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Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation
Penack, O., Marchetti, M., Aljurf, M., Arat, M., Bonifazi, F., Duarte, R. F., Giebel, S., Greinix, H., Hazenberg, M. D., Kröger, N., et al
The Lancet. Haematology. 2024
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Full text
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Editor's Choice
Abstract
Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.
PICO Summary
Population
Panel of 22 experts and one methdologist convened by the European Society for Blood and Marrow Transplantation (EBMT)
Intervention
Update of the EBMT consensus recommendations
Comparison
Outcome
Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD.
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Ruxolitinib in patients with graft versus host disease (GvHD): findings from a compassionate use program
Pattipaka, T., Sarp, S., Nakhaei, P., Güneş, S.
Bone marrow transplantation. 2024
Abstract
The ruxolitinib compassionate use (CU) program offered ruxolitinib to patients ≥2 years of age with confirmed steroid-resistant acute or chronic graft-versus-host disease (aGvHD and cGvHD, respectively). Data from 1180 patients (n = 775, 370 and 35 with cGvHD, aGvHD, and non-specified GvHD, respectively) were analyzed. Most patients had severe cGvHD (56%) or stage III/IV aGvHD (70%) disease and had previously received corticosteroids ( > 80%); ruxolitinib was requested primarily as a second-/third-line option. Patients <12 and ≥12 years old most often received the recommended ruxolitinib doses (5 mg twice daily [BID] and 10 mg BID, respectively); however, 23% and 30% of ≥12 year olds with cGvHD and aGvHD, respectively, received the lower dose of 5 mg BID. Notably, corticosteroid usage decreased with ruxolitinib treatment; at the initial ruxolitinib request, 81% and 91% of patients with cGvHD and aGvHD, respectively, were receiving corticosteroids whereas at resupply, 62% and 64%, respectively, were receiving corticosteroids. Eighty two percent of evaluable patients with cGvHD had a complete or partial response to treatment and 56% of evaluable patients with aGvHD had a best response of grade 0/I. These findings demonstrate the rapid and positive effects of ruxolitinib in patients with GvHD in a real-world setting.
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Molecular Biomarkers in Ocular Graft-versus-Host Disease: A Systematic Review
Bohlen, J., Gomez, C., Zhou, J., Martinez Guasch, F., Wandvik, C., Sunshine, S. B.
Biomolecules. 2024;14(1)
Abstract
Ocular graft-versus-host disease (oGVHD) affects ~50% of post-stem cell transplant patients and is the only form of GVHD diagnosed without a biopsy. As it must be distinguished from other dry eye diseases, there is a need to identify oGVHD biomarkers to improve diagnosis and treatment. We conducted a systematic review of 19 scholarly articles published from 2018 to 2023 including articles focused on adult patients diagnosed with oGVHD following allogeneic hematopoietic stem cell transplant and used biomarkers as the outcome measure. Articles that were not original investigations or were not published in English were excluded. These clinical investigations explored different molecular oGVHD biomarkers and were identified on 3 October 2023 from the Scopus, PubMed, and Embase databases by using search terms including ocular graft-versus-host disease, biomarkers, cytokines, proteomics, genomics, immune response, imaging techniques, and dry-eye-related key terms. The Newcastle-Ottawa scale for case-control studies was used to assess bias. From the 19 articles included, cytokine, proteomic, lipid, and leukocyte profiles were studied in tear film, as well as ocular surface microbiota and fluorescein staining. Our findings suggest that cytokine profiling is the most studied oGVHD biomarker. Additionally, variations correlating these biomarkers with disease state may lead to a more targeted diagnosis and therapeutic approach. Limitations include language bias, publication bias, and sampling bias, as well as a lack of appropriate controls for included studies.
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Graft-versus-host disease after an outpatient peripheral blood hematopoietic cell transplant using reduced-intensity conditioning: a single-center LATAM experience
Jaime-Pérez, J. C., Meléndez-Flores, J. D., Valdespino-Valdes, J., Gómez-De León, A., Colunga-Pedraza, P. R., Gutiérrez-Aguirre, C. H., Cantú-Rodríguez, O. G., Gómez-Almaguer, D.
Expert review of hematology. 2024;:1-10
Abstract
BACKGROUND HLA compatibility predicts allogeneic hematopoietic cell transplant (allo-HCT) and graft-versus-host disease (GvHD) outcomes. There is insufficient information regarding GvHD outcomes for outpatient HLA-identical and haploidentical-HCT employing reduced-intensity conditioning (RIC). RESEARCH DESIGN AND METHODS We compare GvHD outcomes between donor types and report risk factors associated with GvHD. Stem cell source was T-cell replete peripheral blood. GvHD prophylaxis was post-transplant cyclophosphamide (PT-CY), mycophenolic acid, and calcineurin inhibitors for haploidentical (n = 107) and oral cyclosporine (CsA) plus methotrexate i.v. for HLA-identical (n = 89) recipients. RESULTS One hundred and ninety-six HCT transplant patients were included. aGvHD and cGvHD frequency were similar between HCT types. aGvHD severity was comparable, but severe cGvHD was less frequent in the haploidentical group (p = .011). One-hundred-day cumulative incidence (CI) of aGvHD for haploidentical and HLA-identical was 31% and 33% (p = .84); 2-year CI of cGvHD was 32% and 38% (p = .6), respectively. Haploidentical recipients had less steroid-refractory cGvHD (p = .043). Patients with cGvHD had less 2-year relapse (p = .003); both aGvHD and cGvHD conferred higher OS (p = .010 and p = .001), respectively. Male sex was protective for steroid-refractory cGvHD (p = .028). CONCLUSIONS Acute and chronic GvHD rates were comparable between HLA-identical and haploidentical transplant groups. cGvHD severity was lower in the haploidentical group.
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The Role of IL-6, IL-10, and TNF-α in Ocular GVHD Following Allogeneic Transplantation
Chen, Y., Zhuang, X., Wang, L., Xu, Y., Sun, Z., Ren, Y., Chen, F., Ma, X., Tang, X., Zhang, X.
Ocular immunology and inflammation. 2024;:1-8
Abstract
PURPOSE To figure out the roles of tear inflammatory cytokines in Ocular graft-versus-host disease (oGVHD) symptoms by analyzing tear cytokine levels and related factors. METHODS This prospective study involved 27 post-HSCT patients and 19 controls with dry eye disease. Analyses included tear cytokine (IL-6, IL-10, and TNF-α), ocular surface evaluation, and conjunctival impression cell examination. Tear cytokine levels were evaluated in three grades of corneal epithelial lesions. The study also analyzed the correlation between tear cytokine levels and ocular surface parameters. Tear cytokine levels were then used in a Receiver Operating Characteristic (ROC) curve and linear regression model to predict oGVHD related factors. RESULTS IL-6 has good diagnostic efficacy in oGVHD related dry eye. Elevated levels of tear IL-6 and TNF-α were observed in the group with severe corneal epithelial lesions. IL-6 levels were positively correlated with corneal fluorescein staining (CFS), eyelid margin hyperemia, conjunctival lesions, and meibum secretion. IL-6 showed excellent predictive ability with Area Under the Curve (AUC) values all greater than 0.70 (p < 0.05). IL-10 and TNF-α were negatively correlated with the meibomian gland proportion and conjunctival goblet cell (GC) density, while TNF-α was positively correlated with CFS and eyelid margin hyperemia. CONCLUSION Dry eye symptoms related to ocular GVHD, can be partly diagnosed and assessed using various tear cytokine level detection methods.
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Ruxolitinib for the treatment of acute and chronic graft-versus-host disease in children: a systematic review and individual patient data meta-analysis
Baccelli, F., Gottardi, F., Muratore, E., Leardini, D., Grasso, A. G., Gori, D., Belotti, T., Prete, A., Masetti, R.
