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Petty AJ, Cardones AR, Jin YJ, Jain V, Hocke E, Pathak HB, Mitra A, Gregory SG, Selim MA, Zhang JY. Insights into Keratinocyte and Immunologic Landscape in Cutaneous Graft-Versus-Host Disease through Single-Cell Transcriptomics. JID INNOVATIONS 2025; 5:100373. [PMID: 40492027 PMCID: PMC12146041 DOI: 10.1016/j.xjidi.2025.100373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/13/2025] [Accepted: 04/10/2025] [Indexed: 06/11/2025] Open
Abstract
Cutaneous manifestations are the most common presenting sign of chronic graft-versus-host disease (GVHD), and the extent of cutaneous involvement is also highly correlated with prognosis. Very little is understood about the underlying pathogenesis underpinning injury at this location, especially the contribution of keratinocytes and other structural skin cells. We performed single-cell RNA sequencing to compare the transcriptome of epidermal and dermal chronic GVHD samples with that of healthy control samples. Our findings reveal unique nonimmunologic and immunologic changes in epidermal keratinocytes and dermal immune cells. Specifically, we observed upregulation of alarmins and inflammatory cytokines and downregulation of anti-reduction-oxidation and activator protein-1 pathway genes in the keratinocyte compartments. In dermal immune cell subsets, we showed increased CD8+ T, CD4+ T, CD4+Foxp3+ regulatory T, and NK cells in chronic GVHD, accompanied by increased signals of leukocyte functions, inflammatory responses, cytolysis, and macrophage M1 polarization. Finally, we also delineated the donor versus recipient cellular origin of nonimmune and immune cell populations in sex-mismatched chronic GVHD. Taken together, these data reveal complex keratinocyte and immune responses in cutaneous chronic GVHD, supporting future studies of skin cell contributions to pathogenesis and potential local treatment strategies.
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Affiliation(s)
- Amy J. Petty
- Department of Dermatology, Duke University, Durham, North Carolina, USA
| | - Adela Rambi Cardones
- Department of Dermatology, Duke University, Durham, North Carolina, USA
- Division of Dermatology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Yingai Jane Jin
- Department of Dermatology, Duke University, Durham, North Carolina, USA
| | - Vaibhav Jain
- Molecular Genomic Core, Duke University, Durham, North Carolina, USA
| | - Emily Hocke
- Molecular Genomic Core, Duke University, Durham, North Carolina, USA
| | - Harsh B. Pathak
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Amrita Mitra
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Simon G. Gregory
- Molecular Genomic Core, Duke University, Durham, North Carolina, USA
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
| | - M. Angelica Selim
- Department of Pathology, Duke University, Durham, North Carolina, USA
| | - Jennifer Y. Zhang
- Department of Dermatology, Duke University, Durham, North Carolina, USA
- Department of Pathology, Duke University, Durham, North Carolina, USA
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Mishra SB, Kawali A, Mahendradas P, Shetty R. Disseminated Varicella-Zoster Virus-Associated Acute Retinal Necrosis in a Post-Bone Marrow Transplant Patient. Ocul Immunol Inflamm 2025:1-3. [PMID: 40346926 DOI: 10.1080/09273948.2025.2503327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/30/2025] [Accepted: 05/03/2025] [Indexed: 05/12/2025]
Abstract
PURPOSE This case report highlights the risk of viral infections, particularly acute retinal necrosis (ARN), in patients undergoing immunosuppressive therapy for graft-versus-host disease (GVHD) following bone marrow transplantation. METHODS A 45-year-old male with aplastic anaemia who underwent a bone marrow transplantation developed GVHD and was treated with ruxolitinib and tacrolimus. The patient presented with ocular symptoms and was diagnosed with pseudodendritic keratitis in the right eye and ARN in the left eye. The diagnosis was confirmed through PCR analysis of the anterior chamber tap. RESULTS The patient's right eye symptoms were resolved with topical acyclovir and supportive care, achieving a best-corrected visual acuity of 6/6. Following systemic and intravitreal antiviral therapy, ARN resolved in left eye with thinning and retinal detachment. The patient was not cleared for surgery due to his compromised systemic condition. CONCLUSION Our case highlights the disseminated and asymmetric nature of herpes zoster infection in the context of severe immunosuppression. This emphasizes the need to balance effective GVHD treatment and reinforces the importance of ongoing vigilance and timely management of these high-risk individuals.
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Affiliation(s)
- Sai Bhakti Mishra
- Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, India
| | - Ankush Kawali
- Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, India
| | | | - Rohit Shetty
- Department of Uveitis and Ocular Immunology Services, Narayana Nethralaya, Bangalore, India
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Escamilla-Gómez V, García Gutiérrez V, Alcalde-Mellado P, Astibia-Mahillo B, Chinea-Rodriguez A, López-Corral L, Acera-Gómez M, Torres Ochando MK, Borrero Borrego A, González Pinedo L, Zudaire Ripa T, González Vicent M, Benzaquén A, Izquierdo Garcia I, Asensi Cantó P, Montoro J, Martín-Domínguez FM, Orti G, Valcárcel D, Benitez-Carabante MI, Diaz-de-Heredia C, Cañamero E, Ferrá C, García-Cadenas I, Redondo S, Sisinni L, Perez-Martínez A, Mussetti A, Garcia-Mañó L, Palomo-Moraleda MDP, González-Sierra PA, Jurado M, Perez-Simon JA. Ruxolitinib in acute and chronic graft-versus-host disease: real life long-term experience in a multi-center study for adult and pediatric patients, on behalf of the GETH-TC. Bone Marrow Transplant 2025; 60:353-362. [PMID: 39663471 DOI: 10.1038/s41409-024-02483-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 11/13/2024] [Accepted: 11/19/2024] [Indexed: 12/13/2024]
Abstract
Ruxolitinib has been approved for the treatment of adults and pediatric patients ≥12 years with steroid refractory graft-versus-host disease (GvHD). However, real-life studies are needed to confirm the results of clinical trials and further assess its efficacy in special populations. We performed a descriptive, retrospective, multi-center study of 352 adults and 42 pediatric patients treated with ruxolitinib for steroid-refractory acute or chronic GvHD. Among 119 and 233 adult patients with acute and chronic GvHD, overall response rate (ORR) was 58.8% (CR 33.6%) and 65.7% (CR 18.5%), respectively. Corticosteroids were withdrawn in 59.2% and 40.1%, and ruxolitinib in 47.2% and 34.8% in the acute and chronic groups of responders. Among 29 and 13 pediatric patients with acute and chronic GvHD, ORR was 82.7% (CR 51.7%) and 100% (CR 23%), respectively. Among responder patients, corticosteroids were withdrawn in 72.7% and 50%, and ruxolitinib in 75% and 30.7% in both groups respectively. Ruxolitinib in the real world setting, showed similar results as compared to clinical trials. Its efficacy is maintained in subsequent lines of treatment. In the pediatric population, the data are more favorable. In the long-term follow-up, corticosteroids, ruxolitinib and other inmunosuppressive drugs could be eliminated in a remarkably proportion of patients.
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Affiliation(s)
- Virginia Escamilla-Gómez
- Servicio de hematologia, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Valentín García Gutiérrez
- Hematology Service, Hospital Universitario Ramón y Cajal. IRYCIS, Universidad de Alcalá, Madrid, Spain.
| | - Patricia Alcalde-Mellado
- Servicio de hematologia, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Beatriz Astibia-Mahillo
- Hematology Service, Hospital Universitario Ramón y Cajal. IRYCIS, Universidad de Alcalá, Madrid, Spain
| | - Anabelle Chinea-Rodriguez
- Hematology Service, Hospital Universitario Ramón y Cajal. IRYCIS, Universidad de Alcalá, Madrid, Spain
| | - Lucía López-Corral
- Department of Hematology, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
| | - Marina Acera-Gómez
- Department of Hematology, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
| | | | - Asunción Borrero Borrego
- Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | - Leslie González Pinedo
- Hematology Department, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain
| | | | - Marta González Vicent
- Hematopoietic Transplant Department, Hospital Universitario Niño Jesús, Madrid, Spain
| | - Ana Benzaquén
- Hematology Department, Hospital Clínico Universitario de Valencia, Instituto de Investigación Sanitaria INCLIVA, Valencia, Valencia, Spain
| | | | - Pedro Asensi Cantó
- Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Juan Montoro
- Hematology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Francisco Manuel Martín-Domínguez
- Servicio de hematologia, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain
| | - Guillermo Orti
- Hematology Department, HospitalUniversitario Vall d´Hebron, Barcelona, Spain
| | - David Valcárcel
- Hematology Department, HospitalUniversitario Vall d´Hebron, Barcelona, Spain
| | - Maria Isabel Benitez-Carabante
- Hematology and Oncology Department, Division of Pediatric Hematology and Oncology, Hospital Universitario Vall d´Hebron, Barcelona, Spain
| | - Cristina Diaz-de-Heredia
- Hematology and Oncology Department, Division of Pediatric Hematology and Oncology, Hospital Universitario Vall d´Hebron, Barcelona, Spain
| | - Eloi Cañamero
- Hematology Deparment, HospitalUniversitario Germans Trias i Pujol - Institut Català d'Oncologia, Barcelona, Spain
| | - Christelle Ferrá
- Hematology Deparment, HospitalUniversitario Germans Trias i Pujol - Institut Català d'Oncologia, Barcelona, Spain
| | | | - Sara Redondo
- Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Luisa Sisinni
- Hemato-Oncology Pediatric Service, HospitalUniversitario La Paz, Madrid, Spain
| | | | - Alberto Mussetti
- Department of Hematology, Hospital Duran i Reynals, Instituto Catalán de Oncología, L'Hospitalet De Llobregat, Barcelona, Spain
| | | | | | | | - Manuel Jurado
- Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria, Granada, Spain
| | - Jose A Perez-Simon
- Servicio de hematologia, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS)/CSIC, Universidad de Sevilla, Sevilla, Spain.
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Chen W, Wang Z, Liu Z, Fu B, Xing T, You J, Hu J. Belumosudil in pediatric patients with chronic graft-versus-host disease after failed multi-line therapy: a case series. Ann Hematol 2025; 104:1241-1247. [PMID: 39661130 PMCID: PMC11971124 DOI: 10.1007/s00277-024-06128-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/26/2024] [Indexed: 12/12/2024]
Abstract
Belumosudil is a selective small molecule inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2) indicated for patients with glucocorticoid-refractory chronic graft-versus-host disease (cGVHD). Despite its approval for ages 12-18, there is limited pediatric data available. This case series presents three 12-year-old patients with severe cGVHD who had failed multiple lines of therapy. Case #1 received treatment for 210 days with belumosudil, prednisone, cyclosporine A, mycophenolate mofetil, and ruxolitinib. Initial assessments showed skin and joint fascia involvement (National Institutes of Health score 3), along with oral cavity, ocular, and pulmonary involvement (score 2). Following treatment, all affected organs demonstrated at least a partial response (PR), with an overall assessment of PR. Case #2 was treated for 205 days with belumosudil, tacrolimus, and ruxolitinib. Baseline assessments indicated involvement of the skin and joint fascia (score 3), and the oral cavity and eyes (score 2). Most organs achieved PR or complete response (CR), resulting in an overall PR. Case #3 underwent 121 days of therapy with belumosudil, prednisone, and tacrolimus, showing similar baseline organ involvement as Case #2. The treatment resulted in an overall PR, with improvement noted in the skin, oral cavity, eyes, and joint fascia. The Lee cGVHD symptom scale scores improved meaningfully for all patients over time. There was no recurrence of the primary disease or any fatalities. Adverse events were limited to grade 1-2 severity. This case series indicates that belumosudil may be effective in 12-year-old pediatric patients with severe, multi-organ cGVHD refractory to multiple treatments. The findings suggest that belumosudil-based regimens can be feasible and well-tolerated in this population, providing preliminary evidence for its potential therapeutic effects in clinical management.
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Affiliation(s)
- Wenting Chen
- Hainan General Hospital, Haikou, China
- Hainan Hospital of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, China
- School of Biomedical Engineering, Hainan University, Haikou, China
| | - Zhi Wang
- Hainan Hospital of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, China
| | - Zhouyang Liu
- Beijing Jingdu Children's Hospital, Beijing, China
| | - Bin Fu
- Department of Hematology, Xiangya Hospital of Central South University, Changsha, China
| | - Tingting Xing
- Hainan Hospital of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, China
| | - Jianhua You
- Hainan Hospital of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Qionghai, China.
