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Yoon SH, Kang SH, Kim H, Choi ES, Im HJ, Koh KN. Incidence, risk factors, and outcomes of transplant-associated thrombotic microangiopathy in pediatric patients after allogeneic hematopoietic cell transplantation: a single-institution prospective study. Bone Marrow Transplant 2025; 60:447-457. [PMID: 39815034 DOI: 10.1038/s41409-024-02506-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 01/18/2025]
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication in hematopoietic cell transplantation (HCT). Given the rarity of prospective pediatric studies on TA-TMA, this study aimed to evaluate the incidence, survival outcomes, and risk factors for predicting early the development of TA-TMA in a pediatric population following allogeneic HCT. We conducted a prospective analysis of 173 pediatric patients to evaluate the incidence, survival outcome, and risk factors of TA-TMA. The cumulative incidence of TA-TMA at one-year post-HCT was 4.7% (95% CI, 2.2-8.6%). Patients with TA-TMA showed significantly poorer 1-year overall survival (OS) rate, 50.0% ± 17.7% compared to 85.4% ± 2.8% in those without TA-TMA (p = 0.008). Additionally, the non-relapse mortality (NRM) rate was higher in the TA-TMA group at 12.5% (95% CI, 3.7-55.8%) versus 7.0% (95% CI, 2.8-10.1%) (p = 0.598). A urine protein/creatinine ratio ≥ 1 mg/mg on day 30 post-HCT was significantly associated with TA-TMA occurrence (adjusted HR, 9.5; [95% CI], 1.28-70.39; p = 0.028). This study showed the significantly unfavorable clinical outcomes associated with TA-TMA in pediatric patients and emphasized the importance of early identification of patients at risk. Further research is needed to explore additional strategies for early detection and intervention to improve outcomes.
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Affiliation(s)
- Su Hyun Yoon
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung Han Kang
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyery Kim
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Choi
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ho Joon Im
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Nam Koh
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Faggioli P, Galeazzi M, Ferrari C, Capelli F, Marchesi C, Marchionni L, Castelnovo L, Tamburello A, Capparelli E, Campidelli C, Mazzone A. Macrophage activation syndrome successfully treated with eculizumab and emapalumab: a case report. Front Immunol 2025; 16:1555415. [PMID: 40196116 PMCID: PMC11973329 DOI: 10.3389/fimmu.2025.1555415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Accepted: 02/20/2025] [Indexed: 04/09/2025] Open
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, often referred to as macrophage activation syndrome (MAS) in the context of autoimmune disease-induced forms. We report the case of a 41-year-old woman with a previous diagnosis of Crohn's disease complicated by dermatomyositis, who was admitted in our hospital for the acute onset of fever, pancytopenia, and disseminated intravascular coagulation (DIC). The laboratory findings documented hyperferritinemia, hypertransaminasemia, increased lactate-dehydrogenase (LDH), hypertriglyceridemia, and elevation of inflammatory indices, along with complement consumption. MAS was confirmed by examination of the bone marrow. Consequently, the patient was treated with high doses of glucocorticoids, subcutaneous anakinra, and intravenous immunoglobulin (IVIg). Due to the persistence of signs of thrombotic microangiopathy, we started therapy with eculizumab which stabilized the patient without improvement, so we added emapalumab, resulting in clinical improvement and normalization of blood tests.
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Affiliation(s)
- Paola Faggioli
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Marianna Galeazzi
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Carlotta Ferrari
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Francesca Capelli
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Chiara Marchesi
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Lucia Marchionni
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Laura Castelnovo
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Antonio Tamburello
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Eugenio Capparelli
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Cristina Campidelli
- Department of Pathological Anatomy, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
| | - Antonino Mazzone
- Department of Internal Medicine, Azienda Socio Sanitaria Territoriale (ASST) Ovest Milanese, Legnano, MI, Italy
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Cortes-Santiago N, Deutsch G, Patel KR, Silva-Carmona M, Henderson C, Sartain SE, Bhar S, Pogoriler J. The Pathology of Pulmonary Disease After Pediatric Hematopoietic Stem Cell Transplantation. Am J Surg Pathol 2024; 48:1201-1214. [PMID: 39072367 DOI: 10.1097/pas.0000000000002267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Pulmonary complications continue to cause significant morbidity and mortality in posthematopoietic stem cell transplantation (HSCT) settings. The histopathology of pulmonary diseases in the post-HSCT context is poorly characterized, especially in the pediatric population. We sought to characterize the pathologic spectrum of pulmonary disease post-HSCT in a pediatric cohort. Fifty-six specimens, including 53 biopsy specimens, corresponding to 53 patients, were identified. Biopsy slides were reviewed and assigned to diagnostic categories (infectious, graft-versus-host disease, vasculopathy, indeterminate, and others) by consensus among 3 pediatric pulmonary pathologists, taking into consideration pathologic, clinical, radiologic, and laboratory findings. The most common diagnostic category was infection (n=20). Vasculopathy, mostly in the form of fibromyxoid intimal expansion, was very common in the entire cohort (n=26) and was the sole finding in a small subset of patients (n=5), with particularly poor outcomes. A subset of biopsies remained indeterminate (n=10), and the findings in this cohort were dominated by acute lung injury. The latter group had a poor prognosis, with a short biopsy-to-death interval. The overall clinicopathologic concordance was 40%, most commonly agreeing in the infectious category. Finally, wedge biopsies led to a change in management in 69% of cases versus 23% of limited procedures (i.e., core needle biopsies). Our results suggest that while infectious complications continue to be common post-HSCT, other findings such as vasculopathy and acute lung injury portend a particularly poor prognosis and should be actively sought and reported.
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Affiliation(s)
- Nahir Cortes-Santiago
- Department of Pediatrics, Section of Hematology, Baylor College of Medicine; Texas Children's Hospital, Houston, TX
| | - Gail Deutsch
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine; Department of Laboratories, Seattle Children's Hospital, Seattle, WA
| | - Kalyani R Patel
- Department of Pediatrics, Section of Hematology, Baylor College of Medicine; Texas Children's Hospital, Houston, TX
| | - Manuel Silva-Carmona
- Department of Pediatrics, Division of Pulmonary Medicine, Baylor College of Medicine; Texas Children's Hospital, Houston, TX
| | - Carolyn Henderson
- Department of Pediatric Pulmonology, Emory University, Children's Healthcare of Atlanta, Atlanta, GA
| | - Sarah E Sartain
- Department of Pediatrics, Section of Hematology, Baylor College of Medicine; Texas Children's Hospital, Houston, TX
| | - Saleh Bhar
- Department of Pediatrics, Divisions of Hematology-Oncology and Critical Care Medicine, Pediatric Bone Marrow Transplantation and Cellular Therapy, Baylor College of Medicine; Texas Children's Hospital, Houston, TX
| | - Jennifer Pogoriler
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
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Zhou X, Ye Y, Jin A, Pan Z, Xu Z, Ding S, Yan J, Cheng Y, Huang Y, Cao K, Xie W, Zhang J, Xu L, Zhou W, Huang L. Development and implementation of evidence-based, nurse-leading early warning model and healthcare quality improvement project for transplant-associated thrombotic microangiopathy: a mixed-methods, before-and-after study. BMC Nurs 2024; 23:535. [PMID: 39113009 PMCID: PMC11304727 DOI: 10.1186/s12912-024-02093-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 06/13/2024] [Indexed: 08/11/2024] Open
Abstract
OBJECTIVE The early identification and diagnosis of transplant-associated thrombotic microangiopathy (TA-TMA) are essential yet difficult in patients underwent hematopoietic stem cell transplantation (HSCT). To develop an evidence-based, nurse-leading early warning model for TA-TMA, and implement the healthcare quality review and improvement project. METHODS This study was a mixed-methods, before-and-after study. The early warning model was developed based on quality evidence from literature search. The healthcare quality review and improvement project mainly included baseline investigation of nurse, improvement action and effectiveness evaluation. The awareness and knowledge of early parameter of TA-TMA among nurses and the prognosis of patients underwent HSCT were compared before and after the improvement. RESULTS A total of 1 guideline, 1 evidence synthesis, 4 expert consensuses, 10 literature reviews, 2 diagnostic studies, and 9 case series were included in the best evidence. The early warning model including warning period, high-risk characteristics and early manifestation of TA-TMA was developed. The improvement action, including staff training and assessment, suspected TA-TMA identification and patient education, was implemented. The awareness and knowledge rate of early parameter of TA-TMA among nurses significantly improved after improvement action (100% vs. 26.7%, P < 0.001). The incidence of TA-TMA was similar among patients underwent HSCT before and after improvement action (2.8% vs. 1.2%, P = 0.643), while no fall event occurred after improvement action (0 vs. 1.2%, P < 0.001). CONCLUSION The evidence-based early warning model and healthcare quality improvement project could enhance the awareness and knowledge of TA-TMA among healthcare providers and might improve the prognosis of patients diagnosed with TA-TMA.
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Affiliation(s)
- Xiaoyu Zhou
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Yishan Ye
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Aiyun Jin
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Zhengwen Pan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Zhe Xu
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Shuyi Ding
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Jiali Yan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Yin Cheng
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Yixuan Huang
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Kai Cao
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Wei Xie
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Jianli Zhang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Liwei Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Weiwei Zhou
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China
| | - Lihua Huang
- Department of Nursing, The First Affiliated Hospital, Zhejiang University School of Medical, Hangzhou, China.
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Kafa K, Hoell JI. Transplant-associated thrombotic microangiopathy in pediatrics: incidence, risk factors, therapeutic options, and outcome based on data from a single center. Front Oncol 2024; 14:1399696. [PMID: 39050576 PMCID: PMC11266128 DOI: 10.3389/fonc.2024.1399696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/24/2024] [Indexed: 07/27/2024] Open
Abstract
Background Transplant-associated thrombotic microangiopathy (TA-TMA) is a critical complication of hematopoietic stem cell transplantation. Awareness about TA-TMA has increased in recent years, resulting in the implementation of TA-TMA screening in most centers. Methods Retrospective analysis of children who underwent autologous or allogeneic hematopoietic stem cell transplantation at our center between January 2018 and December 2022 was conducted to evaluate the incidence, clinical features, and outcomes of TA-TMA following the administration of different therapeutic options. Results A total of 45 patients comprised the study cohort, of whom 10 developed TA-TMA with a cumulative incidence of 22% by 100 days after transplantation. Patients with and without TA-TMA in our cohort displayed an overall survival of 80% and 88%, respectively (p = 0.48), and a non-relapse mortality of 0% and 5.7%, respectively (p = 0.12), at 1 year after transplantation. Risk factors for TA-TMA development included allogeneic transplantation and total body irradiation-based conditioning regime. Among the 10 patients with TA-TMA, 7 did not meet the high-risk criteria described by Jodele and colleagues. Of these seven patients, two responded to calcineurin-inhibitor withdrawal without further therapy and five developed multiorgan dysfunction syndrome and were treated with anti-inflammatory steroids (prednisone), and all responded to therapy. The three patients with high-risk TA-TMA were treated with complement blockade or prednisone, and all responded to therapy. Conclusion TA-TMA is a multifactorial complication with high morbidity rates. Patients with high-risk TA-TMA may benefit from complement blockade using eculizumab. No consensus has been reached regarding therapy for patients who do not meet high-risk criteria. Our analysis showed that these patients may respond to anti-inflammatory treatment with prednisone.
