Methylation of ESR1 and Tumour Suppressor Genes Together Constitute an Independent Outcome Predictor in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 803-803 ◽  
Author(s):  
Corine J. Hess ◽  
Johannes Berkhof ◽  
Fedor Denkers ◽  
Gert J. Ossenkoppele ◽  
Gerrit Jan Schuurhuis ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Promoter Methylation ◽  
Myeloid Leukemia ◽  
Total Population ◽  
Risk Group ◽  
Methylation Status ◽  
Methylation Index ◽  
Group B ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML) promoter methylation has been observed for the estrogen receptor (ESR1) as well as for a number of Tumor Suppressor Genes (TSGs). These individual aberrancies were suggested to be part of a general methylation defect in subsets of AML patients, rather than random events. The objective of this study was to assess whether aberrant promoter methylation of multiple genes, as observed in AML samples, are associated and whether such associations render impact on clinical outcome. By Methylation-Specific Multiplex Ligation Probe Amplification (MS-MLPA) the methylation status of 26 TSGs was determined in bone marrow samples of 119 primary AML patients and 5 control individuals. No promoter methylation was detected in any of the controls, while at least one TSG was methylated in 59/119 patients. Methylation was observed in 12 out of 26 assessed sites, most frequently for ER, CDKN2B/p15, and IGSF4 (28–36% of all patients). A substantial intra-class correlation of 0.38 existed between methylation of different TGSs. ESR1 methylation (34/119) strongly predicted concurrent methylation of TSGs, OR 7.33 (95%CI 4.13–12.99). A regression model that included both the ESR1 methylation status and the number of methylated TSGs (methylation index), showed both parameters to be independent oppositely directed predictors for overall survival (OS), HR 0.06 (95%CI 0.01–0.33; p=.001) and HR 1.92 (95%CI 1.19–3.10; p=.007), respectively. In line with this observation, a higher methylation index was found to yield a significant negative effect on patient OS in both the ESR1 methylated (ESR1+) and ESR1 unmethylated (ESR1−) subgroups. Combining ESR1 methylation status with the absence or presence of promoter methylation of other TSGs (TSG+ or TSG−); yielded 4 patient subgroups with large differences in OS in univariate analysis (p=.0001, figure 1A). In multivariate analysis that included, FLT3-status, age at diagnosis, cytogenetics and achievement of CR, the predictive impact of the 4-group division on OS was maintained, HR 2.12 (95%CI 1.04–4.29; p=.037). Moreover, the combination identified a good prognostic patient subgroup (n=15, median OS 39 month) within the intermediate cytogenetic risk group (n=54, median OS 8.3 month), figure 1B. In conclusion, concurrent methylation occurs frequent in AML and is best predicted by ESR1 methylation. Methylation of ESR1 and methylation of other TSGs represent processes with independent predictivity. When combined, they constitute a unique and powerful factor for predicting overall survival, both in the total AML population as well as within the intermediate cytogenetic risk group. Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B) Figure 1. Overall Survival based on the methylation status of ER (ER+/ER) combined with the absence or presence of methylation of TSGs (TSG+/TSG−) for the total population (A) and confined to the intermediate cytogenetic risk group (B)

Acute Myeloid Leukemia with Myelodysplasia-Related Changes (MRC) Did Not Show Inferior Outcomes Compared to Those without MRC,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3563-3563
Author(s):  
Jee Hyun Kong ◽  
Hyun Ae Jung ◽  
Hee Kyung Ahn ◽  
Silvia Park ◽  
Hee-Jin Kim ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Univariate Analysis ◽  
Group A ◽  
Group B ◽  
Group D ◽  
Acute Myeloid

Abstract Abstract 3563 The distinctive features of the World Health organization (WHO) classification compared to French-America-British Co-operative group (FAB) classification of acute myeloid leukemia is the new morphological entity “AML with multilineage dysplasia (MLD)”, and now this subgroup has been renamed as 'AML with myelodysplasia-related change (MRC)”. It generally accepted that dysplasia was most frequently noted in older individual, is often associated with an unfavorable cytogenetic profiles and unfavourable response to therapy. However it is still controversial. Therefore, we evaluated the impact of MRC on overall survival (OS) and leukemia free survival (LFS) in acute myeloid leukemia patients. A total of 644 adult AML patients diagnosed at Samsung Medical Center (SMC) between Sep.1994 and Oct. 2010 were enrolled. We reviewed their medical histories, clinical parameters, hemogram data, bone marrow aspirate and cytogenetic studies, and reclassified them into AML with of MRC and without MRC groups. Of 664 patients, 543 patients were received induction chemotherapy, among them, 84 patients demonstrated MRC and 451 patients did not. Median age was 50 (15–88) years old, and 57.1% of patients were male. Median follow up period was 77.3 [0–191] months. AML without MRC group had more favorable cytogenetic risk, higher WBC counts and LDH levels than those with MRC. However, other variable such as age, sex, hemoglobin level, absolute neutrophil, and peripheral blast count, induction chemotherapy regimen, hematopoietic stem cell transplantation, CR1 (complete response after induction chemotherapy), CRp (complete recovery of platelet), and relapse rate were not different between two groups. Since FLT3-ITD and NPM1 tests were introduced into laboratory work after 2005, results of these tests were available only in 158 and 75 patients respectively, and these were not different between two groups. In univariate analysis, advanced age (>65 years) predicted worse LFS (median LFS [95% C.I.]; ° Â65 years vs >65 years; 9.3[7.2–11.4] vs 5.9[4.6–7.2] months, p =0.014). In terms of OS, young age (p=0.000), female (p=0.000), favorable cytogenetic risk (p=0.000), CR1 (p=0.000), CRp (p=0.000), absence of relapse (p=0.000), and HSCT (p=0.000) showed a higher probability of longer OS (Table 1). The presence of MRC, FLT3-ITD, and NPM1 did not affect OS (Table 1).Table 1.Summary of univariate analysis for overall survival.Median OS (months) [95% C.I.] or mean OS ± SD (months)pAge°Â65 years47.9 [17.1 – 78.6]0.000>65 years13.1 [5.9 – 20.4]SexMale23.2 [16.5 – 30.0]0.000¢Female112.2 [ – ]Cytogenetic risk¢Favorable107.0±7.40.000Intermediate28.0 [19.0 – 36.9]Unfavorable10.8 [7.8 – 13.7]Unknown17.5 [6.8 – 28.1]MRCAbsence35.9 [6.6 – 65.2]0.081Presence19.0 [6.9 – 31.0]CR1¢Yes112.2 [–]0.000No3.6 [1.1 – 6.1]CRp¢Yes70.9±4.40.000No54.8 [18.5 – 91.1]RelapseYes21.5 [17.2 – 25.9]0.000No17.5 [–]HSCT¢Auto86.2±5.60.000¢Allo83.8±6.5Not done17.5 [10.8 – 24.1]FLT3-ITDPositive8.2 [0–26.1]0.595Negative29.5 [20.9–38]NPM1¢Positive104.1±11.00.978¢Negative78.9±15.0¢“median survival not reached Next, we analyzed MRC effect in each variable to OS. The presence MRC did not affect OS of each group which divided according to the age (Figure 1. A and B), sex, cytogenetic risk groups (Figure 1. C and D), relapse, CR1, HSCT, and FLT3-ITD, though AML with MRC group had tendancy to have poor survival rate in intermediate cytogenetic risk group (Figure 1. C). However in patients who did not acheived CRp or showed NPM1, the presence of MRC correlated with shorter OS.Figure 1.Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D).Figure 1. Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D). In this study, patients with MRC did not show inferior outcomes than those without MRC. Therefore it is not necessary to decide different treatment strategy according to the presence of MRC Disclosures: No relevant conflicts of interest to declare.

