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Incidence and Risk Factors of Early Onset VOD/SOS Differ in Younger vs Older Adults After Stem Cell Transplantation
Marcoux, C., Saliba, R. M., Wallis, W., Khazal, S. J., Ragoonanan, D., Rondon, G., Tewari, P., Popat, U. R., Oran, B., Olson, A. L., et al
Blood advances. 2024
Abstract
Veno-occlusive disease (VOD) is a rare but potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). While increasing awareness and modern transplant techniques have mitigated risk, the interaction of historic risk factors in the current era with post-transplant cyclophosphamide (PTCy) is unknown. We performed a retrospective single center analysis of adult patients 18 years or older undergoing allo-SCT (N=1561) using predominately PTCy as GVHD prophylaxis (72%). We found a higher rate of VOD at 16.8% (20/119) in those aged ≤ 25 years compared to 3.8% (55/1442) in those >25 years, with unique predictors of VOD within each cohort. Multivariate classification and regression tree (CART) analysis confirmed age as the primary independent determinant of the rate of VOD. Within patients aged 18-25 years, disease risk index (DRI) (31% with high/very high DRI vs 12% low/intermediate DRI; p=0.03) and prior lines of chemotherapy (24% with >1 vs 6% with ≤1, p=0.03) were the strongest predictors of VOD. Incidence of VOD in patients > 25 years of age consistently ranged between 3-5% across most risk factors evaluated, with only hepatic factors (baseline elevation of bilirubin, aspartate transferase (AST), alanine aminotransferase (ALT)) or gemtuzumab exposure associated with increased rates of VOD. There was no significant difference in rates of VOD in those receiving PTCy compared to those receiving alternate GVHD prophylaxis. Our data highlight the differences in incidence and predictors in VOD between younger (≤25) and older (>25) adults undergoing allo-SCT.
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Post-Transplant Complications in Patients Undergoing Autologous Hematopoietic Cell Transplantation (HCT)-A Comparative Analysis of Home Care versus Hospitalized Patients
Garcés-Carrasco, A. M., Santacatalina-Roig, E., Carretero-Márquez, C., Chover-Sierra, E., Martínez-Sabater, A., Balaguer-López, E.
Medicina (Kaunas, Lithuania). 2023;60(1)
Abstract
Background and Objectives: The increase in indications for hematopoietic cell transplants (HCTs) has led to the development of new care options after said transplant, such as home care after transplantation, which improves the patients' quality of life. The main purpose of this research is to analyze the differences in the appearance of post-transplant complications between patients having underwent autologous HCT with at-home post-transplant modalities and those under in-hospital post-transplant care. Materials and Methods: An observational, analytical, longitudinal, and retrospective study of cases and controls. All transplanted people in the domiciliary model since 2020 are included as cases (20 subjects). For each case, two controls (40 subjects) are proposed among patients who received an autologous transplant in a hospital in the last five years with a similar demographic and pathological base profile in each case. Results: No significant differences were found between cases and controls, except for the Karnofsky value, which was higher in people receiving home treatment (91.7% vs. 87.74%; p = 0.05). The average number of days of the process post-transplantation was more significant at home (processing days 22.4 ± 2.6; post-transplantation days of 16.4 ± 2.08 versus 21.21 ± 4.18, with a mean of 15.51 ± 3.96 days post-transplant (days of the process p = 0.022; days post-transplant p = 0.002)). There is a more significant presence of neutropenic fever, mucositis, and positive blood cultures in the post-transplant patients who remain in the hospital. In contrast, the patients receiving home care post-transplantation undergo significantly more weight loss. Regarding the odds ratio of the appearance of adverse events, in the hospital setting, it is up to 8.5 times more likely to encounter neutropenic fever, 4.63 times more likely for mucositis, and 6.65 times more likely for the presence of pathogens in blood cultures. Conclusions: The home care modality in the post-transplant phase does not show an inferiority in conditions in the management and safety of the patient concerning the appearance of adverse events. However, more significant weight loss is detected in patients at home, and an increased risk of episodes of neutropenic fever, mucositis, and positive blood cultures for patients in hospital settings.
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Lung Injury Prediction Model in Bone Marrow Transplantation: A Multicenter Cohort Study
Herasevich, S., Schulte, P. J., Hogan, W. J., Alkhateeb, H., Zhang, Z., White, B. A., Khera, N., Roy, V., Gajic, O., Yadav, H.