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Affiliation(s)
- Kinan Kafa
- Department of Pediatric Hematology and Oncology, University Hospital Halle (Saale), Halle, Germany
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Benítez Carabante MI, Bueno D, Alonso García L, López Torija I, Marsal J, Fernandez Navarro JM, Uria Oficialdegui ML, Panesso M, Molina B, Beléndez Bieler C, Palomo P, Pérez Martínez A, Diaz-de-Heredia C. Use of Eculizumab in Pediatric Patients with High-Risk Transplantation-Associated Thrombotic Microangiopathy: Outcomes and Risk Factors Associated with Response and Survival. A Retrospective Study on Behalf of the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC). Transplant Cell Ther 2024; 30:601.e1-601.e13. [PMID: 38521410 DOI: 10.1016/j.jtct.2024.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/12/2024] [Accepted: 03/17/2024] [Indexed: 03/25/2024]
Abstract
Transplantation-associated thrombotic microangiopathy (TA-TMA) is associated with high morbidity and mortality. Although survival has improved significantly with the introduction of eculizumab, the need for improvement remains, especially in high-risk patients. This study aimed to describe the results obtained with eculizumab in a pediatric cohort with the attempt to define which risk factors could determine the response to treatment. We designed a national multicenter retrospective study of children treated with eculizumab for high-risk TA-TMA. The study cohort comprised 29 patients who had undergone a first (n = 28) or second (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for malignant (n = 17) or nonmalignant (n = 12) disease. The median time from HSCT to TA-TMA diagnosis was 154 days (interquartile range [IQR], 103 to 263 days). Eleven patients (38%) who were initially diagnosed with low- to intermediate-risk TA-TMA progressed to high-risk TA-TMA (hrTA-TMA), within a median time of 4 days (IQR, 1 to 33 days). SC5b-9 was increased in 90% of 20 patients in whom it was measured. Renal (n = 12), pulmonary (n = 1), and intestinal (n = 1) biopsy confirmed the diagnosis in 12 of 14 patients (85%). Seventeen patients (58%) had extrarenal involvement with serositis (n = 13; 44,8%), pulmonary (n = 12; 41,4%), gastrointestinal (n = 8; 27.6%), cardiovascular (n = 7; 24.1%), or central nervous system (CNS) (n = 2; 6.9%) involvement. The median time from hrTA-TMA diagnosis to the initiation of eculizumab was 7 days (IQR, 1 to 8 days). Overall, 19 patients (65.5%) responded to eculizumab, of whom 17 (58.6%) achieved a complete response and 2 (6.9%) achieved a partial response. The remaining 10 patients (34.5%) did not show any of response. The overall response rate to eculizumab for TA-TMA was 27.59% (95% confidence interval [CI], 14.87% to 47.66%) at 1 month, 55.17% (95% CI, 38.43% to 73.48%) at 3 months, and 62.07% (95% CI, 45.10% to 79.13%) at 6 months after eculizumab initiation. In multivariate analysis, the pulmonary involvement decreased the probability of response (hazard ratio [HR], .18; P = .0298). The 1-year overall survival (OS) was 55.2% (95% CI, 35.6% to 71.0%) for the whole cohort and 83.3% (95% CI, 56.7% to 94.3%) for patients who responded to eculizumab. Pulmonary involvement (HR, 14.93; P = .0043) and CNS involvement (HR, 8.63; P = .0497) were associated with a statistically significant decrease in survival. We found that patients diagnosed with hrTA-TMA with pulmonary involvement had a poor response to eculizumab, and that patients with pulmonary and CNS involvement had significantly decreased survival. Given these results, we hypothesize that providing eculizumab therapy at an early stage of the disease before organ damage is established might significantly improve the response and, consequently, survival.
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Affiliation(s)
- María Isabel Benítez Carabante
- Division of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - David Bueno
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario La Paz, idiPAZ Research Institute, Madrid, Spain
| | - Laura Alonso García
- Division of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Iván López Torija
- Department of Pediatric Hematology and Oncology, Hospital Santa Creu i Sant Pau, Barcelona, Spain
| | - Julia Marsal
- Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Barcelona, Spain
| | | | - María Luz Uria Oficialdegui
- Division of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Melissa Panesso
- Division of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain
| | - Blanca Molina
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Cristina Beléndez Bieler
- Department of Pediatric Hematology and Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Pilar Palomo
- Department of Pediatric Hematology and Oncology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Antonio Pérez Martínez
- Department of Pediatric Hematology and Oncology, Hospital Infantil Universitario La Paz, idiPAZ Research Institute, Madrid, Spain
| | - Cristina Diaz-de-Heredia
- Division of Pediatric Hematology and Oncology, Hospital Universitari Vall d´Hebron, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
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Cao XY, Zhang JP, Lu Y, Zhao YL, Liu DY, Xiong M, Sun RJ, Wei ZJ, Zhou JR, Zhang X, Yang JF, Li J, Lu P. A safety and efficacy study of allogeneic haematopoietic stem cell transplantation for refractory and relapsed T-cell acute lymphoblastic leukaemia/lymphoblastic lymphoma patients who achieved complete remission after autologous CD7 chimeric antigen receptor T-cell therapy. Br J Haematol 2024; 204:2351-2364. [PMID: 38613241 DOI: 10.1111/bjh.19445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/22/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024]
Abstract
CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy has shown promising initial complete remission (CR) rates in patients with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia and lymphoblastic lymphoma (T-ALL/LBL). To enhance the remission duration, consolidation with allogeneic haematopoietic stem cell transplantation (allo-HSCT) is considered. Our study delved into the outcomes of 34 patients with r/r T-ALL/LBL who underwent allo-HSCT after achieving CR with autologous CD7 CAR-T therapy. These were compared with 124 consecutive T-ALL/LBL patients who received allo-HSCT in CR following chemotherapy. The study revealed that both the CAR-T and chemotherapy cohorts exhibited comparable 2-year overall survival (OS) (61.9% [95% CI, 44.1-78.1] vs. 67.6% [95% CI, 57.5-76.9], p = 0.210), leukaemia-free survival (LFS) (62.3% [95% CI, 44.6-78.4] vs. 62.0% [95% CI, 51.8-71.7], p = 0.548), non-relapse mortality (NRM) rates (32.0% [95% CI, 19.0-54.0] vs. 25.3% [95% CI, 17.9-35.8], p = 0.288) and relapse incidence rates (8.8% [95% CI, 3.0-26.0] vs. 15.8% [95% CI, 9.8-25.2], p = 0.557). Patients aged ≤14 in the CD7 CAR-T group achieved high 2-year OS and LFS rates of 87.5%. Our study indicates that CD7 CAR-T therapy followed by allo-HSCT is not only effective and safe for r/r T-ALL/LBL patients but also on par with the outcomes of those achieving CR through chemotherapy, without increasing NRM.
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Affiliation(s)
- Xing-Yu Cao
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Jian-Ping Zhang
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Yue Lu
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Yan-Li Zhao
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - De-Yan Liu
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Min Xiong
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Rui-Juan Sun
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Zhi-Jie Wei
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Jia-Rui Zhou
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Xian Zhang
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Jun-Fang Yang
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
| | - Jingjing Li
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Institute of Hematology, Beijing, China
| | - Peihua Lu
- Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Hospital, Beijing, China
- Beijing Lu Daopei Institute of Hematology, Beijing, China
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Sawyer J, Elliott T, Orton L, Sowell H, Gatwood K, Shultes K. Prevention and management of acute toxicities from conditioning regimens during hematopoietic stem cell transplantation. Clin Hematol Int 2024; 6:1-10. [PMID: 38817311 PMCID: PMC11087001 DOI: 10.46989/001c.94952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 11/13/2023] [Indexed: 06/01/2024] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) remains the only curative option for several hematological malignancies. Its use has continued to grow, with an estimated 23,500 transplants performed annually in the United States alone. The acute toxicities that occur from conditioning chemotherapy can impact the peri-transplant period and have substantial implications on patients' tolerability and outcomes, irrespective of the treatment of their disease. Chemotherapy-induced nausea vomiting (CINV), mucositis, transplant-associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome, also known as a veno-occlusive disease (SOS/VOD) can all have significant implications for patients. These acute complications begin with the start of conditioning chemotherapy and add to potential toxicity for patients throughout the early post-transplant period, from Day +30 for CINV, mucositis, and SOS, and which can continue through at least Day +100 with the onset of TA-TMA. These toxicities must be prevented and managed appropriately. This review will summarize the literature surrounding them and guide their management.
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Affiliation(s)
- Jana Sawyer
- PharmacyVA Tennessee Valley Healthcare System
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Ito S, Saito A, Sakurai A, Watanabe K, Karakawa S, Miyamura T, Yokosuka T, Ueki H, Goto H, Yagasaki H, Kinoshita M, Ozeki M, Yokoyama N, Teranishi H. Eculizumab treatment in paediatric patients diagnosed with aHUS after haematopoietic stem cell transplantation: a HSCT-TMA case series from Japanese aHUS post-marketing surveillance. Bone Marrow Transplant 2024; 59:315-324. [PMID: 38102212 PMCID: PMC10920193 DOI: 10.1038/s41409-023-02161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 10/26/2023] [Accepted: 11/22/2023] [Indexed: 12/17/2023]
Abstract
Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21-58) and the median doses of eculizumab was three (IQR;2-5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95-555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.
