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  • American Society of Hematology  (3)
  • Arai, Yasuyuki  (3)
  • 1
    In: Blood Advances, American Society of Hematology, Vol. 4, No. 13 ( 2020-07-14), p. 3169-3179
    Kurzfassung: Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, so far, no large cohort study determined the risk factors and the most effective therapeutic strategies for TA-TMA. Thus, the present study aimed to clarify these clinical aspects based on a large multicenter cohort. This retrospective cohort study was performed by the Kyoto Stem Cell Transplantation Group (KSCTG). A total of 2425 patients were enrolled from 14 institutions. All patients were aged ≥16 years, presented with hematological diseases, and received allo-HSCT after the year 2000. TA-TMA was observed in 121 patients (5.0%) on day 35 (median) and was clearly correlated with inferior overall survival (OS) (hazard ratio [HR], 4.93). Pre- and post-HSCT statistically significant risk factors identified by multivariate analyses included poorer performance status (HR, 1.69), HLA mismatch (HR, 2.17), acute graft-versus-host disease (aGVHD; grades 3-4) (HR, 4.02), Aspergillus infection (HR, 2.29), and veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS; HR, 4.47). The response rate and OS significantly better with the continuation or careful reduction of calcineurin inhibitors (CNI) than the conventional treatment strategy of switching from CNI to corticosteroids (response rate, 64.7% vs 20.0%). In summary, we identified the risk factors and the most appropriate therapeutic strategies for TA-TMA. The described treatment strategy could improve the outcomes of patients with TA-TMA in the future.
    Materialart: Online-Ressource
    ISSN: 2473-9529 , 2473-9537
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2020
    ZDB Id: 2876449-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4554-4554
    Kurzfassung: [Introduction] Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, given its relatively low incidence, no large cohort-based study has determined TA-TMA risk factors and its impact on overall survival (OS) or the most effective therapeutic interventions. Recombinant human soluble thrombomodulin (rTM) is a promising therapeutic option; with dual antithrombosis and anti-inflammation activities, a single-center small cohort study in Japan reported rTM to be effective against TA-TMA. This study aimed to clarify risk factors for TA-TMA development and the efficacy of various TA-TMA therapies in a multicenter large cohort. [Methods] This retrospective cohort study conducted by the Kyoto Stem Cell Transplantation Group enrolled adult patients (age ≥ 16 years) with hematological diseases who underwent allogenic HSCT after 2000. Cumulative TA-TMA incidence was calculated using Gray's test; death from any cause was a competing risk. We evaluated OS in patients with or without TA-TMA using the Simon-Makuch method and compared it using the Cox proportional hazard model with TA-TMA development as a time-dependent covariate. Correlations were analyzed between each pre- or post-transplant factor and TA-TMA development using Gray's test. Factors significant in the univariate analysis were subjected to the multivariate analysis using the Fine-Gray proportional hazards model. We evaluated the effect of each therapeutics on response using a logistic regression model. [Results] We enrolled 2,430 patients [median age at HSCT, 50 (range: 16-74) years] from 14 institutes. Overall, 1,234 patients were transplanted for acute myeloid leukemia or myelodysplastic syndrome, followed by acute lymphoblastic leukemia (n = 381) and non-Hodgkin lymphoma (n = 351). Overall, 1,219 patients (50.2%) had advanced disease (non-remission status) at HSCT. The HCT-CI score was higher ( ≥3) in 213 patients (8.8%), and 360 (14.8%) were transplanted at poorer performance statuses (PS 2-4). In total, 471 patients (19.4%) received related bone marrow transplantation (BMT), 423 (17.4%) received related peripheral blood stem cell transplantation (PBSCT), 871 (35.8%) unrelated-BMT, and 665 (27.4%) unrelated cord blood transplantation. HLA was mismatched in 1,461 (60.1%) patients. After HSCT, TA-TMA was observed in 123 patients; the cumulative incidence of TA-TMA 12 months after HSCT was 5.0%; TA-TMA occurred at a median of 36 days (range: 3-482) (Figure 1). TA-TMA was correlated with a remarkably inferior OS [hazard ratio (HR), 4.93; 95% confidence interval (CI), 4.03-6.02; P 〈 0.001] when treating TA-TMA as a time-dependent covariate. In the multivariate analysis, poorer PS [HR, 1.64; 95% CI, 1.05-2.58; P = 0.03] , higher HCT-CI [HR, 1.70, 95% CI, 1.02-2.83; P = 0.04], and HLA-mismatch [HR, 2.06; 95% CI, 1.34-3.17; P = 0.001] were significant pre-transplantation risk factors for TA-TMA. Post-transplantation factors (acute GVHD (Grade 3-4) [HR, 2.51; 95% CI, 1.64-3.85; P 〈 0.001] and veno-occlusive disease (VOD/SOS) [HR, 3.70; 95% CI, 2.05-6.70; P 〈 0.001]) were also significant risk factors for TA-TMA in the multivariate analysis. No infections (bacterial, viral, or fungal) were significantly related to TA-TMA incidence. Regarding therapeutic interventions, 36 (29.3%) patients received rTM-including treatment, 6 (5%) were treated with rTM alone, and 30 (24.4%) were treated with rTM and FFP (14; 11%), PE (5; 4%), or both FFP and PE (11; 9%). No significant differences in response rate [OR, 0.99; 95% CI, 0.39-2.52; P = 0.98] and OS [HR, 0.93; 95% CI, 0.58-1.49; P = 0.77] between the groups treated with or without rTM were identified. The results showed similar trends in other therapeutic interventions. [Conclusion] This study clarified the incidence of TA-TMA, its impact on clinical outcomes, risk factors including post-transplantation factors, and therapy efficacies. Patients with poor PS, high HCT-CI scores, and HLA-mismatched donors were high-risk patients; the development of severe acute GVHD and VOD/SOS also increased the risk of TA-TMA. rTM administration or other treatments did not improve patient outcomes. Therefore, strategies to avoid TA-TMA are essential. Intensification of the GVHD and VOD/SOS prophylaxis or treatment for these high-risk patients may reduce TA-TMA and improve HSCT outcomes. Figure 1 Disclosures Imada: Novartis Pharma K.K.: Honoraria; Takeda Pharmaceutical Co.,LTD.: Honoraria; Celgene K.K.: Honoraria; Bristol-Meyer Squibb K.K.