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1.
Risk factors for hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation in a letermovir-exposed CMV-free population receiving PTCy
Galli, E., Metafuni, E., Gandi, C., Limongiello, M. A., Giammarco, S., Mattozzi, A., Santangelo, R., Bacigalupo, A., Sorà, F., Chiusolo, P., et al
European journal of haematology. 2024
Abstract
Hemorrhagic cystitis (HC) is a highly impacting complication in allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 12%-37% of patients. The impact of transplant- and patient-specific variables has been described, with a possible role for JCV and BKV, which may be cooperating with cytomegalovirus (CMV). Here, we analyze 134 letermovir-exposed, CMV-free patients, treated with the same cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, describing risk factors for HC. The overall incidence of HC was 23%. Patients with HLA mismatched transplant, higher comorbidity score, and receiving three alkylating agents with TBF (thiotepa, busulfan, and fludarabine) conditioning regimen had a higher risk of HC in multivariate analysis (OR: 4.48, 6.32, and 1.32, respectively). A HC-score including male gender, TBF conditioning, and HLA-mismatch stratifies the risk of HC in the first 100 days after HSCT. The role of BKV and JCV was not highly impacting in those patients, suggesting a possible synergistic effect between CMV and JCV in causing HC. HC can be interpreted as the combination of patient-related factors, chemotherapy-related toxicities-especially due to alkylating agents-and immunological elements.
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2.
Detection of bronchiolitis obliterans syndrome using nitrogen multiple breath washout in children post-haemopoietic stem cell transplant
Westrupp, N., Berry, C. D., Cole, T., Shanthikumar, S., Welsh, L.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) is a severe complication following haemopoietic stem cell transplantation (HSCT) and is often undetected until there is significant deterioration in pulmonary function. Lung clearance index (LCI(2.5)) derived from the nitrogen multiple breath washout (N(2)MBW) test may be more feasible and sensitive than spirometry, which is currently used for surveillance and detection of BOS. OBJECTIVE We aimed to examine the feasibility of performing surveillance N(2)MBW in children post-HSCT, and in an exploratory analysis, determine if LCI(2.5) led to earlier detection of BOS when compared to spirometric indices. STUDY DESIGN Participants aged 5 - 17 years were recruited prior to receiving HSCT into a prospective, single-centre, feasibility study at the Royal Children's Hospital, Melbourne. N(2)MBW and spirometry were performed within the month prior to transplant and repeated at 3, 6, 9 and 12 months post-transplant. Data were also collected on the presence of graft-versus-host (GVHD) disease in any organ, including the lungs. RESULTS Twenty-one (12 male) children with a mean age of 13.4 (range 9.2-17.1) years at recruitment participated in this study. Prior to HSCT, all participants had normal LCI(2.5), while 16 (76%) demonstrated normal forced expiratory volume in 1 second (FEV(1)). Ninety-nine percent of N(2)MBW tests were technically acceptable, compared with 66% of spirometry tests. Three participants developed BOS, while two participants died of other respiratory complications. At 6 and 12 months post-transplant, the BOS group had increases in LCI(2.5) ranging from 3 to 5 units and mean reductions in FEV(1) % predicted of 40% to 53% relative to pre HSCT values, respectively. In those who developed BOS, post-HSCT LCI(2.5) values were significantly worse when compared with the no BOS group (p<0.001). Relative changes in LCI(2.5) and FEV(1) were both predictive of BOS at 6 months post HSCT. CONCLUSION This study demonstrates that N(2)MBW is a more feasible test compared with spirometry in children post HSCT. However, in an exploratory analysis, LCI(2.5) did not lead to earlier detection of BOS, when compared to spirometry.
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3.