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Affiliation(s)
- Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
| | - Atsuro Saito
- Department of Hematology and Oncology, Children's Cancer Center, Kobe Children's Hospital, 1-6-7 Minatojimaminamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
| | - Ayako Sakurai
- Department of Pediatrics, Japanese Red Cross Narita Hospital, Iida-cho, Narita, Chiba, 286-8523, Japan
| | - Kenichiro Watanabe
- Department of Hematology and Oncology, Shizuoka Children's Hospital, 860 Urushiyama, Aoi-ku, Shizuoka, 420-8660, Japan
| | - Shuhei Karakawa
- Department of Pediatrics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Takako Miyamura
- Department of Pediatrics, Osaka University Graduate School of Medicine, 2-15 Yamadaoka Suita-shi, Osaka, 565-0871, Japan
| | - Tomoko Yokosuka
- Division of Hematology/Oncology, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama, Kanagawa, 232-8555, Japan
| | - Hideaki Ueki
- Department of Pediatrics, Japanese Red Cross Narita Hospital, Iida-cho, Narita, Chiba, 286-8523, Japan
| | - Hiroaki Goto
- Division of Hematology/Oncology, Kanagawa Children's Medical Center, 2-138-4 Mutsukawa, Minami-ku, Yokohama, Kanagawa, 232-8555, Japan
| | - Hiroshi Yagasaki
- Pediatrics, Nihon University Itabashi hospital, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo, 173- 8610, Japan
| | - Mariko Kinoshita
- Division of Pediatrics, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake-cho, Miyazaki, 889-1692, Japan
| | - Michio Ozeki
- Department of Pediatrics, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Norifumi Yokoyama
- Department of Pediatrics, Gifu Municipal Hospital, 7-1 Kashima-cho, Gifu, Gifu, 500-8513, Japan
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10
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Koo J, Ziady AG, Reynaud D, Abdullah S, Luebbering N, Kahn S, Langenberg L, Strecker L, Lake K, Dandoy CE, Lane A, Myers KC, Sabulski A, Good S, Nalapareddy K, Solomon M, Siefert ME, Skala E, Jodele S, Davies SM. Increased Body Mass Index Augments Endothelial Injury and Clinical Outcomes after Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 2023; 29:704.e1-704.e8. [PMID: 37625594 PMCID: PMC10840974 DOI: 10.1016/j.jtct.2023.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 08/11/2023] [Accepted: 08/20/2023] [Indexed: 08/27/2023]
Abstract
Higher body mass index (BMI) is characterized as a chronic inflammatory state with endothelial dysfunction. Endothelial injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) puts patients at risk for such complications as transplantation-associated thrombotic microangiopathy (TA-TMA) and acute graft-versus-host-disease (aGVHD). To evaluate the impact of increased BMI on endothelial injury after allo-HSCT in pediatric and young adult patients, we conducted a retrospective cohort study evaluating 476 consecutive allo-HSCT children and young adult recipients age 0 to 20 years. Our analysis was subdivided based on distinct age categories (<2 years and 2 to 20 years). BMI was considered as a variable but was also expressed in standard deviations from the mean adjusted for age and sex (z-score), based on established criteria from the World Health Organization (age <2 years) and the Centers for Disease Control and Prevention (age 2 to 20 years) to account for differences associated with age. Primary endpoints included the incidences of TA-TMA and aGVHD. Increased BMI z-score was associated with TA-TMA after allo-HSCT in patients age <2 years (median, 18.1; IQR, 17 to 20; P = .006) and in patients age 2 to 20 years (median, 18.7; IQR, 16 to 21.9; P = .02). Higher BMI z-score correlated with TA-TMA risk in both age groups, with a BMI z-score of .9 in the younger cohort and .7 (IQR, -.4 to 1.6; P = .04) in the older cohort. Increased BMI z-score was associated with an increased risk of TA-TMA in a multivariate analysis of the entire cohort (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.05 to 1.37; P = .008). Multivariate analysis also demonstrated that patients with BMI in the 85th percentile or greater had an increased risk of developing TA-TMA compared to those with a lower BMI percentile (OR, 2.66; 95% CI, 1.62 to 4.32; P < .001). Baseline and day +7 ST2 levels were elevated in subjects with TA-TMA compared to those without TA-TMA in both age groups. Baseline sC5b-9 concentration was not correlated with BMI z-score, but sC5b-9 concentration was increased markedly by 7 days post-allo-HSCT in patients age <2 years who later developed TA-TMA compared to those who never developed TA-TMA (P = .001). The median BMI z-score was higher for patients with aGVHD compared to patients without aGVHD (.7 [range, -3.9 to 3.9] versus .2 [range, -7.8 to 5.4]; P = .03). We show that high BMI is associated with augmented risk of endothelial injury after HSCT, specifically TA-TMA. These data identify a high-risk population likely to benefit from early interventions to prevent endothelial injury and prompt treatment of established endothelial injury.
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Affiliation(s)
- Jane Koo
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
| | - Assem G Ziady
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Damien Reynaud
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Sheyar Abdullah
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Nathan Luebbering
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Seth Kahn
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Department of Politics, Princeton University, Princeton, New Jersey
| | - Lucille Langenberg
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Lauren Strecker
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Kelly Lake
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Christopher E Dandoy
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Adam Lane
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Kasiani C Myers
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Anthony Sabulski
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Samantha Good
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kodandaramireddy Nalapareddy
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Michael Solomon
- Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Matthew E Siefert
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Emily Skala
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
| | - Stella M Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
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11
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Cao XY, Zhang JP, Zhao YL, Xiong M, Zhou JR, Lu Y, Sun RJ, Wei ZJ, Liu DY, Zhang X, Yang JF, Lu P. Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant. Front Immunol 2023; 14:1191382. [PMID: 37469510 PMCID: PMC10352576 DOI: 10.3389/fimmu.2023.1191382] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/13/2023] [Indexed: 07/21/2023] Open
Abstract
Background Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. Methods A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. Results The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). Conclusions Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
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Affiliation(s)
- Xing-yu Cao
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Jian-ping Zhang
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Yan-li Zhao
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Min Xiong
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Jia-rui Zhou
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Yue Lu
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Rui-juan Sun
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Zhi-jie Wei
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - De-yan Liu
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Xian Zhang
- Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Jun-fang Yang
- Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Peihua Lu
- Department of Hematology, Hebei Yanda Lu Daopei Hospital, Langfang, China
- Beijing Lu Daopei Institute of Hematology, Beijing, China
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12
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Cortes-Santiago N, Patel KR, Wu H, Sartain SE, Bhar S, Silva-Carmona M, Pogoriler J. Pulmonary Histopathologic Findings in Pediatric Patients After Hematopoietic Stem Cell Transplantation: An Autopsy Study. Pediatr Dev Pathol 2023; 26:362-373. [PMID: 37165556 DOI: 10.1177/10935266231170101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
BACKGROUND Pathologic characterization of pulmonary complications following hematopoietic stem cell transplantation (HSCT) is limited. We describe lung findings in pediatric patients who died following HSCT and attempt to identify potential clinical associations. METHODS Pathology databases at Texas Children's Hospital and the Children's Hospital of Philadelphia were queried (2013-2018 CHOP and 2017-2018 TCH). Electronic medical records and slides were reviewed. RESULTS Among 29 patients, 19 received HSCT for hematologic malignancy, 8 for non-malignant hematologic disorders, and 2 for metastatic solid tumors. Twenty-five patients (86%) showed 1 or more patterns of acute and organizing lung injury. Sixty-two percent had microvascular sclerosis, with venous involvement noted in most cases and not correlating with clinical history of pulmonary hypertension, clinical transplant-associated thrombotic microangiopathy, irradiation, or graft-versus-host disease. Features suggestive of graft-versus-host-disease were uncommon: 6 patients had lymphocytic bronchiolitis, and only 2 patients had evidence of bronchiolitis obliterans (both clinically unexpected), both with a mismatched unrelated donor transplant. CONCLUSIONS Acute and subacute alveolar injury (diffuse alveolar damage or organizing pneumonia) is common in pediatric patients who died following HSCT and is difficult to assign to a specific etiology. Microvascular sclerosis was frequent and did not correlate with a single distinct clinical feature.
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Affiliation(s)
- Nahir Cortes-Santiago
- Department of Pathology and Immunology, Texas Children's Hospital, Houston, TX, USA
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Kalyani R Patel
- Department of Pathology and Immunology, Texas Children's Hospital, Houston, TX, USA
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Hao Wu
- Department of Pathology, Yale School of Medicine and Yale New Haven Hospital, New Haven, CT, USA
| | - Sarah E Sartain
- Department of Pediatrics, Section of Hematology/Oncology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
| | - Saleh Bhar
- Department of Pediatrics, Section of Hematology/Oncology and Critical Care Medicine, Bone Marrow Transplantation, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
| | - Manuel Silva-Carmona
- Department of Pediatrics, Section of Pulmonology, Texas Children's Hospital/Baylor College of Medicine, Houston, TX, USA
| | - Jennifer Pogoriler
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA
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13
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Use of eculizumab in children with allogeneic haematopoietic stem cell transplantation associated thrombotic microangiopathy - a multicentre retrospective PDWP and IEWP EBMT study. Bone Marrow Transplant 2023; 58:129-141. [PMID: 36333550 DOI: 10.1038/s41409-022-01852-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 09/24/2022] [Accepted: 10/13/2022] [Indexed: 11/06/2022]
Abstract
Terminal complement blockade by humanised monoclonal antibody eculizumab has been used to treat transplantation-associated thrombotic microangiopathy (TA-TMA) in recent years. This retrospective international study conducted by the Paediatric Diseases (PDWP) and Inborn Error Working Party (IEWP) of the European Society for Blood and Marrow Transplantation (EBMT) describes outcome and response of 82 paediatric patients from 29 centres who developed TA-TMA and were treated with eculizumab between January 2014 and May 2019. The median time from hematopoietic stem cell transplantation (HSCT) to TA-TMA manifestation was 92 days (range: 7-606) and from TA-TMA diagnosis to the start of eculizumab treatment 6 days (range: 0-135). Most patients received eculizumab weekly (72%, n = 55) with a standard weight (kg)-based dose (78%, n = 64). Six months from beginning of eculizumab therapy, the cumulative incidence of TA-TMA resolution was 36.6% (95% CI: 26.2-47) and the overall survival (OS) was 47.1% (95% CI: 35.9-57.5). All 43 patients with unresolved TA-TMA died. The cause of death was HSCT-related in 41 patients. This study also documents poor outcome of patients without aGvHD and their frequent concomitant viral infections. Considering recent publications, intensified eculizumab dosing and complement monitoring could potentially improve upon outcomes observed in this study.
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14
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Hayden J, O'Donnell G, deLaunois I, O'Gorman C. Endothelial Peripheral Arterial Tonometry (Endo-PAT 2000) use in paediatric patients: a systematic review. BMJ Open 2023; 13:e062098. [PMID: 36657756 PMCID: PMC9853225 DOI: 10.1136/bmjopen-2022-062098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVES Endo Peripheral Artery Tonometry (EndoPAT-2000) is a non-invasive technology for measuring endothelial dysfunction (ED). The reactive hyperaemia index (RHI) is resulted and is low when ED is present. We aim to synthesise the literature on paediatric ED that used Endo-PAT analysis. DESIGN A comprehensive systematic review was conducted from January 2015 to March 2021. The databases included Cochrane, MEDLINE EBSCO, EMBASE (Ovid), PUBMED and CINAHL EBSCO. Exclusion criteria were: (1) If a study used a different device, for example, (2) If the study had no results. Inclusion criteria were: (1) Published in the English, (2) more than 50% of study subjects were in the paediatric age range, (3) data relevant to paediatric age range children could be extrapolated from all data, where not all study subjects were children. RESULTS Following the removal of duplicates, 156 articles were initially identified. Following exclusion, 50 articles were included for review. We have subdivided these papers into different systems for ease of reference and have reported our findings in six tables: patients with type 1/2 diabetes, obesity, cardiovascular, respiratory, psychiatric conditions and miscellaneous diseases. For each, the study design, population, control group (if available), RHI results and conclusions were reported. CONCLUSIONS A number of papers using Endo-PAT for children with various chronic diseases have evidence of ED. However, in many cases, there has only been a single cohort study using Endo-PAT. Further studies are required to validate these findings and to help characterise the cardiovascular risk profile of children with chronic disease. Further studies are also required that will characterise more completely the cardiovascular risk profile of these children.Consensus on other vascular risk markers that could be included in future studies is ideal and if accomplished, this would facilitate meta-analyses of studies of relatively rare conditions.
