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  • American Society of Hematology  (5)
  • Onishi, Tatsuhito  (5)
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  • American Society of Hematology  (5)
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  • 1
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1528-1528
    Abstract: The Wilms' tumor gene (WT1), originally discovered as a tumor suppressor has been proven to have an oncogenic role in leukemia and several other cancers. WT1 mRNA expression levels in peripheral blood (PBWT1) has been reported as a useful marker for the risk evaluation of myelodysplastic syndrome (MDS). In the era of hypomethylating agents, the significance of PBWT1 on MDS prognosis is still unknown. This study aimed to clarify the impact of pre-treatment PBWT1 levels on overall response (OR) and overall survival (OS) in MDS patients treated with azacitidine (AZA). Patients and Methods We retrospectively analyzed all patients from March 2011 to March 2013 with World Health Organization 2008 defined MDS, CMML or AML with 20–30% bone marrow blasts who received AZA treatment in our department for at least one cycle (37.5–75.0 mg/m2/day during 7 days, every 28 days). Patients' peripheral blood specimens were collected before AZA initiation, mRNA was extracted from leukocytes using the RNeasy Mini-Kit (Qiagen, Valencia, CA), and the amount containing WT1 mRNA was measured using a WT1 mRNA Assay Kit (Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan). Hematologic response was evaluated according to International Working Group 2006. OR was defined as a best overall response of complete remission (CR), partial remission, marrow CR, or hematologic improvement. Univariate analyses for OR were carried out using Fisher's exact test. Factors associated with at least borderline significance (p 〈 0.10) were subjected to a multivariate analysis, using logistic regression model. OS was estimated according to the Kaplan-Meier method. Multivariate analysis was performed with proportional hazard Cox model, including all variables with p 〈 0.10 in univariate analyses. Results Of 55 patients enrolled, pre-treatment PBWT1 levels were available in 41 patients and the median level was 790 copies/µg RNA (range, less than 50–310000). Baseline characteristics according to PBWT1 levels (≤ 790 [lower group] [n = 21] and 〉 790 [higher group] [n = 20] ) are summarized in Table 1. Median number of AZA treatment cycles was 4 (range, 1–18). Four patients (2 in higher group, and 2 in lower group) received allogeneic stem cell transplantation (alloSCT) after AZA treatment. OR rates were significantly lower in PBWT1 higher group than lower group (30.0 vs 71.4%, p = 0.03). In univariate analysis, other significant risk factors or with borderline significance for OR were higher serum ferritin levels ( 〉 1000 ng/ml) and RBC transfusion dependency ≥ 4 units/8 weeks. In multivariate analysis, higher PBWT1 levels independently predicted reduced likelihood of OR (odds ratio = 0.212, 95% CI 0.01-0.95, p = 0.02). OS was significantly inferior in PBWT1 higher group as shown in Figure 1. In univariate analysis, other significant factor was Revised International Prognostic Scoring System (IPSS-R) risk groups (high risk defined as IPSS-R high or higher, and low risk defined as IPSS-R intermediate or lower). In multivariate analysis, higher PBWT1 levels (hazard ratio [HR] = 9.75, 95% CI 1.22-77.58, p = 0.03) and IPSS-R high risk (HR=7.04, 95% CI 1.43-34.48, p = 0.02) were independent predictors for OS. Conclusion Our results suggest that PBWT1 can predict both response and survival of MDS patients treated with AZA. Although salvage therapy including alloSCT can affect the survival, poor survival might result from inferior response rates in PBWT1 high patients. In MDS with high PBWT1, restoration of epigenetically silenced tumor suppressor genes with AZA might not induce apoptosis. We propose that alternative therapeutic strategies should be sought in MDS patients with high PBWT1 levels. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4551-4551