Clinical Useful Prognostic Index for Adult Patients with Acute Myeloid Leukemia in First Relapse.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2011-2011
Author(s):  
Dimitri A. Breems ◽  
Wim L.J. Van Putten ◽  
Bob Lowenberg
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Prognostic Index ◽  
Free Interval ◽  
First Relapse ◽  
One Year ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract The treatment of acute myeloid leukemia (AML) in first relapse is associated with unsatisfactory rates of complete responses that are usually short lived. Previously proposed prognostic classification methods serving therapeutic decisions and evaluation of investigational treatment strategies at relapse of AML have been based on the duration of the relapse free interval and have largely neglected the influence of other known prognostic factors. Here we present an improved clinically useful prognostic index. This index has been developed from a multivariate analysis of 667 AML patients in first relapse among 1540 newly diagnosed non-M3 AML patients of age 15 to 60 years entered into three successive HOVON/SAKK Collaborative Group trials. The score, which has a range of 0 to 14 points, uses four relevant parameters. The parameters are: length of relapse free interval after first complete remission (more than 18 months: 0 points; 7 to 18 months: 3 points; 6 months or less: 5 points), cytogenetics at diagnosis (t(16;16) or inv(16): 0 points; t(8;21): 3 points; other cytogenetics: 5 points), age at relapse (35 years or younger: 0 points; 36 to 45 years: 1 point; older than 45 years: 2 points) and whether or not a previous stem cell transplantation (SCT) has been undertaken in first complete remission (no SCT: 0 points; previous SCT: 2 points). These points were assigned following estimations of the relative values of each of these factors contributing to outcome. Ultimately, three risk groups were defined: a favorable prognostic group A (0 to 6 points; overall survival of 70% at one year and 46% at five years), an intermediate risk group B (7 to 9 points; overall survival of 49% at one year and 18% at five years), and an unfavorable risk group C (10 to 14 points; overall survival of 16% at one year and 4% at five years). Thus, four commonly applied clinical parameters may identify among patients with AML in first relapse those for salvage or investigational therapy.