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Affiliation(s)
- Jenny Hayden
- Department of Paediatrics, University Hospital Limerick, Limerick, Ireland
| | - Gill O'Donnell
- Department of Paediatrics, University Hospital Limerick, Limerick, Ireland
| | | | - Clodagh O'Gorman
- Paediatrics, Graduate Entry Medical School, University of Limerick, Limerick, Ireland
- University Hospital Limerick, Dooradoyle, Limerick, Ireland
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15
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Holloway MR, Fountaine T, Henrichs K, Feeney T, Andolina J, O'Dwyer K, Liesveld J, Blumberg N, Huselton E. Association of crystalloid fluid infusion with intravascular hemolysis and organ dysfunction in hematopoietic stem cell transplant patients. Transfus Apher Sci 2023:103641. [PMID: 36653255 DOI: 10.1016/j.transci.2023.103641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 12/11/2022] [Accepted: 01/12/2023] [Indexed: 01/14/2023]
Abstract
Endothelial cell activation and injury is common after hematopoietic stem cell transplant (HSCT) and is associated with many post-transplant complications. An underexplored mechanism of endothelial cell damage in this population is the infusion of normal saline (NS, 0.9 % sodium chloride) and other crystalloids, as NS use is associated with adverse outcomes in other patient populations. We hypothesized that the infusion of unbalanced crystalloids during HSCT may lead to changes in biomarkers commonly associated with red blood cell (RBC) hemolysis in patients before and after infusion, and that markers of endothelial and end-organ damage during admission may be associated with markers of hemolysis and total crystalloid use. Samples were collected from 97 patients. From pre-fluid infusion to post-fluid infusion, mean haptoglobin decreased (11.7 ug/ml vs 8.4 ug/ml; p < 0.0001), hemopexin decreased (549 vs 512 μg/ml; p = 0.005), and red cell distribution width (RDW) decreased (15.7 vs 15.6; p = 0.0009). During admission (mean 19.4 days, SD 9.9), all markers of tissue and organ damage, including mean creatinine, lactate dehydrogenase (LDH), blood urea nitrogen (BUN), total bilirubin, AST, and ALT, increased from admission to peak levels (p < 0.0001). On linear regression, fluid volume (ml/kg) of crystalloid infusion positively predicted post-fluid infusion cell-free hemoglobin (r(96) = 0.34, p < 0.0001), free heme (r(96) = 0.36, p < 0.0001), and peak LDH during admission (r(75) = 0.23, p = 0.041), and negatively predicted post-fluid infusion hemopexin (r(96) = - 0.34, p < 0.0001). Unbalanced crystalloids may contribute to hemolysis and endothelial damage in HSCT patients. Alternatives such as buffered crystalloid solutions (PlasmaLyte, Lactated Ringer's) may be worth investigating in this population.
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Affiliation(s)
- Melissa R Holloway
- University of Rochester School of Medicine & Dentistry, 601 Elmwood Ave., PO Box 255, Rochester, NY 14642, USA.
| | - Thomas Fountaine
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA; Tmunity Therapeutics Inc., 3020 Market Street, Suite 535, Philadelphia, PA 19104, USA.
| | - Kelly Henrichs
- Department of Pathology and Laboratory Medicine (Transfusion Medicine), University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
| | - Tate Feeney
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA.
| | - Jeffrey Andolina
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA.
| | - Kristen O'Dwyer
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA.
| | - Jane Liesveld
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA.
| | - Neil Blumberg
- Department of Pathology and Laboratory Medicine (Transfusion Medicine), University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
| | - Eric Huselton
- Department of Medicine, Division of Hematology-Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, 90 Crittenden Blvd., Rochester, NY 14642, USA.
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16
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Yamaguchi M, Mizuno M, Kitamura F, Iwagaitsu S, Nobata H, Kinashi H, Banno S, Asai A, Ishimoto T, Katsuno T, Ito Y. Case report: Thrombotic microangiopathy concomitant with macrophage activation syndrome in systemic lupus erythematosus refractory to conventional treatment successfully treated with eculizumab. Front Med (Lausanne) 2023; 9:1097528. [PMID: 36698804 PMCID: PMC9868404 DOI: 10.3389/fmed.2022.1097528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Thrombotic microangiopathy (TMA) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Macrophage activation syndrome (MAS) is also a rare, life-threatening hyperinflammatory condition that is comorbid with SLE. However, the association between TMA and MAS in patients with SLE has rarely been assessed, and the difficulty of diagnosing these conditions remains prevalent. The efficacy of eculizumab has been reported for SLE patients whose conditions are complicated with TMA. However, no study has investigated the therapeutic efficacy of eculizumab for TMA concomitant with SLE-associated MAS. Herein, we report the first case of TMA concomitant with SLE-associated MAS that was initially refractory to conventional immunosuppressive therapy but showed remarkable recovery after eculizumab treatment. Furthermore, we evaluated serum syndecan-1 and hyaluronan levels, which are biomarkers of endothelial damage. We found that these levels decreased after the administration of eculizumab, suggesting that TMA was the main pathology of the patient. This case illustrates that it is important to appropriately assess the possibility of TMA during the course of SLE-associated MAS and consider the use of eculizumab as necessary.
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Affiliation(s)
- Makoto Yamaguchi
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Masashi Mizuno
- Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumiya Kitamura
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Shiho Iwagaitsu
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hironobu Nobata
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Hiroshi Kinashi
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Shogo Banno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Akimasa Asai
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Takayuki Katsuno
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan,Department of Nephrology and Rheumatology, Aichi Medical University Medical Center, Okazaki, Japan
| | - Yasuhiko Ito
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan,*Correspondence: Yasuhiko Ito,
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Michael M, Bagga A, Sartain SE, Smith RJH. Haemolytic uraemic syndrome. Lancet 2022; 400:1722-1740. [PMID: 36272423 DOI: 10.1016/s0140-6736(22)01202-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 11/05/2022]
Abstract
Haemolytic uraemic syndrome (HUS) is a heterogeneous group of diseases that result in a common pathology, thrombotic microangiopathy, which is classically characterised by the triad of non-immune microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. In this Seminar, different causes of HUS are discussed, the most common being Shiga toxin-producing Escherichia coli HUS. Identifying the underlying thrombotic microangiopathy trigger can be challenging but is imperative if patients are to receive personalised disease-specific treatment. The quintessential example is complement-mediated HUS, which once carried an extremely high mortality but is now treated with anti-complement therapies with excellent long-term outcomes. Unfortunately, the high cost of anti-complement therapies all but precludes their use in low-income countries. For many other forms of HUS, targeted therapies are yet to be identified.
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Affiliation(s)
- Mini Michael
- Division of Pediatric Nephrology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
| | - Arvind Bagga
- Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Sarah E Sartain
- Pediatrics-Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA
| | - Richard J H Smith
- Department of Otolaryngology, Pediatrics and Molecular Physiology & Biophysics, The University of Iowa, Iowa City, IA, USA
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18
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Chan WYK, Ma ALT, Chan EYH, Kan ANC, Ng WF, Lee PPW, Cheuk DKL, Chiang AKS, Leung W, Chan GCF. Epidemiology and outcomes of pediatric transplant-associated thrombotic microangiopathy in Hong Kong. Pediatr Transplant 2022; 26:e14366. [PMID: 35860972 DOI: 10.1111/petr.14366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/13/2022] [Accepted: 07/08/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) is an under-recognized yet potentially devastating complication of hematopoietic stem cell transplantation (HSCT) which had increased awareness in recent years. This report summarizes the demographics and outcomes of pediatric TA-TMA in Hong Kong. METHODS All patients aged below 18 years who underwent HSCT in the Hong Kong Children's Hospital and were diagnosed to have TA-TMA during the 2-year period from April 1, 2019 to March 31, 2021 were included. RESULTS A total of 73 transplants (51 allogeneic and 22 autologous) in 63 patients had been performed. Six patients (four males and two females) developed TA-TMA at a median duration of 2.5 months post-HSCT. The incidence rate was 9.52%. Of the six TA-TMA patients, five underwent allogenic one underwent autologous HSCT, respectively. Three of them were histologically proven. All four patients with cyclosporine had stopped the drug once TA-TMA was suspected. Median six doses of eculizumab were administered to five out of six patients. Three patients died (two due to fungal infection and one due to acute-on-chronic renal failure) within 3 months upon diagnosis of TA-TMA. Among three survivors, two stabilized with mild stage 2 chronic kidney disease (CKD) while the other suffered from stage 5 end-stage CKD requiring lifelong dialysis. CONCLUSION In conclusion, recognition and diagnosis of TA-TMA are challenging. Early recognition and prompt administration of complement blockage with eculizumab may be beneficial in selected cases. Further prospective research studies are recommended to improve the management and outcomes of TA-TMA.
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Affiliation(s)
- Wilson Yau Ki Chan
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Alison Lap Tak Ma
- Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Eugene Yu Hin Chan
- Pediatric Nephrology team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Amanda Nim Chi Kan
- Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Wai Fu Ng
- Department of Pathology, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Pamela Pui Wah Lee
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Daniel Ka Leung Cheuk
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Alan Kwok Shing Chiang
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Wing Leung
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
| | - Godfrey Chi Fung Chan
- Paediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation Team, Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong Special Administrative Region, China
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19
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Thompson GL, Kavanagh D. Diagnosis and treatment of thrombotic microangiopathy. Int J Lab Hematol 2022; 44 Suppl 1:101-113. [PMID: 36074708 PMCID: PMC9544907 DOI: 10.1111/ijlh.13954] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 07/28/2022] [Indexed: 12/01/2022]
Abstract
Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic haemolytic anaemia and end organ damage. TMAs have varying underlying pathophysiology and can therefore present with an array of clinical presentations. Renal involvement is common as the kidney is particularly susceptible to the endothelial damage and microvascular occlusion. TMAs require rapid assessment, diagnosis, and commencement of appropriate treatment due to the high morbidity and mortality associated with them. Ground-breaking research into the pathogenesis of TMAs over the past 20 years has driven the successful development of targeted therapeutics revolutionizing patient outcomes. This review outlines the clinical presentations, pathogenesis, diagnostic tests and treatments for TMAs.
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Affiliation(s)
- Gemma L Thompson
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - David Kavanagh
- Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,National Renal Complement Therapeutics Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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20
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Yang W, Qin M, Jia C, Yang J, Chen W, Luo Y, Jing Y, Wang B. Pediatric acute myeloid leukemia patients with KMT2A rearrangements: a single-center retrospective study. Hematology 2022; 27:583-589. [PMID: 35617149 DOI: 10.1080/16078454.2022.2071797] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
PURPOSE Pediatric acute myeloid leukemia (AML) with KMT2A rearrangements has a very different prognosis. Poor outcomes cannot be avoided even after hematopoietic stem cell transplantation. In order to investigate the prognosis and efficacy, we conducted a retrospective analysis. PATIENTS AND METHODS We retrospectively analyzed a total of 32 children with KMT2A rearrangements AML treated in our hospital between January 2015 and February 2021. RESULTS The proportion of patients with KMT2A-rearranged in the medium-risk group of overall survival (OS) and event-free survival (EFS) was 100%. No differences in OS, EFS and cumulative incidence of relapse (CIR) were detected between the haploidentical hematopoietic stem cell transplantation (haplo-HSCT) and full matched HSCT (P = 0.289, P = 0.303, P = 0.303). Acute graft-versus-host disease (aGVHD) was often detected in the haplo-HSCT cohort, while full matched HSCT had no obvious aGVHD, assessed as≤1 grade (P < 0.05). Patients in the medium-risk pediatric group could acquire 100% OS and EFS only after chemotherapy. There was no significant difference in OS, EFS and CIR between full matched HSCT and haploidentical transplantation in pediatric AML with KMT2A rearrangements, but full matched HSCT seemed to have a lower death rate. The severity of aGVHD in the full matched HSCT was less than that in the haploidentical transplantation group. CONCLUSION The primary choice of donor can be HLA-matched sibling donors or matched unrelated donors for children with AML with KMT2A rearrangements, and the secondary choice can be haploid donors.
