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1.
Upregulation of HIF-1α contributes to complement activation in transplantation-associated thrombotic microangiopathy
Qi, J., Pan, T., You, T., Tang, Y., Chu, T., Chen, J., Fan, Y., Hu, S., Yang, F., Ruan, C., et al
British journal of haematology. 2022
Abstract
Transplantation-associated thrombotic microangiopathy (TA-TMA) is a severe complication of haematopoietic stem cell transplantation (HSCT). Complement activation is involved in the development of TA-TMA. However, the underlying mechanism is unclear. Therefore, 21 samples of TA-TMA and 1:1 matched controls were measured for hypoxia-inducible factor-1α (HIF-1α) and complement protein. The mechanism was investigated both in vitro and in vivo. In this study, we found that levels of HIF-1α were significantly higher in TA-TMA patients than that in non-TA-TMA controls. Upregulation of HIF-1α induced an increase in membrane-bound complement C3 and dysfunction of human umbilical vein endothelial cells (HUVECs) in vitro. Increasing HIF-1α in vivo led to C3 and C5b-9 deposition in the glomerular endothelial capillary complex, thrombocytopenia, anaemia, and increased serum lactate dehydrogenase (LDH) levels in wild-type (WT) but not in C3(-/-) mice subjected to HSCT. High platelet aggregation in peripheral blood and CD41-positive microthrombi in the kidney were also found in dimethyloxallyl glycine (DMOG)-treated mice, recapitulating the TA-TMA phenotype seen in patients. Comprehensive analysis, including DNA array, luciferase reporter assay, chromatin immunoprecipitation (ChIP)-seq, and quantitative polymerase chain reaction (PCR), revealed that HIF-1α interacted with the promoter of complement factor H (CFH) to inhibit its transcription. Decreased CFH led to complement activation in endothelial cells.
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2.
Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation
Zhou, M., Qi, J., Gu, C., Wang, H., Zhang, Z., Wu, D., Han, Y.
Therapeutic advances in hematology. 2022;13:20406207221127532
Abstract
BACKGROUND Thrombocytopenia post hematopoietic stem-cell transplantation (HCT) usually contributes to poor outcomes with no standardized treatment. Eltrombopag and romiplostim can be feasible for post-HCT thrombocytopenia, but the use of avatrombopag has not yet been evaluated. OBJECTIVES We aimed to evaluate the efficacy and safety of avatrombopag treatment in patients diagnosed with post-HCT thrombocytopenia. DESIGN In this retrospective study, we evaluated the efficacy and safety of avatrombopag treatment in a cohort of 61 patients diagnosed with thrombocytopenia post HCT in our clinical center. METHODS Avatrombopag was initiated at 20 mg daily, with a dosage adjustment to achieve platelet recovery to >20 × 10(9)/l independent from transfusion for 7 consecutive days (overall response, OR) or to >50 × 10(9)/l free from transfusion for 7 consecutive days (complete response, CR). Factors influencing OR and CR were studied in univariate and multivariate analyses, respectively. Within the follow-up, adverse events like myelofibrosis, thrombosis, and organ toxicities were monitored carefully. RESULTS The overall response rate (ORR) to avatrombopag was 68.9% and the cumulative incidence (CI) of OR was 69.1%. The complete response rate (CRR) and the CI of CR were both 39.3%. The median days from avatrombopag initiation to OR and CR were 21 and 25 days, respectively. An adequate number of megakaryocytes before the initiation of avatrombopag was an independent protective factor of avatrombopag treatment for OR (hazard ratio, HR = 4.628, 95% confidence interval 1.92-11.15, p = 0.0006) and CR (HR = 4.892, 95% confidence interval 1.58-15.18, p = 0.006). Avatrombopag was well tolerated in all patients with no severe adverse events. CONCLUSION Our findings suggested that avatrombopag can be optional for thrombocytopenia post HCT.