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jiong Hu
- Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Shah R, Murphy D, Logue M, Jerkins J, Jallouk A, Adetola K, Oluwole O, Jayani R, Biltibo E, Kim TK, Sengsayadeth S, Chinratanalab W, Kitko C, Savani B, Dholaria B. Multidisciplinary Management of Morbidities Associated with Chronic Graft-Versus-Host Disease. Clin Hematol Int 2024; 6:74-88. [PMID: 39469117 PMCID: PMC11514143 DOI: 10.46989/001c.124926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 07/27/2024] [Indexed: 10/30/2024] Open
Abstract
Chronic graft-versus-host disease (cGVHD) represents a common long-term complication after allogeneic hematopoietic stem cell transplantation (HSCT). It imposes a significant morbidity burden and is the leading cause of non-relapse mortality among long-term HSCT survivors. cGVHD can manifest in nearly any organ, severely affecting the quality of life of a transplant survivor. While the mainstay of treatment has remained systemic immunosuppression with glucocorticoids, progress has been made within the last few years with approvals of three oral agents to treat steroid-refractory cGVHD: ibrutinib, ruxolitinib, and belumosudil. Iatrogenesis contributes a significant portion of the morbidity experienced by patients with cGVHD, primarily from glucocorticoids. This review highlights the myriad impacts of cGVHD, including and beyond the traditional organ systems captured by the National Institutes of Health Consensus Criteria, including iatrogenic complications of long-term immunosuppression. It presents the implications of cGVHD and its treatment on cardiovascular and metabolic health, bone density, endocrine function, sexual health, and ocular and pulmonary disease and outlines a framework around the comprehensive multidisciplinary approach for its evaluation and management.
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Affiliation(s)
- Rahul Shah
- Division of Cancer Medicine The University of Texas MD Anderson Cancer Center
- Department of Medicine Vanderbilt University Medical Center
| | - Danielle Murphy
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Melissa Logue
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - James Jerkins
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Andrew Jallouk
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Kassim Adetola
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Olalekan Oluwole
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Reena Jayani
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Eden Biltibo
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Tae K Kim
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Salyka Sengsayadeth
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Wichai Chinratanalab
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Carrie Kitko
- Division of Hematology/Oncology, Department of Pediatrics Vanderbilt University Medical Center
| | - Bipin Savani
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
| | - Bhagirathbhai Dholaria
- Division of Hematology/Oncology, Department of Medicine Vanderbilt University Medical Center
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O'Brien H, Murray J, Orfali N, Fahy RJ. Pulmonary complications of bone marrow transplantation. Breathe (Sheff) 2024; 20:240043. [PMID: 39360022 PMCID: PMC11444492 DOI: 10.1183/20734735.0043-2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 07/15/2024] [Indexed: 10/04/2024] Open
Abstract
Bone marrow transplantation, now often known as haematopoietic stem cell transplantation (HSCT), is a complex choreographed procedure used to treat both acquired and inherited disorders of the bone marrow. It has proven invaluable as therapy for haematological and immunological disorders, and more recently in the treatment of metabolic and enzyme disorders. As the number of performed transplants grows annually, and with patients enjoying improved survival, a knowledge of both early and late complications of HSCT is essential for respiratory trainees and physicians in practice. This article highlights the spectrum of respiratory complications, both infectious and non-infectious, the timeline of their likely occurrence, and the approaches used for diagnosis and treatment, keeping in mind that more than one entity may occur simultaneously. As respiratory issues are often a leading cause of short- and long-term morbidity, consideration of a combined haematology/respiratory clinic may prove useful in this patient population.
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Affiliation(s)
- Helen O'Brien
- Division of Respiratory Medicine, St James Hospital, Dublin, Ireland
- These authors contributed equally
| | - John Murray
- Division of Respiratory Medicine, St James Hospital, Dublin, Ireland
- These authors contributed equally
| | - Nina Orfali
- Division of Haematology, St James Hospital, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Ruairi J. Fahy
- Division of Respiratory Medicine, St James Hospital, Dublin, Ireland
- School of Medicine, Trinity College Dublin, Dublin, Ireland
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Sharma NR, Pokhrel M, Lamichhane P, Paudel S, Rivera Boadla ME, Kc P, Alvarez B. Every Fever Not Merely Due to Antibiotic Deficiency: Chronic Graft-Versus-Host Disease Case Report. Cureus 2024; 16:e71367. [PMID: 39539862 PMCID: PMC11558026 DOI: 10.7759/cureus.71367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/13/2024] [Indexed: 11/16/2024] Open
Abstract
This case report presents a 53-year-old female patient with a history of acute lymphoblastic leukemia (ALL) who developed chronic graft-versus-host disease (cGVHD) following an allogeneic bone marrow transplant, leading to significant respiratory distress and notable skin findings, including hyperpigmentation and chronic non-healing ulcers. The patient's clinical course illustrates the diverse manifestations of cGVHD, emphasizing the importance of recognizing that not all febrile episodes in post-transplant patients are attributable solely to infection. A multidisciplinary approach was essential for accurate diagnosis and management, underscoring the need for comprehensive evaluation of symptoms in immunocompromised patients. This case contributes to the understanding of cGVHD's clinical implications and highlights the necessity for ongoing research in its management.
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Affiliation(s)
- Nava R Sharma
- Internal Medicine, Maimonides Medical Center, Brooklyn, USA
- Medicine, Manipal College of Medical Science, Pokhara, NPL
| | | | | | - Sumitra Paudel
- Public Health, The University of Southern Mississippi, Hattiesburg, USA
- Research Volunteer, Maimonides Medical Center, Brooklyn, USA
| | | | - Prabal Kc
- Internal Medicine, Rasuwa District Hospital, Kathmandu, NPL
| | - Barbara Alvarez
- Infectious Disease, Maimonides Medical Center, Brooklyn, USA
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[Chinese expert consensus on the diagnosis and treatment of chronic graft-versus-host disease (2024)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:713-726. [PMID: 39307718 PMCID: PMC11535560 DOI: 10.3760/cma.j.cn121090-20240611-00217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Indexed: 12/06/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation, which significantly impacts patients' survival and quality of life. In recent years, notable progress has been made in the diagnosis, prevention, and treatment of cGVHD, driven by the emergence of novel therapies such as targeted drugs and the advancement of clinical research. This consensus, based on the latest developments in cGVHD research and growing data from evidence-based medicine, has been revised and updated from the "Chinese consensus on the diagnosis and management of chronic graft-versus-host disease (2021)" to better guide clinical practice.
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He J, Zheng F, Zhang L, Cai J, Ogawa Y, Tsubota K, Liu S, Jin X. Single-cell RNA-sequencing reveals the transcriptional landscape of lacrimal gland in GVHD mouse model. Ocul Surf 2024; 33:50-63. [PMID: 38703817 DOI: 10.1016/j.jtos.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/02/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
PURPOSE To investigate the global transcriptional landscape of lacrimal gland cell populations in the GVHD mouse model. METHODS Single-cell RNA sequencing and further bioinformatic analysis of dissociated lacrimal gland (LG) cells from the mouse model were performed. Parts of transcriptional results were confirmed by immunofluorescence staining. RESULTS We identified 23 cell populations belonging to 11 cell types. In GVHD LG, the proportion of acinar cells, myoepithelial cells, and endothelial cells was remarkably decreased, while T cells and macrophages were significantly expanded. Gene expression analysis indicated decreased secretion function, extracellular matrix (ECM) synthesis, and increased chemokines of myoepithelial cells. A newly described epithelial population named Lrg1high epithelial cells, expressing distinct gene signatures, was exclusively identified in GVHD LG. The fibroblasts exhibited an inflammation gene pattern. The gene pattern of endothelial cells suggested an increased ability to recruit immune cells and damaged cell-cell junctions. T cells were mainly comprised of Th2 cells and effective memory CD8+ T cells. GVHD macrophages exhibited a Th2 cell-linked pattern. CONCLUSIONS This single-cell atlas uncovered alterations of proportion and gene expression patterns of cell populations and constructed cell-cell communication networks of GVHD LG. These data may provide some new insight into understanding the development of ocular GVHD.
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Affiliation(s)
- Jingliang He
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Fang Zheng
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Li Zhang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | | | - Yoko Ogawa
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan; Tsubota Laboratory, Inc., Tokyo, Japan
| | - Shan Liu
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
| | - Xiuming Jin
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China.
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10
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Buck AM, LaFranchi BH, Henrich TJ. Gaining momentum: stem cell therapies for HIV cure. Curr Opin HIV AIDS 2024; 19:194-200. [PMID: 38686850 PMCID: PMC11155292 DOI: 10.1097/coh.0000000000000859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
PURPOSE OF REVIEW Durable HIV-1 remission has been reported in a person who received allogeneic stem cell transplants (SCTs) involving CCR5 Δ32/Δ32 donor cells. Much of the reduction in HIV-1 burden following allogeneic SCT with or without donor cells inherently resistant to HIV-1 infection is likely due to cytotoxic graft-versus-host effects on residual recipient immune cells. Nonetheless, there has been growing momentum to develop and implement stem cell therapies that lead to durable long-term antiretroviral therapy (ART)-free remission without the need for SCT. RECENT FINDINGS Most current research leverages gene editing techniques to modify hematopoietic stem cells which differentiate into immune cells capable of harboring HIV-1. Approaches include targeting genes that encode HIV-1 co-receptors using Zinc Finger Nucleases (ZFN) or CRISPR-Cas-9 to render a pool of adult or progenitor cells resistant to de-novo infection. Other strategies involve harnessing multipotent mesenchymal stromal cells to foster immune environments that can more efficiently recognize and target HIV-1 while promoting tissue homeostasis. SUMMARY Many of these strategies are currently in a state of infancy or adolescence; nonetheless, promising preclinical and first-in-human studies have been performed, providing further rationale to focus resources on stem cell therapies.
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Affiliation(s)
- Amanda M Buck
- Division of Experimental Medicine, University of California San Francisco, San Francisco, California, USA
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Guinan E, Heuston C, Sheill G, Chonghaile MN, Orfali N. Health professionals' perceptions of prehabilitation before haematopoietic cell transplantation to optimise candidacy in older adults. Support Care Cancer 2024; 32:465. [PMID: 38926198 PMCID: PMC11208210 DOI: 10.1007/s00520-024-08659-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024]
Abstract
PURPOSE Haematologic malignancies for the most part are diseases of the elderly. Haematopoietic stem cell transplantation (HSCT) remains the only potentially curative strategy for many patients but carries substantial morbidity and mortality risks, particularly in frail or co-morbid patients. Pre-transplant optimisation of key targets through prehabilitation may have significant clinical impact. METHODS We utilised qualitative methodology (semi-structured interviews) to gain insights and understanding of the perceptions of medical, nursing and allied health professionals towards prehabilitation before haematopoietic cell transplantation to optimise candidacy in older adults. Thematic analysis was performed using a qualitative descriptive approach completed in duplicate by two researchers. RESULTS Between August and October 2023, eleven health professionals participated from four large cancer centres across the island of Ireland (n = 3 consultant haematologists, n = 7 specialist haematology nurses and n = 1 senior haematology physiotherapist). Four major themes were identified. The themes comprehensive biopsychosocial care and increasing demand for transplant in older patients highlight the unique challenges impacting older adults who receive HSCT. The multimodality pathways of care theme highlights the heterogeneity of treatment pathways across different clinical sites and disease types. This has implications for the prehabilitation: logistics and benefits theme, which indicated strong support for prehabilitation but emphasised that implementation must consider national reach and context. CONCLUSIONS There is broad national multidisciplinary interest in the development of prehabilitation programmes for patients being considered for transplant. Our results will inform the development of services in this area in consideration of national reach, malignancy-specific pathways and the unique factors associated with older age.
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Affiliation(s)
- E Guinan
- Discipline of Physiotherapy, Trinity College Dublin, Dublin, Ireland.
