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  • 1
    In: Leukemia Research, Elsevier BV, Vol. 36, No. 7 ( 2012-07), p. e146-e148
    Type of Medium: Online Resource
    ISSN: 0145-2126
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2012
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  • 2
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2076-2076
    Abstract: Background Cytomegalovirus (CMV) establishes lifelong latency after primary infection under the control of the immune system because of the numerous virus evasion strategies that interfere with the host immune response at many levels. Human leukocyte antigen (HLA)-restricted cytotoxic T lymphocytes (CTLs) are involved in the early immune response and are an important defense mechanism in CMV infections, reactivation, and related diseases. Furthermore, an assessment of the clonal diversity of T cell responses against CMV infection provides important insight into the molecular basis of T cell immunodominance. In this single-center study, we tried to demonstrate a specific correlation between the donor HLA genotype and cumulative incidence of CMV reactivation and disease. Patients and methods We retrospectively analyzed 613 donors and recipients diagnosed with acute myeloid leukemia (AML) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched siblings (n=260), matched unrelated donors (n=167), or haploidentical family donors (n=186) from 2012 to 2017. The CMV-related disease was diagnosed with aggressive procedures in suspicious tissues such as the eyes, gastrointestinal tract, or respiratory tract. The cumulative incidence of overall CMV-related diseases was 12.3% (n=71; range, 9.8 - 15.2), and in each matched sibling, matched unrelated, and haploidentical family donor allo-HSCT group were 6.1% (range, 3.6-9.6), 14.4% (9.2-20.7), and 19.4% (14.0-25.5), respectively. Except for seven patients, all 64 patients developed CMV disease in the CMV reactivation state. We determined the genotypes of the HLA-A, B, C, and DRB1 alleles in 613 donors and recipients by sequencing method and further selected 560 (91.4%) CMV IgG seropositive donors to identify the genetic influence of donor HLA according to CMV infection. Results We first analyzed the relationship between entire donor HLA allotypes and the cumulative incidence of CMV-related disease, then subdivided the donor groups by CMV IgG seropositivity. In the CMV IgG seropositive donor group, we conducted subgroup analysis to identify any difference in CMV-related disease incidence according to types of allo-HSCT. As a result, an entire donor CMV serostatus, three genotype alleles, HLA A*3004 (OR 2.8; p-value 0.044), B*5101 (OR 2.3; p-value 0.003), and DRB1*0901 (OR 2.3; p-value 0.004), demonstrated a statistically significant odds ratio (OR) value with the proper number of patients. However, in the donor CMV IgG seropositive subgroup, two allotypes, HLA B*5101 (OR 2.0; p-value 0.003) and DRB1*0901 (OR 2.7; p-value 0.002), remained. Interestingly, the HLA DRB1*0901 allele showed a concrete association (OR 6.0; p-value 〈 0.001, and p(c)-value 0.002) between CMV IgG seropositive donor HLA and the CMV-related disease incidence of the recipient, especially in the haploidentical allo-HSCT setting. The HLA-B*5101 allele showed a statistically significant association in the IgG seropositive donor subgroup with the matched unrelated allo-HSCT recipient and in the IgG seronegative donor subgroup. HLA-DRB1*1302 showed a promising value as the protective marker (OR 0.2; p-value 0.041) only in the IgG seropositive donor subgroup with the matched unrelated allo-HSCT recipient category. HLA-A*2402 (OR 3.6; p-value 0.048) was only significant in the IgG seropositive donor subgroup with the matched sibling and haploidentical allo-HSCT recipient category. HLA-DR*1501 (OR 2.6; p-value 0.039) was only significant in the IgG seropositive donor subgroup with the matched sibling allo-HSCT recipient category. Conclusion This study demonstrated that certain donor alleles, donor CMV IgG serostatus, and types of allo-HSCT, especially the seropositive donor HLA-DR*0901 allele in the haploidentical allo-HSCT setting, significantly correlated with high CMV-related disease incidence and might be considered risk markers for suitable donor selection. Additionally, the specific donor HLA allele showed either protective or aggravated CMV-related disease incidence in a different allo-HSCT setting. For patients receiving various types of allo-HSCT, a strategic approach to donor selection with careful consideration of donor HLA allotype is important and intensive CMV reactivation monitoring may be required, especially in acute GVHD under active steroid pulse treatment. Disclosures Kim: BMS: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ilyang: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 3
