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1.
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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2.
Topical treatment of oral chronic graft-versus-host- disease in hematopoietic stem cell transplant recipients: A systematic review
Haas, L., Cruz-Pamplona, M.
Journal of clinical and experimental dentistry. 2023;15(5):e420-e427
Abstract
BACKGROUND Oral graft-versus-host disease (GVHD) is a common complication of hematopoietic stem cell transplantation. This study systematically reviewed Randomized Controlled Trials (RCTs) with the objective to investigate the effectiveness and side effects of topical agents used for the treatment of oral GVHD. MATERIAL AND METHODS The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were followed to perform this study. An electronic search of four databases was conducted. RCTs published between January 2011 and March 2022 were included that were carried out on hematopoietic stem cell transplant recipients receiving topical treatment for oral GVHD. The Critical Appraisal Skills Program (CASP) standard checklist for RCTs was used for the bias risk evaluation. RESULTS Five RCTs were included for the qualitative synthesis of results. Two RCTs were linked to a certain risk of bias. Budesonide caused the highest overall treatment response. Malic acid, clobetasol, and dexamethasone increased resting salivary flow rates. Curcumin in orabase shows similar results to corticosteroid treatment. Adverse effects were observed in populations receiving budesonide, dexamethasone, clobetasol, and tacrolimus. Most frequent adverse effects were burning sensations, fungal infections, and gastrointestinal disorders, but none of them were severe. CONCLUSIONS Given the small number of RCTs performed and the heterogeneity of the different study designs, it is difficult to draw direct comparisons. Malic acid appears to be effective for the treatment of graft-versus-host disease-induced xerostomia. Budesonide had the highest overall response rates but was also associated with the highest number of adverse effects. Further research is needed to manifest those findings. Key words:Hematopoietic stem cell transplant, oral graft-versus-host disease, topical treatment.
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3.
Efficacy and Safety of Ibrutinib for Chronic Graft-Versus-Host Disease: A Systematic Review
Santosa, D., Rizky, D., Tandarto, K., Kartiyani, I., Yunarvika, V., Ardini, D. N. E., Setiawan, B., Pangarsa, E. A., Suharti, C.
Asian Pacific journal of cancer prevention : APJCP. 2023;24(12):4025-4033
Abstract
INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) serves as a potentially curative intervention for various hematologic disorders. However, its utility can be limited by the emergence of chronic graft-versus-host disease (cGVHD). The clinical manifestations of cGVHD result from a complex immune response characterized by the involvement of both B and T cells. Ibrutinib, a pharmacological agent, acts as an inhibitor of Bruton's tyrosine kinase (BTK) pathway, which becomes activated through the B-cell receptor and regulates B-cell survival. By exerting inhibitory effects on both BTK and inhibitor of interleukin-2 inducible T-cell kinase (ITK), ibrutinib exhibits promise as a therapeutic approach for managing cGVHD. Ibrutinib may be considered as a viable treatment option for active cGVHD in cases where patients exhibit an inadequate response to corticosteroid-based therapies. This systematic review seeks to assess the efficacy and safety of ibrutinib in the context of cGVHD patient management. METHOD We incorporated search engines from PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. The study was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Assessing The Methodological Quality of Systematic Review (AMSTAR). We used Risk of Bias- 2 (RoB-2) tool for assess the risk of bias in randomized controlled studies (RCTs) and Newcastle Ottawa Scale (NOS) for observational and open-label studies. RESULTS A total of 7 studies were included in this study consisted of four open-label studies, two retrospective cohort studies, and one RCT study. These studies compared Ibrutinitib with standard therapies. Two studies investigated the pediatric population, and five studies investigated the adult population. Overall, these studies reported the overall response rate (ORR) of ibrutinib for cGVHD were 54%-78%. The results showed that in pediatric patients, the ORR were 54-78%. The results also showed that in adult patients, the ORR were 67%-76%. The most common adverse effects observed across the seven studies included pyrexia, diarrhea, abdominal pain, cough, nausea, stomatitis, vomiting, headache, bleeding and bruising, infection, muscle aches, fatigue, oral bleeding, elevated transaminases, lower gastrointestinal bleeding, persistent dizziness, sepsis, pneumonia, reduced platelet count, exhaustion, sleeplessness, peripheral edema, and fatigue. CONCLUSION The majority of studies have indicated that ibrutinib exhibits a high ORR and provides long-lasting responses, while also having manageable side effects.