    Abstract: The prognosis of elderly patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) is poor, even in the patients who achieved good response after induction therapy. In order to undertake allogeneic stem cell transplantation (allo-SCT) with reduced toxicity and without total body irradiation (TBI), we conducted a combination regimen consisted of fludarabine, busulfan, and melphalan (Flu/Mel/Bu) for reduced intensity stem cell transplantation (RIST) conditioning. Patients and methods Among a total of 50 patients who underwent Flu/Mel/Bu conditioning between 2004 and 2012 in our institute, 32 patients with myeloid malignancies were retrospectively reviewed. Disease status was defined by WHO classification 2008. Therapy consisted of fludarabine 25 mg/m2 for five days (125mg/m2) and melphalan 50mg/m2 for two days (100mg/m2), both by intravenous infusion. Busulfan 2 mg/kg was administered orally for two days (4mg/kg) between 2004 and 2006, and intravenously at 1.6 mg/kg for two days (3.2mg/kg) between 2007 and 2012. Results Among the 32 eligible patients, 18 were female and 14 male. Seventeen patients were diagnosed with AML, 14 with MDS and one with chronic myelomonocytic leukemia (CMML). Median age was 59 years (32-66 years), and the median follow-up period was 1337 days (12-3043 days).Disease status of AML was complete remission (CR)1 (5), CR2 (10), CR3 (1) and CR4 (1), respectively, and all CR1 patients had poor risk factors. Disease status of MDS was RA (4), RARS (2), RCMD (1), RAEB-1 (5) and RAEB-2 (2), respectively. Three patients of RAEB conducted induction chemotherapy and two patients achieved CR. Donor sources consisted of 22 of unrelated bone marrow (URBM), 5 of related bone marrow (RBM), 3 related peripheral blood (RPB), and 2 of unrelated cord blood (URCB), respectively. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus plus short term methotrexate (TAC+sMTX) (25) and cyclosporin plus methotrexate (CsA+sMTX) (7). The cumulative incidence of grade II-IV acute GVHD was 31.7% and chronic GVHD was 85.9%. Five-year non-relapse mortality (NRM) was 15.9% and the 5-year relapse rate was 18.8%. One-year overall survival (OS) was 81.2% (95%CI 62.9-91.1), 5-year OS was 74.6% (95%CI 55.5-86.4), one-year progression free survival (PFS) was 78.1% (95%CI 59.5-88.9), 5-year PFS was 65.4% (95%CI 44.2-80.2). Fourteen patients were older than 60 years, and both 5-year OS and PFS of this group were 85.7% (95%CI 53.9-96.2). For AML, one-year OS was 82.4% (95%CI 54.7-93.9), 5-year OS 70.1% (95%CI 42.3-86.3), one-year PFS was 76.5% (95%CI 48.8-90.4) and 5-year PFS was 61.8% (95%CI 32.9-81.2). Five-year NRM was 11.8% and the 5-year relapse rate was 26.5%. For MDS, both one-year OS and 5-year OS were 78.6% (95%CI 47.2-92.5), and both one-year PFS and 5-year PFS were 69.8% (95%CI 37.8-87.6). Five-year NRM was 21.4% and the 5-year relapse rate was 8.7%.On the other hand, we conducted 32 allo-SCT for myeloid malignancies (22 of AML in CR and 10 of MDS) with conventional conditioning regimens of cyclophosphamide (Cy) and TBI or Bu and Cy between 2004 and 2012. Median age was 36.5 years (20-54 years), and the median follow-up period was 1191 days (38-3366 days).Disease status of AML was CR1 (14), and CR2 (8), respectively. Disease status of MDS was RA (3), RARS (2), RCMD (1), RAEB-1 (4), RAEB-2 (1), and MDS-U (1), respectively. Four patients of RAEB conducted induction chemotherapy and achieved CR. Donor sources were URBM (15), RBM (11), CB (5) and RPB (1), respectively. GVHD prophylaxis consisted of TAC+sMTX (17) and CsA+sMTX (15).The outcomes of Flu/Mel/Bu were not statistically inferior to those of conventional regimens with one-year OS of (81.2% vs. 87.1%, p=0.564) and 5-year OS of (74.6% vs. 78.0%, p=0.564), and one-year PFS of (78.1% vs. 83.9%, p=0.183) and 5-year PFS of (65.4% vs. 80.4%, p=0.183). Conclusions Flu/Mel/Bu was tolerable, and produced good outcomes and may be a candidate for curative conditioning regimen of RIST, especially for patients with myeloid malignancies in controlled status. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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    Location Call Number Limitation Availability
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  • 3
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1636-1636
    Abstract: Background: Previous studies have shown that the absolute lymphocyte count (ALC) in peripheral blood at diagnosis may be an independent prognostic factor of IPI for patients with diffuse large B-cell lymphoma (DLBCL). In the rituximab era, the U.S. National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) was developed to improve the risk stratification of DLBCL in comparison to the existing IPI. Therefore, the aim of this study was to clarify the impact of ALC at diagnosis on event free survival (EFS) and overall survival (OS) on analysis performed with factors included in NCCN-IPI. Patients and methods: We retrospectively reviewed the ALC of 413 patients with newly diagnosed DLBCL treated with R-CHOP at our hospital between January 2005 and March 2013. Primary central nervous system lymphoma patients were excluded from this study. ALC was determined in all patients from complete blood count with differential white blood count at the time of diagnosis, and prior to therapy administration. EFS and OS were