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N-acetylcysteine as prophylactic therapy for transplant-associated thrombotic microangiopathy: a randomized, placebo-controlled trial
Pan, T., Qi, J., Tang, Y., Yao, Y., Chen, J., Wang, H., Yang, J., Xu, X., Shi, Q., Liu, Y., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication for patients undergoing hematopoietic stem cell transplantation (HSCT). N-acetylcysteine (NAC) has recently been considered as a potential treatment for patients with thrombotic thrombocytopenic purpura. OBJECTIVES To assess the value of NAC for the prevention of TA-TMA, we conducted a prospective study at the First Affiliated Hospital of Soochow University. STUDY DESIGN This open-label, randomized placebo-controlled trial included 160 patients who were scheduled to receive allogeneic HSCT. Participants were randomly assigned 1:1 to either oral NAC (50 mg/kg daily from 9 days before HSCT to 30 days after HSCT) or placebo treatment. The primary outcome was the incidence of TA-TMA. Overall survival (OS) and event-free survival (EFS) were assessed between NAC and placebo cohorts. RESULTS The incidence of TA-TMA in the NAC cohort was 9.1% (95% confidence interval (CI), 0.02-0.162), compared with 23% (95% CI, 0.132-0.328) in placebo cohort, with a rate ratio of 0.34 (95% CI, 0.123-0.911; p=0.039). The median time to onset of TA-TMA was 60 (interquartile range [IQR] 42-129) and 36 (IQR 30.5-51) days in the NAC and control groups, respectively (p=0.063). The 2-year rates of OS in the NAC and placebo groups were 75.4% (95% CI, 2.865-7.353) and 63.0% (95% CI, 0.508-0.735), respectively, with a hazard ratio (HR) of 0.622 (95% CI, 0.334-1.155; p=0.132). The EFS rate was 25.8% in NAC patients and 8.1% in placebo patients, with an HR of 0.254 (95% CI, 0.094-0.692; p=0.024). The median time of EFS was 60 and 38 days in NAC and placebo cohorts. CONCLUSION Our findings suggest that NAC may be a potential treatment to reduce TA-TMA incidence.
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4.
The Clinical Value of Procalcitonin in the Neutropenic Period After Allogeneic Hematopoietic Stem Cell Transplantation
Shan, M., Shen, D., Song, T., Xu, W., Qiu, H., Chen, S., Han, Y., Tang, X., Miao, M., Sun, A., et al
Frontiers in immunology. 2022;13:843067
Abstract
The diagnostic value of procalcitonin and the prognostic role of PCT clearance remain unclear in neutropenic period after allogeneic hematopoietic stem cell transplantation introduction. This study evaluated 219 febrile neutropenic patients (116, retrospectively; 103, prospectively) who underwent allo-HSCT from April 2014 to March 2016. The area under the receiver operator characteristic curve (AUC) of PCT for detecting documented infection (DI) was 0.637, and that of bloodstream infection (BSI) was 0.811. In multivariate analysis, the inability to decrease PCT by more than 80% within 5-7 days after the onset of fever independently predicted poor 100-day survival following allo-HSCT (P = 0.036). Furthermore, the prognostic nomogram combining PCTc and clinical parameters showed a stable predictive performance, supported by the C-index of 0.808 and AUC of 0.813 in the primary cohort, and C-index of 0.691 and AUC of 0.697 in the validation cohort. This study demonstrated the diagnostic role of PCT in documented and bloodstream infection during the neutropenic period after allo-HSCT. PCTc might serve as a predictive indicator of post-HSCT 100-day mortality. A nomogram based on PCTc and several clinical factors effectively predicted the 100-day survival of febrile patients and may help physicians identify high-risk patients in the post-HSCT neutropenic period.
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5.
Acute graft-versus-host disease increase risk and accuracy in prediction model of transplantation-associated thrombotic microangiopathy in patients with myelodysplastic syndrome
Zhang, Z., Wang, H., Qi, J., Tang, Y., Cai, C., Zhou, M., Pan, T., Wu, D., Han, Y.
Annals of hematology. 2022
Abstract
Allogeneic hematopoietic stem cell transplantation is the only curative therapy for patients with myelodysplastic syndrome. Transplantation-associated thrombotic microangiopathy (TA-TMA) remains a cause of death after transplantation. This study assessed the risk factors of TA-TMA and established a prediction model for this complication. We launched a real-world study from 303 MDS patients after allo-HSCT from Dec 1, 2007, to Jun 1, 2018. Logistic regression was used to analyze risk factors and to establish a nomogram. The accuracy of the model was assessed by C-index and calibration curve. TA-TMA class was associated with an over twofold increase in the risk of death (HR 2.66, 95% CI 1.39-5.09, p = 0.003). Stage III or IV acute graft-versus-host disease (aGVHD) (OR: 6.17, 95% CI: 2.19-17.18, p < 0.001) and occurrence time of aGVHD were the risk factors for TA-TMA. Next, we put these two variants and the other three variants into the prediction model via multivariate Lasso regression. In order to quantify the contribution of each factor, a nomogram was generated and displayed (C index of 0.783). TA-TMA predicts worsened outcomes of overall survival. A cross-validated multivariate score including aGVHD occurrence showed excellent concordance and efficacy of predicting TA-TMA in HSCT patients.
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6.
Low-dose decitabine for refractory prolonged isolated thrombocytopenia after HCT: a randomized multicenter trial
Tang, Y., Chen, J., Liu, Q., Chu, T., Pan, T., Liang, J., He, X. F., Chen, F., Yang, T., Ma, X., et al
Blood advances. 2021;5(5):1250-1258
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Abstract
Refractory prolonged isolated thrombocytopenia (RPIT) is an intractable complication after allogeneic hematopoietic cell transplantation (HCT), which often leads to poor prognosis. A clinical study was designed to validate the efficacy and safety of low-dose decitabine for RPIT after HCT and explore the related underlying mechanisms. Eligible patients were randomly allocated to receive 1 of 3 interventions: arm A, low-dose decitabine (15 mg/m2 daily IV for 3 consecutive days [days 1-3]) plus recombinant human thrombopoietin (300 U/kg daily); arm B, decitabine alone; or arm C, conventional treatment. The primary end point was the response rate of platelet recovery at day 28 after treatment. Secondary end points included megakaryocyte count 28 days after treatment and survival during additional follow-up of 24 weeks. Among the 91 evaluable patients, response rates were 66.7%, 73.3%, and 19.4% for the 3 arms, respectively (P < .001). One-year survival rates in arms A (64.4% ± 9.1%) and B (73.4% ± 8.8%) were similar (P = .662), and both were superior to that in arm C (41.0% ± 9.8%; P = .025). Megakaryocytes, endothelial cells (ECs), and cytokines relating to megakaryocyte migration and EC damage were improved in patients responding to decitabine. This study showed low-dose decitabine improved platelet recovery as well as overall survival in RPIT patients after transplantation. This trial was registered at www.clinicaltrials.gov as #NCT02487563.
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Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party
Bazarbachi, A. H., Al Hamed, R., Labopin, M., Halaburda, K., Labussiere, H., Bernasconi, P., Schroyens, W., Gandemer, V., Schaap, N. P. M., Loschi, M., et al
Bone marrow transplantation. 2020
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR?=?6.6; p?=?0.001 and OR?=?3.3; p?=?0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.
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Efficacy and Safety of Eculizumab in the Treatment of Transplant-Associated Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis
Zhang, R., Zhou, M., Qi, J., Miao, W., Zhang, Z., Wu, D., Han, Y.
Frontiers in immunology. 2020;11:564647
Abstract
BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation (HSCT). Eculizumab has been used in the treatment of TA-TMA, and several studies have confirmed the benefit of Eculizumab in patients with TA-TMA. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Eculizumab for TA-TMA. MATERIALS AND METHODS We searched PubMed and Embase for studies on the efficacy and safety of Eculizumab in TA-TMA patients. Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR). Safety outcomes were adverse events (AEs), including infection, sepsis, impaired liver function, infusion reactions, and death. RESULTS A total of 116 patients from six studies were subjected to meta-analysis. The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71% (95% CI: 58-82%), 32% (95% CI: 11-56%), and 52% (95% CI: 40-65%), respectively. Only one patient presented with a severe rash, and infection was the most common AEs. The main causes of death were infection and GvHD. CONCLUSION Current evidence suggests that Eculizumab improves SR and ORR in patients with TA-TMA and that Eculizumab is well tolerated. However, the number of studies is limited, and the findings are based mainly on data from observational studies. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed.
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Central nervous system complications caused by 3-4 grade aGVHD in adult patients occurred in HLA-mismatched recipients majorly after allogeneic hematopoietic stem cell transplantation
Ke, P., Bao, X., Qiu, H., Zhuang, J., Hu, X., Wu, X., Liu, Y., Wu, D., Xue, S., Zhang, X., et al
Bone marrow transplantation. 2019
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10.
Oral cryotherapy for oral mucositis management in patients receiving allogeneic hematopoietic stem cell transplantation: a prospective randomized study
Lu, Y., Zhu, X., Ma, Q., Wang, J., Jiang, P., Teng, S., Zhou, L., Wu, D., Wang, H.
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2019
Abstract
PURPOSE To explore the best schedule of oral cryotherapy for the prevention of oral mucositis in recipients of myeloablative hematopoietic stem cell transplantation (HSCT). METHODS A prospective randomized study was conducted to recruit allogeneic HSCT recipients, who were then randomly allocated into four arms to accept the following: oral cryotherapy during the whole course (arm A) or second half of the course (arm B) of cytotoxic agents administration, regular oral cryotherapy twice a day (arm C), or conventional oral care without cryotherapy (arm D). Status of oral mucositis was daily assessed from the first day of conditioning to the 15th day post-HSCT. A myeloablative conditioning regimen was used which was composed of busulfan, cyclophosphamide, and cytarabine. RESULTS Totally 160 cases were consecutively enrolled in this study, and 145 cases were eligible for oral mucositis assessment. Both arm A and arm B were associated with a lower incidence and short duration of severe mucositis (≥ grade 3), although no statistical difference was found between these two groups (p = 0.463, p = 0.678). The highest incidence of severe mucositis was observed in arm C. Recovery of mucositis also had a significant diversity among the 4 arms (F = 4.133, p = 0.008). CONCLUSIONS Risk and outcome of severe oral mucositis could be ameliorated by oral cryotherapy during the administration of cytotoxic agents for allogeneic HSCT patients receiving non-radiation myeloablative conditioning regimen, and a half-course schedule could acquire a comparable efficacy compared with the whole-course schedule.