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The Importance of New EBMT Criteria on the Diagnosis of Veno-Occlusive Liver Disease in Children
Füssiová, M., Švec, P., Horáková, J., Sedláček, P., Rohoň, P., Celec, P., Boďová, I., Adamčáková, J., Sýkora, T., Dobšinská, V., et al
Journal of clinical medicine. 2023;12(3)
Abstract
BACKGROUND Early recognition and specific therapy facilitate a favorable disease course in hepatic venous-occlusive disease (HVOD) following hematopoietic stem cell transplantation (HCT). Diagnostic and classification criteria, published by the European Society for Blood and Marrow Transplantation (EBMT), better account for clinical differences in disease presentation in pediatric populations. OBJECTIVES To compare the course of HVOD in children before and after the implementation of new EBMT criteria. MATERIAL AND METHODS The study retrospectively evaluates 26 HVODs in 179 children treated in a single HCT unit (Slovakia) comparing the period of 2014-2017 using the Baltimore and modified Seattle criteria with the period of 2018-2021, when new EBMT criteria were adopted. RESULTS No difference in HVOD incidence (11.2% vs. 14.8%, p = 0.46) and in time of diagnosis post-HCT (15.6 days vs. 15.7 days, p = 0.75) was found. With EBMT criteria we observed more frequent anicteric disease at diagnosis (50% vs. 87.5%, p = 0.04), lower serum bilirubin at diagnosis (3.4 mg/dL vs. 1.23 mg/dL, p = 0.045), and non-significant trends of shorter defibrotide treatment (21.7 days vs. 15.6 days, p = 0.73), decreased mortality (30% vs. 6.2%, p = 0.10) and shorter hospitalization (73.1 days vs. 59.6 days, p = 0.54). CONCLUSIONS Different time periods around the implementation of new criteria are evaluated, underling that pediatric EBMT criteria for post-transplant HVOD diagnosis appear more sensitive.
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Extracorporeal membrane oxygenation in adults receiving haematopoietic cell transplantation: an international expert statement
Di Nardo, M., MacLaren, G., Schellongowski, P., Azoulay, E., DeZern, A. E., Gutierrez, C., Antonelli, M., Antonini, M. V., Beutel, G., Combes, A., et al
The Lancet. Respiratory medicine. 2023
Abstract
Combined advances in haematopoietic cell transplantation (HCT) and intensive care management have improved the survival of patients with haematological malignancies admitted to the intensive care unit. In cases of refractory respiratory failure or refractory cardiac failure, these advances have led to a renewed interest in advanced life support therapies, such as extracorporeal membrane oxygenation (ECMO), previously considered inappropriate for these patients due to their poor prognosis. Given the scarcity of evidence-based guidelines on the use of ECMO in patients receiving HCT and the need to provide equitable and sustainable access to ECMO, the European Society of Intensive Care Medicine, the Extracorporeal Life Support Organization, and the International ECMO Network aimed to develop an expert consensus statement on the use of ECMO in adult patients receiving HCT. A steering committee with expertise in ECMO and HCT searched the literature for relevant articles on ECMO, HCT, and immune effector cell therapy, and developed opinion statements through discussions following a Quaker-based consensus approach. An international panel of experts was convened to vote on these expert opinion statements following the Research and Development/University of California, Los Angeles Appropriateness Method. The Appraisal of Guidelines for Research and Evaluation statement was followed to prepare this Position Paper. 36 statements were drafted by the steering committee, 33 of which reached strong agreement after the first voting round. The remaining three statements were discussed by all members of the steering committee and expert panel, and rephrased before an additional round of voting. At the conclusion of the process, 33 statements received strong agreement and three weak agreement. This Position Paper could help to guide intensivists and haematologists during the difficult decision-making process regarding ECMO candidacy in adult patients receiving HCT. The statements could also serve as a basis for future research focused on ECMO selection criteria and bedside management.
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Prospective clinical and biomarker validation of the ASTCT consensus definition for transplant-associated thrombotic microangiopathy (TA-TMA)
Ma, S., Bhar, S., Guffey, D., Kim, R. B., Jamil, M., Amos, C. I., Lee, S. J., Hingorani, S. R., Sartain, S. E., Li, A.
Transplantation and cellular therapy. 2023
Abstract
INTRODUCTION Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications post-allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging due to non-standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study and to compare the impact and outcomes of employing the current clinical TMA definition (cTMA) versus the new consensus definition. METHODS We included patients aged 0 to 18 years who underwent their first allo-HCT from May 2021 to January 2023 at Texas Children's Hospital. We compared the incidence, biomarkers, and outcomes of TA-TMA applying the previous and recently proposed screening algorithms and definitions. RESULTS While the classic microangiopathic hemolytic anemia (MAHA)-based cTMA definition led to an incidence of 12.7%, the ASTCT-HR definition doubled the incidence to 28.5% by day 100. In contrast to patients with concordant diagnosis (+/+) who had significantly worse post-transplant survival, those reclassified as TA-TMA by the new definition only (-/+) had significantly different prognosis (100% survival at day 100) despite the lack of TMA-directed therapy. Furthermore, biomarkers of the terminal and alternative complement pathways (sC5b9 and Ba, respectively) were significantly elevated around day 15 in the concordant group (+/+) but not in the discordant group (-/+) when compared to the non-TMA patients. CONCLUSIONS The recently proposed ASTCT consensus TA-TMA diagnosis is more sensitive and allows earlier recognition of manifestation that requires closer clinical monitoring but risks over-diagnosis and over-treatment. We recommend additional prospective validation.
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[Cardiac complications following allogeneic hematopoietic stem cell transplantation: Recommendations of the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC)]
Ahmad, I., Souchet, L., Hamzy, F., Ceballos, P., Desbrosses, Y., Ravinet, A., Turlure, P., Villate, A., Borel, C., Benbarkat, H., et al
Bulletin du cancer. 2022
Abstract
Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can lead to early cardiac complications as well as late sequelae. A cardiac evaluation is essential in the pre-transplant assessment given the patient's comorbidities and previous chemotherapy treatments received. Various thresholds of cardiac function are recommended as eligibility criteria. The rise of haplo-identical transplantation with the use of post-transplant high-dose cyclophosphamide (PT-Cy) as a prophylaxis against graft-versus-host disease (GVHD) is accompanied by a resurgence of cardiological concerns. Arrhythmias are also a concern and the list of drugs implicated in this complication is growing. The rare occurrence of cardiac GVHD has been reported, although the entity is not well defined. Finally, although long-term follow-up recommendations exist, they are not accompanied by specific targets for cardiovascular risk factors, the presence of which is nevertheless increased after HSCT. In the framework of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) practice harmonization workshops held in Lille in September 2019, the prophylaxis, the diagnostic approach and the treatments of cardiac complication following HSCT were reviewed after analysis of published studies.
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Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplant Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation (EBMT), American Society for Transplantation and Cellular Therapy (ASTCT), Asia-Pacific Blood and Marrow Transplantation Group (APBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR)
Schoettler, M., Carreras, E., Cho, B., Dandoy, C. E., Ho, V. T., Jodele, S., Moissev, I., Sanchez-Ortega, I., Srivastava, A., Atsuta, Y., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND/RATIONALE Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplant (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis and multiple criteria are proposed without universal application. While some patients have a self-resolving disease, others progress to multi-organ failure and/or death. Poor prognostic features are also not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers have precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives, forming an expert panel to come to a consensus on diagnostic and prognostic criteria. METHODS The panel reviewed literature, generated consensus statements using the Delphi Method regarding diagnostic and prognostic features of TA-TMA, and identified future directions of investigation. SUMMARY OF CONSENSUS STATEMENTS Consensus was reached on four key concepts. 1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue. However, a biopsy is not required. 2) Consensus diagnostic criteria are proposed using modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥ 4/7 following features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment, hemoglobin decline by ≥1 gm/dL, or new onset transfusion dependence, thrombocytopenia defined as failure to achieve platelet engraftment, higher than expected transfusion needs, refractory to platelet transfusions, or ≥ 50% reduction in baseline platelet count after full platelet engraftment, lactate dehydrogenase (LDH) >ULN, schistocytes, hypertension, sC5b-9>ULN and proteinuria (≥ 1mg/mg random urine protein creatinine ratio, rUPCR). 3) Patients with any of the following features have an increased risk of non-relapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2X ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft versus host disease, or infection (bacterial or viral). 4) All allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. If patients are diagnosed with TA-TMA, they should be risk stratified. Patients with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. FUTURE DIRECTIONS We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indication, and transplant characteristics. As these criteria are broadly utilized, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Lastly, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications such as steroid-refractory GVHD and infection, is critically needed.
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Clinical practice guideline for the prevention of oral and oropharyngeal mucositis in pediatric cancer and hematopoietic stem cell transplant patients: 2021 update
Patel, P., Robinson, P. D., Baggott, C., Gibson, P., Ljungman, G., Massey, N., Ottaviani, G., Phillips, R., Revon-Rivière, G., Treister, N., et al
European journal of cancer (Oxford, England : 1990). 2021;154:92-101
Abstract
PURPOSE To update the 2015 clinical practice guideline for the prevention of oral mucositis in pediatric cancer or hematopoietic stem cell transplant (HSCT) patients. METHODS We performed seven systematic reviews of mucositis prevention. Three reviews included randomized controlled trials (RCTs) conducted in pediatric and adult patients evaluating cryotherapy, keratinocyte growth factor (KGF) or photobiomodulation therapy with a focus on efficacy. Three reviews included studies of any design conducted in pediatric patients evaluating these same interventions with a focus on adverse events and feasibility. One review included all RCTs of any intervention for mucositis prevention in pediatric patients. Primary outcome was severe oral mucositis. RESULTS We included 107 unique studies of cryotherapy (22 RCTs and 4 pediatric studies); KGF (15 RCTs and 12 pediatric studies); photobiomodulation therapy (29 RCTs and 8 pediatric studies) and any intervention (31 pediatric RCTs). Effects on severe mucositis reduction from RCTs were cryotherapy risk ratio (RR) 0.49 and 95% confidence interval (CI) 0.31-0.76; palifermin RR 0.81 and 95% CI 0.69-0.95 and photobiomodulation therapy RR 0.40 and 95% CI 0.27-0.60. Cryotherapy was not feasible in young children while photobiomodulation therapy was feasible across age groups. Palifermin was associated with adverse effects. CONCLUSIONS Cryotherapy should be used for older cooperative pediatric patients who will receive short infusions of melphalan or 5-fluorouracil. Intraoral photobiomodulation therapy (620-750 nm spectrum) should be used in pediatric patients undergoing autologous or allogeneic HSCT and for pediatric head and neck carcinoma patients undergoing radiotherapy. Palifermin should not be used routinely in pediatric cancer or HSCT patients.
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Candidacy for Extracorporeal Life Support in Children After Hematopoietic Cell Transplantation: A Position Paper From the Pediatric Acute Lung Injury and Sepsis Investigators Network's Hematopoietic Cell Transplant and Cancer Immunotherapy Subgroup
Zinter, M. S., McArthur, J., Duncan, C., Adams, R., Kreml, E., Dalton, H., Abdel-Azim, H., Rowan, C. M., Gertz, S. J., Mahadeo, K. M., et al
Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2021
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Abstract
OBJECTIVES The last decade has seen improved outcomes for children requiring extracorporeal life support as well as for children undergoing hematopoietic cell transplantation. Thus, given the historically poor survival of hematopoietic cell transplantation patients using extracorporeal life support, the Pediatric Acute Lung Injury and Sepsis Investigators' hematopoietic cell transplantation and cancer immunotherapy subgroup aimed to characterize the utility of extracorporeal life support in facilitating recovery from critical cardiorespiratory illnesses in pediatric hematopoietic cell transplantation patients. DATA SOURCES All available published data were identified using a set of PubMed search terms for pediatric extracorporeal life support and hematopoietic cell transplantation. STUDY SELECTION All articles that provided original reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support were included. Sixty-four manuscripts met search criteria. Twenty-four were included as primary reports of pediatric hematopoietic cell transplantation patients who underwent extracorporeal life support (11 were single case reports, four single institution case series, two multi-institution case series, and seven registry reports from Extracorporeal Life Support Organization, Pediatric Heath Information System, and Virtual Pediatric Systems). DATA EXTRACTION All 24 articles were reviewed by first and last authors and a spread sheet was constructed including sample size, potential biases, and conclusions. DATA SYNTHESIS Discussions regarding incorporation of available evidence into our clinical practice were held at biannual meetings, as well as through email and virtual meetings. An expert consensus was determined through these discussions and confirmed through a modified Delphi process. CONCLUSIONS Extracorporeal life support in hematopoietic cell transplantation patients is being used with increasing frequency and potentially improving survival. The Pediatric Acute Lung Injury and Sepsis Investigators hematopoietic cell transplantation-cancer immunotherapy subgroup has developed a framework to guide physicians in decision-making surrounding extracorporeal life support candidacy in pediatric hematopoietic cell transplantation patients. In addition to standard extracorporeal life support considerations, candidacy in the hematopoietic cell transplantation population should consider the following six factors in order of consensus agreement: 1) patient comorbidities; 2) underlying disease necessitating hematopoietic cell transplantation; 3) hematopoietic cell transplantation toxicities, 4) family and patient desires for goals of care; 5) hematopoietic cell transplantation preparatory regimen; and 6) graft characteristics. Although risk assessment may be individualized, data are currently insufficient to clearly delineate ideal candidacy. Therefore, we urge the onco-critical care community to collaborate and capture data to provide better evidence to guide physicians' decision-making in the future.
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Extracorporeal membrane oxygenation in children receiving haematopoietic cell transplantation and immune effector cell therapy: an international and multidisciplinary consensus statement
Di Nardo, M., Ahmad, A. H., Merli, P., Zinter, M. S., Lehman, L. E., Rowan, C. M., Steiner, M. E., Hingorani, S., Angelo, J. R., Abdel-Azim, H., et al
The Lancet. Child & adolescent health. 2021
Abstract
Use of extracorporeal membrane oxygenation (ECMO) in children receiving haematopoietic cell transplantation (HCT) and immune effector cell therapy is controversial and evidence-based guidelines have not been established. Remarkable advancements in HCT and immune effector cell therapies have changed expectations around reversibility of organ dysfunction and survival for affected patients. Herein, members of the Extracorporeal Life Support Organization (ELSO), Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network (HCT and cancer immunotherapy subgroup), the Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation (EBMT), the supportive care committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC), and the Pediatric Intensive Care Oncology Kids in Europe Research (POKER) group of the European Society of Pediatric and Neonatal Intensive Care (ESPNIC) provide consensus recommendations on the use of ECMO in children receiving HCT and immune effector cell therapy. These are the first international, multidisciplinary consensus-based recommendations on the use of ECMO in this patient population. This Review provides a clinical decision support tool for paediatric haematologists, oncologists, and critical care physicians during the difficult decision-making process of ECMO candidacy and management. These recommendations can represent a base for future research studies focused on ECMO selection criteria and bedside management.
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Veno-occlusive Disease in HSCT Patients: Consensus-based Recommendations for Risk Assessment, Diagnosis, and Management by the GITMO Group
Bonifazi, F., Sica, S., Angeletti, A., Marktel, S., Prete, A., Iori, A. P., Olivari, D., Rossetti, G., Bertaina, A., Botti, S., et al
Transplantation. 2020
Abstract
Variation in clinical practice affects veno-occlusive disease (VOD) management, mainly in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT). Disputes about diagnostic criteria, treatment and prophylaxis, due to the lack of high-quality data, are at the base of this variability. With the aim of limiting inconsistency in clinical care, thus improving both patient outcomes and data collection reliability, the Italian Society of Stem cell transplant (GITMO) launched a collaborative effort to formulate recommendations based on integration of available evidence and expert's consensus. A systematic method, according to US National Institute of Health (NIH) guidelines and Italian National System for Guidelines, was used. Twenty-nine recommendations were approved with a strong (20) or weak (9) level of agreement, while 26 were rejected. In particular, the Panel pointed out the need to achieve an early diagnosis, encouraging the adoption of EBMT criteria and the prompt use of ultrasonography. Moreover, our experts strongly recommended in favour of prophylactic use of ursodeoxicolic acid (UDCA). As soon as a VOD diagnosis is established, treatment with defibrotide should be started for at least 21d. A number of areas of uncertainty, particularly concerning risk stratification and use of diagnostic tools such as elastography has been identified and discussed.
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Nursing role in the assessment and care of hepatic sinusoidal obstruction syndrome patients: a consensus paper by the "Gruppo Italiano Trapianto di Midollo Osseo"
Botti, S., Agreiter, I., Orlando, L., Gargiulo, G., Bonifazi, F., Banfi, M. M., Cappucciati, L., Caffarri, C., De Cecco, V., Deiana, G. M., et al
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2020
Abstract
PURPOSE Sinusoidal obstruction syndrome (SOS) is one of the most serious complications post haematopoietic stem cell transplantation (HSCT). The diagnosis of SOS is clinical, but nurses should be involved in the pre-transplant risk assessment period and play a crucial role in the early detection of signs and symptoms during and after hospitalization. The aim of this work is to achieve a consensus on nurses' behaviour in caring for SOS. METHODS On behalf of the Italian Group for Bone and Marrow Transplantation (GITMO), a promoter committee was established to put in place a consensus conference approach. A multidisciplinary group of GITMO together with four nurses, three haematology physicians and one patient representative acted as jury, who reviewed the reports and wrote recommendations and suggestions. Recommendations gaining 100% of consensus were considered 'Golden Points of Care'; if a consensus was achieved by ≥ 75% of the jury's members, those recommendations were defined as 'Good Practices'. RESULTS Eighteen papers written by nurses as first authors have been identified. Golden Points of Care and Good Practices were worked out for the following topics: nurses' role in general, nurses' role in pre-transplant assessment, pre-transplant risk assessment and risk stratification, baseline monitoring, suspected mild or moderate SOS, suspected severe or very severe SOS and late-onset cases. CONCLUSION SOS is relatively rare; therefore, a holistic approach to the patients' needs considering nursing role as essential may result in better care outcomes.