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Affiliation(s)
- Wei Yang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Maoquan Qin
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Chenguang Jia
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Jun Yang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Wei Chen
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Yanhui Luo
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Yuanfang Jing
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
| | - Bin Wang
- Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, People's Republic of China
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21
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Leimi L, Jahnukainen K, Olkinuora H, Meri S, Vettenranta K. Early vascular toxicity after pediatric allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2022; 57:705-711. [PMID: 35177827 PMCID: PMC9090633 DOI: 10.1038/s41409-022-01607-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 01/27/2022] [Accepted: 02/01/2022] [Indexed: 11/08/2022]
Abstract
Treatment-related mortality and morbidity remain a challenge in hematopoietic stem cell transplantation (HSCT). In this retrospective, single-center study, we analyzed endothelial damage as a potential, common denominator and mechanism for the adverse effects. We evaluated the prevalence of key vascular complications and graft-versus-host disease among 122 pediatric patients with an allogeneic HSCT between 2001 and 2013. The spectrum and frequency of acute adverse events emerging ≤100 days post transplant were graded according to the CTCAE 4.03 and analyzed. We identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome, veno-occlusive disease/sinusoidal obstruction syndrome or thrombotic microangiopathy. The patients had a poorer overall survival (77% versus 26%, p < 0.001). Nearly one half (56/122, 45.9%) had at least one, severe (grade 3 or 4) adverse event. Patients with vascular complications had more often edema/effusions (p = 0.023), thrombocytopenia (p = 0.001), gastrointestinal bleeding (p < 0.001), acute kidney injury (p < 0.001), ascites (p < 0.001) or bilirubin increase (p = 0.027). These endotheliopathy-related adverse events appeared early post HSCT, varied in their clinical phenotype and predicted a poor outcome. An unrelated donor but not previous exposure to leukemia or irradiation-based conditioning was identified as a risk factor for vascular complications and endotheliopathy.
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Affiliation(s)
- Lilli Leimi
- University of Helsinki, Helsinki University Hospital, Children's Hospital, and Pediatric Research Center, Helsinki, Finland.
| | - Kirsi Jahnukainen
- University of Helsinki, Helsinki University Hospital, Children's Hospital, and Pediatric Research Center, Helsinki, Finland
- NORDFERTIL Research Lab Stockholm, Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm, Sweden
| | - Helena Olkinuora
- University of Helsinki, Helsinki University Hospital, Children's Hospital, and Pediatric Research Center, Helsinki, Finland
| | - Seppo Meri
- Department of Bacteriology and Immunology and Translational Immunology Research Program, University of Helsinki, and Diagnostic Center, Helsinki University Hospital, Helsinki, Finland
| | - Kim Vettenranta
- University of Helsinki, Helsinki University Hospital, Children's Hospital, and Pediatric Research Center, Helsinki, Finland
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22
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Milone G, Bellofiore C, Leotta S, Milone GA, Cupri A, Duminuco A, Garibaldi B, Palumbo G. Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology. J Clin Med 2022; 11:jcm11030623. [PMID: 35160072 PMCID: PMC8837122 DOI: 10.3390/jcm11030623] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.
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23
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Gavriilaki E, Ho VT, Schwaeble W, Dudler T, Daha M, Fujita T, Jodele S. Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy. Exp Hematol Oncol 2021; 10:57. [PMID: 34924021 PMCID: PMC8684592 DOI: 10.1186/s40164-021-00249-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/27/2021] [Indexed: 12/30/2022] Open
Abstract
Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening syndrome that occurs in adult and pediatric patients after hematopoietic stem cell transplantation. Nonspecific symptoms, heterogeneity within study populations, and variability among current diagnostic criteria contribute to misdiagnosis and underdiagnosis of this syndrome. Hematopoietic stem cell transplantation and associated risk factors precipitate endothelial injury, leading to HSCT-TMA and other endothelial injury syndromes such as hepatic veno-occlusive disease/sinusoidal obstruction syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, capillary leak syndrome, and graft-versus-host disease. Endothelial injury can trigger activation of the complement system, promoting inflammation and the development of endothelial injury syndromes, ultimately leading to organ damage and failure. In particular, the lectin pathway of complement is activated by damage-associated molecular patterns (DAMPs) on the surface of injured endothelial cells. Pattern-recognition molecules such as mannose-binding lectin (MBL), collectins, and ficolins—collectively termed lectins—bind to DAMPs on injured host cells, forming activation complexes with MBL-associated serine proteases 1, 2, and 3 (MASP-1, MASP-2, and MASP-3). Activation of the lectin pathway may also trigger the coagulation cascade via MASP-2 cleavage of prothrombin to thrombin. Together, activation of complement and the coagulation cascade lead to a procoagulant state that may result in development of HSCT-TMA. Several complement inhibitors targeting various complement pathways are in clinical trials for the treatment of HSCT-TMA. In this article, we review the role of the complement system in HSCT-TMA pathogenesis, with a focus on the lectin pathway.
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Affiliation(s)
- Eleni Gavriilaki
- Hematology Department-BMT Unit, G Papanikolaou Hospital, Leof. Papanikolaou, Pilea Chortiatis 570 10, Thessaloniki, Greece.
| | - Vincent T Ho
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA
| | - Wilhelm Schwaeble
- Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES, UK
| | - Thomas Dudler
- Discovery and Development, Omeros Corporation, 201 Elliott Ave W, Seattle, WA, 98119, USA
| | - Mohamed Daha
- Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands
| | - Teizo Fujita
- Department Fukushima Prefectural General Hygiene Institute, 61-Watari-Nakakado, Fukushima, Fukushima, 960-8141, Japan
| | - Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
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24
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Luft T, Dreger P, Radujkovic A. Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation. Bone Marrow Transplant 2021; 56:2326-2335. [PMID: 34253879 PMCID: PMC8273852 DOI: 10.1038/s41409-021-01390-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/08/2021] [Accepted: 06/22/2021] [Indexed: 01/26/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (alloSCT) carries the promise of cure for many malignant and non-malignant diseases of the lympho-hematopoietic system. Although outcome has improved considerably since the pioneering Seattle achievements more than 5 decades ago, non-relapse mortality (NRM) remains a major burden of alloSCT. There is increasing evidence that endothelial dysfunction is involved in many of the life-threatening complications of alloSCT, such as sinusoidal obstruction syndrome/venoocclusive disease, transplant-associated thrombotic microangiopathy, and refractory acute graft-versus host disease. This review delineates the role of the endothelium in severe complications after alloSCT and describes the current status of search for biomarkers predicting endothelial complications, including markers of endothelial vulnerability and markers of endothelial injury. Finally, implications of our current understanding of transplant-associated endothelial pathology for prevention and management of complications after alloSCT are discussed.
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Affiliation(s)
- Thomas Luft
- Department Medicine V, University of Heidelberg, Heidelberg, Germany.
| | - Peter Dreger
- Department Medicine V, University of Heidelberg, Heidelberg, Germany.
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25
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Pulmonary Complications of Pediatric Hematopoietic Cell Transplantation. A National Institutes of Health Workshop Summary. Ann Am Thorac Soc 2021; 18:381-394. [PMID: 33058742 DOI: 10.1513/annalsats.202001-006ot] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Approximately 2,500 pediatric hematopoietic cell transplants (HCTs), most of which are allogeneic, are performed annually in the United States for life-threatening malignant and nonmalignant conditions. Although HCT is undertaken with curative intent, post-HCT complications limit successful outcomes, with pulmonary dysfunction representing the leading cause of nonrelapse mortality. To better understand, predict, prevent, and/or treat pulmonary complications after HCT, a multidisciplinary group of 33 experts met in a 2-day National Institutes of Health Workshop to identify knowledge gaps and research strategies most likely to improve outcomes. This summary of Workshop deliberations outlines the consensus focus areas for future research.
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26
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Yang LP, Liu X, Zhang XH. [Advances in the diagnosis and management of transplant-associated thrombotic microangiopathy]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:693-699. [PMID: 34547882 PMCID: PMC8501284 DOI: 10.3760/cma.j.issn.0253-2727.2021.08.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Indexed: 12/02/2022]
Affiliation(s)
- L P Yang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China
| | - X Liu
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China
| | - X H Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing 100044, China
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27
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Minoia F, Tibaldi J, Muratore V, Gallizzi R, Bracaglia C, Arduini A, Comak E, Vougiouka O, Trauzeddel R, Filocamo G, Mastrangelo A, Micalizzi C, Kasapcopur O, Unsal E, Kitoh T, Tsitsami E, Kostik M, Schmid JP, Prader S, Laube G, Maritsi D, Jelusic M, Shenoi S, Vastert S, Ardissino G, Cron RQ, Ravelli A. Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients. J Pediatr 2021; 235:196-202. [PMID: 33836183 DOI: 10.1016/j.jpeds.2021.04.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/07/2021] [Accepted: 04/02/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). STUDY DESIGN International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. RESULTS Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. CONCLUSIONS The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.
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Affiliation(s)
- Francesca Minoia
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
| | - Jessica Tibaldi
- IRCCS Istituto Giannina Gaslini, Genoa, Italy; Università degli Studi di Genova, Genoa, Italy
| | | | | | | | | | | | | | | | - Giovanni Filocamo
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | | | - Ozgur Kasapcopur
- Istanbul University-Cerrahpasa, Department of Pediatric Rheumatology, Istanbul, Turkey
| | - Erbil Unsal
- Department of Pediatric Rheumatology, Dokuz Eylul University Childrens' Hospital, Izmir, Turkey
| | - Toshiyuki Kitoh
- Laboratory of Pediatrics, Aichi Gakuin University School of Pharmacy, Nagoya, Japan
| | - Elena Tsitsami
- 1st Department of Pediatrics, University of Athens, Children's Hospital Aghia Sophia, Athens, Greece
| | - Mikhail Kostik
- Saint-Petersburg State Pediatric Medical University, Saint-Petersburg, Russia
| | - Jana Pachlopnik Schmid
- Universitäts-Kinderspital, Zürich, Switzerland; University of Zurich, Zurich, Switzerland
| | | | - Guido Laube
- Universitäts-Kinderspital, Zürich, Switzerland
| | | | - Marija Jelusic
- University of Zagreb School of Medicine, Zagreb, Croatia
| | | | | | | | - Randy Q Cron
- Children's Hospital of Alabama, Birmingham, AL, USA
| | - Angelo Ravelli
- IRCCS Istituto Giannina Gaslini, Genoa, Italy; Università degli Studi di Genova, Genoa, Italy; Sechenov First Moscow State Medical University, Moscow, Russian Federation
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28
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La Valle A, Crocco M, Chiarenza DS, Maghnie M, d'Annunzio G. Endothelial impairment evaluation by peripheral arterial tonometry in pediatric endocrinopathies: A narrative review. World J Diabetes 2021; 12:810-826. [PMID: 34168730 PMCID: PMC8192248 DOI: 10.4239/wjd.v12.i6.810] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/30/2021] [Accepted: 05/15/2021] [Indexed: 02/06/2023] Open
Abstract
Endothelial dysfunction (ED) is characterized by an imbalance between vasodilator and vasoconstriction agents. Several pathological conditions clinically diagnosed in childhood and adolescence are characterized by ED and increased risk for early development of microangiopathic and macroangiopathic impairment, in particular type 1 diabetes mellitus (T1DM), T2DM, obesity, metabolic syndromeand pituitary dysfunction associated to various endocrinopathies. More recently insulin resistance following chemotherapy or radiotherapy for tumors, bone marrow transplantation for hematological malignancies (i.e., cancer survivors), or immunosuppressive treatment for solid organ transplantation has been observed. Assessment of ED by means of non-invasive techniques is the gold standard for early ED detection before clinical manifestation. It is aimed to recognize patients at risk and to avoid the development and progression of more serious illnesses. Reactive hyperemia-peripheral artery tonometry is a noninvasive technique to assess peripheral endothelial function by measuring modifications in digital pulse volume during reactive hyperemia, and represents a non-invasive, reproducible and operator-independent tool able to detect precocious ED. This narrative review aimed to provide an overview of the most important papers regarding ED detection by EndoPat 2000 in children and adolescents with different endocrine diseases. A comprehensive search of English language articles was performed in the MEDLINE database without using other search filters except the publication interval between 2005 and 2020.
