normal Acute Myeloid Leukemia within the European LeukemiaNet ‘Favorable' Genetic Category

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 417-417
Author(s):  
Klaus H. Metzeler ◽  
Heiko Becker ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Jessica Kohlschmidt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Free Survival ◽  
Disease Free ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Abstract 417 Mutations in the additional sex combs like-1 (ASXL1) gene have been identified in patients (pts) with myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemia (AML). We present here the first study on ASXL1 mutations in adult primary cytogenetically normal (CN-)AML, and report their associations with clinical and molecular characteristics, treatment outcomes, and gene- and microRNA- (miR-)expression profiles. We studied 423 primary CN-AML pts, aged 18–83 years (y) and treated on cytarabine/daunorubicin-based frontline protocols, for ASXL1 exon 12 mutations (frame shift and nonsense changes) and other prognostic gene mutations [FLT3-internal tandem duplications (ITD) and tyrosine kinase domain mutations, MLL partial tandem duplications, and mutations in NPM1, CEBPA, WT1, IDH1, IDH2 and TET2]. ASXL1mutations were 5 times more common in older (≥60y) than in younger (<60y) pts [38/234 (16.2%) vs 6/189 (3.2%); P<.001], and subsequent analyses therefore focused on older CN-AML pts. Compared to ASXL1-wild type (-wt) pts, ASXL1-mutated (-mut) pts very rarely carried NPM1 mutations (P<.001) or FLT3-ITD (P=.002), but more often had CEBPA mutations (P=.01). ASXL1-mut pts also had lower white blood counts (P=.02), lower blast percentages in blood (P<.001) and bone marrow (P=.04), and tended to have higher platelet counts (P=.06) and more frequently be male (P=.08) than ASXL1-wt pts. Among older primary CN-AML pts, those with mutated ASXL1 had a lower complete remission (CR) rate (53% vs 71%; P=.04) and shorter disease-free survival (DFS; P=.03; 3y rates, 10% vs 19%), overall survival (OS; P=.006; 3y rates, 5% vs 23%) and event-free survival (EFS; P=.002; 3y rates, 5% vs 14%; Fig. A) than ASXL1-wt pts. Due to the strong associations of ASXL1 mutations with NPM1-wt, absent FLT3-ITD and mutated CEBPA, we studied their prognostic impact within the genetic categories defined in the European LeukemiaNet (ELN) guidelines [ELN Favorable (Fav): CN-AML with mutated CEBPA and/or mutated NPM1 without FLT3-ITD; ELN Intermediate-I: all remaining CN-AML pts]. ELN Fav/ASXL1-mut pts had a lower CR rate (50%) compared with ELN Fav/ASXL1-wt pts (82%; P=.04). All 6 ELN Fav/ASXL1-mut pts who achieved CR relapsed within 13 months, while 27% of ELN Fav/ASXL1-wt pts were alive and disease-free at 3y. All ELN Fav/ASXL1-mut pts died within 18 months after enrollment, whereas 34% of ELN Fav/ASXL1-wt pts were alive at 3y (OS, P<.001). EFS of ELN Fav/ASXL1-mut pts also was significantly worse than for ELN Fav/ASXL1-wt pts (P<.001; 3y rates, 0% vs 22%; Fig. B). Multivariable analyses confirmed that ASXL1 mutations associated with lower CR rates (P=.03), shorter DFS (P<.001), OS (P<.001) and EFS (P<.001) only among ELN Fav pts, after adjusting for other risk factors. In contrast, ASXL1 mutations were not associated with outcomes in the ELN Intermediate-I group. Further exploratory analyses in molecular subgroups suggested that ASXL1 mutations may be associated with particularly unfavorable outcomes [ie, shorter OS (P<.001) and EFS (P=.02)] among CEBPA-mut pts. Gene- and miR-expression profiles were derived using Affymetrix HG-U133 plus 2.0 and custom-made miR microarrays. We identified an ASXL1 mutation-associated gene-expression signature comprising 67 differentially expressed genes (92 probe-sets), including upregulation of WNT pathway co-receptor LRP6, cytochrome P450 enzyme CYP1B1, and GJA1 (connexin 43, mediating stem cell-stroma interactions in the bone marrow). No significant signature of differentially expressed miRs was found. In conclusion, in this first study of ASXL1 mutations focusing on primary CN-AML, we demonstrate that they associate with inferior outcomes in older pts, particularly within the ELN Fav genetic group. We also report the first ASXL1-mutation associated gene-expression signature in CN-AML that may provide useful insight into the biology of ASXL1-mut AML, and help design novel treatment approaches for this high-risk group of older pts.FigureFigure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 436 ◽  
Author(s):  
Victor Pallarès ◽  
Montserrat Hoyos ◽  
M. Chillón ◽  
Eva Barragán ◽  
M. Prieto Conde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Markers ◽  
Response To Treatment ◽  
Intermediate Risk ◽  
Patient Subgroup ◽  
Acute Myeloid

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment.

Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group

2009 ◽  
Vol 27 (24) ◽  
pp. 4007-4013 ◽  
Author(s):  
Ichiro Tsukimoto ◽  
Akio Tawa ◽  
Keizo Horibe ◽  
Ken Tabuchi ◽  
Hisato Kigasawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Death Rate ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
Intermediate Risk ◽  
Free Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

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