Biomarker-guided preemption of steroid-refractory graft-versus-host disease with α-1-antitrypsin

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 3 alpha. We conducted a multicenter proof-of-concept "preemptive" treatment trial of alpha-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 = 5.56). 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

Evaluation of Elafin as a Prognostic Biomarker in Acute Graft-versus-Host Disease

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3 alpha) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3 alpha in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3 alpha were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3 alpha or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P =.19). OS at 6 months (68% versus 68%; P >.99) and 4-week response (78% versus 78%; P =.98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3 alpha. The addition of elafin to the other 2 biomarkers did not improve the AUC. Our data indicate that serum elafin concentrations measured at the initiation of systemic treatment for acute GVHD did not predict 6-month NRM, OS, or treatment response in a multicenter population of patients treated systemically for acute GVHD. As seen in previous studies, serum concentrations of the GI GVHD biomarkers ST2 and REG3 alpha were significant predictors of NRM, and the addition of elafin levels did not improve their accuracy. These results underscore the importance of GI disease in driving NRM in patients who develop acute GVHD. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved

Assessment of systemic and gastrointestinal tissue damage biomarkers for GVHD risk stratification

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3 alpha via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3 alpha, and ST2 + REG3 alpha) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained >= 1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3 alpha, 0.73; ST2 + REG3 alpha, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints

IAPT chromosome data 33

Taxonomy: This study was supported by Agencia Nacional de Promoción Científica y Técnica (ANPCyT) grant no. PICT-2017-4203 and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), and a postdoctoral fellowship from CONICET to AVR.Fil: Marhold, Karol. Slovak Academy of Sciences. Institute of Botany; Eslovaquia. Karlova Univerzita (cuni); República ChecaFil: Kucera, Jaromír. Slovak Academy of Sciences. Institute of Botany; EslovaquiaFil: Acuña, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Akopian, Janna A.. Armenian National Academy of Sciences; ArmeniaFil: de Almeida, Erton M.. Universidade Federal de Pernambuco; Brasil. Universidade Federal da Paraíba; BrasilFil: Alves, Marccus V.. Universidade Federal da Paraíba; BrasilFil: Amorim, Bruno. Museu da Amazônia; Brasil. Universidade do Estado do Amazona; BrasilFil: An'kova, Tatyana V.. Academia de Ciencias de Rusia; RusiaFil: Arora, Jaya. University of Delhi; IndiaFil: Aytaç, Zeki. Gazi Üniversitesi; TurquíaFil: Baez, Jesica Mariana. Universidade Federal de Pernambuco; Brasil. Leibniz Institute of Plant Genetics and Crop Plant Research; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cavalcanti, Taciana Barbosa. Parque Estação Biológica; BrasilFil: Calvente, Alice. Universidade de Sao Paulo; Brasil. Universidade Federal do Rio Grande do Norte; BrasilFil: Catalan, Pilar. Tomsk State University; Rusia. Universidad de Zaragoza; EspañaFil: Chernyagina, Olga A.. Academia de Ciencias de Rusia; RusiaFil: Chernysheva, Olga A.. Academia de Ciencias de Rusia; RusiaFil: Cordeiro, Joel M. P.. Universidade Estadual da Paraiba; BrasilFil: Daviña, Julio Rubén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas; ArgentinaFil: Deanna, Rocío. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas; Argentina. State University of Colorado at Boulder; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Delgado, Luis. Universidad de Salamanca; EspañaFil: Dias Silva, Yhanndra K.. Universidade Federal de Pernambuco; BrasilFil: Elliott, Tammy L.. University of Cape Town; Sudáfrica. University of Montreal; CanadáFil: Erst, Andrey S.. Tomsk State University; Rusia. Academia de Ciencias de Rusia; RusiaFil: Felix, Leonardo P.. Universidade Federal da Paraíba; BrasilFil: Forni Martins, Eliana R.. Universidade Estadual de Campinas; BrasilFil: Gallego, Francisca. Universidad de Salamanca; EspañaFil: Facco, Marlon Garlet. Universidade de Brasília; BrasilFil: Gianini Aquino, Analía Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas; ArgentinaFil: Gomes de Andrade, Maria J.. Universidade do Estado da Bahia; BrasilFil: Rua, Gabriel Hugo. Universidad de Buenos Aires. Facultad de Agronomía. Departamento de Recursos Naturales y Ambiente. Cátedra de Botánica Agrícola; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin