scholarly journals CD97 Is Associated with Poor Overall Survival in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2794-2794
Author(s):  
Vijaya Pooja Vaikari ◽  
Sharon Wu ◽  
Houda Alachkar
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) is a heterogeneous, hematologic malignancy characterized by clonal proliferation of myeloid precursors. Overall survival for patients with AML remains dismal (<50% for younger patients and <10% for older patients) due to high relapse rates, necessitating the identification of novel therapeutic targets. CD97 is a glycoprotein belonging to the EGF-TM7 molecule family, a subgroup of adhesion G-protein coupled receptors. CD97 was shown to play a role in cell migration, adhesion and interaction with cell surface proteins and components of the extracellular matrix. In several solid cancers, CD97 association with integrin was shown to regulate invasion, migration, angiogenesis, and poor survival outcome. Even though CD97 is normally expressed on myeloids and leukocytes, there is sparse data related to its expression on myeloid leukemia cells. In this study, we characterized CD97 expression in patients with AML using publically available data sets to determine its association with patient's clinical and molecular characteristics and clinical outcome. Methods: CD97 mRNA (RNA Seq V2 RSEM) expression and Z-score data was downloaded from TCGA. We generated Kaplan-Meier survival curves to compare overall (OS) and event-free (EFS) survival between patients with CD97 high (Z≥1) and CD97 low (Z<1) expression after stratification by age, cytogenetic status, transplant status and NPM1 mutation status. Association between CD97 expression and patient clinical and molecular characteristics was performed by Mann-Whitney U's non-parametric t-test and Fisher's exact test. STATA 12.0 SE was used to perform a Cox Proportional Hazards Model. Results: Patients with cytogenetically normal AML (CN-AML) had significantly higher CD97 expression than cytogenetically abnormal AML (CA-AML) (1.31 fold, p=0.023). Patients with high CD97 expression had significantly higher WBC count (median: 56.1 vs 13.1, p=0.004) and % bone marrow blasts (median: 83 vs 71%, p=0.019). CD97 was significantly higher in patients with NPM1 mutation (n=48) compared with patients with NPM1 wild type (n=125) (1.56 fold, p<0.000). CD97 was also significantly higher in patients with FLT3 mutation (ITD and point mutations) (n=49) compared with patients with FLT3 wild type (n=124) (1.4 fold, p=0.0008). Additionally, CD97 was significantly lower in the patients with RUNX1 mutation (n=17) compared with wildtype gene (n=156) (42.1% lower; p=0.0002). The OS of the CD97 high was significantly shorter than that of the CD97 low patients (median: 7.35 vs. 24.1 months; p=0.0015). Patients with CD97 high expression had significantly shorter EFS than that of CD97 low (median: 5.35 vs. 12 months; p=0.0015). Furthermore, in CN-AML CD97 high patients had shorter OS than CD97 low patients in CN-AML (median: 7.5 vs 20.5 months; p=0.0045; Figure 3B). In multivariate survival analysis, CD97 high expression was associated with shorter OS when adjusted for age, cytogenetic risk and transplant status (HR= 1.96; 95% Cl: 1.19-3.24; p=0.009). Because CD97 expression was associated with NPM1 mutation in AML, we stratified patients according to NPM1 mutational status and found that in patients with wildtype NPM1, CD97 high expression was associated with significantly shorter OS (Median survival: 6.35 vs 22.3 months; P= 0.0081) and EFS (Median survival: 5.35 vs 13.4 months; P=0.0006). In patients with NPM1 mutation, a similar but not significant association was observed with CD97 high expression and shorter OS (median survival: 7.5 vs 24.1 months; P=0.1) and EFS (median survival: 5.8 vs 11.1 months; P=0.27). Furthermore, in patients ≥ 60; CD97 high expression was associated with shorter OS compared with CD97 low (median survival 3.3 vs 11 months; p=0.0019) and EFS (Median survival 2.9 vs 9.2 months; p=0.0092). Similar but not significant association was observed in in patients<60 (Median OS: 27.5 vs 53.9; p=0.2) and (Median EFS 8.5 vs 53.9; p=0.2). Conclusion: Patients with high CD97 expression had shorter OS and EFS. CD97 was higher in CN-AML compared with CA-AML patients. Additionally, high CD97 was also associated with NPM1 mutation. Our findings demonstrate that CD97 expression contributes to the clinical outcome of patients with AML, particularly in older patients. This study provides rationale for further functional and mechanistic studies aiming to understand the role of CD97 in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients

2021 ◽  
Author(s):  
Mike Dennis ◽  
Ian Thomas ◽  
Cono Ariti ◽  
Laura Upton ◽  
Alan K Burnett ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Intensive Chemotherapy ◽  
Wild Type ◽  
Flt3 Inhibitor ◽  
Acute Myeloid

Survival for older patients with acute myeloid leukaemia (AML) unsuitable for intensive chemotherapy is unsatisfactory. Standard non intensive therapies have low response rates and only extend life by a few months. Quizartinib is an oral Fms-like tyrosine kinase 3 (FLT3) inhibitor with reported activity in wild type patients. As part of the AML LI trial we undertook a randomised evaluation of low dose ara-C (LDAC) with or without quizartinib in patients not fit for intensive chemotherapy. Overall, survival was not improved (202 patients), but in the 27 FLT3-ITD patients the addition of quizartinib to LDAC improved response (p=0.05) with CR/CRi for quizartinib + LDAC in 5/13 (38%) v 0/14 (0%) in patients receiving LDAC alone. Overall survival (OS) in these FLT3-ITD positive patients was also significantly improved at 2 years for quizartinib + LDAC; hazard ratio 0.36 (95% confidence intervals 0.16, 0.85), (p=0.04). Median OS was 13.7 months compared to 4.2 months with LDAC alone. This is the first report of a FLT3 targeted therapy added to standard non-intensive chemotherapy that has improved survival in this population. Quizartinib merits consideration for future triplet based treatment approaches. (Clinical trial numbers: ISRCTN No: ISRCTN40571019 EUDRACT Number: 2011-000749-19).

scholarly journals High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jun Li ◽  
Zheng Ge
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Adverse Outcomes ◽  
High Expression ◽  
Micro Rnas ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

scholarly journals CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia

2018 ◽  
Vol 36 (26) ◽  
pp. 2684-2692 ◽  
Author(s):  
Jeffrey E. Lancet ◽  
Geoffrey L. Uy ◽  
Jorge E. Cortes ◽  
Laura F. Newell ◽  
Tara L. Lin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Remission Rate ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Secondary Acute Myeloid Leukemia ◽  
Acute Myeloid

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Usefulness of Charlson Comorbidity Index to Predict Early Mortality and Overall Survival in Older Patients With Acute Myeloid Leukemia

2020 ◽  
Vol 20 (12) ◽  
pp. 804-812.e8 ◽  
Author(s):  
Prajwal Dhakal ◽  
Valerie Shostrom ◽  
Zaid S. Al-Kadhimi ◽  
Lori J. Maness ◽  
Krishna Gundabolu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Charlson Comorbidity Index ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Early Mortality ◽  
Comorbidity Index ◽  
Acute Myeloid

Lack of Association of Mutations in IDH1, IDH2, DNMT3A with Outcome in Older Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents (± Histone Deacetylase Inhibitors).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2483-2483
Author(s):  
Farhad Ravandi ◽  
Keyur P. Patel ◽  
Rajyalakshmi Luthra ◽  
Sherry A. Pierce ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Histone Deacetylase ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hypomethylating Agents ◽  
Idh Mutations ◽  
Acute Myeloid

