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1.
Early clinical, histological, and immunohistochemical findings in suspected acute graft-versus-host disease and their association with patient outcomes
Garcia-Romero, M. T., Saez-de-Ocariz, M., Hernandez-Zepeda, C., Reyes, M., Garcia de la Puente, S., Ridaura-Sanz, C., Lopez-Hernandez, G., Olaya-Vargas, A.
Pediatric dermatology. 2020
Abstract
BACKGROUND/OBJECTIVES Acute graft-versus-host disease (aGVHD) is a serious condition after allogeneic hematopoietic stem cell transplantation (HSCT), frequently involving skin, gut, and liver. It can be difficult to diagnose early, yet this is vital for adequate management. We sought to identify initial clinical and histopathological features in children with suspected GVHD and the association with clinical course and outcomes. METHODS Retrospective study of patients with skin biopsies for suspected aGVHD from 2006 to 2016. We collected demographic and clinical information, histologic, and immunohistochemical (IHC) findings, and outcomes during follow-up. Bivariate and multivariate analyses were done to identify risk factors associated with remission, development of severe/life-threatening aGVHD, and mortality. RESULTS We included 42 patients, 15 females. Skin manifestations occurred 51 days (median) after HSCT. On biopsy, 76.2% had mild (stage 1-2) skin aGVHD; during the course of the disease, severity and systemic involvement increased to global grade III/IV in 66.6%. All patients received treatment; 15 are in remission from aGVHD and 23 have died. Histologic features were diagnostic in 83.3%. On bivariate and multivariate analysis, we identified initial clinical and histologic findings that were associated with the measured outcomes: odds of remission from aGVHD were increased when focal vacuolar changes were found on skin biopsy (OR 6.028; 95%CI:1.253-28.992) but decreased by initial hepatic aGVHD (OR 0.112; 95%CI: 0.017-0.748); severe/life-threatening aGVHD was associated with initial gastrointestinal aGVHD (OR 6.054; 95%CI:1.257-29.159); and odds of mortality were decreased with male donor (OR 0.056; 95%CI:0.004-0.804), nulliparous female donor (OR 0.076; 95%CI:0.009-0.669), and focal vacuolar changes on skin biopsy (OR 0.113; 95%CI:0.017-0.770). CONCLUSIONS We found novel indicators predictive of remission, severity, and mortality in children with aGVHD. Further studies of this condition in children are needed.
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2.
Outcomes of unrelated donor stem cell transplantation with or without anti-thymocyte globulin used as graft-versus-host disease prophylaxis in patients with acute leukaemia and myelodysplastic syndrome
Gener, G., Batlle, M., Morgades, M., Jiménez, M. J., Ferrà, C., Ribera, J. M.
Medicina clinica. 2020
Abstract
BACKGROUND AND PURPOSE Graft-versus-host disease (GVHD) and infections are complications after allogeneic stem cell transplantation (alloSCT). Anti-thymocyte globulin (ATG) is a strategy used as prophylaxis for GVHD. The study analyses the outcomes and frequency of infections with or without ATG after an unrelated donor alloSCT in patients with acute leukaemia and myelodysplastic syndrome. PATIENTS AND METHODS Retrospective study of patients receiving an unrelated donor alloSCT between December 2007 and April 2019. The main outcomes were analysed according to use or not of ATG. RESULTS Sixty-six patients were included. No significant differences were found between the ATG group (n=50) vs. no-ATG group (n=16) in overall survival, cumulative incidence of relapse, cumulative incidence of non-relapse mortality or cumulative incidence of acute GVHD or chronic GVHD. There was a greater frequency of infections in the ATG group (60 vs. 19%, P=.004). CONCLUSIONS In this study, no differences were shown in the main outcomes of alloSCT based on the use of ATG, although more infections were documented in the ATG group.
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3.
Biomarker-guided preemption of steroid-refractory graft-versus-host disease with a-1-antitrypsin
Gergoudis, S. C., DeFilipp, Z., Özbek, U., Sandhu, K. S., Etra, A. M., Choe, H. K., Kitko, C. L., Ayuk, F., Aziz, M., Baez, J., et al
Blood advances. 2020;4(24):6098-6105
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Editor's Choice
Abstract
Steroid-refractory (SR) acute graft-versus-host disease (GVHD) remains a major cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT), but its occurrence is not accurately predicted by pre-HCT clinical risk factors. The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP) identifies patients who are at high risk for developing SR GVHD as early as 7 days after HCT based on the extent of intestinal crypt damage as measured by the concentrations of 2 serum biomarkers, suppressor of tumorigenesis 2 and regenerating islet-derived 3a. We conducted a multicenter proof-of-concept "preemptive" treatment trial of a-1-antitrypsin (AAT), a serine protease inhibitor with demonstrated activity against GVHD, in patients at high risk for developing SR GVHD. Patients were eligible if they possessed a high-risk MAP on day 7 after HCT or, if initially low risk, became high risk on repeat testing at day 14. Thirty high-risk patients were treated with twice-weekly infusions of AAT for a total of 16 doses, and their outcomes were compared with 90 high-risk near-contemporaneous MAGIC control patients. AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%, P = .56). We conclude that real-time biomarker-based risk assignment is feasible early after allogeneic HCT but that this dose and schedule of AAT did not change the incidence of SR acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT03459040.
PICO Summary
Population
Patients assessed as having a high risk of developing GvHD, using the MAGIC algorithm probability (MAP) (n=30)
Intervention
Pre-emptive treatment with a-1-antitrypsin (AAT) (n=30)
Comparison
Control patients – near contemporaneous high-risk patients in MAGIC centres (n=90)
Outcome
AAT treatment was well tolerated with few toxicities, but it did not lower the incidence of SR GVHD compared with controls (20% vs 14%).
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Challenging and Practical Aspects of Nutrition in Chronic Graft-versus-Host Disease
Pereira, A. Z., Gonçalves, S. E. A., Rodrigues, M., Hamerschlak, N., Flowers, M. E.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020;26(11):e265-e270
Abstract
There is a paucity of information about nutrition in chronic graft-versus-host disease (GVHD). The role of nutrition is important because malnutrition is strongly associated with severe chronic GVHD manifestations. There is a high prevalence of metabolic syndrome and osteoporosis in this setting. Here we review the literature, describe main aspects of nutrition and discuss macronutrients (ie, vitamins), micronutrients (ie, Mg, Zn, Ca, and K) and supplements (probiotics and omega 3 fatty acids). A search was carried out in March 2020 using PubMed. Databases were screened for searching terms in titles and abstracts referring to chronic GVHD, nutrition intervention, protein, and body composition. Data were extracted for the following outcomes: nutrition, nutrition intervention, chronic GVHD, nutrition deficiencies, diet, vitamin, dry eye, probiotic, protein, and body composition. In this report, we summarize interventional nutrition studies reported in oncology and metabolic syndrome settings and describe our nutritional clinical practice in hematopoietic cell transplantation and chronic GVHD. The impact of nutrition evaluation and intervention on muscle mass loss, dry eye, dysgeusia, metabolic syndrome, osteoporosis, and comorbidities associated with chronic GVHD need to be studied prospectively.
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Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease
Pereira, A. Z., Vigorito, A. C., Almeida, A. M., Candolo, A. A., Silva, A. C. L., Brandao-Anjos, A. E. P., Sa, B. L., Souza, C. L. S., Castro Junior, C. G., Oliveira, J. S. R., et al
Einstein (Sao Paulo, Brazil). 2020;18:eAE4799
Abstract
The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease was approved by Sociedade Brasileira de Transplante de Medula Ossea , with the participation of 26 Brazilian hematopoietic stem cell transplantation centers. It describes the main nutritional protocols in cases of Graft- versus -host disease, the main complication of hematopoietic stem cell transplantation.
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6.
Functional and phylogenetic alterations in gut microbiome are linked to graft-versus-host disease severity
Payen, M., Nicolis, I., Robin, M., Michonneau, D., Delannoye, J., Mayeur, C., Kapel, N., Bercot, B., Butel, M. J., Le Goff, J., et al
Blood advances. 2020;4(9):1824-1832
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Abstract
Acute graft-versus-host disease (aGVHD) is the main complication of hematopoietic stem cell transplantation (HSCT). Changes in gut microbiota composition have been associated with subsequent aGVHD, and reconstitution of healthy microbiota is currently being explored as a therapeutic approach. However, the specific actors in the intestinal ecosystem involved in the pathologic process at the time of aGVHD onset are not yet fully known. We prospectively collected stool samples from patients who underwent allogeneic HSCT. Patients sampled at aGVHD onset were compared with non-GVHD patients. To identify phylogenetic and functional signatures of the disease process, we determined fecal short-chain fatty acid (SFCA) profiles and used high-throughput DNA sequencing and real-time quantitative polymerase chain reaction to assess the microbiota composition. Microbiota alterations were highly specific of gastrointestinal (GI) aGVHD severity. Bacterial biomass and alpha-diversity were lower in severe aGVHD. We identified several bacterial signatures associated with severe aGVHD at disease onset; a negative correlation was observed with anaerobic bacteria of the Lachnospiraceae, especially the Blautia genus, and Ruminococcaceae families. In parallel, in severe aGVHD patients, we showed a dramatic decrease in the levels of the main SFCAs: acetate (75.8%), propionate (95.8%), and butyrate (94.6%). Mild aGVHD patients were characterized by conserved levels of propionate and Blautia propionate producers. Butyrate was significantly decreased in all GI aGVHD stages, representing a potential diagnostic marker of the disease. Specific microbiota and metabolic alterations were thus associated with aGVHD severity and may be useful for diagnostic and pathophysiologic purposes.