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3430-3430
    Abstract: Abstract 3430 Background: Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with aplastic anemia (AA) unsuitable for hematopoietic stem cell transplantation. The standard ATG preparation in AA had been horse ATG because of the larger experience and the results already reported with this preparation. Due to the unavailability of the horse ATG since 2006, rabbit ATG became the only available ATG preparation in Korea. But, there are only limited data about the therapeutic efficacy of rabbit ATG as first-line IST in AA. Method: We retrospectively investigated the outcome of 58 evaluable patients among 62 patients with AA treated with IST using rabbit ATG as front line between March 2006 and April 2010 at our institution. 70.7% of enrolled patients were very severe (n=18) or severe AA (n=23). All patients received rabbit ATG (Thymoglobulin®, 2.5mg/kg per day for 5 days) with methylprednisolone and cyclosporine A. Response rate (RR) was assessed at 3, 6, 9, 12 and 18 months after IST. Results: After IST, overall RR was 27.8%, 50.8%, 52.8%, 52.8% and 56.7% after 3, 6, 9, 12 and 18 months, respectively. Complete response (CR) rates were 0.8%, 1.8%, 5.6%, 9.6% and 21.2% after 3, 6, 9, 12 and 18 months, respectively. Median time to achieve partial response (PR) and CR were 93 (range; 12∼977 days) and 381 (range; 12–614) days. Among 31 responders, 10 patients (32.3%) relapsed. Median time between response and relapse were 396 days (range; 254∼681 days). Estimated overall survival and failure free survival at 3 years from ATG treatment were 85.8% and 42.8%, respectively. Age ( 〉 45) at the use of ATG was an independent predictor of overall survival and overall response (p=0.033 and 0.027) in univariate analysis. Other factors such as disease severity, pre-ATG hematological parameters (absolute lymphocyte count and absolute reticulocyte count) were not associated with overall survival and failure free survival. Conclusion: These data indicate that rabbit ATG was as effective as horse ATG based on other recently published data. But, the response time of rabbit ATG treatment is longer than that of horse ATG treatment. Especially, more than half of patients who achieved CR required time over 1 year after ATG treatment. Rabbit ATG can be effective IST regimen comparable to horse ATG, but it takes longer time to achieve sufficient response. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 4
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4395-4395
    Abstract: Background: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder. Immunosuppressive therapy or allogeneic stem cell transplantation (SCT) are recommended depending on severity of the disease, patient's age and availability of donor. In addition, many patients require blood transfusions as supportive management, which lead to the development of iron overload. Previous studies have shown a negative impact of pretransplant iron overload on overall survival (OS), mortality, and infection in patients undergoing allogeneic stem cell transplantation (SCT). Although the use of oral iron-chelating agent, deferasirox, has been increased, the impact of pretransplant iron chelating therapy (ICT) on the transplant outcomes in patients with SAA was uncertain. Methods: This study included 109 iron overloaded patients with SAA who underwent allogeneic SCT between March 2002 and December 2012. All patients had available pretransplant serum ferritin data. Among them, 50 patients were received pretransplant ICT with deferasorox, when their serum ferritin was more than 1000 ¥ìg/L, whereas 59 patients had more than 1000 ¥ìg/L of serum ferritin but did not received ICT (era before availability of deferasirox). Results: Fifty-five men and 54 women were assessed. Their median age was 34 years (range, 15-59 years). The patients received grafts from either a HLA identical sibling (N=55) or an unrelated donor (N=54). Primary engraftment was achieved in all, but 5 patients developed secondary graft failure. After a median follow-up of 38.3 (range, 6.1-124.9) months for survivors, there was not statistical difference of overall survival (OS) between the patients