Abstract Abstract 2483 Background: Mutations of several genes believed to be important in the methylation apparatus of the cell have been recently described in patients with acute myeloid leukemia (AML) but their presence has not been correlated with a worse or better outcome using hypomethylating agents. Methods: We evaluated the association of mutations in IDH1, IDH2, DNMT3A, and EZH2 with the outcome [complete response (CR) rate, event free survival (EFS) and overall survival (OS)] among patients older than 60 with AML (≥ 20% blasts) treated with hypomethylating agents as their first line of treatment. TET2 mutations were not evaluated due to lack of available material. Results: Among the 68 patients (median age 72 years; range, 60 – 83) with available data, 11 patients (16%) had IDH1 or IDH2 mutations (mutually exclusive) and 10 patients (15%) had DNMT3A mutations with 5 patients (7%) having both IDH and DNMT3A mutations. Cytogenetics was diploid in 19 (28%), abnormal chromosome 5/7 and/or complex in 27 (40%), trisomy 8 in 5 (7%), miscellaneous in 14 (21%), and insufficient in 3 (4%). Presence of IDH mutations was associated with a diploid karyotype and the presence of NPM1 mutations (p=.03 and p=.02, respectively) but not with FLT3- ITD or RAS mutations (present in 7 and 4 patients, respectively). DNMT3A mutations were not associated with any specific karyotype or with the presence of NPM1, FLT3-ITD, or RAS mutations. None of the 68 patients had EZH2 mutations. All patients were treated with hypomethylating agents [decitabine in 39 (57%) and 5-azacytidine in 29 (43%)] with 42 patients (62%) receiving concomitant histone deacetylase inhibitor therapy (SAHA or valproic acid). Overall, 17 patients (25%) achieved CR; the presence of IDH or DNMT3A mutations or both was not associated with achievement of CR. With a median duration of follow-up of 60 months, the median EFS is 3.3 months (range, 0.25 – 3.75 months) and the median overall survival is 6 months (range, 0.25 – 90.5 months). Presence of IDH mutations was not associated with an impact on EFS (p=.29) or OS (p=.14). Similarly, DNMT3A mutations were not associated with an effect on EFS (p=.21) or OS (p=.58). The presence of both IDH and DNMT3A mutations was also not associated with a better or worse response, EFS, or OS as compared with patients with neither mutation. Conclusion: We were not able to detect an association between presence of IDH1/2 and DNMT3A mutations and outcome in this elderly population of patients with AML treated with epigenetic modulators. Disclosures: Ravandi: Johnson and Johnson: Honoraria; Celgene: Research Funding. Off Label Use: Use of decitabine, 5-azacytidine, SAHA, and valproic acid in the treatment of older patients with AML. Garcia-Manero:Celgene: Research Funding. Cortes:Celgene: Research Funding; Eisai: Research Funding.

Body mass index (BMI) influence on survival in adult patients with newly diagnosed acute myeloid leukemia (AML)/high-risk MDS: Retrospective study of 130 patients from a single institution.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18011-e18011
Author(s):  
Mohamed Abdelfatah ◽  
Ali Al-Ameri ◽  
Zeyad Kanaan ◽  
Ahmed Malkawi ◽  
Nairmeen Awad Haller
Keyword(s):  
Body Mass Index ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Median Survival ◽  
Survival Benefit ◽  
Myeloid Leukemia ◽  
Normal Weight ◽  
Adult Patients ◽  
Newly Diagnosed ◽  
Acute Myeloid