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Nippon Shinyaku Co.,Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria. Takaori-Kondo:Kyowa Kirin: Research Funding; Chugai: Research Funding; Takeda: Research Funding; Ono: Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2304-2304
    Kurzfassung: Abstract 2304 Background: Hemorrhagic cystitis (HC) is a major complication after allogeneic hematopoietic stem cell transplantation (SCT), and is life-threatening in severe cases. Early onset HC is usually due to toxic effects of conditioning regimen, while late onset HC is caused by viral or bacterial infection, and GVHD. In order to find out risk factors and to analyze prognosis of late onset HC, we retrospectively reviewed data in our institution from 1996 through 2009. Patients and Methods: We analyzed 232 cases having underwent allogeneic SCT (AML; 65, MDS; 42, ALL; 44, ML; 44, others; 37), excluding 22 patients who received second allogeneic transplantation. The median age at SCT was 47 years old (range, 13–72), and median follow-up of survivors was 1529 days (range, 99–4822) after SCT. One-hundred and eleven patients received from related donor, and 121 from unrelated. Conditioning was myeloablative in 139 cases, and reduced intensity (RIC) in 93. Myeloablative regimen was cyclophosphamide (CY) plus total body irradiation (TBI) in 79 cases, and busulfan (BU) plus CY in 54, while RIC regimen was fludarabine (Flu) plus melphalan (Mel) plus BU in 52, and Flu plus Mel plus TBI in 12. Disease status at SCT was controlled (partial or complete remission) in 164 cases, and progressive in 68. Prophylaxis for acute GVHD consisted of calcineurin inhibitor (cyclosporine; 106 cases, tacrolimus; 126 cases), short term methotrexate (158 cases), and corticosteroid (73 cases). Acute GVHD occurred in 121 cases, 92 of them were grade II-IV, and 74 were treated with corticosteroid. Cytomegalovirus (CMV) antigenemia was positive in 82 cases after engraftment. Definition of late onset HC was microscopic or macroscopic hematuria with urinary symptoms occurring after 7 days from SCT. Urine culture and virological analysis (polymerase chain reaction of CMV, adenovirus [ADV], and BK virus DNA) were carried out in all cases with HC. Treatment was mainly hydration and intravenous hemostat, including intravenous immunoglobulin (IVIg) and antiviral agents. Results: HC was reported in 43 cases on a median of 36 days (range, 7–469) after SCT, and 31 of them (72.1%) recovered after a median of 21 days (range, 2–252). Cumulative incidence of HC after 1 year from SCT was 21.6% (95% confidence interval [CI] 18.3–24.7%). In univariate analysis, risk factors identified included age over 45 years old (p=0.04), progressive disease status at SCT (p=0.04), myeloablative conditioning (p=0.04), acute GVHD grade II-IV treated with corticosteroid (p=0.01), and positivity of CMV antigenemia after SCT (p 〈 0.01). On multivariate analysis, older age (p 〈 0.01, hazard ratio [HR] 2.63), myeloablative conditioning (p 〈 0.01, HR 4.32), and positivity of CMV antigenemia (p 〈 0.01, HR 3.61) remained independent predictors. Each HC case was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1; 12, grade 2; 19, grade 3; 12, grade 4 to 5; none), and we defined moderate as grade 1 or 2, and severe as grade 3 or more. In subgroup analysis of patients with HC, myeloablative conditioning (p=0.11, Odd's ratio [OR] 5.24) and positivity of ADV in urine (p=0.10, OR 3.17) tended to be associated with severe HC. Recovery rate from HC was inferior and median duration from onset to recovery was longer in severe HC (25.0%, 121 days) with significance (p 〈 0.01) compared with moderate HC (90.3%, 17.7 days). Using of IVIg or antiviral agent (vidarabine, gancyclovir, or foscarnet) did not improve recovery rate in both groups. Overall survival (OS) at 1 year after day 35 landmark had no significance between cases with and without HC (59.7%, 56.7%, p=0.70), significantly poor in severe cases (16.7%, p 〈 0.01) compared to cases with moderate HC and cases without HC. Treatment-related mortality (TRM) at 1 year after day 35 landmark was 25.0% with HC and 29.0% without HC (p=0.35), while 59.1% in patients with severe HC (p=0.01). Conclusion: Five significant risk factors of HC such as older age, progressive disease status, myeloablative conditioning, acute GVHD, and CMV antigenemia were found out in this study. OS and TRM of patients with all the grade of HC were equivalent to those without HC, while severe HC significantly elevated TRM and shortened OS. Severity of HC was related to myeloablative regimen and ADV in urine. Any successful attempts to prevent severe HC have not been established yet, and novel prophylactic and pre-emptive strategies are warranted. Disclosures: No relevant conflicts of interest to declare.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2010
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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