Clinical Characterization of Acute Myeloid Leukemia with Myelodysplasia-Related Changes as Defined by the 2008 WHO Classification System.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 922-922
Author(s):  
Olga K Weinberg ◽  
Mahesh Seetharam ◽  
Li Ren ◽  
Lisa Ma ◽  
Katie Seo ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Risk Group ◽  
Who Criteria ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Background: Although some studies have validated the 2001 WHO classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification system has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC) that now includes 1) AML arising from myelodysplastic syndrome (MDS), 2) AML with MDS-related cytogenetic abnormalities, and 3) AML with multilineage dysplasia. An individual case may fall into this category by meeting any of the criteria. The goal of the current study is to clinically characterize this newly defined AML-MRC subgroup. Methods: One-hundred consecutive AML patients diagnosed at Stanford University Hospital between 2005 and 2007 with adequate material for mutation analysis were studied. Cases were classified using the 2008 WHO criteria. Diagnostic cytogenetic findings were reviewed and patients were stratified into risk groups using Southwest Oncology Group criteria. Available flow cytometry immunophenotyping results were reviewed and all samples were tested for NPM, FLT3 (ITD and D835) and CEBPA mutations. Clinical parameters including hemogram data at time of diagnosis were reviewed. Clinical follow-up including overall survival (OS), progression free survival (PFS) and complete remission (CR) rates were retrospectively determined. Kaplan-Meier methods and univariate and multivariate Cox proportional hazards regression analysis were used to compare the clinical data. Results: The cases included 57 males and 43 females with a median age of 56 (range 17–81). Cytogenetic risk-group stratification resulted in 9 patients with favorable, 65 with intermediate and 19 with unfavorable risk status. Using the 2008 WHO criteria, there were 48 AML-MRC, 40 AML not otherwise specified (AML-NOS), 9 AML with either t(8;21), inv(16) or t(15;17), and 3 therapy related AMLs. Overall, 26 patients had a NPM1 mutation (16 of which were FLT3 mutated), 25 had FLT3-ITD, 8 had FLT3-D835 and 9 had a CEBPA mutation (3 of which were FLT3 mutated). Compared to AML-NOS, patients with AML-MRC were significantly older (59 vs 51 years, p=0.014) and presented with lower hemoglobin (9 vs 11.2 g/dL, p=0.044), lower platelets (47 vs 54 K/uL, p=0.059), unfavorable cytogenetics (14/46 vs 3/36, p=0.014) and exhibited a decreased frequency of CEBPA mutation (0/46 vs 7/40, p=0.001) as compared to AML-NOS. Based on the flow cytometry immunophenotyping, the blasts from patients with AML-MRC more frequently expressed CD14 compared to AML-NOS (10/46 vs 4/36, p=0.048). Clinical outcome data showed that patients with AML-MRC had a significantly worse OS, PFS and CR compared to AML-NOS (Figure, all p<0.0001). Even after excluding the 14 patients with unfavorable cytogenetics from the AML-MRC group, the remaining patients with AML-MRC (defined solely by the presence of multilineage dysplasia) had worse outcomes compared to all AML-NOS patients (OS, p=0.013; PFS, p=0.012; CR, p=0.0076). Among 65 patients with intermediate risk cytogenetics, the outcome difference between the AML-MRC and AML-NOS groups remained significant (OS, p=0.0292; PFS, p=0.0232), also indicating prognostic significance of multilineage dysplasia. Within the AML-MRC group, univariate analysis showed that low platelets (<20,000/mm3), FLT3-D835 mutation and MDS-related cytogenetics correlated with OS (p=0.0456, p=0.0265, p=0.002 respectively) and PFS (p=0.0478, p=0.0626, p=0.001). A multivariate Cox proportional hazard analysis, performed on the entire group, identified unfavorable cytogenetic risk group, advanced age (> 60), FLT3-ITD and AML-MRC status as significant predictors of worse OS with the following respective hazard ratios: 2.82 (95% CI, 1.52–5.26), 2.11 (1.01–4.42), 1.98 (1.01–3.90), 1.92 (1.01–3.65). Conclusion: The newly defined WHO category of AML-MRC exhibits a significantly worse clinical outcome compared to AML-NOS and is predictive of worse overall survival in the multivariate analysis of AML patients, independent of age or cytogenetic risk group. These findings support the clinical, morphologic and cytogenetic criteria for this 2008 WHO AML category. Figure Figure

Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4874-4874
Author(s):  
Shamail Butt ◽  
Pascal Akl ◽  
Himanshu Bhardwaj ◽  
Samer A Srour ◽  
Terry Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Intermediate Risk ◽  
Cebpa Mutations ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

Patients With t(8;21)(q22;q22) and Acute Myeloid Leukemia Have Superior Failure-Free and Overall Survival When Repetitive Cycles of High-Dose Cytarabine Are Administered

1999 ◽  
Vol 17 (12) ◽  
pp. 3767-3775 ◽  
Author(s):  
John C. Byrd ◽  
Richard K. Dodge ◽  
Andrew Carroll ◽  
Maria R. Baer ◽  
Colin Edwards ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Group B ◽  
To Receive ◽  
Leukemia Group ◽  
Acute Myeloid

PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either ≥ three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared. RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or ≥ three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P = .03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received ≥ three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P = .04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received ≥ three cycles of high-dose cytarabine. CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.