- Trinity St James's Cancer Institute, Dublin, Ireland.
| | - C Heuston
- Department of Physiology, Trinity College Dublin, Dublin, Ireland
| | - G Sheill
- Trinity St James's Cancer Institute, Dublin, Ireland
- Department of Physiotherapy, St James's Hospital, Dublin, Ireland
| | - M Ní Chonghaile
- Trinity St James's Cancer Institute, Dublin, Ireland
- National Adult Stem Cell Transplant Unit, St James's Hospital, Dublin, Ireland
| | - N Orfali
- Trinity St James's Cancer Institute, Dublin, Ireland
- National Adult Stem Cell Transplant Unit, St James's Hospital, Dublin, Ireland
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12
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Wang Y, Liu Q, Deng L, Ma X, Gong Y, Wang Y, Zhou F. The roles of epigenetic regulation in graft-versus-host disease. Biomed Pharmacother 2024; 175:116652. [PMID: 38692061 DOI: 10.1016/j.biopha.2024.116652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/03/2024] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) is utilized as a potential curative treatment for various hematologic malignancies. However, graft-versus-host disease (GVHD) post-aHSCT is a severe complication that significantly impacts patients' quality of life and overall survival, becoming a major cause of non-relapse mortality. In recent years, the association between epigenetics and GVHD has garnered increasing attention. Epigenetics focuses on studying mechanisms that affect gene expression without altering DNA sequences, primarily including DNA methylation, histone modifications, non-coding RNAs (ncRNAs) regulation, and RNA modifications. This review summarizes the role of epigenetic regulation in the pathogenesis of GVHD, with a focus on DNA methylation, histone modifications, ncRNA, RNA modifications and their involvement and applications in the occurrence and development of GVHD. It also highlights advancements in relevant diagnostic markers and drugs, aiming to provide new insights for the clinical diagnosis and treatment of GVHD.
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Affiliation(s)
- Yimin Wang
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qi Liu
- The First Clinical Medical School, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lei Deng
- Department of Hematology, the 960th Hospital of the People's Liberation Army Joint Logistics Support Force, Jinan, China
| | - Xiting Ma
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China
| | - Yuling Gong
- Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yifei Wang
- Department of Cardiovascular, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Fang Zhou
- Department of Hematology, the 960th Hospital of the People's Liberation Army Joint Logistics Support Force, Jinan, China.
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13
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Wang SL, Sun GY, Zhu XY, Xu XM, Ye F, Li SL, Chen S. [The prognostic value of colonoscopy grading for acute graft-versus-host disease in patients with malignant hematological disorders after unrelated cord blood transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:462-467. [PMID: 38964920 PMCID: PMC11270501 DOI: 10.3760/cma.j.cn121090-20231206-00293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Indexed: 07/06/2024]
Abstract
Objective: To investigate the prognostic value of enteroscopic grading for the prognostic assessment of patients with malignant hematological diseases who developed intestinal acute graft-versus-host disease (IT-aGVHD) after unrelated cord blood transplantation (UCBT) . Methods: Fifty patients with IT-aGVHD who developed hormone resistance after UCBT from June 2016 to June 2023 at Anhui Provincial Hospital were collected to compare the effective and survival rates of IT-aGVHD treatment in the group with milder enteroscopic mucosal injury (27 cases, enteroscopic grading of Ⅰ and Ⅱ) and the group with more severe injury (23 cases, enteroscopic grading of Ⅲ and Ⅳ) and to retrospectively analyze the factors affecting patients' prognosis. Results: Patients in the mild and severe groups had an effective rate of 92.6% and 47.8% at 28 days after colonoscopy (P<0.001), 81.5% and 39.1% at 56 days after colonoscopy (P=0.002), with optimal effective rate of 92.6% and 65.2% (P=0.040), respectively, and the differences were statistically significant. The multifactorial analysis found that enteroscopic grading was an independent risk factor affecting the effective rate of IT-aGVHD treatment. The overall survival rate at 2 years after colonoscopy was 70.4% (95% CI 52.0% -88.8% ) and 34.8% (95% CI 14.8% -54.8% ) for patients in the mild and severe groups, respectively, and the difference was statistically significant (P=0.003). Multifactorial analysis revealed that enteroscopic grading, cytomegalovirus infection status, second-line treatment regimen, and patients' age were independent risk factors for survival. Conclusion: The treatment efficacy and prognosis of patients in the group with less severe enteroscopic injury (grades Ⅰ and Ⅱ) were better than those in the group with more severe injury (grades Ⅲ and Ⅳ) .
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Affiliation(s)
- S L Wang
- Department of Gastroenterology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - G Y Sun
- Department of Haematology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - X Y Zhu
- Department of Haematology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - X M Xu
- Department of Gastroenterology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - F Ye
- Department of Gastroenterology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - S L Li
- Clinical Pathology Centre, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
| | - S Chen
- Department of Gastroenterology, The First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital), Hefei 230001, China
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14
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Kantor NB, Tovar A, Wang T, Galor A. How does ocular graft-versus-host disease fit under the dry eye umbrella? A review. Clin Exp Ophthalmol 2024; 52:167-185. [PMID: 38204146 PMCID: PMC10939887 DOI: 10.1111/ceo.14347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 11/28/2023] [Accepted: 12/11/2023] [Indexed: 01/12/2024]
Abstract
Graft-versus-host disease (GVHD) is a systemic disease that can affect multiple organs as a consequence of an allogeneic haematopoietic stem cell transplant. One organ system that is often affected in GVHD is the eyes. Ocular GVHD (oGVHD) may involve various structures within the eye including the lacrimal glands, eyelids, conjunctiva, cornea, and nasolacrimal ducts, and is a source of morbidity in patients with GVHD. Common presenting features of GVHD overlap with dry eye disease (DED), including decreased tear production, epithelial disruption, and Meibomian gland dysfunction (MGD). In this review, we aim to compare oGVHD and DED to better understand the similarities and differences between the conditions, with a focus on pathophysiology, risk factors, clinical features, and treatments.
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Affiliation(s)
- Nicole B. Kantor
- Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
- Surgical Services, Miami Veterans Affairs Medical Center, Miami, FL, USA
| | | | - Trent Wang
- Division of Transplantation and Cellular Therapy, Sylvester Comprehensive Cancer Center, Adult Stem Cell Transplant Program, University of Miami Hospital and Clinics, Miami, FL, USA
| | - Anat Galor
- Bascom Palmer Eye Institute, University of Miami, Miami, FL, USA
- Surgical Services, Miami Veterans Affairs Medical Center, Miami, FL, USA
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15
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McNeil AJ, Parks K, Liu X, Jiang B, Coco J, McCool K, Fabbri D, Duhaime EP, Dawant BM, Tkaczyk ER. Crowdsourcing Skin Demarcations of Chronic Graft-Versus-Host Disease in Patient Photographs: Training Versus Performance Study. JMIR DERMATOLOGY 2023; 6:e48589. [PMID: 38147369 PMCID: PMC10777279 DOI: 10.2196/48589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 10/02/2023] [Accepted: 10/24/2023] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) is a significant cause of long-term morbidity and mortality in patients after allogeneic hematopoietic cell transplantation. Skin is the most commonly affected organ, and visual assessment of cGVHD can have low reliability. Crowdsourcing data from nonexpert participants has been used for numerous medical applications, including image labeling and segmentation tasks. OBJECTIVE This study aimed to assess the ability of crowds of nonexpert raters-individuals without any prior training for identifying or marking cGHVD-to demarcate photos of cGVHD-affected skin. We also studied the effect of training and feedback on crowd performance. METHODS Using a Canfield Vectra H1 3D camera, 360 photographs of the skin of 36 patients with cGVHD were taken. Ground truth demarcations were provided in 3D by a trained expert and reviewed by a board-certified dermatologist. In total, 3000 2D images (projections from various angles) were created for crowd demarcation through the DiagnosUs mobile app. Raters were split into high and low feedback groups. The performances of 4 different crowds of nonexperts were analyzed, including 17 raters per image for the low and high feedback groups, 32-35 raters per image for the low feedback group, and the top 5 performers for each image from the low feedback group. RESULTS Across 8 demarcation competitions, 130 raters were recruited to the high feedback group and 161 to the low feedback group. This resulted in a total of 54,887 individual demarcations from the high feedback group and 78,967 from the low feedback group. The nonexpert crowds achieved good overall performance for segmenting cGVHD-affected skin with minimal training, achieving a median surface area error of less than 12% of skin pixels for all crowds in both the high and low feedback groups. The low feedback crowds performed slightly poorer than the high feedback crowd, even when a larger crowd was used. Tracking the 5 most reliable raters from the low feedback group for each image recovered a performance similar to that of the high feedback crowd. Higher variability between raters for a given image was not found to correlate with lower performance of the crowd consensus demarcation and cannot therefore be used as a measure of reliability. No significant learning was observed during the task as more photos and feedback were seen. CONCLUSIONS Crowds of nonexpert raters can demarcate cGVHD images with good overall performance. Tracking the top 5 most reliable raters provided optimal results, obtaining the best performance with the lowest number of expert demarcations required for adequate training. However, the agreement amongst individual nonexperts does not help predict whether the crowd has provided an accurate result. Future work should explore the performance of crowdsourcing in standard clinical photos and further methods to estimate the reliability of consensus demarcations.
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Affiliation(s)
- Andrew J McNeil
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, United States
| | - Kelsey Parks
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Xiaoqi Liu
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, United States
| | - Bohan Jiang
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, United States
| | - Joseph Coco
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nasvhille, TN, United States
| | | | - Daniel Fabbri
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nasvhille, TN, United States
| | | | - Benoit M Dawant
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, United States
| | - Eric R Tkaczyk
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, United States
- Department of Biomedical Informatics, Vanderbilt University Medical Center, Nasvhille, TN, United States
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16
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Linn SM, Novitzky-Basso I, Patriquin C, Pasic I, Lam W, Law A, Michelis FV, Gerbitz A, Viswabandya A, Lipton J, Kumar R, Mattsson J, Barth D, Kim DDH. Single centre retrospective analysis of extracorporeal photopheresis (ECP) therapy in patients heavily pre-treated for chronic graft-versus-host disease (cGvHD) with steroid failure. Leuk Res 2023; 134:107387. [PMID: 37734221 DOI: 10.1016/j.leukres.2023.107387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 09/02/2023] [Accepted: 09/06/2023] [Indexed: 09/23/2023]
Abstract
BACKGROUND Extracorporeal photopheresis (ECP) is recommended as a second- or later-line therapy for chronic GvHD (cGvHD). Benefits include reasonable response with avoidance of intense systemic immunosuppression, which can translate into lowering the risk of systemic toxicity and opportunistic infection. METHODS We evaluated 75 patients treated with ECP for cGvHD from 2007 to 2021 at Princess Margaret Cancer Centre, and analyzed overall response rate (ORR) and clinical benefit (CB) at 3, 6 and 12 months plus other long-term treatment outcomes. RESULTS With a median follow-up of 72 months, a gradual increase in ORR was noted over time: 21% (16 out of 75 patients), 57% (36/63) and 70% (32/46) at month 3, 6 and 12, respectively. Gradual increase in CB was also observed over time with CB rate of 23% (17/75), 62% (39/63), and 76% (35/46) at months 3, 6 and 12, respectively. A total of 27 failures (36%) were noted, due to: 1) ECP resistance requiring switch to other therapy (n = 14, 19%), 2) non-relapse mortality (n = 10, 13%), 3) relapse of primary disease (n = 1, 1%) or 4) ECP procedure-related complication (n = 1, 1%, line infection), with 20 deaths (27%) observed. Failure-free survival (FFS) and overall survival (OS) rates were 68.3% and 85.9% at 12 months, respectively. After starting ECP, the proportions of patients who completely discontinued steroids were 17%, 32%, and 64% at months 3, 6 and 12, respectively. CONCLUSION ECP is an effective treatment option for heavily pre-treated cGvHD patients.
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Affiliation(s)
- Swe Mar Linn
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada
| | - Igor Novitzky-Basso
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada
| | - Christopher Patriquin
- Apheresis Program, Division of Medical Oncology and Haematology, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Ivan Pasic
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Wilson Lam
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Arjun Law
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Fotios V Michelis
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Armin Gerbitz
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Auro Viswabandya
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Jeffrey Lipton
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Rajat Kumar
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Jonas Mattsson
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - David Barth
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada
| | - Dennis Dong Hwan Kim
- Hans Messner Allogeneic Transplant Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, University Health Network, Canada; Faculty of Medicine, Department of Medicine, University of Toronto, Canada.
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17
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Izzo A, Pellegrino RA, Locci G, Cesaretti M. Acute graft versus host disease after liver transplantation: where do we stand? Minerva Surg 2023; 78:537-544. [PMID: 36883938 DOI: 10.23736/s2724-5691.23.09868-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Graft-versus-host disease (GVHD) is a rare complication after liver transplantation (LT), with an estimated incidence rate of 0.5% to 2% and a mortality rate as high as 75%. The classical target organs of GVHD include the intestines, liver, and skin. The damage of these organs is not easy to detect for the clinician as there is no widely accepted clinical or laboratory diagnostic tests; as a result, diagnosis and initiation of therapy are often delayed. Moreover, without prospective clinical trials to reference, evidence guiding therapy is limited. This review summarized the current knowledge, the potential applications and the clinical relevance of GVHD after LT, highlighting novel approaches in grading and management of GVHD.
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Affiliation(s)
- Alessandro Izzo
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari, Italy
| | | | - Giorgia Locci
- Department of Pathology, Brotzu Hospital, Cagliari, Italy
| | - Manuela Cesaretti
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari, Italy -
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18
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Zhang X, He J, Zhao K, Liu S, Xuan L, Chen S, Xue R, Lin R, Xu J, Zhang Y, Xiang AP, Jin H, Liu Q. Mesenchymal stromal cells ameliorate chronic GVHD by boosting thymic regeneration in a CCR9-dependent manner in mice. Blood Adv 2023; 7:5359-5373. [PMID: 37363876 PMCID: PMC10509672 DOI: 10.1182/bloodadvances.2022009646] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 06/15/2023] [Accepted: 06/18/2023] [Indexed: 06/28/2023] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Mature donor T cells within the graft contribute to severe damage of thymic epithelial cells (TECs), which are known as key mediators in the continuum of acute GVHD (aGVHD) and cGVHD pathology. Mesenchymal stromal cells (MSCs) are reportedly effective in the prevention and treatment of cGVHD. In our previous pilot clinical trial in patients with refractory aGVHD, the incidence and severity of cGVHD were decreased, along with an increase in levels of blood signal joint T-cell receptor excision DNA circles after MSCs treatment, which indicated an improvement in thymus function of patients with GVHD, but the mechanisms leading to these effects remain unknown. Here, we show in a murine GVHD model that MSCs promoted the quantity and maturity of TECs as well as elevated the proportion of Aire-positive medullary TECs, improving both CD4+CD8+ double-positive thymocytes and thymic regulatory T cells, balancing the CD4:CD8 ratio in the blood. In addition, CCL25-CCR9 signaling axis was found to play an important role in guiding MSC homing to the thymus. These studies reveal mechanisms through which MSCs ameliorate cGVHD by boosting thymic regeneration and offer innovative strategies for improving thymus function in patients with GVHD.
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Affiliation(s)
- Xin Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiabao He
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Ke Zhao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Shiqi Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Li Xuan
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Shan Chen
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Rongtao Xue
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Ren Lin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Jun Xu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Yan Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Sun Yat-Sen University, Guangzhou, China
| | - Hua Jin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Clinical Medical Research Center of Hematology Diseases of Guangdong Province, Guangzhou, China
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19
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Choi HJ, Yu XZ. ER stress: an emerging regulator in GVHD development. Front Immunol 2023; 14:1212215. [PMID: 37744326 PMCID: PMC10511645 DOI: 10.3389/fimmu.2023.1212215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.
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Affiliation(s)
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States
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20
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Walsh CA, Yi JC, Leisenring WM, Syrjala KL. Social Support, Coping, and Cancer-Related Health Burden in Long-term Survivors Treated with Hematopoietic Stem Cell Transplantation as Adolescents or Young Adults. J Adolesc Young Adult Oncol 2023; 12:496-502. [PMID: 36282798 PMCID: PMC10457605 DOI: 10.1089/jayao.2022.0105] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Purpose: Long-term adolescent and young adult hematopoietic stem cell transplantation (HCT) survivors face complex physical and psychological treatment effects that contribute to cancer-related health burden. We aimed to identify the role of social support and coping strategies on cancer-related health burden. Methods: This cross-sectional analysis included HCT recipients from the INSPIRE trial [NCT00799461], who received their first transplant between ages 15 and 39. As our primary outcome, we used the health burden subscale of the Cancer and Treatment Distress measure. We assessed correlates using the Short Form-36v2 physical component summary, brief Coping Orientation to Problems Experienced (COPE), and ENRICHD Social Support Inventory. We used hierarchical multivariable linear regression to identify factors associated with cancer-related health burden, with the first step including sociodemographic and clinical factors, the second step adding physical function, and the third step including social support and coping. Results: Participants (N = 293) were 52% male and 93% white, non-Hispanic, with a mean age of 30.2 (standard deviation 6.6) at first transplant. In step one, sex accounted for ∼3% of the variance (p = 0.006). Adding physical function explained an additional 33% of the variance (p = <0.001). Social support and coping strategies explained 11% of the variance (p = <0.001). The final model explained 47% of the variance; better physical function, more social support, and active coping were associated with lower cancer-related health burden, while female sex, venting, and distraction were associated with higher cancer-related health burden. Conclusion: Supporting physical function and fostering social support and active coping may help mitigate cancer-related health burden in this population. Clinical Trial Registration: NCT00799461.
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Affiliation(s)
- Casey A. Walsh
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- University of Washington, School of Medicine, Seattle, Washington, USA
| | - Jean C. Yi
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Wendy M. Leisenring
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Karen L. Syrjala
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- University of Washington, School of Medicine, Seattle, Washington, USA
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21
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Assmann JL, Vlachonikola E, Kolijn PM, Agathangelidis A, Pechlivanis N, Papalexandri A, Stamatopoulos K, Chatzidimitriou A, Langerak AW. Context-dependent T-cell Receptor Gene Repertoire Profiles in Proliferations of T Large Granular Lymphocytes. Hemasphere 2023; 7:e929. [PMID: 37469801 PMCID: PMC10353713 DOI: 10.1097/hs9.0000000000000929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 06/12/2023] [Indexed: 07/21/2023] Open
Abstract
T cell large granular lymphocyte (T-LGL) lymphoproliferations constitute a disease spectrum ranging from poly/oligo to monoclonal. Boundaries within this spectrum of proliferations are not well established. T-LGL lymphoproliferations co-occur with a wide variety of other diseases ranging from autoimmune disorders, solid tumors, hematological malignancies, post solid organ, and hematopoietic stem cell transplantation, and can therefore arise as a consequence of a wide variety of antigenic triggers. Persistence of a dominant malignant T-LGL clone is established through continuous STAT3 activation. Using next-generation sequencing, we profiled a cohort of 27 well-established patients with T-LGL lymphoproliferations, aiming to identify the subclonal architecture of the T-cell receptor beta (TRB) chain gene repertoire. Moreover, we searched for associations between TRB gene repertoire patterns and clinical manifestations, with the ultimate objective of discriminating between T-LGL lymphoproliferations developing in different clinical contexts and/or displaying distinct clinical presentation. Altogether, our data demonstrates that the TRB gene repertoire of patients with T-LGL lymphoproliferations is context-dependent, displaying distinct clonal architectures in different settings. Our results also highlight that there are monoclonal T-LGL cells with or without STAT3 mutations that cause symptoms such as neutropenia on one end of a spectrum and reactive oligoclonal T-LGL lymphoproliferations on the other. Longitudinal analysis revealed temporal clonal dynamics and showed that T-LGL cells might arise as an epiphenomenon when co-occurring with other malignancies, possibly reactive toward tumor antigens.
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Affiliation(s)
- Jorn L.J.C. Assmann
- Laboratory for Medical Immunology, Department of Immunology, Erasmus MC, Rotterdam, Netherlands
| | | | - Pieter M. Kolijn
- Laboratory for Medical Immunology, Department of Immunology, Erasmus MC, Rotterdam, Netherlands
| | | | - Nikolaos Pechlivanis
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Greece
| | | | - Kostas Stamatopoulos
- Institute of Applied Biosciences, Centre for Research and Technology Hellas, Greece
| | | | - Anton W. Langerak
- Laboratory for Medical Immunology, Department of Immunology, Erasmus MC, Rotterdam, Netherlands
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22
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Algeri M, Becilli M, Locatelli F. Ruxolitinib as the first post-steroid treatment for acute and chronic graft-versus-host disease. Expert Rev Clin Immunol 2023; 19:1299-1313. [PMID: 37606511 DOI: 10.1080/1744666x.2023.2249230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 08/14/2023] [Indexed: 08/23/2023]
Abstract
INTRODUCTION Acute and chronic graft-versus-host disease (GvHD) are potentially life-threatening complications occurring after allogeneic stem cell transplantation (allo-HSCT). Although steroids represent the first-line treatment for both conditions, in those patients who do not adequately benefit from steroid therapy, standardized treatment algorithms are lacking. In recent years, ruxolitinib has emerged as the most promising agent for the second-line therapy of steroid-refractory (SR)-GvHD. AREAS COVERED This review will summarize the biological properties and the mechanistic aspects that justify the therapeutic role of ruxolitinib in GvHD. In addition, current treatment options for SR-GvHD will be briefly discussed. Finally, results of the most relevant clinical trials on the use of ruxolitinib for SR-GvHD will be analyzed, with a particular focus on two phase-III randomized trials in which ruxolitinib demonstrated its superiority in comparison with the best available therapy. EXPERT OPINION Ruxolitinib has considerably improved the outcome of patients with SR-acute/chronic-GvHD and should be regarded as the standard-of-care option when corticosteroids fail or cannot be tapered. Nevertheless, a number of questions still remain unanswered and significant room for improvement exists. Additional observations derived from a longer follow-up will certainly increase our expertise in the management of this powerful therapy.
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Affiliation(s)
- Mattia Algeri
- Department of Haematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
- Department of Health Science, Magna Grecia University of Catanzaro, Catanzaro, Italy
| | - Marco Becilli
- Department of Haematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Franco Locatelli
- Department of Haematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
- Department of Life Sciences and Public Health, Catholic University of the Sacred Heart, Rome, Italy
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23
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El Sayed R, Shankar KM, Mankame AR, Cox CS. Innovations in cell therapy in pediatric diseases: a narrative review. Transl Pediatr 2023; 12:1239-1257. [PMID: 37427072 PMCID: PMC10326759 DOI: 10.21037/tp-23-92] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 05/25/2023] [Indexed: 07/11/2023] Open
Abstract
Background and Objective Stem cell therapy is a regenerative medicine modality that has the potential to decrease morbidity and mortality by promoting tissue regeneration or modulating the inflammatory response. An increase in the number of clinical trials investigating the efficacy and safety of stem cell therapy in pediatric diseases has led to advancements in this field. Currently, multiple sources and types of stem cells have been utilized in the treatment of pediatric diseases. This review aims to inform researchers and clinicians about preclinical and clinical stem cell therapy trials in pediatric patients. We discuss the different types of stem cells and the wide spectrum of stem cell therapy trials for pediatric diseases, with an emphasis on the outcomes and advancements in the field. Methods PubMed and clinicaltrials.gov databases were searched on October 28, 2022 using the following Medical Subject Headings (MeSH) terms "stem cell" or "stem cell therapy" with an age filter <18 years. Our search was limited to publications published between 2000 and 2022. Key Content and Findings Diverse sources of stem cells have different properties and mechanisms of action, which allow tailored application of stem cells according to the pathophysiology of the disease. Advancements in stem cell therapies for pediatric diseases have led to improvements in clinical outcomes in some pediatric diseases or in quality of life, such therapies represent a potential alternative to the current treatment modalities. Conclusions Stem cell therapy in pediatric diseases has shown promising results and outcomes. However, further studies focusing on the implementation and optimal treatment timeframe are needed. An increase in preclinical and clinical trials of stem cell therapy targeting pediatric patients is required to advance our therapeutic applications.
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Affiliation(s)
- Razan El Sayed
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center for Translational Injury Research, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Karan Michael Shankar
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Atharwa Rajan Mankame
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
| | - Charles S. Cox
- Department of Pediatric Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Center for Translational Injury Research, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
- Department of Surgery, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA
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24
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Kadri N, Amu S, Iacobaeus E, Boberg E, Le Blanc K. Current perspectives on mesenchymal stromal cell therapy for graft versus host disease. Cell Mol Immunol 2023; 20:613-625. [PMID: 37165014 DOI: 10.1038/s41423-023-01022-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 04/07/2023] [Indexed: 05/12/2023] Open
Abstract
Graft versus host disease (GvHD) is the clinical condition in which bone marrow-derived mesenchymal stromal cells (MSCs) have been most frequently studied. In this review, we summarize the experience from clinical trials that have paved the way to translation. While MSC-based therapy has shown an exceptional safety profile, identifying potency assays and disease biomarkers that reliably predict the capacity of a specific MSC batch to alleviate GvHD has been difficult. As GvHD diagnosis and staging are based solely on clinical criteria, individual patients recruited in the same clinical trial may have vastly different underlying biology, obscuring trial outcomes and making it difficult to determine the benefit of MSCs in subgroups of patients. An accumulating body of evidence indicates the importance of considering not only the cell product but also patient-specific biomarkers and/or immune characteristics in determining MSC responsiveness. A mode of action where intravascular MSC destruction is followed by monocyte-efferocytosis-mediated skewing of the immune repertoire in a permissive inflammatory environment would both explain why cell engraftment is irrelevant for MSC efficacy and stress the importance of biologic differences between responding and nonresponding patients. We recommend a combined analysis of clinical outcomes and both biomarkers of disease activity and MSC potency assays to identify patients with GvHD who are likely to benefit from MSC therapy.
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Affiliation(s)
- Nadir Kadri
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sylvie Amu
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ellen Iacobaeus
- Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
| | - Erik Boberg
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
| | - Katarina Le Blanc
- Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Department of Cell Therapies and Allogeneic Stem Cell Transplantation Karolinska University Hospital, Stockholm, Sweden.
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25
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Zavaro M, Dangot A, Bar-Lev TH, Amit O, Avivi I, Ram R, Aharon A. The Role of Extracellular Vesicles (EVs) in Chronic Graft vs. Host Disease, and the Potential Function of Placental Cell-Derived EVs as a Therapeutic Tool. Int J Mol Sci 2023; 24:ijms24098126. [PMID: 37175831 PMCID: PMC10179565 DOI: 10.3390/ijms24098126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/19/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Chronic graft-versus-host disease (cGVHD) presents with dermal inflammation and fibrosis. We investigated the characteristics of extracellular vesicles (EVs) obtained from cGVHD patients, and their potential effects on human dermal fibroblast (NHDF) cells. The anti-inflammatory and anti-fibrotic effects of placental EVs were also explored given their known anti-inflammatory properties. Fourteen cGVHD patients' EVs contained higher levels of fibrosis-related proteins, TGFβ and α-smooth muscle actin (αSMA), compared to EVs from thirteen healthy subjects. The exposure of NHDF cells to the patients' EVs increased the NHDF cells' TGFβ and αSMA expressions. Placental EVs derived from placental-expanded cells (PLX) (Pluri Inc.) and human villous trophoblast (HVT) cells expressing the mesenchymal markers CD29, CD73, and CD105, penetrated into both the epidermal keratinocytes (HACATs) and NHDF cells. Stimulation of the HACAT cells with cytokine TNFα/INFγ (0.01-0.1 ng/µL) reduced cell proliferation, while the addition of placental EVs attenuated this effect, increasing and normalizing cell proliferation. The treatment of NHDF cells with a combination of TGFβ and placental HVT EVs reduced the stimulatory effects of TGFβ on αSMA production by over 40% (p = 0.0286). In summary, EVs from patients with cGVHD can serve as a biomarker for the cGVHD state. Placental EVs may be used to regulate dermal inflammation and fibrosis, warranting further investigation of their therapeutic potential.
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Affiliation(s)
- Mor Zavaro
- Hematology Research Laboratory, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6195001, Israel
| | - Ayelet Dangot
- Hematology Research Laboratory, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6195001, Israel
| | - Tali Hana Bar-Lev
- Hematology Research Laboratory, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Odelia Amit
- The BMT Unit, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Irit Avivi
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6195001, Israel
- Hematology Department, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Ron Ram
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6195001, Israel
- The BMT Unit, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
| | - Anat Aharon
- Hematology Research Laboratory, Hematology Division, Tel-Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6195001, Israel
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26
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Salhotra A, Sandhu K, O'Hearn J, Ali H, Nakamura R, Modi BG. A critical review of belumosudil in adult and pediatric patients with chronic graft-versus-host disease. Expert Rev Clin Immunol 2023; 19:241-251. [PMID: 36440483 DOI: 10.1080/1744666x.2023.2152330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin -21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway. AREAS COVERED In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable. EXPERT OPINION Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs.
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Affiliation(s)
- Amandeep Salhotra
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Karamjeet Sandhu
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - James O'Hearn
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Haris Ali
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Ryotaro Nakamura
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Badri G Modi
- Department of Surgery, Division of Dermatology, City of Hope National Medical Center, Duarte, CA, USA
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27
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A Multiparameter Prognostic Risk Score of Chronic Graft-versus-Host Disease Based on CXCL10 and Plasmacytoid Dendritic Cell Levels in the Peripheral Blood at 3 Months after Allogeneic Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 2023; 29:302.e1-302.e8. [PMID: 36796518 DOI: 10.1016/j.jtct.2023.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/26/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023]
Abstract
Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). There are no biomarkers that can consistently predict its occurrence. We aimed to evaluate whether numbers of antigen-presenting cell subsets in peripheral blood (PB) or serum chemokine concentrations are biomarkers of cGVHD occurrence. The study cohort comprised 101 consecutive patients undergoing allogeneic HSCT between January 2007 and 2011. cGVHD was diagnosed by both modified Seattle criteria and National Institutes of Health (NIH) criteria. Multicolor flow cytometry was used to determine the number of PB myeloid dendritic cells (DCs), plasmacytoid DCs, CD16+ DCs, and CD16+ and CD16- monocytes, as well as CD4+ and CD8+ T cells, CD56+ natural killer cells, and CD19+ B cells. Serum concentrations of CXCL8, CXCL10, CCL2, CCL3, CCL4, and CCL5 were measured by a cytometry bead array assay. At a median of 60 days after enrollment, 37 patients had developed cGVHD. Patients with cGVHD and those without cGVHD had comparable clinical characteristics. However, previous acute GVHD (aGVHD) was strongly correlated with later cGVHD (57% versus 24%, respectively; P = .0024). Each potential biomarker was screened for its association with cGVHD using the Mann-Whitney U test. Biomarkers that differed significantly (P < .05) between patients with cGVHD and those without cGVHD were analyzed by receiver operating characteristic (ROC) curve analysis to select the variables predicting cGVHD with an area under the ROC curve (AUC) >.5 and a P value <.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 ≥592.650 pg/mL (hazard ratio [HR], 2.655; 95% confidence interval [CI], 1.298 to 5.433; P = .008), pDC ≥2.448/μL (HR, .286; 95% CI, .142 to .577; P < .001) and previous aGVHD (HR, 2.635; 95% CI, 1.298 to 5.347; P = .007). A risk score was derived based on the weighted coefficients of each variable (2 points each), resulting in the identification of 4 cohorts of patients (scores of 0, 2, 4, and 6). In a competing risk analysis to stratify patients at differing risk levels of cGVHD, the cumulative incidence of cGVHD was 9.7%, 34.3%, 57.7%, and 100% in patients with scores of 0, 2, 4, and 6, respectively (P < .0001). The score could nicely stratify the patients based on the risk of extensive cGVHD as well as NIH-based global and moderate to severe cGVHD. Based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of .791 (95% CI, .703 to .880; P < .001). Finally, a cutoff score ≥4 was identified as the optimal cutoff by Youden J index with a sensitivity of 57.1% and a specificity of 85.0%. A multiparameter score including a history of previous aGVHD, serum CXCL10 concentration, and number of pDCs in the PB at 3 months post-HSCT stratify patients at varying risk levels of cGVHD. However, the score needs to be validated in a much larger independent and possibly multicenter cohort of patients undergoing transplantation from different donor types and with distinct GVHD prophylaxis regimens.
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28
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Oyama T, Matsuda K, Honda A, Maki H, Masamoto Y, Murakami D, Toya T, Sakurai M, Kataoka K, Doki N, Kurokawa M. Clinical characteristics of steroid-responsive but dependent chronic graft-versus-host disease: a multicenter retrospective analysis. Int J Hematol 2023; 117:260-268. [PMID: 36251231 DOI: 10.1007/s12185-022-03471-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 10/11/2022] [Accepted: 10/11/2022] [Indexed: 02/03/2023]
Abstract
Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation. The clinical importance of long-term corticosteroid dependency in steroid-responsive cGVHD is undetermined. We retrospectively reviewed the data of 120 consecutive patients who received systemic steroid therapy for cGVHD between January 2007 and December 2018 at three institutions. Among patients with steroid-responsive cGVHD, those who successfully tapered off corticosteroids within 1 year were defined as the early withdrawal group (EW-cGVHD) and others were defined as the dependent group (Dp-cGVHD). Twenty-six patients were classified as EW-cGVHD and 55 as Dp-cGVHD. The proportion of men was significantly higher and performance status was significantly better in EW-cGVHD. The 5-year overall survival and cGVHD recurrence-free survival rates were significantly higher in EW-cGVHD than Dp-cGVHD (96% vs. 68%, p = 0.017 and 84% vs. 41%, p = 0.002, respectively). While the relapse-free survival rate did not differ significantly (84% vs. 65%, p = 0.15), the proportion of patients requiring readmission, mainly due to cGVHD recurrence or infection, was significantly increased in Dp-cGVHD (38% vs. 84%, p < 0.001). In summary, steroid dependency in cGVHD for more than 1 year was significantly associated with poor transplant outcomes.
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Affiliation(s)
- Takashi Oyama
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Kensuke Matsuda
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Akira Honda
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Hiroaki Maki
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Yosuke Masamoto
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan
| | - Daisuke Murakami
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan
| | - Takashi Toya
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan
| | - Masatoshi Sakurai
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Medicine, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-Ku, Tokyo, 113-8677, Japan
| | - Mineo Kurokawa
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
- Department of Cell Therapy and Transplantation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-Ku, Tokyo, 113-8655, Japan.
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29
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Raman HS, Kim SE, DeAngelo DJ, Stevenson KE, Neuberg D, Winer ES, Wadleigh M, Garcia JS, Kim AS, Stone RM, Ho VT, Luskin MR. Intensity of induction regimen and outcomes among adults with Ph+ALL undergoing allogeneic hematopoietic stem cell transplantation. Leuk Res 2023; 125:107004. [PMID: 36577290 DOI: 10.1016/j.leukres.2022.107004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Tyrosine kinase inhibitors (TKIs) are essential for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and have allowed for effective, low intensity induction regimens including no or minimal chemotherapy. Whether the use of low intensity induction regimens impacts outcomes after allogeneic hematopoietic stem cell transplant (alloHCT) is less understood. We identified consecutive adult patients with Ph+ ALL undergoing alloHCT in first complete remission (CR1) at our center from 2010 to 2021 and examined the impact of pre-transplant induction intensity on outcomes. Among the 87 identified patients, 44 (51%) received low intensity induction and 43 (49%) received induction with high intensity chemotherapy. Patients receiving low intensity induction were older (median age 60 vs. 47 years, p < 0.01). Following induction, measurable residual disease (MRD) negativity by BCR::ABL1 RT-PCR was similar in the low and high intensity induction cohorts (54% and 52% respectively). Receipt of reduced intensity transplant conditioning was not associated with intensity of induction regimen (39% vs. 19% in low vs. high, respectively, p = 0.06). At a median follow-up of 21 months from transplant, there was no difference between low and high intensity induction with respect to 2-year disease-free survival (58% vs. 56%), 2-year overall survival (62% vs. 63%), 2-year cumulative incidence of relapse (9% vs. 17%), and 2-year non-relapse mortality (33% vs. 29%). We also found no difference in outcomes when patients were segmented by both induction and conditioning regimen intensities. Our retrospective analysis suggests that induction intensity does not impact post-transplant outcomes among patients with Ph+ ALL transplanted in CR1.
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Affiliation(s)
- Hari S Raman
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
| | - Se Eun Kim
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Daniel J DeAngelo
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | | | - Donna Neuberg
- Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Eric S Winer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Martha Wadleigh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Jacqueline S Garcia
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Annette S Kim
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
| | - Richard M Stone
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Vincent T Ho
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
| | - Marlise R Luskin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Ritacco C, Köse MC, Courtois J, Canti L, Beguin C, Dubois S, Vandenhove B, Servais S, Caers J, Beguin Y, Ehx G, Baron F. Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells. iScience 2023; 26:106085. [PMID: 36843851 PMCID: PMC9947306 DOI: 10.1016/j.isci.2023.106085] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/12/2022] [Accepted: 01/25/2023] [Indexed: 02/02/2023] Open
Abstract
Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versus-leukemia effects have remained debated. Here, we studied the mechanisms of xenogeneic GVHD (xGVHD) prevention by PTCy in different humanized mouse models. We observed that PTCy attenuated xGVHD. Using flow cytometry and single-cell RNA-sequencing, we demonstrated that PTCy depleted proliferative CD8+ and conventional CD4+ T cells but also proliferative regulatory T cells (Treg). Further, T-cell receptor β variable region sequencing (TCRVB) analyses demonstrated that highly xenoreactive T-cell clones were depleted by PTCy. Although Treg frequencies were significantly higher in PTCy-treated than in control mice on day 21, xGVHD attenuation by PTCy was not abrogated by Treg depletion. Finally, we observed that PTCy did not abrogate graft-versus-leukemia effects.