American journal of respiratory and critical care medicine. 2023
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Abstract
RATIONALE Pulmonary complications contribute significantly to non-relapse mortality following hematopoietic stem cell transplantation (HCT). Identifying high-risk patients can help enroll such patients into clinical studies to better understand, prevent and treat post-transplant respiratory failure syndromes. OBJECTIVE Develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. METHODS Patients underwent HCT between January 1, 2019, and December 31, 2021. Those in Rochester, Minnesota formed the derivation cohort and those from Scottsdale, Arizona or Jacksonville, Florida formed the validation cohort. The primary outcome was development of acute respiratory distress syndrome (ARDS), with secondary outcomes including need for invasive/noninvasive ventilation. Predictors were based on prior case-control studies. MEASUREMENTS AND MAIN RESULTS Of 2450 patients undergoing stem cell transplantation, there were 1718 hospitalizations (888 patients) in the training cohort and 1005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from pre-hospital predictors and 11 points from post-transplant or early (<24h) in-hospital predictors. The model performed well for predicting ARDS (C-statistic = 0.905, 95%CI: 0.870-0.941) and need for invasive/noninvasive ventilation (C-statistic = 0.863, 95%CI: 0.828-0.898). The test cohort differed markedly in demographic, medical and hematologic characteristics. The model performed well in this setting as well for predicting ARDS (C-statistic = 0.841 (95%CI: 0.782-0.900) and need for invasive/noninvasive ventilation (C-statistic = 0.872, 95%CI: 0.831-0.914). CONCLUSION A novel prediction model incorporating data elements from the pre-transplant, post-transplant and early in-hospital domains can reliably predict development of post-HCT acute respiratory failure.
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Intensive Care Risk and Long-Term Outcomes in Pediatric Allogeneic Hematopoietic Cell Transplant Recipients
Zinter, M. S., Brazauskas, R., Strom, J., Chen, S., Bo-Subait, S., Sharma, A., Beitinjaneh, A., Dimitrova, D., Guilcher, G., Preussler, J. M., et al
Blood advances. 2023
Abstract
Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in ICU utilization and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6,995 pediatric HCT patients age ≤21 years who underwent 1st allogeneic HCT between 2008-2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years post-HCT), and was linked to demographic background, pre-transplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7% but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pre-transplant organ function, and alloreactivity risk-factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (p<0.001). Thus, while ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select high-risk patients.
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HokUS-10 scoring system predicts the treatment outcome for sinusoidal obstruction syndrome after allogeneic hematopoietic stem cell transplantation
Shiratori, S., Okada, K., Sugita, J., Nishida, M., Iwai, T., Ota, S., Hashimoto, D., Teshima, T.
Scientific reports. 2023;13(1):17374
Abstract
Hepatic sinusoidal obstruction syndrome (SOS) is a severe and life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a multi-center retrospective study to evaluate the utility of our ultrasonographic scoring system for the diagnosis of SOS (HokUS-10) in predicting SOS-related mortality (SOS-RM). We analyzed a total of 42 patients who developed SOS after HSCT. The cumulative incidences of SOS-RM, non-relapse mortality (NRM), and overall survival at day 180 after the diagnosis of SOS were 26.4%, 28.8% and 54.5%, respectively. The area under the receiver operating characteristic curve analysis showed that the optimal cut-off value of HokUS-10 total score to predict SOS-RM was 8 points after the treatment of SOS. In the individual HokUS-10 score, ascites and portal vein flow-related scores (PV mean velocity and PV flow direction) after the treatment of SOS were shown as significant risk factors for SOS-RM. Our study suggested that US findings after the treatment can predict the treatment outcomes for SOS.
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Association of atrial fibrillation and outcomes in patients undergoing bone marrow transplantation
Krishan, S., Munir, M. B., Khan, M. Z., Al-Juhaishi, T., Nipp, R., DeSimone, C. V., Deshmukh, A., Stavrakis, S., Barac, A., Asad, Z. U. A.
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2023;25(5)
Abstract
AIMS: Haematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for several malignant and non-malignant haematologic conditions. Patients undergoing HSCT are at an increased risk of developing atrial fibrillation (AF). We hypothesized that a diagnosis of AF would be associated with poor outcomes in patients undergoing HSCT. METHODS AND RESULTS The National Inpatient Sample (2016-19) was queried with ICD-10 codes to identify patients aged >50 years undergoing HSCT. Clinical outcomes were compared between patients with and without AF. A multivariable regression model adjusting for demographics and comorbidities was used to calculate the adjusted odds ratio (aOR) and regression coefficients with corresponding 95% confidence intervals and P-values. A total of 50 570 weighted hospitalizations for HSCT were identified, out of which 5820 (11.5%) had AF. Atrial fibrillation was found to be independently associated with higher inpatient mortality (aOR 2.75; 1.9-3.98; P < 0.001), cardiac arrest (aOR 2.86; 1.55-5.26; P = 0.001), acute kidney injury (aOR 1.89; 1.6-2.23; P < 0.001), acute heart failure exacerbation (aOR 5.01; 3.54-7.1; P < 0.001), cardiogenic shock (aOR 7.73; 3.17-18.8; P < 0.001), and acute respiratory failure (aOR 3.24; 2.56-4.1; P < 0.001) as well as higher mean length of stay (LOS) (+2.67; 1.79-3.55; P < 0.001) and cost of care (+67 529; 36 630-98 427; P < 0.001). CONCLUSION Among patients undergoing HSCT, AF was independently associated with poor in-hospital outcomes, higher LOS, and cost of care.