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Affiliation(s)
- Alberto La Valle
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Marco Crocco
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Decimo Silvio Chiarenza
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Mohamad Maghnie
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
- Pediatric Clinic and Endocrinology, IRCCS Giannina Gaslini Institute, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa16147, Italy
| | - Giuseppe d'Annunzio
- Pediatric Clinic and Endocrinology, IRCCS Istituto Giannina Gaslini, Genoa16147, Italy
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29
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A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant. Blood Adv 2021; 5:1-11. [PMID: 33570619 DOI: 10.1182/bloodadvances.2020003455] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 11/22/2020] [Indexed: 12/26/2022] Open
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation (HSCT). A single-center prospective screening study has shown that the incidence of TA-TMA is much higher than prior retrospective studies that did not systematically screen. These data have not been replicated in a multicenter study. Our objective was to determine the incidence and risk factors for TA-TMA and compare outcomes of pediatric HSCT patients with and without TA-TMA. Patients were prospectively screened for TA-TMA at participating centers using a simple to implement and inexpensive strategy from the start of the preparative regimen through day +100. TA-TMA was diagnosed if ≥4 of 7 laboratory/clinical markers diagnostic for TA-TMA were present concurrently or if tissue histology showed TA-TMA. A total of 614 patients (359 males; 58%) received prospective TA-TMA screening at 13 pediatric centers. TA-TMA was diagnosed in 98 patients (16%) at a median of 22 days (interquartile range, 14-44) posttransplant. Patients with TA-TMA had significantly increased bloodstream infections (38% [37/98] vs 21% [107/51], P ≤ .001), mean total hospitalization days (68; 95% confidence interval [CI], 63-74 vs 43; 95% CI, 41-45; P ≤ .001), and number of days spent in the intensive care unit (10.1; 95% CI, 6.4-14; vs 1.6; 95% CI, 1.1-2.2; P ≤ .001) in the first 100 days after HSCT compared with patients without TA-TMA. Overall survival was significantly higher in patients without TA-TMA (93%; 490/516) compared with patients with TA-TMA (78%; 76/98) (P ≤ .001). These data support the need for systematic screening for TA-TMA and demonstrate the feasibility and efficacy of an easy to implement strategy to do so.
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30
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Rotz SJ, Ryan TD, Hayek SS. Cardiovascular disease and its management in children and adults undergoing hematopoietic stem cell transplantation. J Thromb Thrombolysis 2021; 51:854-869. [PMID: 33230704 PMCID: PMC8085022 DOI: 10.1007/s11239-020-02344-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2020] [Indexed: 02/07/2023]
Abstract
Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for many malignancies, hemoglobinopathies, metabolic diseases, bone marrow failure syndromes, and primary immune deficiencies. Despite the significant improvement in survival afforded by HSCT, the therapy is associated with major short and long-term morbidity and mortality. Cardiovascular complications such as cardiomyopathy, arrhythmias, pulmonary hypertension, and pericardial effusions are increasingly recognized as potential outcomes following HSCT. The incidence of cardiac complications is related to various factors such as age, co-morbid medical conditions, whether patients received cardiotoxic chemotherapy prior to HSCT, the type of HSCT (autologous versus allogeneic), and the specific conditioning regimen. Thus, the cardiovascular evaluation has become a core component of the pre-transplant assessment, however, the practice differs from center to center as national guidelines and contemporary high-quality studies are lacking. We review the incidence of cardiotoxicity in pediatric and adult HSCT, potential mechanisms of injury, and effects on long-term outcomes. We also discuss the possible therapeutic approaches when disease arises, as well as the indications and need for surveillance before, during, and after transplantation.
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Affiliation(s)
- Seth J Rotz
- Department of Pediatric Hematology, Oncology, and Blood and Marrow Transplantation, Pediatric Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
| | - Thomas D Ryan
- Department of Pediatrics, University of Cincinnati College of Medicine, and Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Salim S Hayek
- Division of Cardiology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA
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31
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Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis. Bone Marrow Transplant 2021; 56:1805-1817. [PMID: 33875812 PMCID: PMC8338557 DOI: 10.1038/s41409-021-01283-0] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 03/08/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023]
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality. The triad of endothelial cell activation, complement dysregulation, and microvascular hemolytic anemia has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis. Recent advances have implicated complement as a major contributor and the therapeutic potential of complement inhibition has been explored. Eculizumab has emerged as an effective therapy and narsoplimab (OMS721) has been granted priority review by the FDA. Large studies performed mostly in pediatric patients suggest that earlier recognition and treatment may lead to improved outcomes. Here we present a clinically focused summary of recently published literature and propose a diagnostic and treatment algorithm.
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32
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Valério P, Barreto JP, Ferreira H, Chuva T, Paiva A, Costa JM. Thrombotic microangiopathy in oncology - a review. Transl Oncol 2021; 14:101081. [PMID: 33862523 PMCID: PMC8065296 DOI: 10.1016/j.tranon.2021.101081] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 12/31/2022] Open
Abstract
Thrombotic microangiopathy is a syndrome triggered by a wide spectrum of situations, some of which are specific to the Oncology setting. It is characterized by a Coombs-negative microangiopathic haemolytic anemia, thrombocytopenia and organ injury, with characteristic pathological features, resulting from platelet microvascular occlusion. TMA is rare and its cancer-related subset even more so. TMA triggered by drugs is the most common within this group, including classic chemotherapy and the latest targeted therapies. The neoplastic disease itself and hematopoietic stem-cell transplantation could also be potential triggers. Evidence-based medical guidance in the management of cancer-related TMA is scarce and the previous knowledge about primary TMA is valuable to understand the disease mechanisms and the potential treatments. Given the wide spectrum of potential causes for TMA in cancer patients, the aim of this review is to gather the vast information available. For each entity, pathophysiology, clinical features, therapeutic approaches and prognosis will be covered.
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Affiliation(s)
- Patrícia Valério
- Nephrology Department, Setúbal Hospital Center, Portugal Rua Camilo Castelo Branco 175, 2910-549 Setúbal, Portugal.
| | - João Pedro Barreto
- Laboratory Diagnosis Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Hugo Ferreira
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Teresa Chuva
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - Ana Paiva
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
| | - José Maximino Costa
- Nephrology Department, Portuguese Oncology Institute of Porto, Portugal Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal
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33
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[Chinese consensus on the diagnosis and management of transplant-associated thrombotic microangiopathy (2021)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:177-184. [PMID: 33910301 PMCID: PMC8081937 DOI: 10.3760/cma.j.issn.0253-2727.2021.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Indexed: 01/04/2023]
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34
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Emberesh M, Rubinstein JD, Young J, Benoit SW, Dandoy CE, Weiss BD. Tolerance of dinutuximab therapy for treatment of high-risk neuroblastoma in two patients with end-stage renal disease on dialysis. Pediatr Blood Cancer 2021; 68:e28852. [PMID: 33381917 DOI: 10.1002/pbc.28852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 11/03/2020] [Accepted: 11/30/2020] [Indexed: 01/19/2023]
Abstract
Autologous hematopoietic cell transplant (aHCT) has a significant survival advantage in patients with high-risk (HR) neuroblastoma. Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication and may result in chronic renal disease leading to delay in subsequent posttransplant therapy and limitations of treatment options. Dinutuximab represents an important therapeutic advance in the treatment of pediatric HR neuroblastoma, but historically has not been administered in patients with GFR < 60 mL/m2 /min. Here, we present the safe outcome of dinutuximab administration while on renal replacement therapy in two cases of HR neuroblastoma with end-stage renal disease secondary to TA-TMA.
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Affiliation(s)
- Myesa Emberesh
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jeremy D Rubinstein
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jennifer Young
- Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Stefanie W Benoit
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.,Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Christopher E Dandoy
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Brian D Weiss
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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35
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Elbahlawan L, Bissler J, Morrison RR. Continuous Renal Replacement Therapy: A Review of Use and Application in Pediatric Hematopoietic Stem Cell Transplant Recipients. Front Oncol 2021; 11:632263. [PMID: 33718216 PMCID: PMC7953134 DOI: 10.3389/fonc.2021.632263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/28/2021] [Indexed: 12/29/2022] Open
Abstract
Hematopoietic stem cell transplant (HSCT) is a curative therapy for malignant and non-malignant conditions. However, complications post-HSCT contribute to significant morbidity and mortality in this population. Acute kidney injury (AKI) is common in the post-allogeneic transplant phase and contributes to morbidity in this population. Continuous renal replacement therapy (CRRT) is used often in the setting of AKI or multiorgan dysfunction in critically ill children. In addition, CRRT can be useful in many disease processes related to transplant and can potentially improve outcomes in this population. This review will focus on the use of CRRT in critically ill children in the post-HSCT setting outside the realm of acute renal failure and highlight the benefits and applications of this modality in this high-risk population.
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Affiliation(s)
- Lama Elbahlawan
- Division of Critical Care Medicine, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - John Bissler
- Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children’s Hospital, Memphis, TN, United States
- Department of Pediatrics, St. Jude Children’s Research Hospital, Memphis, TN, United States
| | - R. Ray Morrison
- Division of Critical Care Medicine, St. Jude Children’s Research Hospital, Memphis, TN, United States
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36
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Gomez-Ganda L, Benitez-Carabante MI, Fernandez-Polo A, Muñoz-Lopez M, Renedo-Miro B, Ariceta G, Diaz De Heredia C. Use of Eculizumab in Pediatric Patients With Transplant Associated Thrombotic Microangiopathy. Front Pediatr 2021; 9:761726. [PMID: 34858907 PMCID: PMC8632356 DOI: 10.3389/fped.2021.761726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/06/2021] [Indexed: 01/27/2023] Open
Abstract
Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT) associated with high morbidity and mortality. High-risk TA-TMA (hrTA-TMA) is characterized by multifactorial endothelial damage caused by environmental stressors, dysregulation of the complement system, and genetic predisposition. Complement inhibitors have significantly decreased mortality and are the current treatment of choice. In this article, we describe our experience with the use of eculizumab in pediatric patients diagnosed with hrT-TMA after HSCT. Method: Retrospective study of pediatric patients with hrTA-TMA treated with eculizumab between January 2016 and December 2020. Results: Four pediatric patients aged 1, 12, 14, and 17 years at the time of HSCT were diagnosed with hrTA-TMA and treated with eculizumab during the study. At diagnosis, they all had renal impairment with proteinuria, and hypertension under treatment with at least two antihypertensive drugs. The patient who presented multisystemic involvement died instead of treatment. The three patients with exclusive renal involvement achieved TA-TMA resolution after treatment with eculizumab for 65, 52, and 40.6 weeks and were able to stop treatment. The two patients with follow-up data one year after eculizumab withdrawal sustained a favorable response. Eculizumab was well tolerated, and with adequate vaccination and antibiotic prophylaxis, did not increase the risk of infection. Conclusions: Eculizumab appears to be both safe and effective for the treatment of hrTA-TMA in patients with renal impairment. Early diagnosis and initiation of treatment may improve response. Eculizumab withdrawal can be contemplated in patients who achieve laboratory and clinical resolution of TA-TMA.
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Affiliation(s)
- Laura Gomez-Ganda
- Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Maria Isabel Benitez-Carabante
- Pediatric Oncology and Hematology Service, Hematopoietic Stem Cell Transplantation Section, Vall d'Hebron University Hospital, Barcelona, Spain
| | | | - Marina Muñoz-Lopez
- Pediatric Nephrology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Berta Renedo-Miro
- Pharmacy Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Gema Ariceta
- Pediatric Nephrology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cristina Diaz De Heredia
- Pediatric Oncology and Hematology Service, Hematopoietic Stem Cell Transplantation Section, Vall d'Hebron University Hospital, Barcelona, Spain
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37
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Elhadad S, Chapin J, Copertino D, Van Besien K, Ahamed J, Laurence J. MASP2 levels are elevated in thrombotic microangiopathies: association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab. Clin Exp Immunol 2021; 203:96-104. [PMID: 32681658 PMCID: PMC7405159 DOI: 10.1111/cei.13497] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 12/20/2022] Open
Abstract
Involvement of the alternative complement pathway (AP) in microvascular endothelial cell (MVEC) injury characteristic of a thrombotic microangiopathy (TMA) is well documented. However, the role of the lectin pathway (LP) of complement has not been explored. We examined mannose-binding lectin associated serine protease (MASP2), the effector enzyme of the LP, in thrombotic thrombocytopenic purpura, atypical hemolytic uremic syndrome and post-allogeneic hematopoietic stem cell transplantation (alloHSCT) TMAs. Plasma MASP2 and terminal complement component sC5b-9 levels were assessed by enzyme-linked immunosorbent assay (ELISA). Human MVEC were exposed to patient plasmas, and the effect of the anti-MASP2 human monoclonal antibody narsoplimab on plasma-induced MVEC activation was assessed by caspase 8 activity. MASP2 levels were highly elevated in all TMA patients versus controls. The relatively lower MASP2 levels in alloHSCT patients with TMAs compared to levels in alloHSCT patients who did not develop a TMA, and a significant decrease in variance of MASP2 levels in the former, may reflect MASP2 consumption at sites of disease activity. Plasmas from 14 of the 22 TMA patients tested (64%) induced significant MVEC caspase 8 activation. This was suppressed by clinically relevant levels of narsoplimab (1·2 μg/ml) for all 14 patients, with a mean 65·7% inhibition (36.8-99.4%; P < 0·0001). In conclusion, the LP of complement is activated in TMAs of diverse etiology. Inhibition of MASP2 reduces TMA plasma-mediated MVEC injury in vitro. LP inhibition therefore may be of therapeutic benefit in these disorders.
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Affiliation(s)
- S. Elhadad
- Department of MedicineDivision of Hematology and Medical OncologyWeill Cornell Medical CollegeNew YorkNYUSA
| | - J. Chapin
- Department of MedicineDivision of Hematology and Medical OncologyWeill Cornell Medical CollegeNew YorkNYUSA
- Present address:
CRISPR TherapeuticsCambridgeMAUSA
| | - D. Copertino
- Department of MedicineDivision of Hematology and Medical OncologyWeill Cornell Medical CollegeNew YorkNYUSA
| | - K. Van Besien
- Department of MedicineDivision of Hematology and Medical OncologyWeill Cornell Medical CollegeNew YorkNYUSA
| | - J. Ahamed
- Oklahoma Medical Research FoundationOklahoma CityOKUSA
| | - J. Laurence
- Department of MedicineDivision of Hematology and Medical OncologyWeill Cornell Medical CollegeNew YorkNYUSA
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38
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Zhou L, Wang Y, Zhou F, Ma X, He X. Elevated troponin in hematopoietic stem cell transplantation-associated thrombotic microangiopathy: A case report. THROMBOSIS UPDATE 2020. [DOI: 10.1016/j.tru.2020.100005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Complement blockade for TA-TMA: lessons learned from a large pediatric cohort treated with eculizumab. Blood 2020; 135:1049-1057. [PMID: 31932840 DOI: 10.1182/blood.2019004218] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/04/2020] [Indexed: 01/03/2023] Open
Abstract
Overactivated complement is a high-risk feature in hematopoietic stem cell transplant (HSCT) recipients with transplant-associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience with 64 pediatric HSCT recipients who had high-risk TA-TMA (hrTA-TMA) and multiorgan injury treated with the complement blocker eculizumab. We demonstrate significant improvement to 66% in 1-year post-HSCT survival in treated patients from our previously reported untreated cohort with same hrTA-TMA features that had 1-year post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive course of eculizumab using pharmacokinetic/pharmacodynamic-guided dosing, requiring a median of 11 doses of eculizumab (interquartile range [IQR] 7-20). Treatment was discontinued because TA-TMA resolved at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of treatment were less likely to respond (odds ratio, 0.15; P = .0014) and required more doses of eculizumab (r = 0.43; P = .0004). Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9; P = .0015), and had lower 1-year survival (44% vs 78%; P = .01). Over 70% of survivors had proteinuria on long-term follow-up. The best glomerular filtration rate (GFR) recovery in survivors was a median 20% lower (IQR, 7.3%-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for hrTA-TMA, but some patients with severe disease lacked a complete response, prompting us to propose early intervention and search for additional targetable endothelial injury pathways.
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40
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Mezö B, Horváth O, Sinkovits G, Veszeli N, Kriván G, Prohászka Z. Validation of Early Increase in Complement Activation Marker sC5b-9 as a Predictive Biomarker for the Development of Thrombotic Microangiopathy After Stem Cell Transplantation. Front Med (Lausanne) 2020; 7:569291. [PMID: 33117830 PMCID: PMC7574906 DOI: 10.3389/fmed.2020.569291] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is a multifactorial complication. Complement dysregulation may play an important role in the pathogenesis of TA-TMA. Our previous observations suggested that early increase of soluble C5b-9 (sC5b-9), before the development of other complications, can predict the development of later TA-TMA. The present study aims to validate our earlier findings in an independent cohort enrolling 67 pediatric patients who underwent allogeneic HSCT during the study period (October 2015–January 2019). Five different TA-TMA diagnostic criteria were applied, and all important clinical and laboratory parameters of TA-TMA activity were registered. Complement pathway activities, components and sC5b-9 levels were systematically measured before transplantation and on days 28, 56, and 100 after HSCT. A strong and remarkable association still have been found between early increase of sC5b-9 (10 of 10 patients with TA-TMA vs. 27 of 57 without TA-TMA; P = 0.002) and the development of TA-TMA during 100 days post-transplantation. An increase in sC5b-9 concentration had 100% sensitivity and 53% specificity for TA-TMA in the cohort. All TA-TMA cases have been observed during cyclosporine immunosuppression, no TA-TMA was diagnosed during tacrolimus or mycophenolat mofetil therapy. In the majority of patients TA-TMA was mild and self-limiting, without any signs of organ damage. No additional complement parameters were closely associated with the development of TA-TMA. Early raise of the sC5b-9 activation marker was predictive for later development of TA-TMA throughout the whole study period. In patients with a marked increase, early and frequent monitoring of TA-TMA activity markers should be attempted, to facilitate subsequent therapy decisions in time. However, patients with TA-TMA were only identified during or after cyclosporine immunosuppression. Further studies enrolling higher number of patients are necessary to determine the role of immunosuppression in the pathogenesis of TA-TMA.
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Affiliation(s)
- Blanka Mezö
- Research Laboratory, MTA-SE Research Group of Immunology and Hematology, Department of Internal Medicine and Hematology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Orsolya Horváth
- Pediatric Hematology and Bone Marrow Transplantation Unit, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - György Sinkovits
- Research Laboratory, MTA-SE Research Group of Immunology and Hematology, Department of Internal Medicine and Hematology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Nóra Veszeli
- Research Laboratory, MTA-SE Research Group of Immunology and Hematology, Department of Internal Medicine and Hematology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
| | - Gergely Kriván
- Pediatric Hematology and Bone Marrow Transplantation Unit, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
| | - Zoltán Prohászka
- Research Laboratory, MTA-SE Research Group of Immunology and Hematology, Department of Internal Medicine and Hematology, Hungarian Academy of Sciences, Semmelweis University, Budapest, Hungary
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Pérez I, Redín ME. Red Blood Cells and Platelets Conventional and Research Parameters: Stability Remarks Before Their Interpretation. Lab Med 2020; 51:460-468. [PMID: 31943061 DOI: 10.1093/labmed/lmz083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES To analyze the stability of red blood cells, platelets, and reticulocytes of the research parameters, in combination with the respective conventional parameters, for each analyte; and to quantify the morphological changes in these analytes, to propose a correction factor for each. METHODS Ethylenediaminetetraacetic acid (EDTA) blood specimens from patients were reanalyzed in 2-hour intervals and then, the mean percentage (X¯t%) changes were calculated. To evaluate the stability of the analyzed material, we used different criteria according to within-run and between-batch analytical variation, as well as intraindividual biological variation. Next, the mean deviation percentage of the parameters that undergo time-dependent significant changes was calculated, to obtain a correction factor. RESULTS Several conventional and research parameters showed significant alterations in the stability at an early time after arrival at the laboratory. CONCLUSION Cell variations over time can be quantified and corrected by applying a multiplying factor to the signal obtained in the analyzer.
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Affiliation(s)
| | - Maria Elena Redín
- Department of Laboratory Medicine, Core Laboratory, University Hospital Donostia, Guipuzcoa, Spain
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42
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New insights into risk factors for transplant-associated thrombotic microangiopathy in pediatric HSCT. Blood Adv 2020; 4:2418-2429. [PMID: 32492158 PMCID: PMC7284098 DOI: 10.1182/bloodadvances.2019001315] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 04/16/2020] [Indexed: 12/27/2022] Open
Abstract
This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation-based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD.
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Schoettler M, Lehmann LE, Margossian S, Lee M, Kean LS, Kao PC, Ma C, Duncan CN. Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort. Blood Adv 2020; 4:2536-2547. [PMID: 32516415 PMCID: PMC7284101 DOI: 10.1182/bloodadvances.2019001242] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 04/28/2020] [Indexed: 11/20/2022] Open
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT). Diagnosis is challenging and in the absence of a tissue biopsy, TA-TMA is provisionally diagnosed by meeting clinical criteria. In this study, we describe the prevalence, outcomes, and risk factors for meeting 2 different diagnostic criteria for TA-TMA and for increased transplant-related mortality (TRM). In this retrospective study of 307 pediatric HCT patients, records were reviewed for the first 100 days after HCT. Patients who were diagnosed with TA-TMA by a provider during this time were included. In addition, the Cho et al criteria (2010) and Jodele et al (2014) TA-TMA criteria were applied retrospectively. Eight patients (2.6%) were diagnosed with TA-TMA by their provider. However, on retrospective review, 20% and 36% met the Cho and Jodele criteria for TA-TMA, respectively. Overall survival was significantly worse (P < .0001) and TRM was significantly higher in patients who met criteria for TA-TMA (MC-TA-TMA) (P < .0001). After controlling for comorbid conditions, MC-TA-TMA (hazard ratio [HR], 10.9; P = .0001) and grade 3/4 acute graft-versus-host-disease (aGVHD) (HR 3.5; P = .01) remained independently associated with increased TRM. Among allogeneic HCT recipients, features associated with an increased risk for MC-TA-TMA included ≥2 HCT, concurrent grade 3/4 aGVHD and concurrent infections. Among patients who MC-TA-TMA, LDH ≥2 times the upper limit of normal (P = .001), the need for ≥2 antihypertensive medications (P < .0001), and acute kidney injury (P = .003) were associated with significantly increased TRM.
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Affiliation(s)
- Michelle Schoettler
- Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
- Children's Healthcare of Atlanta/Aflac Cancer Center, Atlanta, GA
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Leslie E Lehmann
- Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Steven Margossian
- Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Maia Lee
- Neuroscience Department, Wellesley College, Wellesley, MA; and
| | - Leslie S Kean
- Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Pei-Chi Kao
- Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
| | - Clement Ma
- Department of Pediatrics, Harvard Medical School, Boston, MA
- Hematology/Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
| | - Christine N Duncan
- Pediatric Hematopoietic Cellular Therapy, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
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Gloude NJ, Dandoy CE, Davies SM, Myers KC, Jordan MB, Marsh RA, Kumar A, Bleesing J, Teusink-Cross A, Jodele S. Thinking Beyond HLH: Clinical Features of Patients with Concurrent Presentation of Hemophagocytic Lymphohistiocytosis and Thrombotic Microangiopathy. J Clin Immunol 2020; 40:699-707. [PMID: 32447592 PMCID: PMC7245179 DOI: 10.1007/s10875-020-00789-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 05/04/2020] [Indexed: 12/14/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation driven mainly by high levels of interferon gamma. The clinical presentation of HLH can have considerable overlap with other inflammatory conditions. We present a cohort of patients with therapy refractory HLH referred to our center who were found to have a simultaneous presentation of complement-mediated thrombotic microangiopathy (TMA). Twenty-three patients had therapy refractory HLH (13 primary, 4 EVB-HLH, 6 HLH without known trigger). Sixteen (69.6%) met high-risk TMA criteria. Renal failure requiring renal replacement therapy, severe hypertension, serositis, and gastrointestinal bleeding were documented only in patients with HLH who had concomitant complement-mediated TMA. Patients with HLH and without TMA required ventilator support mainly due to CNS symptoms, while those with HLH and TMA had respiratory failure predominantly associated with pulmonary hypertension, a known presentation of pulmonary TMA. Ten patients received eculizumab for complement-mediated TMA management while being treated for HLH. All patients who received the complement blocker eculizumab in addition to the interferon gamma blocker emapalumab had complete resolution of their TMA and survived. Our observations suggest co-activation of both interferon and complement pathways as a potential culprit in the evolution of thrombotic microangiopathy in patients with inflammatory disorders like refractory HLH and may offer novel therapeutic approaches for these critically ill patients. TMA should be considered in children with HLH and multi-organ failure, as an early institution of a brief course of complement blocking therapy in addition to HLH-targeted therapy may improve clinical outcomes in these patients.
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Affiliation(s)
- Nicholas J Gloude
- Department of Pediatrics, University of California San Diego, San Diego, USA.,Division of Hematology Oncology, Rady Children's Hospital, San Diego, USA
| | - Christopher E Dandoy
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Stella M Davies
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Kasiani C Myers
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Michael B Jordan
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Rebecca A Marsh
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Ashish Kumar
- Division of Hematology Oncology, Rady Children's Hospital, San Diego, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA
| | - Jack Bleesing
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Ashley Teusink-Cross
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA.,Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
| | - Sonata Jodele
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, USA. .,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
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45
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Hildebrandt GC, Chao N. Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation. Br J Haematol 2020; 190:508-519. [PMID: 32319084 PMCID: PMC7496350 DOI: 10.1111/bjh.16621] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 03/09/2020] [Indexed: 12/16/2022]
Abstract
Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro-inflammatory and pro-apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post-HCT conditions, including veno-occlusive disease/sinusoidal obstruction syndrome, graft-versus-host disease, transplant-associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT-related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.
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Affiliation(s)
| | - Nelson Chao
- Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
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46
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Jodele S, Medvedovic M, Luebbering N, Chen J, Dandoy CE, Laskin BL, Davies SM. Interferon-complement loop in transplant-associated thrombotic microangiopathy. Blood Adv 2020; 4:1166-1177. [PMID: 32208488 PMCID: PMC7094010 DOI: 10.1182/bloodadvances.2020001515] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 02/26/2020] [Indexed: 12/16/2022] Open
Abstract
Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an "interferon-complement loop" that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
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Affiliation(s)
- Sonata Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Mario Medvedovic
- Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH; and
| | - Nathan Luebbering
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Jenny Chen
- Division of Biostatistics and Bioinformatics, Department of Environmental Health, University of Cincinnati, Cincinnati, OH; and
| | - Christopher E Dandoy
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Benjamin L Laskin
- Division of Nephrology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Stella M Davies
- Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
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47
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Sartain S, Shubert S, Wu MF, Wang T, Martinez C. The alternative complement pathway activation product Ba as a marker for transplant-associated thrombotic microangiopathy. Pediatr Blood Cancer 2020; 67:e28070. [PMID: 31774252 DOI: 10.1002/pbc.28070] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 09/24/2019] [Accepted: 10/22/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND Transplant-associated thrombotic microangiopathy (TA-TMA) occurs after hematopoietic stem cell transplantation (HSCT) and is characterized by microvascular thrombosis and end-organ injury particularly of the kidneys. TA-TMA is challenging to diagnose and treat, which can lead to long-term complications and death in patients with severe disease. Studies have shown that genetic abnormalities of the alternative complement pathway (AP) are associated with TA-TMA. We hypothesized that patients with TA-TMA may generate elevated levels of the AP activation product, Ba, compared with HSCT patients without TA-TMA. PROCEDURE We longitudinally measured plasma levels of complement activation products C3a, Ba, and C5a in 14 HSCT patients: 7 with TA-TMA and 7 without TA-TMA. We assessed renal function by calculating estimated glomerular filtration rate (eGFR) and correlated the extent of AP activation with renal dysfunction in both patient populations. RESULTS The median days from HSCT to study enrollment were 154 (39-237) in the TA-TMA group and 84 (39-253) in the HSCT group without TA-TMA. Median Ba levels (ng/mL) at enrollment were 1096.9 (826.5-1562.0) in the TA-TMA group and 725.7 (494.7-818.9) in the HSCT group without TA-TMA (P = 0.007). Over the study duration, Ba levels inversely correlated with eGFR. There were no differences in C3a, C5a, or sC5b9 levels between the two populations at any measured interval. CONCLUSIONS We conclude in this preliminary study that Ba protein may serve as a marker for TA-TMA, and furthermore, that components generated in the early phase of AP activation may be involved in the pathogenesis of renal endothelial injury in TA-TMA.
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Affiliation(s)
- Sarah Sartain
- Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
| | - Stacey Shubert
- Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
| | - Meng-Fen Wu
- Biostatistics Shared Resource, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
| | - Tao Wang
- Biostatistics Shared Resource, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
| | - Caridad Martinez
- Department of Pediatrics, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
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Guo QX, Zhang MY, Wang JG, Zhou F, Liu YQ, Liu JH. [Pulmonary arterial hypertension caused by graft-related thrombotic microangiopathy after ETP-ALL haplotype hematopoietic stem cell transplantation: a case report and literatures review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2020; 41:164-166. [PMID: 32135636 PMCID: PMC7357948 DOI: 10.3760/cma.j.issn.0253-2727.2020.02.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Indexed: 01/23/2023]
Affiliation(s)
- Q X Guo
- Department of Hematology, The General Hospital of Northern Theater Command, Shenyang 110016, China
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García-Martín E, Manrique-Rodríguez S, Martínez Fernández-Llamazares C, Goicoechea-Diezhondino M, Álvarez-Blanco O, García-Morín M, Sanjurjo-Sáez M. Variability in management and outcomes of therapy with eculizumab in atypical hemolytic uremic syndrome. Expert Opin Orphan Drugs 2019. [DOI: 10.1080/21678707.2019.1703108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- Estela García-Martín
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Silvia Manrique-Rodríguez
- Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | | | - Marian Goicoechea-Diezhondino
- Nephrology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Olalla Álvarez-Blanco
- Pediatric Nephrology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marina García-Morín
- Pediatric Oncohematology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - María Sanjurjo-Sáez
- Director of Pharmacy Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
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50
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Zhang C, Tan X, Yao H, Liu Y, Gao L, Gao L, Kong PY, Zhang X. Successful Treatment of Veno-occlusive Disease, Transplantation-Associated Thrombotic Microangiopathy, and Acute Graft-vs-Host Disease in a Patient with Relapsed Epstein-Barr Hemophagocytic Lymphohistiocytosis After Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report. Transplant Proc 2019; 51:3159-3162. [PMID: 31711585 DOI: 10.1016/j.transproceed.2019.02.032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 01/07/2019] [Accepted: 02/03/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Allogenic hematopoietic stem cell transplantation may be the best currently available method to treat relapsed hemophagocytic lymphohistiocytosis (HLH) related to Epstein-Barr virus. The high rate of transplantation-related complications was initially the main obstacle preventing the wider adoption of this protocol; however, the previously more common complications, such as infection and graft failure, have fallen to very low levels with the development of new drugs and methods. Some other complications, such as veno-occlusive disease and transplantation associated thrombotic microangiopathy, are rare after allogenic hematopoietic stem cell transplantation, but the morbidity and mortality associated with them are very high. CASE PRESENTATION A patient with relapsed HLH related to Epstein-Barr virus showed the sequential severe complications of veno-occlusive disease, transplantation-associated thrombotic microangiopathy, and acute graft-vs-host disease after haploidentical transplantation. This patient was successfully treated by stopping administration of calcineurin inhibitors and instead treating with defibrotide, rituximab, CD25 monoclonal antibody, atorvastatin calcium tablets, methylprednisolone, budesonide, continuous plasma exchange, and bedside ultrafiltration. At the last follow-up, the patient had been living disease free for 2 years without any other complications. CONCLUSION Epstein-Barr virus related-HLH patients have severe clinical features and currently poor prognosis. Allogenic hematopoietic stem cell transplantation may be the best way to treat this disease; however, the management of related complications is vital in the improvement of long-term survival.
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Affiliation(s)
- Cheng Zhang
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Xu Tan
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Han Yao
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Yao Liu
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Lei Gao
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Li Gao
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Pei-Yan Kong
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China
| | - Xi Zhang
- Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, People's Republic of China.
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