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Affiliation(s)
- Caroline Ritacco
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Murat Cem Köse
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Justine Courtois
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Lorenzo Canti
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Charline Beguin
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Sophie Dubois
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Benoît Vandenhove
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium
| | - Sophie Servais
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium,Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, Belgium
| | - Jo Caers
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium,Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, Belgium
| | - Yves Beguin
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium,Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, Belgium
| | - Grégory Ehx
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium,Corresponding author
| | - Frédéric Baron
- Hematology Research Unit, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA)-I³, University of Liège, Liège 4000, Belgium,Department of Medicine, Division of Hematology, CHU of Liège, Liège 4000, Belgium,Corresponding author
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Miklos DB, Abu Zaid M, Cooney JP, Albring JC, Flowers M, Skarbnik AP, Yakoub-Agha I, Ko BS, Bruno B, Waller EK, Yared J, Sohn SK, Bulabois CE, Teshima T, Jacobsohn D, Greinix H, Mokatrin A, Lee Y, Wahlstrom JT, Styles L, Socie G. Ibrutinib for First-Line Treatment of Chronic Graft-Versus-Host Disease: Results From the Randomized Phase III iNTEGRATE Study. J Clin Oncol 2023; 41:1876-1887. [PMID: 36608310 PMCID: PMC10082299 DOI: 10.1200/jco.22.00509] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
PURPOSE To present primary and final analyses from the randomized, double-blind, placebo-controlled, phase III iNTEGRATE study, which evaluated the safety and efficacy of ibrutinib with prednisone in previously untreated patients with chronic graft-versus-host disease (cGVHD). METHODS Patients (age ≥ 12 years) with newly diagnosed moderate or severe cGVHD, requiring systemic corticosteroid therapy, and with no prior systemic treatment for cGVHD were randomly assigned 1:1 to receive ibrutinib 420 mg once daily plus prednisone, starting at 1 mg/kg once daily or placebo plus prednisone. The primary end point was response rate at 48 weeks according to 2014 National Institutes of Health Consensus Development Project Criteria. Other end points included event-free survival, duration of response, time to withdrawal of immunosuppressants, improvement in Lee cGVHD Symptom Scale score, overall survival (OS), and safety. RESULTS Ninety-five and 98 patients enrolled in the ibrutinib-prednisone and placebo-prednisone arms, respectively. At 48 weeks, response rates were 41% (ibrutinib-prednisone) and 37% (placebo-prednisone; P = .54). At 33 months of follow-up, median duration of response was 19 months (ibrutinib-prednisone) and 10 months (placebo-prednisone; P = .10). Median event-free survival was 15 months (ibrutinib-prednisone) and 8 months (placebo-prednisone; hazard ratio, 0.76; 95% CI, 0.54 to 1.1; P = .11). Improvement in overall Lee cGVHD Symptom Scale was 43% (ibrutinib-prednisone) and 31% (placebo-ibrutinib; P = .07). Median OS was not reached in either arm. The 24-month Kaplan-Meier OS estimates were 80% for both arms (hazard ratio, 1.06; 95% CI, 0.59 to 1.90). Grade ≥ 3 serious adverse events occurred in 49% (ibrutinib-prednisone) and 47% (placebo-prednisone) of patients. CONCLUSION There was no statistical difference observed in the primary and secondary end points with ibrutinib-prednisone treatment. No new safety signals were observed with ibrutinib treatment in previously untreated patients with cGVHD. The primary end point of iNTEGRATE was not met.
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Affiliation(s)
| | - Mohammad Abu Zaid
- Melvin and Bren Simon Cancer Center (IUSCC), Indiana University, Indianapolis, IN
| | - Julian P Cooney
- Fiona Stanley Hospital, Murdoch, Australia.,University of Western Australia, Crawley, Australia
| | | | - Mary Flowers
- Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Alan P Skarbnik
- John Theurer Cancer Center, Hackensack, NJ.,Novant Health Cancer Institute, Charlotte, NC
| | | | - Bor-Sheng Ko
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan
| | - Benedetto Bruno
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | | | - Jean Yared
- University of Maryland School of Medicine, Greenebaum Comprehensive Cancer Center, Baltimore, MD
| | - Sang Kyun Sohn
- Kyungpook National University Hospital, Daegu, South Korea
| | | | | | | | | | - Ahmad Mokatrin
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | - Yihua Lee
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | | | - Lori Styles
- Pharmacyclics LLC, an AbbVie Company, South San Francisco, CA
| | - Gerard Socie
- AP-HP, Hopital St Louis and University of Paris, Paris, France
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Novitzky-Basso I, Schain F, Batyrbekova N, Webb T, Remberger M, Keating A, Mattsson J. Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease. PLoS One 2023; 18:e0282753. [PMID: 36893113 PMCID: PMC9997892 DOI: 10.1371/journal.pone.0282753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/21/2023] [Indexed: 03/10/2023] Open
Abstract
INTRODUCTION Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. METHODS We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. RESULTS cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. CONCLUSION cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT.
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Affiliation(s)
- Igor Novitzky-Basso
- Princess Margaret Cancer Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Frida Schain
- Janssen Global Services, Stockholm, Sweden
- Schain Research AB, Bromma, Sweden
- Department for Medicine, Division of Hematology, Karolinska Institutet, Stockholm, Sweden
| | - Nurgul Batyrbekova
- SDS Life Science, Stockholm, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Thomas Webb
- Janssen Global Services, High Wycombe, United Kingdom
| | - Mats Remberger
- Department of Medical Sciences, Uppsala University and Clinical Research and Development Unit, Uppsala University Hospital, Uppsala, Sweden
| | - Armand Keating
- Princess Margaret Cancer Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
| | - Jonas Mattsson
- Princess Margaret Cancer Centre, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
- Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation, Department of Medicine, University of Toronto, Toronto, Canada
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- * E-mail:
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Møller DL, Kielsen K, Nielsen CH, Sengeløv H, Pedersen AE, Ryder LP, Müller K. Thymic stromal lymphopoietin levels after allogeneic hematopoietic stem cell transplantation. Immunopharmacol Immunotoxicol 2022; 44:1004-1012. [PMID: 35899395 DOI: 10.1080/08923973.2022.2102989] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thymic stromal lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. METHODS We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry. RESULTS TSLP levels rose after initiation of the conditioning to peak at day +21 after HSCT (p = .03), where TSLP levels correlated with counts of neutrophils (rho = 0.36, p = .04), monocytes (rho = 0.58, p = .006), and lymphocytes (rho = 0.59, p = .02). Overall absolute TSLP levels were not associated with acute or chronic graft-vs-host disease (a/cGvHD). However, patients mounting a sustained increase in TSLP levels at day +90 had a higher risk of cGvHD compared to patients who had returned to pre-conditioning levels at that stage (cumulative incidence: 77% vs. 38%, p = .01). CONCLUSION In conclusion, this study suggests a role of TSLP in immune reconstitution and alloreactivity post-HSCT. lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry.
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Affiliation(s)
- Dina Leth Møller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Katrine Kielsen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Henrik Sengeløv
- Department of Hematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Peter Ryder
- The Tissue Typing Laboratory, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
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Successful Management of Infectious Crystalline Keratopathy with Intrastromal Antibiotic Injections. Case Rep Ophthalmol Med 2022; 2022:5830617. [PMID: 36504920 PMCID: PMC9729021 DOI: 10.1155/2022/5830617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 12/03/2022] Open
Abstract
Purpose. To report the successful treatment of a case of presumed infectious crystalline keratopathy with repeated intrastromal antibiotic injections in a cornea graft in the setting of severe ocular graft-vs.-host-disease (GVHD). Observations. A 62-year-old man with a history of ocular GVHD and tectonic penetrating keratoplasty (PK) for corneal melt from herpes zoster keratopathy developed presumed infectious crystalline keratopathy (ICK) in the corneal graft. Given the patient's complicated ocular history, chronic immunosuppression and new cardiac comorbidities, a therapeutic PK would most likely fail. Efforts were then directed to rescue the graft with minimally invasive approaches. Two separate intrastromal injections of cefuroxime and moxifloxacin successfully treated his ICK. Conclusions and Importance. This case supports a role for repeated intrastromal antibiotic injections in patients with ICK refractory to topical antibiotic therapy, which might eliminate the need for therapeutic PK and preserve vision.
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Mina A, Curtis L, West K, Yau YY, Cowen EW, Hakim F, Pavletic SZ. Collection of peripheral blood mononucleated cells for chronic graft-versus-host disease immunology research: safety and effectiveness of leukapheresis in 132 patients. J Transl Med 2022; 20:519. [DOI: 10.1186/s12967-022-03708-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 10/14/2022] [Accepted: 10/17/2022] [Indexed: 11/09/2022] Open
Abstract
Abstract
Background
Chronic graft-versus-host disease (GVHD) is a major cause of late morbidity and non-relapse mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Its biology, however, remains poorly understood, making the studies of its biology and immunomodulatory therapies a difficult task. Such research is often hampered by lymphopenia which is common in these patients and precludes studies of critical cellular subsets across the spectrum of severity of disease. This study explores the potential of leukapheresis to safely acquire and efficiently store immune cells for immunology research in chronic GVHD.
Methods
This is a cross-sectional study in which 132 consecutively accrued patients undergo optional research leukapheresis and a one-week comprehensive outpatient evaluation. Baseline clinical and laboratory data and efficiency of the procedure were reported.
Results
Ninety-four of 132 patients (71%) achieved the goal collection of 2 × 10^9 PBMNCs with a mean volume processed of 4.6 L. Only mild decreases in hemoglobin, platelet, lymphocyte and monocytes were observed. All adverse events were mild (grade 1) and had resolved by the time of discharge from the apheresis unit.
Conclusion
This study demonstrates feasibility, safety, and efficiency of research leukapheresis in a frail patient population. Results presented promote leukapheresis as a standard research practice option in studies of chronic GVHD in humans which may expedite advances in our understanding of this complex multisystem disease.
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Milosevic E, Babic A, Iovino L, Markovic M, Grce M, Greinix H. Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: A systematic review. Front Immunol 2022; 13:1033263. [DOI: 10.3389/fimmu.2022.1033263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/10/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectivesChronic graft-versus-host disease (cGvHD) is the most frequent cause of late non-relapse mortality after allogeneic haematopoietic stem cell transplantation (alloHCT). Nevertheless, established biomarkers of cGvHD are still missing. The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGvHD provided recommendations for biomarker research. We evaluated to which extent studies on cellular and soluble biomarkers in cGvHD published in the last 10 years complied with these recommendations. Also, we highlight the most promising biomarker candidates, verified in independent cohorts and/or repeatedly identified by separate studies.MethodsWe searched Medline and EMBASE for “cGvHD”, “biomarkers”, “soluble” and “cells” as MeSH terms or emtree subject headings, and their variations on July 28th, 2021, limited to human subjects, English language and last ten years. Reviews, case reports, conference abstracts and single nucleotide polymorphism studies were excluded. Criteria based on the set of recommendations from the NIH group for biomarker research in cGvHD were used for scoring and ranking the references.ResultsA total of 91 references encompassing 15,089 participants were included, 54 prospective, 17 retrospective, 18 cross-sectional, and 2 studies included both prospective and retrospective cohorts. Thirty-five papers included time-matched controls without cGvHD and 20 studies did not have any control subjects. Only 9 studies were randomized, and 8 were multicentric. Test and verification cohorts were included in 11 studies. Predominantly, diagnostic biomarkers were explored (n=54). Assigned scores ranged from 5-34. None of the studies fulfilled all 24 criteria (48 points). Nevertheless, the scores improved during the last years. Three cell subsets (CXCR3+CD56bright NK cells, CD19+CD21low and BAFF/CD19+ B cells) and several soluble factors (BAFF, IL-15, CD163, DKK3, CXCL10 and the panel of ST2, CXCL9, MMP3 and OPN) had the highest potential as diagnostic and/or prognostic biomarkers in cGvHD.ConclusionDespite several limitations of this review (limited applicability for paediatric population, definition of verification, missing data on comorbidities), we identified promising candidate biomarkers for further evaluation in multicentre collaborative studies. This review confirms the importance of the NIH consensus group criteria for improving the quality and reproducibility of cGvHD biomarker research.