Bone marrow transplantation. 2024
Abstract
Steroid-refractory graft-versus-host disease (SR-GvHD) represents a major complication of pediatric allogenic hematopoietic stem cell transplantation. Ruxolitinib, a selective JAK 1-2 inhibitor, showed promising results in the treatment of SR-GvHD in adult trial, including patients >12 years old. This systematic review aims to evaluate ruxolitinib use for SR-GvHD in the pediatric population. Among the 12 studies included, ruxolitinib administration presented slight differences. Overall response rate (ORR) ranged from 45% to 100% in both acute and chronic GvHD. Complete response rates (CR) varied from 9% to 67% and from 0% to 28% in aGvHD and cGvHD, respectively. Individual-patient meta-analysis from 108 children under 12 years showed an ORR and CR for aGvHD of 74% and 56%, respectively, while in cGvHD ORR was 78% but with only 11% achieving CR. Treatment-related toxicities were observed in 20% of patients, including cytopenia, liver toxicity, and infections. Age, weight, graft source, previous lines of therapy, and dose did not significantly predict response, while a higher rate of toxicities was observed in aGvHD patients. In conclusion, ruxolitinib shows promising results in the treatment of SR-GvHD in children, including those under 12 years. Specific pediatric perspective trials are currently ongoing to definitely assess its efficacy and safety.
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A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes
Rosenberger, A., Crossland, R. E., Dressel, R., Kube, D., Wolff, D., Wulf, G., Bickeböller, H., Dickinson, A., Holler, E.
Frontiers in immunology. 2024;15:1280876
Abstract
INTRODUCTION Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. METHODS We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. RESULTS The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10(-8)) and sGvHD (p=7.5x10(-8)). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. DISCUSSION Thus, new genes were identified, potentially influencing the outcome of HSCT.
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Second line extracorporeal photopheresis for cortico-resistant acute and chronic GVHD after allogeneic hematopoietic cell transplantation for hematological malignancies: Long-term results from a real-life study
Michallet, M., Sobh, M., Deloire, A., Revesz, D., Chelgoum, Y., El-Hamri, M., Barraco, F., Labussiere, H., Nicolini, F. E., Hequet, O.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2024;:103899
Abstract
BACKGROUND & OBJECTIVES The primary objective of this observational study was to perform an exhaustive description concerning patients receiving extracorporeal photopheresis (ECP) as second line treatment after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. STUDY DESIGN A total of 106 patients were included, 65 (61%) males and 41 (39%) females with a median age at transplantation of 52 years (range: 20-67). ECP was initiated after transplantation either for acute GVHD [N = 25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N = 5), gut alone (N = 12), gut and liver (N = 8), or chronic GVHD [N = 81 (76%), 15 (14%) limited and 66 (62%) extensive]. RESULTS Among the 25 patients treated for acute GHVD, 67% were responders and among the 81 patients with chronic GVHD, 78% were responders. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56]. Patients with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. There was a significant difference in terms of survival for patients responding to ECP compared to non-responders in both acute and chronic GVHD forms. Acute GVHD grade III-IV, negatively impacted on OS (HR=7.77, 95%CI: 1.7-34), p = 0.007 and on disease relapse HR= 5.88, 95%CI: 1.7-20, p = 0.005. CONCLUSION We demonstrated that ECP is an effective treatment for GVHD in a good proportion of patients with high overall response rate.
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A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults
Khandelwal, P., Langenberg, L., Luebbering, N., Lake, K., Butcher, A., Werling, K., Ramos, K. N., Taggart, C., Choe, H. K., Vasu, S., et al
Blood. 2024
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Editor's Choice
Abstract
Vitamin A plays a key role in the maintenance of gastrointestinal homeostasis and promotes a tolerogenic phenotype in tissue resident macrophages. We conducted a prospective randomized double-blinded placebo-controlled clinical trial in which 80 hematopoietic stem cell transplant recipients were randomized 1:1 to receive pre-transplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 I.U/kg, maximum 250,000 I.U was given prior to conditioning. Primary endpoint was incidence of acute GVHD at day+100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in vitamin A arm and 20% in placebo (p=0.5). Incidence of acute GI GVHD was 2.5% in the vitamin A arm (p=0.09) and 12.5% in placebo at day+180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in placebo (p=0.02) at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day+180 was 0% in vitamin A recipients and 12.5% in placebo (p=0.02) and chronic GVHD incidence 2.7% in the vitamin A recipients and 15% in placebo (p=0.01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in one vitamin A recipient at day+30, which self-resolved. Absolute CCR9+ CD8+effector memory T-cells, reflecting gut T-cell trafficking, were lower in the vitamin A arm at day+30 after HSCT (p=0.01). Levels of serum amyloid A-1, a vitamin A transport protein with pro-inflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower IL-6, IL-8, ST2 levels and likely more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity and reduces GVHD (clinicaltrials.gov NCT03202849).