with ICT and those without ICT (82.3% vs 89.9%, P=0.455). Of note, the possible survival benefit of pretransplant ICT was observed in unrelated transplant setting (93.5% vs. 78.3%, P=0.090). Pretransplant ICT group showed a lower infection rate after SCT compared to those without ICT (34% vs. 59%, P=0.008). For 50 patients receiving pretransplant ICT with deferasirox, median serum ferritin levels decreased from 1995 ¥ìg/L at the initiation of ICT to 1240 ¥ìg/L before SCT. Median duration of ICT before SCT was 3.6 months (range, 0.3-44.2 months), and mean daily dose was 14.8 mg/kg per day. The patients who achieved more than 650 ¥ìg/L decrement of serum ferritin levels from ICT initiation to SCT had a higher OS than the patients with less than 650 ¥ìg/L (96.7% vs. 80.0%, P=0.044). Conclusion: These results indicate that iron overload was associated with a negative impact on outcome after SCT in SAA. Pre-SCT ICT can reduce the incidence of infection after SCT and the possible survival benefit of Pre-SCT ICT was present especially in unrelated donor SCT. Among the patients receiving pretransplant ICT, significant decrement of serum ferritin is a favorable prognostic factor after allogeneic SCT in iron-overloaded patients with SAA Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 5
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3831-3831
    Abstract: Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 6
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3260-3260
    Abstract: Background Transplantation-associated thrombotic microangiopathy (TA-TMA) is a significant complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may affect 20% of recipients on average. A few groups have proposed risk or prognostic factors for TA-TMA, including a recent prospective study in a cohort that included both children and young adults (Jodele et al. Blood 2014), yet there has been no reproduced or validated data for consensus. Furthermore, with rapid advances in transplantation technology such as an increased variety of donors, conditioning regimens, and graft-versus-host disease (GVHD) prophylaxis, currently used diagnostic criteria and risk factors for TA-TMA must be re-evaluated using recent large cohorts. Patients and method The purpose of this study is to investigate risk and prognostic factors for TA-TMA in adult patients with acute myeloid leukemia (AML). TA-TMA was primarily diagnosed with previously published diagnostic criteria proposed by our group (Cho et al. Transplantation 2010). Then, we analyzed TA-TMA incidence, risk, and prognostic factors in two independent cohorts for training (n = 382, 2012-2015, retrospective) and validation (n = 231, 2016-2017, prospective). In particular, predictive factors for TA-TMA in a prospective cohort, including children and young adults as recently suggested by Jodele et al., were evaluated in our adult AML patients. Results In the entire cohort (n = 613), the median TA-TMA onset was 66 (range, 5-511) days from allo-HSCT. Among TA-TMA patients, 33.6% and 32.6% of them suffered from proteinuria and AKI, respectively. Also, 33.2% suffered from preceding or concurrent hemorrhagic cystitis (any grade), and 12.7% suffered from VOD/SOS at the time of TA-TMA diagnosis. Regarding the treatment of TA-TMA, 87.3% of patients discontinued or reduced the calcineurin inhibitor with supportive care, while 12.7%, 5.6%, and 4.2% were treated with total plasma exchange, t-PA, and defibrotide addition to calcineurin inhibitor dose modification, respectively. Thirty percent of patients achieved complete remission, and TA-TMA was related to poor three-year OS. There were no significant clinical characteristic differences between the training and validation cohorts with the exception of more haploidentical allo-HSCT in the validation cohort (training vs. validation; 26.7% vs. 36.4%, p = 0.012), and the cumulative incidence of TA-TMA was significantly (p 〈 0.001) higher among the validation cohort (18.8%) than the training cohort (8.9%). For the risk factors of TA-TMA, univariate and multivariate analyses revealed that LDH 〉 1.5 x upper normal limit (training p = 0.042 and validation p = 0.0042), proteinuria ≥30 mg/dL (training p = 0.0019 and validation p = 0.0012), and ≥Grade I hemorrhagic cystitis (training p = 0.0460 and validation p = 0.0049) were significantly associated with an increased risk of TA-TMA in both the training and validation cohorts. Among patients with TA-TMA, concurrent hemorrhagic cystitis upon diagnosis of TA-TMA was a significant factor