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Boor M, Raber-Durlacher JE, Hazenberg MD, Rozema FR, Laheij AMGA. Taste and smell disturbances in patients with chronic oral graft vs. host disease: An observational study. FRONTIERS IN ORAL HEALTH 2022; 3:934607. [PMID: 36160117 PMCID: PMC9500145 DOI: 10.3389/froh.2022.934607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundA common complication of allogeneic hematopoietic stem cell transplantation (alloHSCT) is chronic oral graft vs. host disease (cGvHD). Oral cGvHD may present as mucosal lesions, salivary gland dysfunction, and trismus. Moreover, taste and smell ability may be affected, but the prevalence, nature and severity of altered taste and smell function, and their impact on quality of life (QoL) are understudied.AimTo identify the prevalence, nature, and severity of taste and smell disturbances, their impact on QoL and to assess whether altered taste/smell ability is associated with oral mucosal cGvHD or hyposalivation.Materials and methodsAlloHSCT recipients at least 100 days post-HSCT and referred for oral cGvHD-related oral complaints were eligible for participation in this cross-sectional study. Manifestations of oral mucosal cGvHD were scored, the (un)stimulated salivary flow was measured, and objective taste and smell ability was evaluated. Subjective taste and smell alterations, and overall and oral health (OH)-related QoL were assessed.ResultsIn total, 45 patients were included, of which objective reduced taste ability (hypogeusia) was identified in 68.9%; 28.9% had reduced smell ability and 11.1% had complete loss of smell. Nevertheless, only 31.1% of patients reported severe taste alterations and 22% reported moderate taste alterations indicating that not all the patients were aware of their altered taste sense. Taste/smell disturbances were not related to oral mucosal cGvHD or hyposalivation. Most alloHSCT recipients reported a decreased OH-related QoL. However, a relation between taste/smell ability and global or OH-related QoL could not be identified.ConclusionTaste and smell disturbances are prevalent among alloHSCT recipients. Most patients reported a decreased OH-related QoL, but the specific impact of taste and smell disturbances remains to be elucidated.
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Affiliation(s)
- Marlou Boor
- Department of Oral Medicine, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- *Correspondence: Marlou Boor
| | - Judith E. Raber-Durlacher
- Department of Oral Medicine, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Oral Maxillofacial Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Mette D. Hazenberg
- Department of Hematology Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Frederik R. Rozema
- Department of Oral Medicine, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Oral Maxillofacial Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Alexa M. G. A. Laheij
- Department of Oral Medicine, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
- Department of Oral Maxillofacial Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
- Department of Preventive Dentistry, Academic Centre for Dentistry (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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Prevalence of neurotrophic keratopathy in patients with chronic ocular graft-versus-host disease. Ocul Surf 2022; 26:13-18. [PMID: 35843560 DOI: 10.1016/j.jtos.2022.07.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/08/2022] [Accepted: 07/09/2022] [Indexed: 11/22/2022]
Abstract
PURPOSE To determine the prevalence, clinical characteristics, and risk factors associated with neurotrophic keratopathy (NK) in patients with chronic ocular graft-versus-host disease (oGVHD). DESIGN Retrospective cohort study. METHODS We performed a chart review of patients diagnosed with chronic oGVHD between January 2015 and December 2018 at a single academic institution and recorded demographic data, systemic and ocular comorbidities, history of hematologic malignancy, transplant characteristics, oGVHD severity scores, and adnexal and ocular examination findings. We determined the prevalence of NK and clinical characteristics associated with NK in these patients. A multivariate logistic regression analysis was performed to determine the risk factors associated with NK in these patients. MAIN OUTCOME MEASURE Prevalence of NK in chronic oGVHD. RESULTS We identified 213 patients diagnosed with chronic oGVHD following hematopoietic stem cell or bone marrow transplantation from our electronic patient database, and the prevalence of NK was 14%. The mean age of oGVHD patients with NK was 62.6 ± 12.9 years; 48% were women, 19 had unilateral NK, and ten had bilateral NK. In the cohort, 56%, 20%, and 24% eyes of the patients had grades 1, 2, and 3 of NK, respectively. The mean time to diagnose NK after transplantation was 52.9 ± 45.4 months. oGVHD patients diagnosed with NK had a significantly higher NIH oGVHD severity score (p = 0.04) and a lower corneal sensation score (p = 0.0001) than those without NK. Our analyses showed a significantly higher CFS score (p = 0.01) and a trend toward lower Schirmer test scores (p = 0.16) and tear break-up times (p = 0.08) in oGVHD patients with NK. Additionally, we observed a significantly higher prevalence of persistent epithelial defect (p = 0.0001), corneal ulceration (p = 0.0001), and corneal perforation (p = 0.005) in oGVHD patients diagnosed with NK. A logistic regression analysis to determine factors associated with NK showed that a higher NIH oGVHD score (odds ratio [OR] = 2.03, p = 0.026) and history of cataract surgery (odds ratio [OR] = 5.03, p = 0.001) are significant risk factors for NK in oGVHD patients. CONCLUSIONS The prevalence of NK in chronic oGVHD patients was 14% during the study period. Our analysis shows that oGVHD patients with a higher NIH oGVHD severity score and previous history of cataract surgery are at a higher risk of developing NK and may develop severe sequelae such as persistent epithelial defect or corneal ulceration.
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Rongvaux-Gaïda D, Dupuis M, Poupon J, Djebrani-Oussedik N, Lemonnier C, Rieger F. High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 2022; 28:679.e1-679.e11. [DOI: 10.1016/j.jtct.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 07/01/2022] [Accepted: 07/01/2022] [Indexed: 11/16/2022]
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Biavasco F, Ihorst G, Wäsch R, Wehr C, Bertz H, Finke J, Zeiser R. Therapy response of glucocorticoid-refractory acute GVHD of the lower intestinal tract. Bone Marrow Transplant 2022; 57:1500-1506. [PMID: 35768570 PMCID: PMC9532244 DOI: 10.1038/s41409-022-01741-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/01/2022] [Accepted: 06/09/2022] [Indexed: 11/23/2022]
Abstract
Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic hematopoietic cell transplantation. While most studies report therapy-response of aGVHD including a cumulative grade of skin, liver and intestinal tract manifestations, there is a lack of information specifically on lower gastrointestinal tract aGVHD (GI-GVHD) therapy-response, which is highly relevant in light of novel therapies that target intestinal regeneration such as IL-22, R-spondin or GLP-2. Here we retrospectively analyzed patients who developed GI-GVHD over a 6-year period. A total of 144 patients developed GI-GVHD and 82 (57%) were resistant to glucocorticoid-therapy (SR). The most commonly used second-line therapy was ruxolitinib (74%). Overall and complete response (CR) to ruxolitinib on day 28 were 44.5% and 13%, respectively. SR-GVHD patients experienced a lower 5-year overall survival (OS) (34.8 vs 53.3%, p = 0.0014) and higher incidence of 12-months non-relapse-mortality (39.2 vs 14.3%, p = 0.016) compared to glucocorticoid-sensitive patients. SR-GI-GVHD patients, that achieved a CR on day 28 after ruxolitinib start, experienced a higher OS compared to non-CR patients (p = 0.04). These findings indicate that therapy response of SR-GI-GVHD to different immunosuppressive approaches is still low, and that novel therapies specifically aiming at enhanced intestinal regeneration should be tested in clinical trials.
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Affiliation(s)
- Francesca Biavasco
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Gabriele Ihorst
- Clinical Trials Center Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Ralph Wäsch
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Claudia Wehr
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Hartmut Bertz
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Jürgen Finke
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany. .,German Cancer Consortium (DKTK), Freiburg, Germany. .,Signalling Research Centres BIOSS and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. .,German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Siamakpour-Reihani S, Cao F, Lyu J, Ren Y, Nixon AB, Xie J, Bush AT, Starr MD, Bain JR, Muehlbauer MJ, Ilkayeva O, Byers Kraus V, Huebner JL, Chao NJ, Sung AD. Evaluating immune response and metabolic related biomarkers pre-allogenic hematopoietic stem cell transplant in acute myeloid leukemia. PLoS One 2022; 17:e0268963. [PMID: 35700185 PMCID: PMC9197059 DOI: 10.1371/journal.pone.0268963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/05/2022] [Indexed: 01/08/2023] Open
Abstract
Although hematopoietic stem cell transplantation (HCT) is the only curative treatment for acute myeloid leukemia (AML), it is associated with significant treatment related morbidity and mortality. There is great need for predictive biomarkers associated with overall survival (OS) and clinical outcomes. We hypothesized that circulating metabolic, inflammatory, and immune molecules have potential as predictive biomarkers for AML patients who receive HCT treatment. This retrospective study was designed with an exploratory approach to comprehensively characterize immune, inflammatory, and metabolomic biomarkers. We identified patients with AML who underwent HCT and had existing baseline plasma samples. Using those samples (n = 34), we studied 65 blood based metabolomic and 61 immune/inflammatory related biomarkers, comparing patients with either long-term OS (≥ 3 years) or short-term OS (OS ≤ 1 years). We also compared the immune/inflammatory response and metabolomic biomarkers in younger vs. older AML patients (≤30 years vs. ≥ 55 years old). In addition, the biomarker profiles were analyzed for their association with clinical outcomes, namely OS, chronic graft versus host disease (cGVHD), acute graft versus host disease (aGVHD), infection and relapse. Several baseline biomarkers were elevated in older versus younger patients, and baseline levels were lower for three markers (IL13, SAA, CRP) in patients with OS ≥ 3 years. We also identified immune/inflammatory response markers associated with aGVHD (IL-9, Eotaxin-3), cGVHD (Flt-1), infection (D-dimer), or relapse (IL-17D, bFGF, Eotaxin-3). Evaluation of metabolic markers demonstrated higher baseline levels of medium- and long-chain acylcarnitines (AC) in older patients, association with aGVHD (lactate, long-chain AC), and cGVHD (medium-chain AC). These differentially expressed profiles merit further evaluation as predictive biomarkers.
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Affiliation(s)
- Sharareh Siamakpour-Reihani
- Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Felicia Cao
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Jing Lyu
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Yi Ren
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Andrew B. Nixon
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Jichun Xie
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Amy T. Bush
- Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Mark D. Starr
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - James R. Bain
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Michael J. Muehlbauer
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Olga Ilkayeva
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Virginia Byers Kraus
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Janet L. Huebner
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Nelson J. Chao
- Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, North Carolina, United States of America
| | - Anthony D. Sung
- Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, North Carolina, United States of America
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42
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Lv K, Hu B, Xu M, Wan L, Jin Z, Xu M, Du Y, Ma K, Lv Q, Xu Y, Lei L, Gong H, Liu H, Wu D, Liu Y. IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity. Exp Hematol Oncol 2022; 11:34. [PMID: 35655245 PMCID: PMC9161463 DOI: 10.1186/s40164-022-00286-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic graft-versus-host disease (cGVHD) remains a major complication during the late phase of allogeneic hematopoietic stem cell transplantation (allo-HSCT). IL-39, a newly described pro-inflammatory cytokine belonging to the IL-12 family, plays a role in lupus development. Recently, IL-39 has been identified as a pathogenic factor in acute GVHD (aGVHD). However, the role of IL-39 in the pathogenesis of cGVHD remains unclear. METHODS We constructed a recombinant IL-39 plasmid and established scleroderma and lupus-like cGVHD models. Quantitative PCR and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-39 expression in mice and patients post transplantation, respectively. Hydrodynamic gene transfer (HGT) was performed to achieve IL-39 overexpression in vivo. Multiparameter flow cytometry, western blotting, and assays in vitro were performed to investigate the effect of IL-39 on cGVHD. RESULTS The relative expression of IL-23p19 and EBi3 was significantly increased in the intestine of cGVHD mice on day 40 post allo-HSCT, and IL-39 levels were significantly elevated in the serum of patients following allo-HSCT. Overexpression of IL-39 significantly aggravated the severity of cGVHD. Increased IL-39 levels promoted T-cell activation and germinal center responses, and may exacerbate thymic damage. Consistently, blocking IL-39 markedly ameliorated immune dysregulation in the cGVHD mice. Furthermore, we found that IL-39 was produced by B cells, CD11b+ cells, and CD8+T cells after activation. Stimulation of IL-39 led to upregulation of the IL-39 receptor on CD4+T cells and further caused activation of the STAT1/STAT3 pathway, through which IL-39 may exert its pro-inflammatory effects. CONCLUSION Our study reveals a critical role for IL-39 in cGVHD pathogenesis and indicates that IL-39 may serve as a potential therapeutic target for cGVHD prevention.
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Affiliation(s)
- Kangkang Lv
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Bo Hu
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Mingzhu Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Li Wan
- Department of Emergency Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziqi Jin
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Mimi Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yuanyuan Du
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Kunpeng Ma
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Quansheng Lv
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China.,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Lei Lei
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Huanle Gong
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Haiyan Liu
- Department of Microbiology and Immunology, Life Sciences Institute, Immunology Translational Research ProgramYong Loo Lin School of MedicineImmunology ProgramNational University of Singapore, Singapore, Singapore.