Late transplant-associated thrombotic microangiopathy verified in bone marrow biopsy specimens is associated with chronic GVHD and viral infections
Hill, W., Sotlar, K., Hautmann, A., Kolb, H. J., Ullmann, J., Hausmann, A., Schmidt, M., Tischer, J., Pham, T. T., Rank, A., et al
European journal of haematology. 2024
Abstract
OBJECTIVES To describe late transplant-associated thrombotic microangiopathy (TA-TMA) as chronic endothelial complication in bone marrow (BM) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS BM specimens along with conventional diagnostic parameters were assessed in 14 single-institutional patients with late TA-TMA (more than 100 days after HCST), including 11 late with history of early TA-TMA, 10 with early TA-TMA (within 100 days), and 12 non TA-TMA patients. Three non-HSCT patients served as control. The time points of BM biopsy were +1086, +798, +396, and +363 days after HSCT, respectively. RESULTS Late TA-TMA patients showed an increase of CD34+ and von Willebrand Factor (VWF)+ microvascular endothelial cells with atypical VWF+ conglomerates forming thickened VWF+ plaque sinus in the BM compared to patients without late TA-TMA and non-HSCT. Severe chronic (p = .002), steroid-refractory GVHD (p = .007) and reactivation of HHV6 (p = .002), EBV (p = .003), and adenovirus (p = .005) were pronounced in late TA-TMA. Overall and relapse-free survival were shorter in late TA-TMA than in patients without late TA-TMA (5-year OS and RFS: 78.6% vs. 90.2%, 71.4% vs. 86.4%, respectively). CONCLUSION Chronic allo-immune microangiopathy in BM associated with chronic, steroid-refractory GVHD and/or viral infections are key findings of late, high-risk TA-TMA, which deserves clinical attention.
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4.
Pre-transplant glomerular hyperfiltration is not a risk factor for increased renal morbidity and mortality in pediatric stem cell transplant patients
Sarkar, N., Myers, K. C., Lane, A., Davies, S. M., Benoit, S. W.
Pediatric blood & cancer. 2024;:e30853
Abstract
Low glomerular filtration rate (GFR) prior to stem cell transplant (SCT) is associated with increased morbidity and mortality. The implications of abnormally high GFRs, or glomerular hyperfiltration, prior to SCT are unknown. Twenty-two of 74 consecutive pediatric SCT patients over 2 years old at a single center were hyperfiltrating prior to SCT, median nuclear medicine GFR 154 mL/min/1.73 m(2) [interquartile range: 146-170]. There was no association between hyperfiltration and any transplant demographics, nor between hyperfiltration and acute kidney injury (p = .8), renal replacement therapy (p = .63), 1-year event-free survival (p = 1), or abnormal creatinine-based estimated GFR at a median follow-up of 4.7 years (p = .73).
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5.
Multiplex proteomics in the identification of potential biomarkers of very severe sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in allogeneic hematopoietic cell transplant patients treated with defibrotide
Vasudevan Nampoothiri, R., Avery, L., Pasic, I., Prassas, I., Diamandis, E., Michelis, F. V.
Acta haematologica. 2024
Abstract
Introduction Despite well-established clinical criteria for diagnosis of SOS/VOD following allogeneic HCT, there is a lack of established diagnostic protein biomarkers. Methods Prospective samples were collected from patients with very severe SOS/VOD at diagnosis and days +3, +7, +14, and +30 post-initiation of defibrotide. Samples from age-matched controls with no VOD were collected at day +14, +30, +60, +90 and +180 following allogeneic HCT. Serum samples were analyzed for 2925 protein levels by antibody-based proximity extension assay (PEA). Mean differences in the log-transformed abundance values were compared using t-tests in a volcano plot. Results Five patients with very severe SOS/VOD and five control patients were compared. Ten proteins were identified that showed a statistically significant and log-transformed 3-fold increase in concentration. They were CALCA, CCL20, GPR37, IGFBP4, IL1RL1, SLC39A14, SPINK4, FABP3, MYL3, and CHCHD10. Four different proteins, namely CD83, LAIR2, CD7, and HEM6 showed a significant decrease with defibrotide treatment. SOS/VOD resolved in 80% (n=4) of patients, while one patient deceased due to SOS/VOD. Conclusion PEA technology identified 10 proteins that were significantly elevated in patients with very severe SOS/VOD. Prospective studies in a larger cohort using this technology may be able to conclusively identify diagnostic protein biomarkers for SOS/VOD.
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6.
