CD25 as an adverse prognostic factor in elderly patients with acute myeloid leukemia

Objectives: CD25 has been reported to be highly expressed in leukemia stem cells and correlated with adverse outcomes in young patients with acute myeloid leukemia (AML). However, the significance of CD25 expression in elderly patients with AML has not yet been investigated.

Methods: We retrospectively analyzed 154 newly diagnosed AML patients aged 60 years or over by flow cytometry.

Results: CD25-positive AML was characterized by high white blood cell counts, secondary AML, rare favorable karyotypes, and positivity for CD34 and CD7 antigens, compared with CD25-negative AML. CD25 positivity was significantly correlated with an inferior complete remission (CR), event-free survival (EFS), and overall survival. Multivariate analysis showed CD25 positivity to be a significant prognostic predictor of CR and EFS. A regimen of low-dose cytarabine and aclarubicin combined with granulocyte-colony-stimulating factor (CAG) led to higher CR rates in the CD25-positive AML patients than intensive chemotherapies. CD25 expression was increased at relapse and in the development of leukemic status from myelodysplastic syndrome or myeloproliferative neoplasm.

Discussion: An effective treatment strategy for elderly patients with CD25-positive AML has not been established. Further studies are needed to evaluate the effect of a CAG regimen and allogenic stem cell transplantation in patients.

Conclusion: CD25 is an independent prognostic factor in elderly AML patients. Alternative therapies for CD25-positive elderly AML patients are needed.     

Age is an independent adverse prognostic factor for overall survival in acute myeloid leukemia in Japan

AIM: To elucidate risk factors for survival of elderly acute myeloid leukemia (AML) patients in a real-world practice by observational study. METHODS: We conducted a population-based study in 213 adult and elderly AML patients (127 males and 86 females) in Kagawa Prefecture, Japan. To construct this cohort, we gathered all data for patients diagnosed with AML at 7 hospitals in Kagawa between 2006 and 2010. The primary end point was overall survival (OS) after AML diagnosis. Unadjusted Kaplan-Meier survival plots were used to determine OS in the overall cohort. Multivariate analysis was used to determine the independent adverse prognostic factors for OS, with the covariates of interest including age, gender, race/ethnicity, CCI, education, median income, metropolitan statistical area size and history of myelodysplastic syndrome. RESULTS: The average population of Kagawa during the study period was 992489, and the incidence of AML was 4.26 per 100000 person-years. A total of 197 patients with non-acute promyelocytic leukemia (non-APL) (119 males and 78 females) were also included. The median age of non-APL patients was 70 years (average 67, range 24-95). The 5-year OS rate was 21.1%. Subsequent analysis by age group showed that the survival rate declined with age; the 5-year OS rates of non-APL patients younger than 64 years, 65-74 years, and older than 75 years were 41.5%, 14.1%, and 8.9%, respectively. Multivariate analysis revealed that unfavorable risk karyotype, older age, poor performance status (PS) (3-4), lack of induction chemotherapy, and antecedent haematological disease were independent prognostic predictors. In the subgroup analysis, we also found that older patients with non-APL had lower complete remission rates and higher early death rates than younger patients, irrespective of PS. However, intensive chemotherapy was a significant predictor for longer survival not only in the patients < 75 years of age, but also in those over 75 with PS 0-2. CONCLUSION: Age would contribute considerable life expectancy to indicate induction chemotherapy with eligible dose of cytotoxic drugs for a favorable case even in advanced elderly.     

Soluble angiopoietin-2/sTie2 receptor ratio is an independent prognostic marker in adult acute myeloid leukemia

Aim  Angiogenesis is the formation of new blood vessels from preexisting one. The angiopoietins act a central role in these process. The aim of the present study is to the assess the impact of the circulating levels of angiopoietin-1 (Angi-1), Angiopoietin-2 (Angi-2), soluble Tie2 receptor (sTie2), and calculated Angi-2/sTie2 ratio on overall survival in 71 acute myeloid leukemia patients and 19 normal controls. Materials and methods  Ang-2, and calculated angi-2/sTie values were significantly higher in AML patients as compared to healthy volunteer (P= 0.002, 0.015 respectively) on the other hand Angi-1 was not significantly different in patients and control. Results  In univariate Cox proportional hazards model Angi-2, sTie2, angi-2/sTie2 ratio were predictive of poor survival. In multivariate analysis the calculated angi-2/sTie2 ratio is independent prognostic factor, with relative risk of 3.939, with 95% confidence interval 0.002–0.001. Conclusion  The calculated angiopoietin-2/sTie2 ratio represent an independent prognostic factor in AML and its value should be considered when considering anti angiogenic therapy.     

p16(INK4a) immunocytochemical analysis is an independent prognostic factor in childhood acute lymphoblastic leukemia

We investigated the prognostic value of p16(INK4a) immunocytochemistry (ICC) analysis in 126 cases of newly diagnosed childhood acute lymphoblastic leukemia (ALL). The incidence of negative p16(INK4a) ICC was 38.1% and was more frequent in T-lineage ALL. Overall survival (OS) and event-free survival (EFS) were significantly higher in patients with positive p16(INK4a) ICC than in patients with negative ICC (6 years OS, 90% versus 63%, P =.0014; 6 years EFS, 77.8% versus 55%, P =.0033). The p16(INK4a) ICC remained a significant prognostic factor within the subgroup of B-precursor ALL. Multivariate analysis showed that negative p16(INK4a) ICC was an independent prognostic factor for OS (relative risk [RR], 3.38; P =.02) and EFS (RR, 2.49; P =.018). Sequential study showed that p16(INK4a) expression remained stable during first relapse in most patients. These findings indicate that p16(INK4a) ICC is an independent factor of outcome in childhood ALL.     

High expression of HILPDA is an adverse prognostic prognostic factor in hepatocellular carcinoma

Hepatocellular carcinoma (LIHC) is a malignant tumor arising from hepatocytes or intrahepatic bile duct epithelial cells, which is one of the common malignancies worldwide. Better identification of liver cancer biomarkers has become one of the current challenges. Although hypoxia inducible lipid droplet associated (HILPDA) has been reported to be associated with tumor progression in a variety of human solid cancers, it has rarely been reported in the field of hepatocellular carcinoma; therefore, in this paper, RNA sequencing data from TCGA were used to analyze the expression of HILPDA and differentially expressed genes (DEGs). In addition, functional enrichment analysis of HILPDA-associated DEGs was performed by GO/KEGG, GSEA, immune cell infiltration analysis and protein-protein interaction network. The clinical significance of HILPDA in LIHC was calculated by Kaplan–Meier Cox regression and prognostic nomogram models. R package was used to analyze the combined studies. Thus, HILPDA was highly expressed in various malignancies, including LIHC, compared with normal samples, and high HILPDA expression was associated with poor prognosis (P < .05). Cox regression analysis showed high HILPDA to be an independent prognostic factor; age and cytogenetic risk were included in the nomogram prognostic model. A total of 1294 DEGs were identified between the high and low expression groups, of which 1169 had upregulated gene expression and 125 had downregulated gene expression. Overall, high expression of HILPDA is a potential biomarker for poor outcome in LIHC.     

The CYP1A1*2a allele is an independent prognostic factor for acute myeloid leukemia

Polymorphisms in carcinogen- and drug-metabolizing enzymes may increase the risk of acute myeloid leukemia (AML) and may influence prognosis. We report that the polymorphic variant of the cytochrome P450 CYP1A1*2A, present in 11.3% of patients, is an independent unfavorable prognostic factor for failure-free and overall survival in patients with AML.     

MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia

The Multidrug Resistance gene (MDR 1) is frequently expressed in acute myeloid leukaemia (AML). MDR 1 is associated with resistance to chemotherapy in vitro and with a poor response rate in AML. We have investigated the prognostic value of MDR 1 expression in relation to other patient characteristics with respect to response and survival.
One hundred and thirty patients aged 0–88 years were treated for de novo AML with standard induction and consolidation chemotherapy. MDR 1 expression was determined by immunocytochemistry. Univariate and multivariate analyses were conducted to identify prognostic factors for reaching complete remission (CR) and for overall survival from diagnosis, in order to compare MDR 1 with known prognostic factors. Univariate analysis showed that higher MDR 1 expression was an adverse prognostic factor for CR ( P  < 0.001), as was higher age ( P  < 0.001) and unfavourable karyotype ( P  < 0.01). These factors were also negative prognostic factors for overall survival ( P  < 0.001, P  < 0.05 and P  < 0.005, respectively). In the multivariate analysis MDR 1 ( P  < 0.001), higher age ( P  < 0.001) and karyotype ( P  < 0.01) were independent adverse prognostic factors for CR as well as for overall survival ( P  < 0.001, P  < 0.005, P  < 0.001, respectively). Our data indicate that MDR 1 expression is a disease-related unfavourable prognostic factor which has a significant impact on complete remission and overall survival in AML. Analysis of MDR 1 may be used to determine prognosis in individual patients.     