for inferior overall survival in the entire cohort (32.3% vs. 5.9%, p = 0.031). Conclusions This study validates the feasibility of diagnostic criteria for TA-TMA proposed by our group with a recent large cohort consisting of training and validation cohorts and points out the role of preceding hemorrhagic cystitis as a risk and prognostic factor for TA-TMA in AML. Of note, proteinuria and elevated LDH prior to the appearance of MAHA proposed by Jodele et al. with a younger population were proven to be useful for predicting the occurrence of TA-TMA among adult populations with AML. Disclosures Kim: Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding. Kim:BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding; Novartis: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 7
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1393-1393
    Abstract: Abstract 1393 Background: Numerous molecular prognostic markers, in addition to specific chromosomal aberrations, have been identified to confer disease pathogenesis and survival outcomes in patients with adult acute myeloid leukemia (AML). Many efforts have been made to identify genetic mutations (e.g., c-kit, FLT3-ITD/TKD, NPM1, WT1, MLL-PTD) and modulated gene expression levels (e.g., BAALC and WT1) that can be used to predict outcomes in patients with cytogenetically normal AML (CN-AML). However, few data associated with core-binding factor AML (CBF-AML) and BAALC or WT1 expressions have been reported, and a consecutive analysis of BAALC and WT1 from diagnosis to hematopoietic stem cell transplantation (HSCT) has not yet been reported. We analyzed serial BAALC and WT1 data in patients with CN-AML and CBF-AML using the real-time quantitative polymerase chain reaction method. Methods: In this single center retrospective study, 1008 newly diagnosed patients with AML (age, 15–85 years; median 45.2 years) with variable karyotypes were initially enrolled from January 2005 to December 2010. Ultimately, we analyzed 335 patients with CN-AML and 156 with CBF-AML. Patients that underwent conservative treatment were excluded. Among 491 patients, we identified FLT3-ITD results in 316 patients (positive in 56 and negative in 260) and NPM1 results in 202 patients (positive in 50 for CN-AML only), and obtained BAALC and WT1 results at the initial diagnosis in 177 patients (126 in CN-AML and 51 in CBF-AML) since we started these laboratory examinations in 2008. In 126 of the patients with CN-AML, 68 underwent HSCT and 58 were treated with chemotherapy alone. In the CBF-AML group, 42 were treated with HSCT and 9 were treated with chemotherapy alone. We analyzed BAALC and WT1 serial data at the initial diagnosis, after the first cycle of induction chemotherapy, and before and after HSCT. An additional analysis included the decreased ratio in the logarithm between diagnosis, pre-HSCT, or post-HSCT. Overall survival (OS) and relapse free survival (RFS) were associated with BAALC and WT1 expression levels along with the treatment timeline, and concomitantly with FLT3, NPM1, and c-kit mutations. Survival and other clinical correlates and prognostic relevance of mutations in patients with CN-AML and CBF-AML were evaluated using the log-rank test, Cox proportional hazard model, and chi-square analyses. Results: In both the CN- and CBF-AML groups, BAALC and WT1 levels at the initial diagnosis had no definite influence on OS when patients were treated with HSCT. In patients with CN-AML, only the chemotherapy-treated group with higher BAALC expression at diagnosis showed poor remission status (p = 0.008) and inferior OS (p = 0.013). Higher BAALC expression at diagnosis resulted in inferior OS in patients with CN-AML and the NPM1 (n = 7 vs. 38, p = 0.002) and FLT3-ITD mutations (n = 14 vs. 19, p = 0.052) in each group, as well as those with both mutations (n = 4 vs. 15, p = 0.000). In contrast, higher WT1 expression at diagnosis resulted in inferior OS in patients with CN-AML without the NPM1 (n = 91, p = 0.022) and FLT3-ITD (n = 92, p = 0.012) mutations in each group, as well as without both mutations (n = 69, p = 0.092). Higher pre-HSCT WT1 expression also resulted in inferior OS (p = 0.002) and RFS (p = 0.015) after HSCT in patients with CN-AML. Pre-HSCT BAALC expression levels and the decrease in the BAALC ratio before HSCT was not significant, but the decrease in the WT1 ratio over 1 logarithm prior to HSCT resulted in superior OS (p = 0.001) and RFS (p = 0.002) in patients with CN-AML. In patients with CBF-AML, the c-kit mutation-positive group showed inferior OS (p = 0.044), and their mean BAALC expression level was exclusively higher than that of other karyotypes (73.4 vs. 19.8, p = 0.000). However, only higher BAALC expression levels at diagnosis were associated with an increased relapse rate and shortened RFS after HSCT (p = 0.023) in our cohort. Other BAALC and WT1 expression level parameters were not significant in patients with CBF-AML. Conclusion: The higher pre-HSCT WT1 expression and a decreased WT1 ratio before HSCT in patients with CN-AML, and higher BAALC expression at diagnosis in patients with CBF-AML resulted in significant changes in OS and RFS after HSCT. Therefore, the impact of combined molecular marker analysis on outcomes of allogeneic HSCT for AML should be considered intensively in order to produce a more defined HSCT plan. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 8
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4398-4398
    Abstract: Background:Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder of hematopoietic stem cells characterized by a somatic mutation in the PIG-A gene, encoding the glycosyl phosphatidylinositol (GPI) moiety. PNH clones lack GPI-anchored proteins (GPI-AP) which inhibit the activation and cytolytic functions of complement. Recently, Eculizumab, humanized monoclonal antibody directed against complement component C5, has used increasingly for the patients with hemolytic PNH. However, the patients with PNH clone and bone marrow failure syndrome (i.e. aplastic anemia) should be treated as their predominant clinical manifestation. Allogeneic stem cell transplantation (SCT) can be curative treatment option especially for PNH patients with combined aplastic anemia (AA). The aim of the present study was to evaluate long-term outcome of allogeneic SCT in patients with AA/PNH. Methods: Total of 27 patients with PNH clones underwent allogeneic SCT at our institution between Jan 1998 and Mar 2014. Among them, seven patients had classic PNH and 20 patients with cytopenia had AA/PNH (with bone marrow evidence of a concomitant AA). We analyzed long-term transplant outcomes in 20 patients with AA/PNH. Results: There were 12 male and 8 female patients with a median age of 34 years (range, 13-51 years). The median interval from the diagnosis to transplantation was 8 months (range; 1-201 months). The median transfusions prior to SCT were 33 units (range; 8-208 units). Pre-transplant GPI-AP deficient neutrophils and erythrocytes were 46% (0-99) and 15.6% (0-88), respectively. Median white blood cell, absolute neutrophil count, hemoglobin, and platelet at transplant were 2.3×109/L, 0.7×109/L, 7.9 g/dL, and 21×109/L, respectively. Median LDH level was 714 U/L (range; 273-6499 U/L) and 11 (55%) patients had LDH ≥1.5x upper normal limit. PNH patients with SAA (n=14), VSAA (n=4), or non-SAA (n=2) received SCT from sibling (s) donor (n=15) or unrelated (u) donor (n=5). The conditioning regimen for s-SCT consisted of fludarabine (180 mg/m2) + cyclophosphamide (CY, 100 mg/kg) + ATG (10 mg/kg) (n=11), or busulfex (12.8 mg/kg) + CY (120mg/kg) (n=4). The conditioning regimen for u-SCT was TBI (fractionated, 800 cGy) + CY (100-120 mg/kg) ± ATG (2.5 mg/kg). GVHD prophylaxis consisted of CsA + MTX in s-SCT and FK506 + mini-MTX in u-SCT, respectively. After a median follow-up of 57 months (range 4.7-122.1), the 5-year estimated OS rates were 90.0 ± 6.7%. Two patients died of treatment-related mortality (TRM), including acute GVHD (n=1) and cerebral hemorrhage (n=1), respectively. Except one patient with early TRM, 19 patients engrafted with no secondary graft-failure. The cumulative incidence of acute GVHD (≥grade II) and chronic GVHD was 25.0 ± 1.0% and 26.3 ± 10.4%, respectively. PNH clones disappeared at median 1.8 months (range 0.9-11.9) after SCT and reemerging of PNH clone was not observed in all patients. Conclusion: This study showed that long-term transplant outcome in patients with AA/PNH were comparable to that of allogeneic SCT in SAA (the 3-year estimated OS rates were 92.7 and 89 % for s-SCT and u-SCT, respectively) at our institution (ASH Annual Meeting Abstracts 2012;120:4151). Therefore, application of allogeneic SCT should be considered in PNH patients with AA in case of availability of well matched donor. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 9
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 492-492