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4.
Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials
Luo, C., Huang, X., Wei, L., Wu, G., Huang, Y., Ding, Y., Huang, Z., Chen, J., Li, X., Zou, Y., et al
Frontiers in immunology. 2023;14:1211171
Abstract
OBJECTIVE Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. METHODS Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. RESULTS Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. CONCLUSIONS Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.
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5.
Safety and efficacy of fecal microbiota transplantation in the treatment of graft-versus-host disease
Qiao, X., Biliński, J., Wang, L., Yang, T., Luo, R., Fu, Y., Yang, G.
Bone marrow transplantation. 2022
Abstract
This article evaluates the efficacy and safety of FMT in the treatment of GVHD after HSCT using a systematic literature search to conduct a meta-analysis constructed of studies involving GVHD patients treated with FMT. 23 studies were included, among which 2 prospective cohort studies, 10 prospective single arm studies, 2 retrospective single arm studies, 2 case series and 7 case reports, comprise a total of 242 patients with steroid-resistant or steroid-dependent GVHD secondary to HSCT who were treated with FMT. 100 cases achieved complete responses, while 61 cases showed partial responses, and 81 cases presented no effect after FMT treatment. The estimate of clinical remission odds ratio was 5.51 (95% CI 1.49-20.35) in cohort studies, and the pooled clinical remission rate is 64% (51-77%) in prospective single arm studies and 81% (62-95%) in retrospective studies, case series and case reports. Five (2.1%) patients had FMT-related infection events, but all recovered after treatment. Other adverse effects were mild and acceptable. Microbiota diversity and composition, donor type, and other related issues were also analyzed. The data proves that FMT is a promising treatment modality of GVHD, but further validation of its safety and efficacy is still needed with prospective control studies.Clinical trial registration: Registered in https://www.crd.york.ac.uk/PROSPERO/ CRD42022296288.
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6.
Efficacy and safety of ruxolitinib in steroid-refractory graft-versus-host disease: A meta-analysis
Fan, S., Huo, W. X., Yang, Y., Shen, M. Z., Mo, X. D.
Frontiers in Immunology. 2022;13:954268
Abstract
Ruxolitinib is an important treatment for steroid refractory graft-versus-host disease (SR-GVHD). Therefore, we reported the updated results of a systematic review and meta-analysis of ruxolitinib as treatment for SR-GVHD. In addition, we wanted to compare the efficacy and safety between children and adults with SR-GVHD. Overall response rate (ORR) after ruxolitinib treatment was chosen as the primary end point. Complete response rate (CRR), infection, myelosuppression, and overall survival (OS) were chosen as secondary end points. A total of 37 studies were included in this meta-analysis, and 1,580 patients were enrolled. ORR at any time after ruxolitinib treatment was 0.77 [95% confidence interval (CI): 0.68-0.84] and 0.78 (95% CI: 0.74-0.81), respectively, for SR-aGVHD and SR-cGVHD. CRR at any time after ruxolitinib treatment was 0.49 (95% CI: 0.40-0.57) and 0.15 (95% CI: 0.10-0.23), respectively, for SR-aGVHD and SR-cGVHD. The ORRs at any time after treatment was highest in mouth SR-cGVHD, followed by skin, gut, joints and fascia, liver, eyes, esophagus, and lung SR-cGVHD. The incidence rate of infections after ruxolitinib treatment was 0.61 (95% CI: 0.45-0.76) and 0.47 (95% CI: 0.31-0.63), respectively, for SR-aGVHD and SR-cGVHD. The incidence rates of overall (grades I-IV) and severe (grades III-IV) cytopenia were 53.2% (95% CI: 16.0%-90.4%) and 31.0% (95% CI: 0.0-100.0%), respectively, for SR-aGVHD, and were 28.8% (95% CI:13.0%-44.6%) and 10.4% (95% CI: 0.0-27.9%), respectively, for SR-cGVHD. The probability rate of OS at 6 months after treatment was 63.9% (95% CI: 52.5%-75.2%) for SR-aGVHD. The probability rates of OS at 6 months, 1 year, and 2 years after treatment were 95% (95% CI: 79.5%-100.0%), 78.7% (95% CI: 67.2%-90.1%), and 75.3% (95% CI: 68.0%-82.7%), respectively, for SR-cGVHD. The ORR, CRR, infection events, and myelosuppression were all comparable between children and adults with SR-GVHD. In summary, this study suggests that ruxolitinib is an effective and safe treatment for SR-GVHD, and both children and adults with SR-GVHD could benefit from ruxolitinib treatment.