Expression of high Km 5'-nucleotidase in leukemic blasts is an independent prognostic factor in adults with acute myeloid leukemia

Cytarabine (ara-C) requires activation into its triphosphorylated form, ara-CTP, to exert cytotoxic activity. Cytoplasmic 5'-nucleotidase (5NT) dephosphorylates ara-CMP, a key intermediate, preventing accumulation of ara-CTP and may reduce cellular sensitivity to the cytotoxic activity of ara-C. To determine whether the level of expression of 5NT is correlated with clinical outcome in patients with acute myeloid leukemia (AML) treated with ara-C, this study analyzed the levels of messenger RNA expression of high Km 5NT by real-time polymerase chain reaction at diagnosis in blast cells of 108 patients with AML. High Km 5NT was expressed at diagnosis in the blast cells of 54% of patients. In univariate analysis, (1) patients whose blast cells contained high levels (values greater than the median value for total population) of high Km 5NT at diagnosis had significantly shorter disease-free survival (DFS) than patients with low levels of high Km 5NT (11 months versus 17.5 months, P =.02) and (2) high levels of high Km 5NT also predicted significantly shorter overall survival (15.7 months versus 39 months, P = .01) in young patients (< or = 57 years; median value for the entire population). In a multivariate analysis taking into account age, karyotype risk, and other factors found to have prognostic significance in univariate analysis, (1) high Km 5NT expression was an independent prognostic factor for DFS and (2) high levels of high Km 5NT also predicted significantly shorter overall survival in young patients. These results demonstrate that the expression of high levels of high Km 5NT in blast cells is correlated with outcome in patients with AML.     

Low-dose cytosine-arabinoside in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

Summary Ten AML- and two MDS-patients in whom conventional chemotherapy was contraindicated or ineffective were treated with low dose ARA-C, 10 mg/m² per 12^hs.c. for 2–4 weeks. Seven patients obtained a complete and two a partial remission. Our findings suggest that low dose ARA-C may act both by induction of differentiation and/or inhibition of proliferation.Supported by the Hamburger Krebsgesellschaft     

Peripheral blood blast clearance is an independent prognostic factor for survival and response to acute myeloid leukemia induction chemotherapy

In patients with acute myeloid leukemia (AML), rapid reduction of circulating blasts with induction chemotherapy may serve as an in vivo marker of chemosensitivity. We performed a retrospective analysis of 363 patients with untreated AML who received induction chemotherapy in order to determine the relationship between day of blast disappearance (DOBD) and complete remission (CR) rates, event‐free survival (EFS), and overall survival (OS). DOBD ≤ 5 vs. >5 was identified as the most discriminating cutoff for OS. DOBD > 5 was observed in 35 patients (9.6%). The CR rate for patients with DOBD ≤ 5 vs. >5 was 74.0 and 28.6%, median EFS was 9.4 and 1.8 months, and median OS was 17.1 and 5.8 months, respectively (P < 0.001 for all). DOBD > 5 was independently associated with a lower CR rate and shorter EFS and OS (P < 0.001 for all). DOBD > 5 retained prognostic significance for EFS and OS when patients were stratified by cytogenetic risk group, de novo vs. secondary or therapy‐related AML, European LeukemiaNet‐based risk groups, and whether CR was achieved. We propose DOBD > 5 as a simple and early marker of disease resistance that identifies patients with poor prognosis who otherwise may not be identified with existing risk stratification systems. Am. J. Hematol. 91:1221–1226, 2016. © 2016 Wiley Periodicals, Inc.     

The combined expression of HOXA4 and MEIS1 is an independent prognostic factor in patients with AML

HOXA4 gene expression is a predictor for outcome in normal karyotypic acute myeloid leukaemia (AML) patients. Given that Meis1 is a co‐factor for Hox genes, we hypothesized that the combined expression of HOXA4 and MEIS1 might add prognostic information in these patients. When diagnostic samples from 246 AML patients were divided into three main groups based on gene expression levels of HOXA4 combined with MEIS1 we found that within the group of patients exhibiting low levels of HOXA4, those with a high expression of MEIS1 had a significantly worse outcome than those exhibiting low MEIS1 expression (P = 0.025). Moreover, this prediction was independent of cytogenetics, mutational status of the NPM1 and FLT3 genes as well as upon WBC and age. To evaluate the possible contribution of regulatory events underlying these observations, 157 patient samples were subjected to promoter hypermethylation analysis. We observed that 77% were HOXA4‐ and 15%MEIS1 hypermethylated and that this epigenetic alteration was highly correlated to the gene expression level (MEIS1: P = 0.001; HOXA4: P = 0.007). Finally, we found a higher expression level and a higher frequency of hypermethylation of HOXA4 among patients with NPM1 mutations. In conclusion, our data show that the combination of low HOXA4 and low MEIS1 gene expression is a favourable predictor for outcome in all AML patients and that the expression levels are governed by the methylation state of these genes.