Nan Young Lee

Multidrug resistance‐1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia

Multidrug resistance‐1 (MDR‐1) gene single nucleotide polymorphisms (SNPs) have been identified as associated with the treatment outcomes of acute myeloid leukemia (AML) in Caucasians; yet, similar evidence is lacking for Asian populations. A total of 101 AML patients were enrolled in the current study. Two MDR1 SNPs (C3435T and G2677T/A) were analyzed with PCR/RFLP assay. As regards C3435T polymorphism, C/C genotype was significantly correlated with lower functional P‐glycoprotein (P‐gp) activity in leukemic blasts (7.5%) compared with C/T (10.7%) or T/T genotype (19.9%, p = 0.029). In genotypic analyses, C/C at −3435 (p = 0.05) and G/G at −2677 (p = 0.04) were strongly associated with a higher probability of complete remission (CR). In addition, the 3‐year event‐free survival (EFS) was higher in G/G genotype at −2677 (60.6%) than nonG/G (21.9%; p = 0.0241), in C/C at −3435 was higher than nonC/C genotype (p = 0.0139), and was higher in GC haplotype homozygote (58.2%) than nonGC homozygote (22.6%; p = 0.0427). In a multivariate analysis, the group without GC haplotype showed worse EFS (p = 0.030), with unfavorable cytogenetic risk (p = 0.008). However, no differences were noted in overall survival according to the MDR1 SNPs (p = 0.491 for C3435T and p = 0.955 for G2677T/A).

Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant.

Abstract:  Objective:  The therapeutic options currently available for treating refractory graft‐vs.‐host disease (GVHD) are limited. Therefore, the present study evaluated the efficacy of mycophenolate mofetil (MMF) as a salvage treatment for acute and chronic GVHD in allograft patients.

Clinical implications of angiogenic factors in patients with acute or chronic leukemia: Hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia

The present study evaluated the serum levels of known angiogenic factors and analysed their prognostic significance in patients with acute or chronic leukemia. Enzyme-linked immunosorbent assays (ELISAs) were performed to quantify the basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with acute myeloid leukemia (AML; 30 patients), acute lymphoblastic leukemia (ALL; 10 patients), and chronic myelogenous leukemia (CML; 14 patients). The levels of VEGF, HGF, angiogenin, and MMP-9 were all significantly higher in patients with CML than in healthy individuals. The HGF levels were also higher in patients with AML than in healthy individuals, plus there was a significant correlation between the HGF level and the white blood cell count, monocyte count, and serum level of lactate dehydrogenase (LDH) in patients with AML. In a univariate analysis, age and HGF level were both found to be significant parameters predictive for an achievement of complete remission (CR) in patients with AML. Meanwhile, in a multivariate analysis using a logistic regression model, the HGF level was the only parameter strongly predictive for CR (P=0.047). The leukemia-free survival (LFS) rate for AML patients with a lower HGF concentration was better than that for AML patients with a higher HGF concentration (1 year LFS rates=75.0% vs. 37.5%, P=0.065). The HGF concentration was an independent prognostic factor for an achievement of CR, plus higher HGF concentrations were associated with a lower survival in patients with AML.

Transplantation with higher dose of natural killer cells associated with better outcomes in terms of non-relapse mortality and infectious events after allogeneic peripheral blood stem cell transplantation from HLA-matched sibling donors.

Abstract:  Background: Little is known about the role of the CD56+ natural killer (NK) cell dose on the outcome of allogeneic peripheral blood stem cell transplantation (PBSCT). Recently, higher dose of NK cells has been associated with a lower incidence of severe graft‐versus‐host disease (GVHD). The current study attempted to evaluate the effect of the NK cell dose on transplant outcomes in allogeneic PBSCT setting. Methods and materials: Sixty‐one cytokine mobilized PBSC recipients were analyzed according to the infused dose of CD34+ cells and NK cells in relation to overall survival (OS), non‐relapse mortality (NRM), GVHD, and infectious events. Results: The group received a higher dose of NK cells (≥5 × 107/kg) showed a lower incidence of NRM (P = 0.0186) and infectious events (P = 0.0107). In a multivariate analysis, a higher dose of NK cells was correlated to better transplant outcomes for NRM (P = 0.042) with CD34+ cell dose (P = 0.018), and for infectious events (P = 0.013) with CD34+ cell dose (P = 0.016). Higher NK cell infusion group also showed a faster immune recovery in serial measurements at days +90, +180, and +365. Conclusions: High dose of NK cells may play an important role in improving transplant outcomes, in terms of reducing NRM and infectious events together with CD34+ cells.

Interleukin-10 gene polymorphism influences the prognosis of T-cell non-Hodgkin lymphomas.

Interleukin‐10 (IL‐10) is one of the cytokines implicated in the pathogenesis of diffuse large B‐cell lymphoma (DLBCL) in which it acts as auto/paracrine growth factor for lymphoma growth. T‐cell non‐Hodgkin lymphoma (NHL) is a heterogeneous disease, the biological basis of which is not fully understood. Some evidence suggests that IL‐10 might be associated with the progression of T‐cell NHLs and that IL‐10 may be involved in a rescue effect, protecting T cells from apoptotic cell death associated with upregulated bcl‐2 expression. The current study evaluated the impact of IL‐10 gene (IL10) polymorphism on the response to chemotherapy and survival in T‐cell NHL. IL10 polymorphisms were determined in 108 patients with T‐cell NHL. The response to chemotherapy was not dependent on IL10 polymorphism, while survival differed significantly according to IL10 polymorphism. The group with ATA haplotype showed superior overall survival (61·2 ± 5·9% vs. 21·2 ± 11·7%, P = 0·001) and failure‐free survival (35·0 ± 5·7% vs. 13·2 ± 8·7%, P = 0·001) compared to those without ATA haplotype. The ATA haplotype was identified as a favourable prognostic factor compared to non‐ATA haplotype (P = 0·037, hazard ratio 2·1), together with international prognostic index (IPI) in a multivariate model for overall survival. In conclusion, IL10 polymorphism may affect the survival of T‐cell NHL patients.

Vascular endothelial growth factor (VEGF) gene (VEGFA) polymorphism can predict the prognosis in acute myeloid leukaemia patients

Increased angiogenesis, mediated by vascular endothelial growth factor (VEGF), was associated with poor prognosis in acute myeloid leukaemia (AML) patients. The current study investigated the impact of VEGF gene (VEGFA) single nucleotide polymorphisms (SNPs) on treatment outcomes for AML. Four VEGFA SNPs were analysed for −2578C>A (rs699947), −460T>C (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci in 138 AML patients. The +936 CC/CT genotype showed strong correlation with favourable leukaemia‐free survival (LFS) at 2 years (51·3%) versus with +936 CC genotype (33·6%, P = 0·03). Strong linkage disequilibrium was noted among loci −2578, −460 and +405, but not with +936. Accordingly, four haplotypes were generated based on the genotypes of −2578, −460 and +405 as follows: CTC (40·2%), CTG (35·0%), ACG (22·0%) and ATC (1·2%). The LFS and event‐free survival (EFS) inversely correlated with CTG haplotype (P = 0·03 for LFS; P = 0·05 for EFS). We scored the VEGFA polymorphism marker based on +936 C>T genotype and CTG haplotype for −2578, −460 and +405, which demonstrated a good correlation with the treatment outcomes: LFS (P = 0·01), EFS (P = 0·03) and overall survival (P = 0·01). The VEGFA +936 C>T genotype and CTG haplotype seemed to have an additive effect to predict the prognosis in AML patients.

Prognostic scoring model based on multi-drug resistance status and cytogenetics in adult patients with acute myeloid leukemia.

Clinical heterogeneicity exists within an acute myeloid leukemia (AML) patient group with the same cytogenetic risk. Multi-drug resistance (MDR) is also regarded as one of the potential prognostic factors for AML. Accordingly, the prognostic scoring model can be generated based on both consideration of cytogenetic risk and the MDR status for AML. The CR rate, event-free (EFS) and overall survival (OS) were analysed according to cytogenetic risk, MDR status and clinical factors. Prognostic score was calculated by the sum of MDR status (0 for negative, 1 for positive) and dichotomized scoring for cytogenetic risk (0 for favorable/intermediate and 1 for unfavorable cytogenetics). MDR expression was noted in 36.6% of the patients and associated with a lower CR rate (p = 0.037). MDR, cytogenetics and the use of SCT were identified as independent prognostic factors for EFS and OS. The CR rate of the group scored with 0, 1 and 2 was 81.4, 66.7, and 44.4%, respectively (p = 0.050). The prognostic scoring model depicted a discriminating role in terms of EFS (p < 0.0001) and OS (p = 0.0001). The prognostic scoring model based on cytogenetic risk and MDR provided an improved method for evaluating the prognosis in AML and helped to stratify the risk of patients with the same cytogenetic risk.

Vascular endothelial growth factor gene polymorphisms may predict the risk of acute graft-versus-host disease following allogeneic transplantation: preventive effect of vascular endothelial growth factor gene on acute graft-versus-host disease.

Microvessel injury is associated with the development of graft-versus-host disease (GVHD), whereas high levels of posttransplantation vascular endothelial growth factor (VEGF) have a protective effect on severe acute GVHD (aGVHD) and transplantation-related mortality. The current study aimed to determine the impact of VEGFA gene single-nucleotide polymorphisms (SNPs) on the risk of aGVHD after allogeneic stem cell transplantation (SCT). Using polymerase chain reaction and restriction fragment length polymorphism, 4 VEGFA SNPs- -2578 C>A (rs699947), -460 T>C (rs833061), +405 G>C (rs2010963), and +936 C>T (rs3025039)-were analyzed in 98 recipients. Strong linkage disequilibrium was noted among loci -2578, -460, and +405, but not among these loci and locus +936. Accordingly, 4 haplotypes were generated based on the genotypes of -2578, -460, and +405: CTC (47.9%), CTG (26.7%), ACG (24.2%), and CCC (1.0%). The group with low VEGF production (ie, +936CT genotype and 2 copies of the ACG haplotype) had a higher incidence of aGVHD. Significant associations were found between the risk of grade 2-4 aGVHD and the +936 CT (P = .006), -2578 AA (P = .003), and -460 CC (P = .002) genotypes and the ACG haplotype (P = .003). No association between the VEGFA SNPs and chronic GVHD was observed. The VEGFA SNPs might predict a lower risk of aGVHD. Our findings suggest that VEGF may have a protective role in the pathogenesis of aGVHD.

Parameters for predicting allogeneic PBSCT outcome of acute myeloid leukemia: cytogenetics at presentation versus disease status at transplantation

In addition to the clinical disease status at transplantation, the cytogenetic risk at presentation also provides critical information for predicting the prognosis or deciding the future therapeutic strategy. As such, the current study examined various parameters, including the cytogenetics at presentation and clinical disease status at transplantation, regarding their effect on the transplant outcomes of acute myeloid leukemia (AML) patients in an allogeneic peripheral blood stem cell transplantation (PBSCT) setting. A total of 36 patients receiving an allogeneic PBSCT from matched sibling donors were included in a state of first complete remission (CR) (n=22, 61%) or beyond the first CR (n=14, 39%). The cytogenetic risk was classified according to Medical Research Council (MRC) 10 criteria: favorable, 7 patients (20%); intermediate, 21 patients (58%); unfavorable eight patients (22%). The 3-year overall survival rates were 80% for the favorable, 63% for the intermediate, and 0% for the unfavorable cytogenetic risk groups (p=0.0002), and 62% for the patients in a state of first CR and 35% for those beyond the first CR (p=0.0524). Multivariate analysis revealed that higher CD34+ cell doses, favorable cytogenetics at presentation, and a lower marrow blast percentage at transplantation were all strongly associated with favorable transplant outcomes, including overall survival (OS), progression-free survival (PFS), and the probability of progression. The cytogenetic risk at presentation was found to be a useful parameter in predicting the transplant outcomes for patients with AML, regardless of the clinical disease status. However, an additive innovative therapeutic strategy is still needed to overcome an unfavorable cytogenetic risk with refractory AML after allogeneic PBSCT.

Multidrug Resistance as a Potential Prognostic Indicator in Acute Myeloid Leukemia with Normal Karyotypes

Introduction: Approximately 45% of adults with acute myeloid leukemia (AML) have normal karyotypes and therefore lack structural abnormalities that can assist in the localization and characterization of molecular defects. The current study attempted to evaluate the potential prognostic role of multidrug resistance (MDR), regarded as one of the potential prognostic factors for the outcome of overall AML, for AML with normal karyotypes. Method and Materials: A functional MDR assay was performed in pretreatment samples from AML patients with normal karyotypes. The complete remission (CR) rate, event-free survival (EFS), and overall survival (OS) were analyzed according to the MDR status and clinical prognostic factors for 88 patients with AML with normal karyotypes. Results: MDR by efflux was expressed in 14 out of 48 evaluable patients (29%) but failed to identify the association with CR (p = 0.124). However, MDR was identified as an independent prognostic factor for EFS and OS (p = 0.013 and 0.046) together with the use of stem cell transplantation (p = 0.009 for EFS and 0.029 for OS) and the WBC count at presentation (p = 0.023 for EFS and 0.034 for OS). Conclusion: The functional MDR assay may provide information on the prognosis of AML patients with normal karyotypes, and it might be a possible guideline for risk-stratified treatment strategies in AML with normal karyotypes.