Prognostic Index for Older Adult Patients with Newly Diagnosed Acute Myeloid Leukemia: The Edouard Herriot Hospital Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4352-4352
Author(s):  
Claudiu Plesa ◽  
Quoc-Hung Le ◽  
Youcef Chelghoum ◽  
Mohamed Elhamri ◽  
Isabelle Tigaud ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Prognostic Score ◽  
Prognostic Index ◽  
Disease Free Survival ◽  
Newly Diagnosed ◽  
Co Morbidity ◽  
Acute Myeloid

Abstract The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of complete responses and long-term overall survival. Therefore, a clinically usefull prognostic index can facilitate therapeutic decision making and evaluation of investigational treatment strategies in this patient population. Overall, 243 of the 432 patients (56%, 95% CI: 51–60%) achieved CR (229 of them after the first induction course and 14 after salvage therapy). The median disease-free survival (DFS) and the median overall survival (OS) of the entire cohort were 8.4 months (95% CI: 7.2–10.1 months) and 8.3 months (95% CI: 7.2–10 months) respectively. A prognostic score is presented based on the multivariate analysis of 432 newly diagnosed non-M3 AML patients aged more than 60 years, selected on the base of their initial performance status and the absence of severe co-morbidity factors, for entering onto five successive clinical trials combining an anthracycline and cytarabine. Four clinically relevant parameters are included in this index: cytogenetics at diagnosis, history of previous hematologic disorder, hematologic features at diagnosis, and LDH level at diagnosis. Using this stratification system, three risk groups were defined: a favorable-risk group A (OS of 39% at 2 years and 21% at 5 years), an intermediate-risk group B (OS of 19% at 2 years and 8% at 5 years), and a poor-risk group (OS of 5% at 2 years and 0% at 5 years). The prognostic index estimates the outcome of elderly AML patients usually selected for intensive chemotherapy trials using four easily determined parameters and might identify patients who are really candidates for this treatment strategy from those for whom investigational therapy or palliation may be most appropriate.

Association of HLA-G Haplotype Risk Model with Overall Survival In Acute Myeloid Leukemia Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2169-2169
Author(s):  
Anja Volbracht ◽  
Juergen R Novotny ◽  
Crista Ochsenfarth ◽  
Magdalena Switala ◽  
Ulrich Frey ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Tumor Escape ◽  
Tumor Immune Escape ◽  
Group A ◽  
Group B ◽  
Acute Myeloid

Abstract Abstract 2169 Introduction: The human leukocyte antigen G (HLA-G) molecule exhibits limited tissue distribution and exerts multiple immunosuppressive functions. Thus, HLA-G expression in tumor cells favors tumor immune escape and tumor progression. The HLA-G gene polymorphism is extremely restricted in comparison to the classical HLA antigens. However, specific HLA-G polymorphisms in exons 3, 4, 5, 7 and parts of the 3′UTR encode for different haplotypes/alleles. Because of the prognostic role of HLA-G in cancer, especially in B-CLL, we investigated here the role of the HLA-G haplotypes in acute myeloid leukemia (AML). Methods: Genotyping was performed on the basis of examining exons 3, 4, 5, 7 and parts of the 3′UTR by pyrosequencing in 166 patients with AML. In total, we found 17 different haplotypes in the cohort. Results: The haplotype distributions between 166 AML patients and 190 healthy controls were significantly different in two alleles, arguing that these two haplotypes of HLA-G on the one hand increases (*01:06, p=0.042) and on the other hand decreases (*01:01:12 variante, p=0.0014) the susceptibility for AML. Next a risk model was generated for overall survival (OS) adapted to specific haplotypes/alleles of the HLA-G gene. The favorable group (A) consisted of the alleles *01:06 and *01:01:20 variant at codon 57 G (12 patients), the intermediate group (B) of *01:01:20, *01:04:10, *01:01:30 and *01:01:41 variant at codon 57 A (113 patients) and the unfavorable group (C) of the remaining 11 alleles (41 patients). The OS for patients in group C was significantly (p=0.02) shorter (median OS 613 days) than for those in group B (median OS 961 days) and A (median OS not reached). Multivariate analysis shows a trend that the risk HLA-G model (Hazard ratio (HR) 1.4, p=0.084) was an independent predictor next to the established prognostic factors cytogenetics (HR 2.1, p=0.001), age (HR 1.8, p=0.009), leucocytes (HR 1.6, p=0.026), ECOG stage (HR 1.5, p=0.006) and platelets (HR 2.1, p=0.015). Moreover, the new risk model was able to further subdivide patients with intermediate cytogenetic risk profile (median OS: group A not reached; group B 987 days; group C 624 days; p=0.10). Conclusion: Our study is the first study demonstrating that the combination of different alleles of the HLA-G gene is associated with the overall survival in AML patients. This fact emphasizes the extensive role of this gene by the tumor escape mechanism and could be responsible for progress in other cancers. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Effectiveness and Survival of 4 Courses of Chemotheray in 321 Children with Acute Myeloid Leukemia in China: A Multicenter, Nonrandomized Clinical Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2596-2596
Author(s):  
Zheng Yong Zhi ◽  
Jian Li ◽  
Xiaoqin Feng ◽  
Mincui Zheng ◽  
Chunfu Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Chi Square ◽  
Chi Square Test ◽  
Group A ◽  
Childhood Aml ◽  
Independent Risk Factors ◽  
Group B ◽  
Acute Myeloid