    Abstract: Abstract 492 Diagnosis and therapeutic decision of gastrointestinal (GI)-graft-versus-host disease (GVHD) mainly rely upon clinical symptoms and exclusion of other causes of GI dysfunction. Particularly, the presence of CMV-GI-disease should be examined with immunostaining of biopsy. However, there have been few reports about the occurrence of CMV-GI-disease in patients with GI-GVHD in the era of preemptive therapy for CMV infection with real-time quantitative polymerase chain reaction (RQ-PCR) and its related outcomes. Between January 2008 to December 2010, 392 adult patients with AML, ALL, MDS, and CML underwent allogeneic stem cell transplantation (SCT) and all had serial monitoring for CMV DNA based on RQ-PCR followed by initiation of preemptive therapy. Ninety-seven percent of recipients and 84% of donors were CMV-seropositive before SCT. Clinical GI-GVHD based on symptoms, stool studies, and endoscopic findings developed in 114 patients (29%) and they were treated by high-dose systemic steroid. Of these patients, 103 patients performed endoscopic biopsies not only at the time of onset of clinical symptoms but also during the clinical course of GI-GVHD in the absence of response to steroid, and all samples from biopsies were immunohistochemically stained. The median age of the 103 patients was 40 years (range, 15–70). These patients consisted of AML (n=59), ALL (n=29), MDS (n=12), and CML (n=3) transplanted from sibling (n=45), unrelated (n=48), familial-mismatched donors (n=8), and umbilical cord donors (n=2). Conditioning regimens consisted of myeloablative (76%) and reduced-intensity regimens (24%). Anti-thymocyte globulin was given as a part of conditioning in 41 patients (40%). GVHD prophylaxis was based on administering calcineurin inhibitor with short-course methotrexate. GI-GVHD was developed as a manifestation of not only acute GVHD (aGVHD, 87%) but also overlap syndrome (13%). Isolated GI-GVHD was 30%. Eighty-nine patients (86%) initially presented with GI-GVHD, whereas 14 patients (14%) developed GI-GVHD after the treatment of GVHD of other organs. Of the 103 patients, 60 (58%) had histologic findings for GI-GVHD (lower gut, n=41, 40%; lower gut + upper gut, n=10, 10%; upper gut, n=9, 8%) and 26 (25%) had positive immunohistochemical stain for CMV-GI-disease (lower gut, n=13, 13%; lower gut + upper gut, n=4, 4%; upper gut, n=9, 8%). The CMV-GI-disease developed at a median time of 56 days after SCT (range, 20–403). Multivariate analyses revealed that older age over 30 years (RR 4.42, 95%CI 1.10–17.84), HLA-mismatched donors (RR 3.41, 95%CI 1.21–9.60), and higher grade of GVHD (grade III+IV aGVHD or severe cGVHD, RR 3.24, 95% CI 1.22–8.60) were significant risk factors for CMV-GI-disease. Most patients (73%) developed CMV-GI-disease after the treatment of GI-GVHD or other organs of GVHD, whereas CMV-GI-disease developed concurrently with GI-GVHD in other 27%. After the anti-viral therapy with ganciclovir or foscarnet, 14 patients (54%) showed complete resolution of CMV-GI-disease, while 12 patients (46%) failed to show any response. There were 4 patterns of development of pathologically proven GI-GVHD and CMV-GI-disease (Figure). GVHD-specific survival of patients with CMV-GI-disease was significantly lower than patients without CMV-GI-disease (36.2% vs. 79.3%, P = 0.002). Patients with both GI-GVHD and CMV-GI-disease (n=18) had significantly inferior GVHD-specific survival than other 3 patterns of development of GI-GVHD and CMV-GI-disease (24.5% vs. 78.2%, P = 0.001). Our data demonstrate 25 percent of patients with clinical GI-GVHD developed CMV-GI-disease during the treatment or at the time of diagnosis of GI-GVHD even in the era of preemptive therapy for CMV disease based on RQ-PCR, especially in older patients, HAL-mismatched transplants, and higher grade of GVHD. Patients with CMV-GI-disease, especially who concurrently had pathologically proven GVHD, had inferior GVHD-specific survival. Thus, we reemphasize the need of endoscopic biopsy with immunohistochemical stain for CMV disease if ever possible at the diagnosis of GI-GVHD as well as in the absence of response to treatment of GVHD, especially in high risk groups, which can facilitate proper selection of treatment. Additionally, novel prophylactic measures such as immunotherapy and drug prophylaxis should be considered in this specific group of patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 10
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3076-3076