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7.
Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan
Sobkowiak-Sobierajska, A., Lindemans, C., Sykora, T., Wachowiak, J., Dalle, J. H., Bonig, H., Gennery, A., Lawitschka, A.
Frontiers in pediatrics. 2022;10:808103
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
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8.
Restoration of the Original Inhabitants: A Systematic Review on Fecal Microbiota Transplantation for Graft-Versus-Host Disease
Alabdaljabar, M. S., Aslam, H. M., Veeraballi, S., Faizee, F. A., Husain, B. H., Iqbal, S. M., Hashmi, S. K.
Cureus. 2022;14(4):e23873
Abstract
A compelling intervention to maintain healthy gut microbiota in graft-versus-host-disease (GVHD) is fecal microbial transplantation (FMT). To examine its role in GVHD, we conducted a systemic literature search using multiple electronic databases. Upon pooling of data, 79 patients from six studies and five case reports were included. Complete remission (CR) occurred in 55.9% of patients, and partial remission (PR) occurred in 26.5% of patients (82.4% overall response rate). A limited number of patients had treatment-related mortality (TRM), while few showed mild gastrointestinal (GI)-related and non-GI adverse effects. None of the studies directly examined the role of FMT in the prevention of GVHD. In conclusion, FMT seems to be a safe and effective strategy for the management of GVHD based on the current evidence. Due to the small number of patients evaluated and the absence of randomized data, one cannot portray FMT as a standard of care yet; however, the low toxicity along with the clinical improvement justifies this modality to be tested in a randomized fashion.
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9.
Rational use of chronic graft-versus-host treatment alternatives: A systematic review
Yeral, M., Boğa, C.
Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis. 2022;:103371
Abstract
Chronic graft versus host disease (cGVHD) is an important transplant complication that affects the quality of life of the recipient by causing organ damage after hematopoietic stem cell transplantation. Prospective controlled studies conducted to date for the treatment of the disease are limited. The results obtained in current studies are not sufficient to establish a standard treatment algorithm. Therefore, clinical experience and adequate clinical observations of the transplant team come to the fore for the treatment strategy to be established. Rational use of available instruments is possible, provided that we understand the mechanisms of the disease and use validated diagnostic and response criteria. In this study, we tried to create a practical workflow by evaluating current literature data.
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10.
Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents
Buder, K., Zirngibl, M., Bapistella, S., Meerpohl, J. J., Strahm, B., Bassler, D., Weitz, M.
The Cochrane database of systematic reviews. 2022;6(6):Cd009898
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Abstract
BACKGROUND Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015. OBJECTIVES To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation. SEARCH METHODS We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. MAIN RESULTS We found no studies meeting the criteria for inclusion in this 2021 review update. AUTHORS' CONCLUSIONS We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.
PICO Summary
Population
Children and adolescents with chronic graft-versus-host disease (GvHD) taking part in randomised controlled trials
Intervention
Extracorporeal photopheresis (ECP) with or without alternative treatment
Comparison
Alternative treatment alone
Outcome
The authors found no studies meeting the criteria for inclusion in this systematic review.