e18011 Background: The incidence of obesity is increasing worldwide and is associated with numerous adverse health outcomes. In AML high body mass index (BMI) is associated with increased risk of treatment-related complications; the overall survival in patients with acute myeloid leukemia is inferior, with most studies conducted in the pediatric population. Aim: To evaluate the effect of increasing (BMI) in the overall survival (OS) of adult patients with AML/High risk MDS. Methods: After obtaining IRB approval, all adult patients with AML diagnosed and treated at our institution (2002–2010) were studied. Data collection included patient demographics, laboratory tests, bone marrow biopsies, BMI, and survival information. We classified the AML patients into two groups according to BMI (kg/m2) classification by WHO; normal Weight 18-25 kg/m2, overweight and obese >25 kg/m2. Chi-Square and T-test were used for between group comparisons and Kaplan-Meier test was applied for survival estimates. Results: Adult patients with newly diagnosed AML (n = 130) had a median age of 55 years (range: 19-90), and 43 (56%) patients were older than 75 years. Seventy-two patients (55%) were male and 58 (45%) were female. 45 patients (35%) in total had complex cytogenetics, 20 patients (15%) had AML arise from MDS.Forty-four patients (34%) were considered normal weight; Eighty-six patients (66%) were classified as overweight or obese. Overall median survival was 28 weeks; patients with BMI 18-25 kg/m2 had a 36-week median survival, while patients with BMI <25 kg/m2 had a 25-week median survival (p<0.499). Conclusions: Overall survival was low in the study population; survival in obese and overweight patients (BMI>25) was slightly lower than normal weight group (18-25 kg/m2), although this did not translate into a survival benefit. Future large scale studies may be needed to further define the role of BMI in survival benefit for these patients.

scholarly journals Combination of Sorafenib and 5-Azacytidine in Older Patients with Untreated Acute Myeloid Leukemia with FLT3-ITDmutation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1611-1611 ◽  
Author(s):  
Maro Ohanian ◽  
Guillermo Garcia-Manero ◽  
Elias J. Jabbour ◽  
Naval Daver ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Median Overall Survival ◽  
Cell Transplant ◽  
Overall Response ◽  
Grade 3 ◽  
Acute Myeloid

Abstract Background: The combination of 5-azacytidine (AZA) and sorafenib has been reported to be a safe and effective strategy in patients with relapsed and/or refractory FLT3-ITD mutated acute myeloid leukemia (AML). We hypothesized that combining sorafenib with AZA, may be used effectively in older patients with untreated AML whose leukemic cells harbor the mutation. Methods: Patients were eligible if they had untreated AML with a FLT3-ITD clone detectable by polymerase chain reaction (at least 10% mutation burden), were 60 years of age or older, and had adequate performance status (ECOG ≤ 2) and organ function. The treatment regimen included AZA 75 mg/m2daily for 7 days combined with sorafenib 400 mg twice daily for 28 days. Cycles were repeated approximately every 4 to 5 weeks. Dose adjustments of both agents, and delay of AZA, based on toxicity were allowed. Results: Overall, 23 patients with untreated AML with a median age of 74 yrs (range, 61-86 yrs) were enrolled. They included 14 (61%) patients with normal cytogenetics, 2 (9%) with complex karyotype, 4 (17%) with other miscellaneous abnormalities, and 3 (13%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all patients with a median allelic ratio of 0.35 (range, 0.01-0.89). The overall response rate in 22 evaluable patients was (77%) including 7 (32%) with CR, 9 (41%) CRi/CRp, and 1 (5%) PR. Patients have received a median of 3 (range, 1-35) treatment cycles with the median number of cycles to response being 2 (range, 1-5) and the median time to achieve response, 1.9 months (range, 0.7-4.3 months). The median duration of CR/CRp/CRi is 14.5 months (range, 1.2-28.7 months). Two (9%) patients have proceeded to allogeneic stem cell transplant. With a median follow-up of 4.2 months (range, 0.9-61.4), 8 patients remain alive, 7 still in remission (CR/CRP/CRi). The median overall survival for the entire group is 8.8 months, and 9.2 months in the 17 responding patients (Figure 1). Treatment-related grade 3/4 adverse events included: grade 3 diarrhea (n=2), grade 3 pneumonitis (n=3), grade 4 sepsis (n=2), grade 3 infections (n=3). When patients treated with AZA + sorafenib (n=23) were compared to a matched cohort of historical patients older than 60 years who were treated with hypomethylator-based therapy without sorafenib (n=20), overall response rates (including CR, CRp, CRi, and PR) were statistically similar (77% vs.31%, respectively; p=0.6). The median overall survival for the two groups were 8.8 months and 9.4 months (p=0.67), respectively. The remission duration for the responding patients treated with AZA+sorafenib was significantly longer (16 months) than those on other hypomethylator-based regimens without sorafenib (3.8 months)(p=0.008) (Figure 2). Conclusions: The combination of AZA and Sorafenib is effective and well tolerated in older patients with untreated FLT3-ITD mutated AML. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Sunesis: Consultancy, Research Funding; Ariad: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Poor Prognosis of Adult Acute Myeloid Leukemia (AML) with High Level of Evi1 and BAALC Transcript.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2994-2994
Author(s):  
Valeria Biggio ◽  
Selim Corm ◽  
Hugues Leroy ◽  
Stephane De Botton ◽  
Christophe Roumier ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Molecular Markers ◽  
Myeloid Leukemia ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
High Expression ◽  
Fab Classification ◽  
Acute Myeloid

