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  • Lee, Jong-Wook  (4)
  • Min, Chang-Ki  (4)
  • Park, Silvia  (4)
  • 2015-2019  (4)
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  • 2015-2019  (4)
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  • 1
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 2759-2759
    Abstract: Background Overexpression of WT1 is a surrogate marker of abnormal myelopoiesis and has been evaluated as a potential tool to assess measurable residual disease (MRD) in myeloid malignancies. Given that lack of consensus on clinically relevant WT1 thresholds and time points in the allogeneic hematopoietic cells transplantation (allo-HSCT) setting, WT1 quantification has not yet gained widespread use despite several pieces of evidence demonstrating the possible role for MRD assessment with the limited numbers of patients. To investigate optimal threshold, time points, and candidates of WT1 quantification in AML, we retrospectively analyzed a large cohort of consecutive patients who underwent allo-HSCT at Catholic Hematology Hospital. Patients and methods This study included 425 consecutive patients with AML who underwent allo-HSCT at CR state from either a matched siblings (n=199), matched unrelated (n=117) or haploidentical family donors (n=109) from 2012 to 2016. Patients were in the first (n=400) or second (n=25) complete remission with a median age of 48 years (range, 18~70). Favorable, intermediate, poor risk groups by 2017 NCCN criteria were 28% (n=120), 49% (n=206), and 23% (n=99), respectively. Bone marrow WT1 levels before, and at 1 or 3 months after allo-HSCT were determined using real-time PCR using the ELN normalized method. We sought to clarify the prognostic relevance of the WT1 quantification regarding the cumulative incidence of relapse (CIR) and survival outcomes. Results With a median follow-up of 39 months (range, two days to 73 months), the 4-year overall survival, disease-free survival, CIR and non-relapse mortality were 63.6%±2.6%, 61.5%±2.6%, 17.9%±2.1% and 24.7%±2.5%, respectively. Analysis of dynamic changes of WT1 levels demonstrated decreased levels at 1 (n=333, mean 86 copies, range 0~1800) and three months (n=346, mean 101 copies, range 0~1670) after allo-HSCT compared to before allo-HSCT (n=425, mean 219 copies, range 0~9630). Relapsed patients had significantly higher WT1 levels before (P=0.018) and at three months (P=0.041) after allo-HSCT, whereas no difference at one month after allo-HSCT (P=0.167). Even the ROC curve analysis revealed that WT1 levels before allo-HSCT were significantly available to predict CIR after allo-HSCT (P 〈 0.001). Among various cut-off levels of WT1 expression (median, 25% from the top, and cut off by ELN), cutoff by ELN (250 copies) was most effective for predicting CIR. The CIR of MRD positive patients (³ 250 copies) before and at three months after allo-HSCT were 43% (vs. 14%, P 〈 0.001) and 35% (vs. 11%, P 〈 0.001), respectively. In multivariate analysis, the WT1-MRD positivity independently predicted the CIR (before, HR=3.5, P 〈 0.001; at three months, HR=7.4, P 〈 0.001), which translated into inferior disease-free survival (P 〈 0.001) and overall survival (P 〈 0.001). In a subgroup analysis with the WT1-MRD positive patients before allo-HSCT (n=44), the WT1-MRD positivity at three months was significantly effective to identify patients with a higher risk for relapse (100% vs. 26%, P 〈 0.001). In subgroup analyses in each risk group by 2017 NCCN criteria, the WT1-MRD positivity before allo-HSCT was significantly effective to predict CIR in the intermediate risk group (57% vs. 12%, P 〈 0.001), whereas no significance in both favorable and poor risk groups. On the other hand, the WT1-MRD positivity at three months after allo-HSCT was effective to predict CIR in the poor risk group (60% vs. 21%, P 〈 0.001). In patients with normal karyotype without NPM1 mutations (n=117), the WT1-MRD positivity before allo-HSCT significantly predict CIR (32% vs. 8%, P=0.001), whereas no difference in patients with NPM1 mutations (n=66) or core-binding factor (CBF) AML (n=102). Conclusions These data suggest standardized bone marrow WT1 levels using the ELN threshold (250 copies) before and at three months after allo-HSCT provided relevant information to predict relapse in AML with intermediate and poor risk groups by 2017 NCCN criteria, respectively. The validated WT1 MRD assay by ELN was revealed to be particularly available in AML without specific MRD markers, such as NPM1 or CBF-AML, and different significance by times points should be considered for clinical applications to identify high-risk AML for relapse, potential candidates for various immunomodulatory approaches. Disclosures Kim: Pfizer: Research Funding; Ilyang: Research Funding; BMS: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 3
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 4
    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
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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