    Abstract: Abstract 3076 Introduction: Maintenance therapy with hypomethylating agents (HMA) after HSCT is being suggested as potentially attractive approach to minimize relapse. Many studies reported the antileukemic and immunomodulatory effects of HMA with a favorable toxicity and a potential to expand the number of hematopoietic stem cells. Under the hypothesis that post-transplant maintenance therapy with decitabine (DAC) may reduce relapse rate, we designed a phase I clinical trial to determine the safe dose of DAC by an adaptive method using pharmacokinetic-pharmacodynamic (PK-PD) mixed effect modeling and simulation (M & S). Methods: Patients who received HSCT for higher-risk MDS and MDS/AML were eligible. The conditioning regimen was i.v. busulfan (6.4 or 12.8mg/m2) and fludarabine (150mg/m2). GVHD prophylaxis was cyclosporine or tacrolimus with methotrexate. ATG was administered to all patients. Patients in the disease remission with appropriate recovery of platelet count (PC 〉 30,000/mm3) and absolute neutrophil count (ANC 〉 1,000/mm3) without grade III/IV acute GVHD received DAC on day 42–90 post-transplant. For each subject, a designated dose of DAC was intravenously given for 5 consecutive days and repeated every 4 weeks up to 12 cycles. A cohort consisted of 3 patients where the same daily dose was given and the initial dose for the first cohort was daily 5 mg/m2. A total of 7 PK samples were collected up to 3 hours after the first dose. PC and ANC were monitored weekly as PD markers. After the 1st cycle, the dose for the next cycle was simulated in each patient with mixed-effect M & S using NONMEM, by which an adjusted dose was expected not to cause grade IV hematological toxicity (PC 〉 25,000 or ANC 〉 500) at the simulated lower limit of 50%. This M & S-guided dose calculation was continued until the cycle 4 and the dose at the 4th cycle was maintained fixed thereafter without further dose re-calculation unless evidences alarming dose adjustment occurred. The initial doses of the next cohorts were also determined by the M & S using the PK and PD data of previous cohorts. Results: Twenty one patients were enrolled and DAC was delivered in 13 patients whose median age was 49 years (19–65). All patients received pre-transplant HMA with DAC (n=7) or azacitidine (n=6) for higher-risk MDS. HMA responses at time of HSCT were 1 CR, 5, marrow CR, 3 stable disease, and 4 progressive disease including 3 MDS/AML. Intensive chemotherapy was given 2 MDS/AML and 1 achieved marrow CR. All patients received peripheral blood stem cells from siblings (n=7) or unrelated donors (n=6). Excluding 1 patient whose data was insufficient for PK/PD modeling, a total of 4 cohorts with 12 patients are under this study so far. Among the subjects, 5 found the maintenance dose for each of them while the others are still in the adjustment steps. ANC showed more sensitive decrease by DAC than PC and the criteria of ANC 〉 500 was the dose-limiting factor in most patients. At the individual level, the predictive performance of our PK-PD model was satisfactory. When the doses were given without M & S individualization (all of the first cycles and arbitrarily-escalated cases at the 2nd cycle), grade IV hematological toxicity occurred 6 times compared to those with M & S-guided dose determination 40% vs. 6.7%). The initial dose was changed from 5 mg/m2/day to 4 (cohort 2), 5 (cohort 3) and 5.5 (cohort 4) as guided by the population PK-PD approach. Many patients showed increasing tendencies of both PC and ANC possibly due to the improvement of graft function; therefore, the dose required to achieve the target nadir was escalated by cycle. DAC-associated nonhematological toxicities were minimal and there was no increase in transplant-related toxicities including GVHD. Conclusion: Judging from the number of toxicity events and study progress, the PK-PD M & S approach might be a better choice to ensure safety in each individual and to adjust dose between cohorts compared to fixed-dose design such as modified Fibonacci method. However, our model has a limitation that the improvement of graft function was not taken into consideration due to the sparseness of individual data. It will be implemented in our final analysis using all the data from this study to recommend optimal maintenance dose. Currently, the optimal initial dose, 5 mg/m2/day, could be estimated by M & S approach when only the 1st cycle data of all the participants were used. Disclosures: Off Label Use: Maintenance therapy with decitabine after hematopoietic stem cell transplantation. Kim:Jassen: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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