Abstract Cytogenetics remain the most powerful prognostic factor in acute myeloid leukemia (AML). However, 50–60 % of those patients (pts) are included in intermediate or unknown karyotypic risk groups. Molecular markers might improve risk classification and recently, 2 groups have reported that the expression of BAALC and EVI1 might be associated with a poor outcome, especially in pts with normal karyotype (Blood.2003;102:1613; Blood2003;101:837). Thus, we retrospectively analyzed the prognostic significance of the expressions level of these genes, by real time quantitative PCR (RQ-PCR) in AML. Patients and methods: 189 adult pts were analyzed: median age was 49 years (range, 19-65), median WBC counts 19 Giga/L (range, 0-602). FAB classification was: M0=22, M1=41,M2=44,M4=37,M5=26,M6=7,M7=1 and unclassified =11. Karyotype was prognostically favorable (n=28), intermediate (n=115, including 80 normal), unfavorable (n=39) and unknown (n=7). All pts received anthracycline-AraC chemotherapy according to French ALFA group multicenter trials (Castaigne et al, Blood 2004; May 13, Epub ahead of print). Complete remission rate was 83 %, median overall survival: 22 months, range 0.1 to 123. RQ-PCR was performed according to the 2 previous paper recommendations. However the housekeeping gene used in this work was TBP (TF2D). Results were expressed using ΔCt method. High levels of EVI1 were defined by ΔCt lower than 11. BAALC (+) pts and (−) pts were defined by ΔCt value lower or higher than 2.45 (ie the median ΔCt for BAALC expression). Results: 24/189 (13%) pts had high expression of EVI1. By comparison to pts without high EVI1 expression, pretreatment variables other than karyotype (including age, WBC counts, FAB classification) were similar in pts with high EVI1 expression. Patients with high EVI1 expression had significantly worse karyotype: none had favorable karyotype, only 4 (17%) had 3q26 abnormalities ((associated with other adverse abnormalities in 3 cases (i.e. -7/7q-)), 3 had 11q23 abnormalities and 9/24 (37.5%) pts normal karyotype. No significant diferencies between pts with high and low EVI1 expression was found for CR rates and DFS, but high EVI1 expression was associated with poorer overall survival ( median:11.7 months versus 26.9 months; p=0.0372). No pretreatment parameters, including karyotype, differed between BAALC (+) (ie pts with BAALC expression lower than the ΔCt median value) and BAALC (−) pts (ie pts with expression greater than the ΔCt median value). Overall CR rate, DFS, OS were similar in BAALC (+) and BAALC (−) pts. However, in the intermediate cytogenetic subgroup (n=115 pts), BAALC (+) pts had lower median DFS (9.7 months versus 19.8 months; p=0.0316) and EFS (4.1 months versus 11.8 months; p=0.0027) than BAALC (−) pts and a trend for poorer OS:16 months versus 27 months (p=0.07). In conclusion: In adult AML patients, high expression of EVI and BAALC are associated with poorer outcome. Determination at diagnosis of the level of those two genes could be helpful for treatment adjustment, especially in the intermediate cytogenetic subgroup. Correlation between EVI1 and BAALC results and those of other molecular markers (CEBPA, RAS, FLT3) mutations will be presented.

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