estimated according to the Kaplan-Meier method. Multivariate analysis was performed with the proportional hazard Cox model. Results: The median ALC was 1.2x10E9/L (range, 0.06-9.0). We set an ALC cut-point at 1.0x10E9/L based on previous studies. The median follow-up duration was 40 months. Baseline characteristics according to ALC ( 〈 1.0x10E9/L[n=145] and 〉 1.0x10E9/L[n=268]) are summarized in Table1. Patients with ALC 〈 1.0x10E9/L had a significantly poorer EFS and OS than patients with ALC 〉 1.0x10E9/L (5-year EFS, 37.0% versus 68.9%, p 〈 0.001; 5-year OS, 46.3% versus 80.0%, p 〈 0.001). On multivariate analysis performed with factors included in IPI and NCCN-IPI, ALC remained an independent predictor of EFS (IPI: hazard ratio [HR] 1.95; 95% confidence interval [CI] 1.43-2.68; p 〈 0.001, NCCN-IPI: HR 1.94; 95%CI 1.42-2.65; p 〈 0.001) and OS (IPI: HR 2.35; 95%CI 1.61-3.42; p 〈 0.001, NCCN-IPI: HR 2.29; 95%CI 1.57-3.33; p 〈 0.001) (Table2). Importantly, within the poor R-IPI group, ALC distinguished patients with different 5-year EFS (24.4% versus 50.4%, p 〈 0.001) and OS (35.7% versus 65.7%, p 〈 0.001). For the high NCCN-IPI group also, ALC distinguished patients with different 5-year EFS (14.8% versus 39.8%, p 〈 0.01) and OS (17.5% versus 54.5%, p 〈 0.001) (Figure1). Conclusions: According to our results, ALC 〈 1.0x10E9/L is an adverse prognostic factor and independent of IPI and NCCN-IPI. ALC might be more successful in identifying high-risk patients in which IPI and NCCN-IPI analysis was unrevealing. Our results suggest that other therapeutic strategies may be more effective in high-risk patients with DLBCL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1654-1654
    Abstract: Background: A consensus is yet to be reached on therole of interim fluorine-18 fluorodeoxyglucose (18F-FDG) position emission tomography-computed tomography (PET-CT) for prognosis in diffuse large B-cell lymphoma (DLBCL), but it has been recently reported that maximum standardized uptake value (SUV max) reduction between baseline and midtherapy may be a better predictor of overall survival (OS) and event free survival (EFS). Patients and Method: 456 patients were newly diagnosed with DLBCL in our institute between February 2007 and January 2013. Primary central nervous system lymphoma or primary effusion lymphoma patients were excluded from this study. All patients who were not perfomed PET were also excluded. In order to determine the predictive value of interim PET-CT and SUV max reduction criteria on OS and EFS for patients with DLBCL, we retrospectively analyzed the PET-CT and SUV max data of 104 first-line DLBCL patients treated with 6 to 8 courses of R-CHOP or R-THPCOP therapy. PET-CT was performed at diagnosis (baseline), and after 2 to 4 courses (interim PET). Interim PET was scheduled two weeks after the second to fourth cycle of immunochemotherapy. A visual analysis of interim PET was done with the use of the Deauville criteria, and an analysis of the SUV max reduction criteria was calculated by [(SUV max reduction from baseline to interim PET)/SUV max at baseline]. For each PET image, the tumor with the most intense 18F-FDG uptake was identified among all foci with the use of a graded color scale. The hottest volumetric region was determined, and the SUV max was calculated. To assess the SUV max, the hottest tumor in any region or organ on interim PET was used for comparison, even if its location differed from the initial hottest tumor in baseline PET. Survival curves were estimated with Kaplan–Meier analysis and compared using the log-rank test. Results: One hundred and four patients were enrolled in this study, and their characteristics are detailed in Table 1. With a median follow-up of 38.5 months, the two-year overall survival and EFS were 83.3% and 73.6%. The results forinterim PET were 66.3% (69/104) negative and 33.7% (35/104) positive, respectively. Interim PET negative versus positive two-year OS was 85.0% (95%CI 0.739-0.917) versus 79.9% (95%CI 0.624-0.899) (P value 0.58), and the two-year EFS was 77.7% (95%CI 0.658-0.860) versus 65.7% (0.476-0.789) (P value 0.24), respectively (Figure 1). The SUV max cutoff values 66% estimated by receiver-operating-characteristic (ROC) analysis to distinguish treatment response were similar to other independent cohort studies at 2 to 4 cycles of induction treatment, and this threshold was chosen to analyze our series. For SUV max data, the two-year OS was 84.4% (95%CI 0.750-0.904) for a SUV max reduction ≥66.0% compared with 75.0% (95%CI 0.408-0.912) for a reduction of 〈 66.0% (P value 0.02). The two-year EFS for the former was 75.7% (95%CI 0.654-0.833) compared with 58.3% (95%CI 0.270-0.801) for the latter (P value 0.03) (Figure 2). Baseline characteristics according to SUV max reduction criteria [SUV max≥66%(n=92),and SUV max 〈 66%(n=12)] are summarized in Table 1. Conclusions: Analysis of the data in our study was unable to demonstrate the predictive value of interim PET for OS and EFS, but SUV max reduction criteria may improve the prognostic value of interim PET. However, the 66% cutoff value must be validated in a larger-scale prospective trial, and further investigation and the standardization of SUV max reduction criteria are needed. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2539-2539
    Abstract: Introduction: Allogeneic hematopoietic cell transplantation (HCT) has curative potential for a variety of hematologic malignancies. However, the success of HCT is heavily dependent on the disease and remission status. Armand et al. recently proposed a disease risk index (DRI) to assess the risk for allogeneic HCT based on the disease and remission status, and could be used to risk stratification on survival (Armand et al Blood 2012), but evaluation of its clinical significance is limited. HCT-comorbidity index (HCT-CI) was developed as a measure of pretransplant organ dysfunctions (Sorror et al Blood 2005), which has been shown to be associated with nonrelapse mortality (NRM). In order to clarify any association between pretransplant factors including DRI and HCT-CI, and respective overall survival (OS), NRM and relapse rate, we retrospectively reviewed the data of patients who underwent allogeneic HCT at our department. Patients and Methods: A total of 305 patients with hematologic malignancies who underwent initial allogeneic HCT at our department between January 2000 and April 2013 were included. After excluding patients with insufficient HCT data, we included a total of 244 patients (138 male, 106 female) with a median age of 49.5 (range 15-69) years. A total of 133 patients received myeloablative conditioning and 111 received reduced-intensity regimens. Stem cell sources were bone marrow (n=177), peripheral blood (n=32), combined peripheral blood and bone marrow (n=1), and cord blood (n=34). A total of 146 patients received tacrolimus-based regimens and 98 patients received cyclosporine-based regimens for GVHD prophylaxis. The DRI has four risk-based categories (low, intermediate, high, and very high) and the HCT-CI has three categories in order of ascending risk (0, 1-2 and ≥3). OS was calculated with the Kaplan-Meier method, compared among groups with the log-rank test, and multivariable Cox regression analyses were used to evaluate factors associated with OS. The cumulative incidence of NRM and relapse were calculated while treating relapse and death without relapse, respectively, as competing events, and competing risk regression analyses were used to evaluate risk factors associated with NRM and relapse. Results: The median follow-up for survivors was 4.7 years (range 0.1-14.2 years). Pretransplant disease risks in the DRI low, intermediate, high, and very high risk groups were 8%, 60%, 25%, and 7%, and 4-year OS in the same groups were 74%, 64%, 35%, and 12%, respectively (Figure 1, p 〈 0.001). Four-year OS among patients with a HCT-CI of 0, 1-2, and ≥3 were 63%, 52%, and 41%, respectively. Multivariable analysis showed a significant association with OS for DRI (high risk hazard ratio [HR] 2.62, p 〈 0.001; very high risk HR 5.26, p 〈 0.001 versus intermediate risk), HCT-CI (HCT-CI ≥3 HR 1.64, p=0.022 versus HCT-CI 0-2), 2-4 performance status (HR 3.10, p 〈 0.001), and donor-recipient ABO minor-mismatch (HR 2.00, p=0.005 versus ABO match). The cumulative incidence of 4-year NRM was 25%, and NRM was significantly associated with HCT-CI (HCT-CI ≥3 HR 2.27, p=0.003 versus HCT-CI 0-2) and 2-4 performance status (HR 3.89, p 〈 0.001). The cumulative incidence of 4-year relapse was 25%, and relapse was significantly associated with DRI (high risk HR 2.26, p=0.012; very high risk HR 8.11, p 〈 0.001 versus intermediate risk). Finally, we reclassified all patients into four risk groups incorporating DRI and HCT-CI: DRI low-intermediate plus HCT-CI 0-2 (group I), DRI low-intermediate plus HCT-CI ≥3, or DRI high plus HCT-CI 0-2 (group II), DRI high plus HCT-CI ≥3 (group III), and DRI very high (group IV). Four-year OS among patients with group I, II, III, and IV were 68%, 47%, 25%, and 12%, respectively (Figure 2, p 〈 0.001). Conclusions: Our results suggest that risk stratification with DRI and HCT-CI for the prognosis of relapse and NRM may be useful for patients undergoing allogeneic HCT. Larger and prospective studies are warranted to more precisely validate these findings. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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