PICO Summary
Population
Children aged 12 months and over with pre transplant vitamin A levels below 75th centile of normal range for age, from a single centre in USA (n=80)
Intervention
A single oral dose of vitamin A of 4000 I.U/kg, maximum 250,000 I.U prior to conditioning pre-transplant (n=40)
Comparison
Placebo (n=40)
Outcome
In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in vitamin A arm and 20% in placebo. Incidence of acute GI GVHD was 2.5% in the vitamin A arm and 12.5% in placebo at day+180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in placebo at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day+180 was 0% in vitamin A recipients and 12.5% in placebo and chronic GVHD incidence 2.7% in the vitamin A recipients and 15% in placebo. The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in one vitamin A recipient at day+30, which self-resolved. Absolute CCR9+ CD8+effector memory T-cells, reflecting gut T-cell trafficking, were lower in the vitamin A arm at day+30 after HSCT. Levels of serum amyloid A-1, a vitamin A transport protein with pro-inflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower IL-6, IL-8, ST2 levels and likely more favorable gut microbiome and short chain fatty acids.
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Diagnostic and prognostic role of elafin in skin acute graft versus host disease: a systematic review
Bhattarai, A., Shah, S., Yadav, R., Dhakal, G., Neupane, R., Paudel, S., Bhandari, P., Abu Serhan, H., Sah, R., Sah, S., et al
Hematology (Amsterdam, Netherlands). 2024;29(1):2293497
Abstract
BACKGROUND AND OBJECTIVE Graft versus host disease (GVHD) is the common complication seen after allogeneic hematopoietic stem cell transplantation (HSCT) and a pleomorphic syndrome that resembles autoimmune and other immunologic disorders, leading to profound immune dysregulation and organ dysfunction. The most common targets of GVHD are skin, gastrointestinal tract and liver. GVHD is classified as acute graft versus host disease (aGvHD) if it occurs within the first 100 days after HSCT and chronic graft versus host disease(cGVHD) if it occurs after day 100. The skin is most frequently and earliest affected by aGvHD, followed by the gastrointestinal tract and liver. An ideal biomarker would predict the onset and severity of clinical acute GVHD and help to direct management, and this is an area of active research regarding the use of biomarkers for diagnosis and prognosis of acute GVHD. Recently, elafin has been identified as a potential plasma biomarker for aGVHD. METHOD We searched the databases PubMed, Cochrane library, and medRxiv for all studies investigating the Diagnostic or prognostic role of elafin in GVHD. We set the search strategy incorporating the search terms, 'elafin', 'graft versus host', and 'GVHD', and operated using the Boolean operators 'AND', and 'OR'. Thus, retrieved articles were then exported on an Excel® sheet, and duplicates were removed. The systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After selecting the study based on inclusion criteria, data on study characteristics and biomarker description was extracted on a pre-determined data extraction table on the Microsoft Excel version. The quality assessment of the included studies was determined using the QUIPS tool. RESULT The search revealed 547 studies and 6 studies that met the eligibility criteria of this review have been included. The major finding of our study is the significant elevation of elafin in skin aGVHD. CONCLUSION Elafin is a significant biomarker for diagnosis and prognosis of skin aGVHD and should be assessed within 2 weeks of the onset of the disease.