Objectives Increasing the intensity of chemotherapy can improve long-term survival in young patients with acute myeloid leukemia, but the number of appropriate courses is still worth exploring. We prospectively used MRC-AML 15 protocol as backbone to designed the C-HUANAN-AML15 protocol, which including 2 courses of inductions and 2 courses of consolidation to treat new diagnosed acute myeloid leukemia children in order to adapt to China's actual situation. The midterm outcome of effectiveness and survival was analyzed in the multicenter of south of China. Patients and methods Total of 321 newly diagnosed childhood AML patients from 9 centers of south of China from November 2014 to December 2018 were included in the study. 194 boys and 127 girls, with median age 6 (0.5-14) years old were enrolled. The median follow-up period was 16 (4 to 73) months up to July 2019. Risk stratifications were based on genetic abnormalities and response to induction chemotherapy . One hundred and seven patients (33.3%),146 patients (45.5%),68 patients (21.2%) were classified as low-risk group (LR), intermediate-risk group (IR) and high-risk group (HR) respectively. The protocol C-HUANAN-AML15 protocol including tandem 2 courses of FLAG-IDA regimen (marked as group A, n=225) , or sequential DAE(3+5+10) and DAE(3+5+8) regimen (marked as group B, n=96) were applied to induction chemotherapy. One course of Homoharringtonine (substitution of Amsacrine in MRC-AML 15 protocol)/ Cytarabine/ Etoposide and one course of Mitoxantrone/ Cytarabine in consolidation chemotherapy were uniform in both groups. 57 patients (39 patients in group A and 18 patients in group B, P=0.752) selected hematopoietic stem cell transplantation (HSCT) after 2-3 courses of chemotherapy. In the 264 patients who only underwent chemotherapy, the LR/IR/HR ratio in the A and B group was 65(34.9%),82(44.1%),39(21.0%) and 34(43.6%),37(47.4%),7(9.0%) respectively (P=0.056). The similarity of clinical data was analyzed by the chi square test and COX proportional hazard function model. Complete remission (CR) rates, treatment related mortalities (TRM), event-free survival (EFS) and overall survival (OS) were compared by Log-Rank chi square test. Results The CR rates in A and B group were 87.6% and 83.3% after 1st course induction regimen, and 92.4% and 89.2% after 2nd course induction regimen, which were not significantly different (P=0.375, 0.337). The 3-year EFS and OS of all patients were 65.8±3.2% and 70.3±3.4% respectively. The 3-year EFS and OS of 264 patients who only received chemotherapy was 65.4±7.4% and 71.7±3.4%. The 3-year EFS of HR, IR and LR in patients who received only chemotherapy were 40.3±8.8%, 62.0±5.2% and 83.5±4.3% respectively (P=0.000). The 3-year OS of HR, IR and LR in patients who received only chemotherapy were 46.9±9.0%, 69.1±5.1% and 86.1±4.0% respectively (P=0.000). The 3-year EFS of A and B group in patients who received only chemotherapy was 70.8±4.0% and 56.7±6.3% (P=0.059); The 3-year OS of A and B group in patients who received only chemotherapy was 78.7±3.6% and 58.6±6.4% (P=0.005). The 3-year EFS and OS of 57 patients who received HSCT was 60.2±8.9% and 65.4±7.4%(P=0.477, 0.821). The EFS of IR and HR patients who received HSCT were superior than that of who received only chemotherapy, but they were not significantly different (78.6±8.6%vs62.4±5.1%, P=0.121; 44.4±12.9%vs38.9±8.8%, P=0.208). Univariate analysis showed that initial white blood cell count (≥50×109/L), RUNX1-RUNX1T1 fusion gene, EVI1 gene positive, FLT3-ITD mutation, no CR after 1st course and 2nd course induction affected 3-year EFS (all P<0.05). Multivariate prognostic analysis with COX proportional hazard function model for EFS showed that EVI1 gene (HR0.397, 95%CI 0.201-0.785, P=0.008) and no CR after 2nd course induction (HR0.319, 95%CI 0.134-0.763, P=0.010) were independent risk factors. Conclusion This prospectively clinical study indicated that intensive induction with FLAG-IDA or DAE followed only 2 courses of consolidation chemotherapy was effective in the LR and IR group, and could be utilized as first line treatment in childhood AML. EVI1 gene positive and no CR after 2nd induction course were independent risk factors for EFS. More effective strategies are needed to be explored for HR group patients, EVI1 gene positive patients and those who cannot achieve CR after 2nd course induction. Figure Disclosures No relevant conflicts of interest to declare.

Impact of Comorbidities on the Outcome of Elderly Patients with Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1976-1976
Author(s):  
Anne Etienne ◽  
Benjamin Esterni ◽  
Aude Charbonnier ◽  
Thomas Prébet ◽  
Diane Coso ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Elevated Serum ◽  
Related Factors ◽  
Group Score ◽  
Acute Myeloid

Abstract Elderly patients with acute myeloid leukemia (AML) have a very poor prognosis, explained by the biologic characteristics of the disease but also by host-related factors including comorbidities. The objective of this study was to determine the prognostic role of comorbidities in this population. Between 1995 and 2004, 133 patients aged 70 years or older with newly diagnosed acute non promyelocytic leukemia, were treated with intensive induction chemotherapy (“3+7” regimen) at a single institution. Comorbidities at diagnosis were retrospectively evaluated using an adapted form of the Charlson Comorbidity index (CCI) (Sorror et al., Blood2004;104:961–968). Seventy-five patients achieved a complete response (CR) (56.4%) and 23 patients died during induction chemotherapy (17.3%). Comorbidity scores at diagnosis were 0 for 83 patients (68%), 1 for 16 patients (13.1%), and > 1 for 23 patients (18.7%). The median overall survival (OS) was 9 months (95% CI: 6–13) and was significantly poorly affected by high leukocyte count (≥ 30 G/l) and elevated serum creatinine level (>1.5 x upper normal limit). By multivariate analysis, we identified 4 adverse prongnostic factors for CR: unfavorable karyotype, leukocytosis ≥ 30 G/l, expression of CD34 on blast cells and a CCI > 1. Age was not found to be a significant prognosic factor for either CR or survival. When a score of 0 or 1 was affected to each prognostic variable, patients could be separated into a low-risk group (score= 0–1; 22% of patients), an intermediate-risk group (score= 2; 41% of patients) and a high-risk group (score≥3 ; 37% of patients), having 87%, 63% and 37% chance of achieving CR following conventional induction chemotherapy, an 8-week mortality rate of 9%, 22% and 34% (p=0.02), and a 2-year overall survival rate above 50%, less than 30% and 15%, respectively (p=0.01). Our results show that comorbidity is an important prognostic factor for elderly patients with AML which may help the physicians’ decision making. Its capture at diagnosis should be prospectively evaluated in larger study for its future use for risk-stratification among elderly patients treated for AML.

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