Utility of the refined EBMT diagnostic and severity criteria 2023 for sinusoidal obstruction syndrome/veno-occlusive disease
Ichikawa, H., Yakushijin, K., Kurata, K., Tsuji, T., Takemoto, N., Joyce, M., Okazoe, Y., Takahashi, R., Matsumoto, S., Sakai, R., et al
Bone marrow transplantation. 2024
Abstract
Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). Early diagnosis of SOS/VOD is associated with improved clinical outcomes. In 2023, the refined European Society for Blood and Marrow Transplantation diagnostic and severity criteria (refined EBMT criteria 2023) have been advocated. The revision has introduced new diagnostic categories, namely; probable, clinical, and proven SOS/VOD. In addition, the Sequential Organ Failure Assessment (SOFA) score has been newly incorporated into the SOS/VOD severity grading. We performed a retrospective analysis to evaluate the utility of these criteria. We analyzed 161 cases who underwent allogeneic HSCT. We identified 53 probable, 23 clinical, and 4 proven SOS/VOD cases. Probable SOS/VOD was diagnosed a median of 5.0 days earlier (interquartile range: 2-13 days, P < 0.001) than that of clinical SOS/VOD. The development of probable SOS/VOD alone was associated with a significantly inferior survival proportion compared to non-SOS/VOD (100-day survival, 86.2% vs. 94.3%, P = 0.012). The SOFA score contributed to the prediction of prognosis. Consequently, the refined EBMT criteria 2023 demonstrated the utility of SOS/VOD diagnosis and severity grading. Further investigations and improvements in these criteria are warranted.
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7.
[Risk Factors of Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation]
Zhang, L. Y., Xiong, Y. Y., Liao, M. Y., Xiao, Q., Tang, X. Q., Luo, X. H., Zhang, H. B., Wang, L., Liu, L.
Zhongguo shi yan xue ye xue za zhi. 2024;32(1):250-256
Abstract
To analyze the risk factors for late-onset hemorrhagic cystitis (LOHC) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), the risk factors for the progression of LOHC to severe LOHC, and the effect of LOHC on survival. METHODS The clinical data of 300 patients who underwent allo-HSCT at the First Affiliated Hospital of Chongqing Medical University from January 2015 to December 2021 were retrospectively analyzed. The relevant clinical parameters that may affect the occurance of LOHC after allo-HSCT were selected for univariate and multivariate analysis. Then, the differences in overall survival (OS) and progression-free survival (PFS) between different groups were analyzed. RESULTS The results of multivariate analysis showed that the independent risk factors for LOHC after allo-HSCT were as follows: age≤45 years old (P =0.039), intensified conditioning regimen with fludarabine/cladribine and cytarabine (P =0.002), albumin≤30 g/L on d30 after transplantation (P =0.007), CMV-DNA positive (P =0.028), fungal infection before transplantation (P =0.026), and the occurrence of grade Ⅱ - Ⅳ aGVHD (P =0.006). In the transplant patients who have already developed LOHC, the occurance of LOHC within 32 days after transplantation (P =0.008) and albumin≤30 g/L on d30 after transplantation (P =0.032) were independent risk factors for the progression to severe LOHC. The OS rate of patients with severe LOHC was significantly lower than that of patients without LOHC (P =0.041). CONCLUSION For the patients aged≤45 years old and with intensified conditioning regimen, it is necessary to be vigilant about the occurrence of LOHC; For the patients with earlier occurrence of LOHC, it is necessary to be vigilant that it develops into severe LOHC. Early prevention and treatment of LOHC are essential. Regular monitoring of CMV-DNA and albumin levels, highly effective antiviral and antifungal therapies, and prevention of aGVHD are effective measures to prevent the occurrence and development of LOHC.
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8.
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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9.
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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10.
Point shear-wave elastography for the diagnosis of veno-occlusive disease in children and young adults
Cañas, T., Suárez, O., Rozas, I., Escribano, M., Molina, B., González-Vicent, M., Maciá, A.
Pediatric radiology. 2023
Abstract
BACKGROUND Hepatic veno-occlusive disease or sinusoidal obstruction syndrome is a potentially life-threatening complication of hematopoietic stem cell transplantation. OBJECTIVE To assess the usefulness of point shear-wave elastography (pSWE) for the early diagnosis of sinusoidal obstruction syndrome (SOS) in children. MATERIALS AND METHODS A retrospective study was carried out in 43 patients with suspected SOS assessed between March 2018 and November 2021. Diagnosis of SOS was confirmed in 28 patients based on the European Society for Blood and Marrow Transplantation diagnostic criteria. Abdominal ultrasound and pSWE of the liver were performed before and after hematopoietic stem cell transplantation on first suspicion of SOS. RESULTS Liver stiffness on initial suspicion was higher in patients diagnosed with SOS and these values increased compared to the pre-transplantation values. A cutoff value of 1.37 m/s was found for the diagnosis of SOS, with an area under the curve of 0.779 (95% CI 0.61-0.93). CONCLUSION Point shear wave elastography of the liver is a promising technique for the early diagnosis of pediatric SOS.