Jin Ho Baek

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).

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.

Phase II study of docetaxel and capecitabine in patients with metastatic or recurrent gastric cancer

Objectives: A phase II study was conducted to evaluate the response rate and safety of a combination regimen of docetaxel plus capecitabine in patients with advanced gastric cancer. Patients and Methods: Patients with previously untreated metastatic or recurrent measurable gastric cancer received i.v. docetaxel 75 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily from day 1 to 14 every 3-week cycle. Results: Thirty-two patients were enrolled in the current study. Of these, 30 patients were assessable for efficacy and 31 assessable for toxicity. One complete response and 13 partial responses were confirmed, giving an overall response rate of 43.8% (95% CI; 25.6–61.9%). The median time to progression and median overall survival for all patients was 5.07 months and 8.4 months, respectively. Grade 3/4 neutropenia occurred in 3 patients (9.7%) and febrile neutropenia was observed in 2 patients (6.3%). Grade 1/2 nausea was observed in 45.2% of patients. Grade 2–3 hand-foot syndrome occurred in 4 patients (12.9%). Conclusions: The combination of docetaxel and capectabine was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.

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.

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.

Biweekly irinotecan and cisplatin as second-line chemotherapy in pretreated patients with advanced gastric cancer: a multicenter phase II study.

The current phase II study was conducted to evaluate the response rate and safety of a combination regimen of biweekly irinotecan plus cisplatin in pretreated patients with advanced gastric cancer. Patients with previously treated metastatic or recurrent gastric cancer received intravenous irinotecan 70 mg/m2 and cisplatin 30 mg/m2 on day 1 and 15 every 4-week cycle. Thirty-two patients were enrolled in the current study. Of these, 31 patients were assessable for efficacy and all for toxicity. No complete response and 5 partial responses were confirmed, giving an overall response rate of 15.6% (95% CI; 2.3-28.9%). The median time to progression and median overall survival for all patients was 113 days and 184 days, respectively. Grade 3/4 neutropenia occurred in 6 patients (18.8%), yet no febrile neutropenia was observed. In addition, grade 3 anorexia was observed in 4 patients (12.5%) and grade 3 diarrhea occurred in 2 patients (6.2%). The combination chemotherapy of biweekly irinotecan and cisplatin was found to be moderately effective and well tolerated in pretreated patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important second-line treatment option for advanced gastric cancer.

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.

Retrospective Multicenter Study of Allogeneic Peripheral Blood Stem Cell Transplantation Followed by Reduced-Intensity Conditioning or Conventional Myeloablative Regimen

This retrospective study compared the results of reduced-intensity conditioning stem cell transplantation (RIST) and a conventional myeloablative regimen (CST) followed by allogeneic peripheral blood stem cell transplantation. In this respect, 63 RISTs and 41 CSTs were performed at 5 transplantation centers in Korea between April 1998 and December 2002. The RIST group had more adverse pretransplant characteristics. More aggressive diseases, like acute myeloid or lymphoblastic leukemia, were included in the CST group, while the RIST group included more indolent diseases, like chronic myeloid leukemia or myeloma (p < 0.001). The incidence of acute graft-versus-host disease (GVHD) grades 2–4 was 29.1 and 57.9% for the RIST and CST groups, respectively (p = 0.010), yet the incidence of chronic GVHD was similar in the two groups (57.4 vs. 71.9%). With a median follow-up of 13 months (0.5–61 months, 17 months in 52 survivors), the 3-year overall (OS) and disease-free survival (DFS) was similar in the RIST and CST groups (p = 0.965 for OS, p = 0.545 for DFS). In a multivariate analysis, RIST (p = 0.010), good performance status (p = 0.006) and a higher CD34+ cell dose (p = 0.008) were all identified as independent favorable prognostic factors for OS. Accordingly, in the current study, RIST produced equivalent or acceptable results compared with CST in terms of OS. Therefore, a prospective randomized trial of RIST and CST is warranted.

Clinical Significance of Platelet Count at day +60 After Allogeneic Peripheral Blood Stem Cell Transplantation

Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor, especially in patients with chronic graft-versus-host disease (GVHD), although various factors were related to the development of TP after allogeneic SCT. Sixty-three patients receiving allogeneic peripheral blood stem cell transplantation (PBSCT) were stratified according to platelet count (PC) at day +60 and analyzed in terms of overall survival (OS) and the incidence of non-relapse mortality (NRM). Ten patients (15.9%) were stratified in group 1 (PC ≤29×109/L), 23 patients (36.5%) in group 2 (PC 30-79×109/L), and 30 patients in group 3 (PC ≥80×109/L). Group 3 was associated with lower incidence of extensive chronic GVHD (p=0.013), better 3-yr OS (p=0.0030), and lower NRM rate (p<0.0001). In multivariate analyses, the PC at day +60 was identified as an independent prognostic factor (p=0.003) together with CD34+ cell dose (p<0.001), disease risk (p=0.004), and acute GVHD (p=0.033) in terms of NRM, and the PC (p=0.047) and CD34+ cell dose (p=0.026) in terms of incidence of infectious events. Measuring the platelet count at day +60 is a simple method for predicting the risk of chronic GVHD development and prognosis after allogeneic PBSCT.