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China. .,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
| | - Yuejun Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Shizi Street 188, Suzhou, 215006, China. .,Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
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Zhu T, Zhang H, Li S, Wu K, Yin Y, Zhang X. Detoxified pneumolysin derivative ΔA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling. Exp Mol Med 2022; 54:601-612. [PMID: 35538212 PMCID: PMC9166762 DOI: 10.1038/s12276-022-00771-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/07/2022] [Accepted: 02/13/2022] [Indexed: 11/29/2022] Open
Abstract
Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ΔA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ΔA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ΔA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ΔA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ΔA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ΔA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy. A mutated form of the bacterial protein pneumolysin offers a new approach to treating acute myeloid leukemia (AML), due to its ability to stimulate cancer cells to undergo a form of cell suicide called apoptosis. Researchers in China led by Xuemei Zhang at Chongquing Medical University studied the effects of a pneumolysin derivative on cultured human and mouse AML cells. They identified the mechanism by which this derivative activates a known molecular signaling system to inhibit the process of autophagy, in which cells routinely ‘clean up’ degraded or unnecessary components during normal maintenance. This inhibition of autophagy then induced the apoptosis that killed cancer cells. The effect became more pronounced when the pneumolysin derivative was combined with the existing autophagy-inhibiting drug chloroquine. The new combination could be safer and more effective than using chloroquine alone.
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Affiliation(s)
- Tao Zhu
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.,Department of Clinical Laboratory, Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, China
| | - Hong Zhang
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.,Department of Laboratory Medicine, The Affiliated Hospital of North Sichuan Medical College, and Department of Laboratory Medicine and Translational Medicine Research Center, North Sichuan Medical College, Nanchong, 637000, China
| | - Sijie Li
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Kaifeng Wu
- Department of Laboratory Medicine, the Third Affiliated Hospital of Zunyi Medical University, Zunyi, 563000, China
| | - Yibing Yin
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China
| | - Xuemei Zhang
- Department of Laboratory Medicine, Key Laboratory of Diagnostic Medicine (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
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44
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Belina ME, Driscoll TA, Blanchard SK, Cardones AR. Ruxolitinib for the treatment of steroid refractory pediatric chronic graft-versus-host disease. Pediatr Dermatol 2022; 39:432-433. [PMID: 35234308 DOI: 10.1111/pde.14965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chronic graft-versus-host disease (cGVHD) of the skin is a serious cause of long-term morbidity and mortality among patients who receive hematopoietic stem cell transplants. Systemic corticosteroids remain first-line treatment for cutaneous cGVHD; however, there is currently no consensus on second-line therapy for steroid-refractory disease. We herein present a case of a pediatric patient with severe cGVHD of the skin, nonresponsive to corticosteroids, who was successfully treated with a prolonged course of ruxolitinib with minimal side effects.
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Affiliation(s)
- Morgan E Belina
- Duke University School of Medicine, Durham, North Carolina, USA
| | - Timothy A Driscoll
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
| | - Sarah K Blanchard
- Department of Dermatology, Duke University Medical Center, Durham, North Carolina, USA
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45
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MicroRNA serum profiles and chronic graft versus host disease. Blood Adv 2022; 6:5295-5306. [PMID: 35443023 DOI: 10.1182/bloodadvances.2021005930] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 03/10/2022] [Indexed: 11/20/2022] Open
Abstract
Chronic graft versus host disease (cGVHD) is the most common long-term complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). During the last decade, the interest of micro RNAs (miRNAs) in the pathophysiological process of cGVHD has increased. The objectives of this study were to investigate a wide range of serum miRNAs in allografted patients and identify associations between miRNAs and cGVHD. The study included 79 allotransplanted adults, where serum samples were obtained one year after the allo-HSCT, and miRNA profiling analysis in serum was performed. 50 of the 79 patients (63%) had signs of cGVHD at the one-year post-allo-HSCT control. miRNA-sequencing analysis revealed 1380 different miRNAs detected for at least one patient, while 233 miRNAs (17%) were detected in more than 70 patients. We identified ten miRNAs that differed significantly between patients with and without cGVHD (p <0.005, false discovery rate (FDR) <0.1), and all or these miRNAs were detected for >75 of the patients. Furthermore, five distinct miRNAs; miR-365-3p, miR-148-3p, miR-122-5p, miR-378-3p, and miR-192-5p, were found to be particularly associated with cGVHD in our analysis and validated by receiver operating characteristics (ROC) analysis. Based on only three miRNAs, miR-365-3p, miR-148-3p, and miR-378-3p, we developed a miRNA signature which by bioinformatic approaches and linear regression model utterly improved our potential diagnostic biomarker model for cGVHD. We conclude that miRNAs are differently expressed among patients with and without cGVHD, although further and larger studies are needed to validate our present findings.
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46
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Peng B, Dou L, Yang J, Wang L, Li F, Gao X, Wang S, Jin X, Wang L, Jia M, Wang S, Li Y, Liu D. Increased risk of nonrelapse mortality post T-cell-replete haploidentical stem cell transplantation in patients with recurrence of acute graft-versus-host disease. Hematol Oncol 2022; 40:743-751. [PMID: 35385135 DOI: 10.1002/hon.2999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 02/07/2022] [Accepted: 03/28/2022] [Indexed: 11/10/2022]
Abstract
Acute graft-versus-host disease (aGVHD) causes significant morbidity and mortality. While most studies focus on classic or late aGVHD, some patients with previous aGVHD achieve complete remission and later develop another episode of aGVHD. Data on recurrence of aGVHD (RaGVHD) are lacking. This study aimed to identify the incidence, risk factors, and impacts of RaGVHD after T-cell-replete haploidentical hematopoietic cell transplantation (haplo-HCT) without posttransplantation cyclophosphamide. We evaluated patients with RaGVHD after haplo-HCT between 2017 and 2019 and compared their outcomes to those of patients with no aGVHD and those of patients with one episode of de novo aGVHD. Of 199 patients included in the analysis, 45 experienced 50 cases of RaGVHD with a 1-year cumulative incidence of 19.0% (95% CI: 14.5-24.6). Grade III-IV aGVHD was more common in RaGVHD than in previous aGVHD (22.2% vs 4.4%, p = 0.01). Female donor to male recipient was strongly associated with RaGVHD (HR: 2.5, p = 0.009). The most common death in patients with RaGVHD was GVHD-related, which was different from controls who mostly died from relapse (p =0.008). RaGVHD was an independent risk factor for chronic GVHD (HR: 2.6, p = 0.006) and nonrelapse mortality (HR: 2.4, p = 0.019) and a significant predictor of lower GVHD relapse-free survival (HR: 1.9, p = 0.020) and cGVHD relapse-free survival (HR: 2.1, p = 0.007). In conclusion, clinical manifestations and negative impacts of RaGVHD needs to be recognized independently. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Bo Peng
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China.,Medical School of Chinese PLA, Beijing, 100853, China
| | - Liping Dou
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China.,Medical School of Chinese PLA, Beijing, 100853, China.,The second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China
| | - Jingjing Yang
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Lili Wang
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Fei Li
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Xiaoning Gao
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Shuhong Wang
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Xiangshu Jin
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Lu Wang
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Mingyu Jia
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Shenyu Wang
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China
| | - Yan Li
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China.,Department of Hematology, Peking University Third Hospital, 49 North Garden Road, Beijing, 100191, China
| | - Daihong Liu
- Department of Hematology, the Fifth Medical Center of Chinese PLA General Hospital, 5th medical center, Beijing, 100071, China.,Medical School of Chinese PLA, Beijing, 100853, China
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Tagami M, Kakehashi A, Katsuyama-Yoshikawa A, Misawa N, Sakai A, Wanibuchi H, Azumi A, Honda S. FOXP3 and CXCR4-positive regulatory T cells in the tumor stroma as indicators of tumor immunity in the conjunctival squamous cell carcinoma microenvironment. PLoS One 2022; 17:e0263895. [PMID: 35358193 PMCID: PMC8970378 DOI: 10.1371/journal.pone.0263895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 01/22/2022] [Indexed: 11/29/2022] Open
Abstract
Conjunctival squamous cell carcinoma (SCC) is the most common ocular surface neoplasia. The purpose of this retrospective study was to examine the role of regulatory T cell (Treg) activity in tumor immunity and investigate the tumor microenvironment as a new treatment focus in conjunctival SCC. Cancer progression gene array and immunohistochemical analyses of FOXP3 as a Treg marker, CD8 as a tumor-infiltrating lymphocyte marker, and CXCR4 expression on activated Tregs were conducted in a series of 31 conjunctival SCC cases. The objective was to investigate the immunoreactive response in tumor cells and stromal cells in the cancer microenvironment. The stroma ratio in tumor cells was investigated by monitoring α-smooth muscle actine (SMA) expression between carcinoma in situ (Tis) and advanced carcinoma (Tadv) (P<0.01). No significant change in PD-L1 expression was observed in this study (P = 0.15). Staining patterns of FOXP3, CD8, and CXCR4 were examined separately between tumor cells and stromal cells in SCC tumors. Differences in staining of FOXP3 in Tregs and CD8 in tumor-infiltrating lymphocytes in tumor stroma in the Tis group were observed compared with the Tadv group (each P<0.01). In addition, double immunostaining of CXCR4/FOXP3 was correlated with progression-free survival (P = 0.049). Double immunostaining of CXCR4/FOXP3 correlated with American Joint Committee on Cancer T-stage, independent of age or Ki67 index (P<0.01). Our results show that FOXP3 and the CXCR4/FOXP3 axis are important pathologic and prognostic factors of ocular surface neoplasia, including SCC. The tumor microenvironment of conjunctival SCC should be considered in the future development of treatment options.
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Affiliation(s)
- Mizuki Tagami
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
- Ophthalmology Department and Eye Center, Kobe Kaisei Hospital, Kobe, Hyogo, Japan
- * E-mail:
| | - Anna Kakehashi
- Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsuko Katsuyama-Yoshikawa
- Ophthalmology Department and Eye Center, Kobe Kaisei Hospital, Kobe, Hyogo, Japan
- Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Hyogo, Japan
| | - Norihiko Misawa
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsushi Sakai
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hideki Wanibuchi
- Department of Molecular Pathology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Atsushi Azumi
- Ophthalmology Department and Eye Center, Kobe Kaisei Hospital, Kobe, Hyogo, Japan
| | - Shigeru Honda
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Osaka City University, Osaka, Japan
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48
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McNeil A, Parks K, Liu X, Saknite I, Chen F, Reasat T, Cronin A, Wheless L, Dawant BM, Tkaczyk ER. Artificial intelligence recognition of cutaneous chronic graft-versus-host disease by a deep learning neural network. Br J Haematol 2022; 197:e69-e72. [PMID: 35322873 DOI: 10.1111/bjh.18141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/28/2022] [Accepted: 03/02/2022] [Indexed: 12/23/2022]
Affiliation(s)
- Andrew McNeil
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA.,Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Kelsey Parks
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Xiaoqi Liu
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA.,Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Inga Saknite
- Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Biophotonics Laboratory, Institute of Atomic Physics and Spectroscopy, University of Latvia, Riga, Latvia
| | - Fuyao Chen
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA.,School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Tahsin Reasat
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Austin Cronin
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Lee Wheless
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Benoit M Dawant
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, Tennessee, USA
| | - Eric R Tkaczyk
- Dermatology Service and Research Service, Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA.,Vanderbilt Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.,Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
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49
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Thangavelu G, Zaiken MC, Mohamed FA, Flynn R, Du J, Rhee SY, Riddle MJ, Aguilar EG, Panoskaltsis-Mortari A, Sanders ME, Blazar BR. Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease. Front Immunol 2022; 13:765319. [PMID: 35359939 PMCID: PMC8963714 DOI: 10.3389/fimmu.2022.765319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 01/26/2022] [Indexed: 02/03/2023] Open
Abstract
Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%-70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.
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Affiliation(s)
- Govindarajan Thangavelu
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Michael C. Zaiken
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Fathima A. Mohamed
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Ryan Flynn
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Jing Du
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Stephanie Y. Rhee
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Megan J. Riddle
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Ethan G. Aguilar
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Angela Panoskaltsis-Mortari
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | | | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
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50
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Song Q, Nasri U, Zeng D. Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model. Front Immunol 2022; 13:844271. [PMID: 35251043 PMCID: PMC8894323 DOI: 10.3389/fimmu.2022.844271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/26/2022] [Indexed: 11/23/2022] Open
Abstract
Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.
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Affiliation(s)
- Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
- *Correspondence: Qingxiao Song,
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
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