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Effect of Ruxolitinib on lung function after allogeneic stem cell transplantation
Bondeelle, L., Chevret, S., Hurabielle, C., Samy, L., Goletto, T., Costantini, A., de Fontbrune, F. S., Michonneau, D., Socié, G., Tazi, A., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. No treatment to date has shown benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of patients treated for sclerotic-type skin cGVHD. Between March 2015 and April 2018, 70 patients were diagnosed with sclerotic-type skin cGVHD. Amongst those, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib incorporating age, myeloablative conditioning, total body irradiation, bronchiolitis obliterans (BOS), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and tobacco at the time of cohort entry, as well as the time from transplantation. Matching 1:1 used a greedy-matching algorithm with replacement, using a caliper of 0.10. We compared both FVC and FEV1 trajectories during the follow-up on the matched samples, using linear mixed effects models. Median follow-up of the 46 matched patients was 58 months (IQR, 32 to 84). Ten patients had a RLD (6 exposed; 4 unexposed) while 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 significantly decreased over time independently of exposure to ruxolitinib (p<0.0001). FEV1 trajectory was similar in exposed and unexposed patients (p= 0.11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.
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Early cessation of a randomised study in acute graft versus host disease: upfront mesenchymal stromal cells with corticosteroids versus corticosteroids alone
Purtill, D., Cirillo, M., Fogarty, J., Tan, D., Cooney, J., Wright, M., Cannell, P., Herrmann, R., Sturm, M.
Bone marrow transplantation. 2020
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9.
Hydrogen in Patients With Corticosteroid-Refractory/Dependent Chronic Graft-Versus-Host-Disease: A Single-Arm, Multicenter, Open-Label, Phase 2 Trial
Qian, L., Liu, M., Shen, J., Cen, J., Zhao, D.
Frontiers in immunology. 2020;11:598359
Abstract
Chronic graft-versus-host-disease (cGVHD) is the leading cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation(HSCT). There is no standard therapy for patients refractory or dependent to corticosteroid treatment. We hypothesized that hydrogen may exert therapeutic effects on cGVHD patients with few side effects. A prospective open-label phase 2 study of hydrogen was conducted. Patients received hydrogen-rich water 4ml/kg orally three times a day. Responses were graded in the skin, mouth, Gastrointestinal(GI), liver, eyes, lungs and joints and fascia every 3 months. A total of 24 patients (median age 27) were enrolled. Of the 24 patients, 18 (75%; 95% CI, 55.1% to 88%) had an objective response. No significant toxicity was observed. The estimated 4-year overall survival rate was 74.7%(95% CI, 54.9%-94.5%). The survival time was significantly prolonged in the response group. The survival rate at 4 years in the response group is significantly higher than the nonresponse group (86.6% vs 0%; p= 0.000132). Hydrogen showed great efficacy on cGVHD patients and long-term administration of hydrogen was not associated with significant toxic effects. The trial was registered at www.ClinicalTrials.Gov, NCT02918188.
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Role of ATG in patients with hematologic diseases undergoing umbilical cord blood transplantation: A systematic review and meta-analysis
Qin, B. Z., Zhang, C., Zhang, R., Wang, L.
Clinical transplantation. 2020;:e13876
Abstract
The role of antithymocyte globulin (ATG) in patients with hematologic diseases undergoing umbilical cord blood transplantation (UCBT) remains controversial. This systematic review and meta-analysis were conducted to comprehensively evaluate this issue. PubMed, Embase and the Cochrane Library were systematically searched. Clinical studies reporting the impact of ATG- vs. non-ATG-containing conditioning regimens on transplantation outcomes were identified. Twenty-five studies were included. ATG significantly prevented grades II-IV and III-IV acute graft-versus-host disease (GVHD) (11 studies, 5020 patients, HR: 0.49, 95% CI: 0.42 to 0.56, P < 0.001; 5 studies, 5490 patients, HR: 0.60, 95% CI: 0.46 to 0.80, P < 0.001) but not chronic GVHD (8 studies, 5952 patients, HR: 0.78, 95% CI: 0.51 to 1.20, P = 0.266). However, use of ATG was associated with increased transplantation-related mortality and inferior overall survival (9 studies, 4244 patients, HR: 1.79, 95% CI: 1.38 to 2.33, P < 0.001; 8 studies, 5438 patients, HR: 1.96, 95% CI: 1.56 to 2.46, P < 0.001). Our study did not recommend routine use of ATG in UCBT. Individualizing the ATG timing and dose based on patient characteristics to retain the prophylactic effects of ATG on GVHD without compromising the survival of UCBT recipients may be reasonable.