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Potential factors for and the prognostic impact of ascites after allogeneic hematopoietic stem cell transplantation
Kubo, H., Imataki, O., Fukumoto, T., Kawanaka, Y., Ishida, T., Kubo, Y. H., Kida, J. I., Uemura, M., Fujita, H., Kadowaki, N.
Scientific reports. 2023;13(1):13005
Abstract
Ascites is sometimes detected after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, since limited information is currently available, its clinical meaning remains unclear. Therefore, we herein examined potential factors for and the impact of ascites on the prognosis of patients after allo-HSCT at our institutes. Fifty-eight patients developed ascites within 90 days of allo-HSCT (small in 34 (16%), moderate-large in 24 (11%)). A multivariate analysis identified veno-occlusive disease/sinusoidal obstruction syndrome (p = 0.01) and myeloablative conditioning (p = 0.01) as significant potential factors for the development of small ascites. Thrombotic microangiopathy (TMA) (p < 0.01) was a significant potential factor for moderate-large ascites. The incidence of both small and moderate-large ascites correlated with lower overall survival (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites) and higher non-relapse mortality rates (p = 0.03 for small ascites and p < 0.01 for moderate-large ascites). Lower OS and higher NRM rates correlated with the incidence of both small and moderate-large ascites. Further investigation is warranted to establish whether the clinical sign of ascites improves the diagnostic quality of TMA in a large-scale study.
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Grading of minor salivary gland immuno-histopathology post-allogenic hematopoietic cell transplantation
Tollemar, V., Arvidsson, H., Häbel, H., Tudzarovski, N., Legert, K. G., Le Blanc, K., Warfvinge, G., Sugars, R. V.
Heliyon. 2023;9(4):e15517
Abstract
The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) pathophysiology's. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0-16 points, Grade (G) 0 to IV). Second, a modified Sjögren's Syndrome focus-score with parenchymal damage was also adapted, (0-10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the histopathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of "likely" sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclusions: Both schemes were verified as being suitable for histological grading to improve assessment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of "no/inactive", "possible" or "likely" cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD.
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Rare variants in complement system genes associate with endothelial damage after pediatric allogeneic hematopoietic stem cell transplantation
Leimi, L., Koski, J. R., Kilpivaara, O., Vettenranta, K., Lokki, A. I., Meri, S.
Frontiers in immunology. 2023;14:1249958
Abstract
INTRODUCTION Complement system has a postulated role in endothelial problems after hematopoietic stem cell transplantation (HSCT). In this retrospective, singlecenter study we studied genetic complement system variants in patients with documented endotheliopathy. In our previous study among pediatric patients with an allogeneic HSCT (2001-2013) at the Helsinki University Children´s Hospital, Finland, we identified a total of 19/122 (15.6%) patients with vascular complications, fulfilling the criteria of capillary leak syndrome (CLS), venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) or thrombotic microangiopathy (TMA). METHODS We performed whole exome sequencing (WES) on 109 patients having an adequate pre-transplantation DNA for the analysis to define possible variations and mutations potentially predisposing to functional abnormalities of the complement system. In our data analysis, we focused on 41 genes coding for complement components. RESULTS 50 patients (45.9%) had one or several, nonsynonymous, rare germline variants in complement genes. 21/66 (31.8%) of the variants were in the terminal pathway. Patients with endotheliopathy had variants in different complement genes: in the terminal pathway (C6 and C9), lectin pathway (MASP1) and receptor ITGAM (CD11b, part of CR3). Four had the same rare missense variant (rs183125896; Thr279Ala) in the C9 gene. Two of these patients were diagnosed with endotheliopathy and one with capillary leak syndrome-like problems. The C9 variant Thr279Ala has no previously known disease associations and is classified by the ACMG guidelines as a variant of uncertain significance (VUS). We conducted a gene burden test with gnomAD Finnish (fin) as the reference population. Complement gene variants seen in our patient population were investigated and Total Frequency Testing (TFT) was used for execution of burden tests. The gene variants seen in our patients with endotheliopathy were all significantly (FDR < 0.05) enriched compared to gnomAD. Overall, 14/25 genes coding for components of the complement system had an increased burden of missense variants among the patients when compared to the gnomAD Finnish population (N=10 816). DISCUSSION Injury to the vascular endothelium is relatively common after HSCT with different phenotypic appearances suggesting yet unidentified underlying mechanisms. Variants in complement components may be related to endotheliopathy and poor prognosis in these patients.
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The salivary proteome in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients: a labelled and label-free proteomics approach
van Leeuwen, S. J. M., Proctor, G. B., Staes, A., Laheij, Amga, Potting, C. M. J., Brennan, M. T., von Bültzingslöwen, I., Rozema, F. R., Hazenberg, M. D., Blijlevens, N. M. A., et al
BMC oral health. 2023;23(1):460
Abstract
BACKGROUND Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM). METHODS In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler. RESULTS A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis. CONCLUSIONS The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively. TRIAL REGISTRATION The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform).