Novel and Promising Strategies for Therapy of Post-Transplant Chronic GVHD

Despite the achievements that have increased viability after the transplantation of allogeneic hematopoietic stem cells (aHSCT), chronic graft-versus-host disease (cGVHD) remains the main cause of late complications and post-transplant deaths. At the moment, therapy alternatives demonstrate limited effectiveness in steroid-refractory illness; in addition, we have no reliable data on the mechanism of this condition. The lack of drugs of choice for the treatment of GVHD underscores the significance of the design of new therapies. Improved understanding of the mechanism of chronic GVHD has secured new therapy goals, and organized diagnostic recommendations and the development of medical tests have ensured a general language and routes for studies in this field. These factors, combined with the rapid development of pharmacology, have helped speed up the search of medicines and medical studies regarding chronic GVHD. At present, we can hope for success in curing this formidable complication. This review summarizes the latest clinical developments in new treatments for chronic GVHD.

[1]  J. Ritz,et al.  Organ-specific response after low-dose interleukin-2 therapy for steroid-refractory chronic graft-versus-host disease , 2022, Blood advances.

[2]  L. Stelmakh,et al.  Favorable outcomes of allogeneic hematopoietic stem cell transplantation with fludarabine–bendamustine conditioning and posttransplantation cyclophosphamide in classical Hodgkin lymphoma , 2022, International Journal of Hematology.

[3]  Chengyang Liu,et al.  Trafficking and persistence of alloantigen-specific chimeric antigen receptor regulatory T cells in Cynomolgus macaque , 2022, Cell reports. Medicine.

[4]  H. Stark,et al.  Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK Pathway , 2022, Leukemia.

[5]  J. Ritz,et al.  A phase 1 study of donor regulatory T-cell infusion plus low-dose interleukin-2 for steroid-refractory chronic graft-vs-host disease , 2022, Blood advances.

[6]  B. Stea,et al.  Feasibility and efficacy of partially replacing post-transplant cyclophosphamide with bendamustine in pediatric and young adult patients undergoing haploidentical bone marrow transplantation. , 2022, Transplantation and cellular therapy.

[7]  Kenichi A. Tanaka,et al.  Heparin-Induced Thrombocytopenia in Patients With Mechanical Circulatory Support. , 2022, Journal of cardiothoracic and vascular anesthesia.

[8]  Shunqing Wang,et al.  Mesenchymal stromal cells plus basiliximab, calcineurin inhibitor as treatment of steroid-resistant acute graft-versus-host disease: a multicenter, randomized, phase 3, open-label trial , 2022, Journal of Hematology & Oncology.

[9]  H. von Bernuth,et al.  Adoptive transfer of ex vivo expanded regulatory T-cells improves immune cell engraftment and therapy-refractory chronic GvHD. , 2022, Molecular therapy : the journal of the American Society of Gene Therapy.

[10]  M. Bilan,et al.  Depolymerization of a fucosylated chondroitin sulfate from Cucumaria japonica: Structure and activity of the product. , 2022, Carbohydrate polymers.

[11]  OUP accepted manuscript , 2022, The Oncologist.

[12]  P. Chiusolo,et al.  The day 100 score predicts moderate to severe cGVHD, transplant mortality, and survival after hematopoietic cell transplantation , 2021, Blood advances.

[13]  M. V. Kiselevskii,et al.  Secretome of Mesenchymal Bone Marrow Stem Cells: Is It Immunosuppressive or Proinflammatory? , 2021, Bulletin of Experimental Biology and Medicine.

[14]  M. Bilan,et al.  Chondroitin Sulfate and Fucosylated Chondroitin Sulfate as Stimulators of Hematopoiesis in Cyclophosphamide-Induced Mice , 2021, Pharmaceuticals.

[15]  T. Luft,et al.  Response to extracorporeal photopheresis therapy of patients with steroid-refractory/-resistant GvHD is associated with up-regulation of Th22 cells and Tfh cells. , 2021, Cytotherapy.

[16]  J. Zwicker,et al.  Heparin-induced thrombocytopenia in patients with COVID-19: a systematic review and meta-analysis , 2021, Blood Advances.

[17]  K. Matsuoka,et al.  Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives , 2021, Frontiers in Immunology.

[18]  S. Bhatia,et al.  Late-occurring venous thromboembolism in allogeneic blood or marrow transplant survivors: a BMTSS-HiGHS2 risk model , 2021, Blood advances.

[19]  M. Belderbos,et al.  Hematopoietic Dysfunction during Graft-Versus-Host Disease: A Self-Destructive Process? , 2021, Cells.

[20]  A. Logan,et al.  Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study , 2021, Blood.

[21]  N. Kröger,et al.  Steroid-refractory chronic graft-versus-host disease: treatment options and patient management , 2021, Bone Marrow Transplantation.

[22]  Depei Wu,et al.  Efficiency and Toxicity of Ruxolitinib as a Salvage Treatment for Steroid-Refractory Chronic Graft-Versus-Host Disease , 2021, Frontiers in Immunology.

[23]  T. Kuznetsova,et al.  The Potency of Seaweed Sulfated Polysaccharides for the Correction of Hemostasis Disorders in COVID-19 , 2021, Molecules.

[24]  G. Cuvelier,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report , 2021, Transplantation and cellular therapy.

[25]  M. MacMillan,et al.  Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes. , 2021, Blood advances.

[26]  N. Sidorova,et al.  Potential Use of Mesenchymal Multipotent Cells for Hemopoietic Stem Cell Transplantation: Pro and Contra , 2021, Journal of pediatric hematology/oncology.

[27]  K. Matsuoka [Graft-versus-host disease: current understanding of immune pathogenesis and clinical treatment]. , 2021, [Rinsho ketsueki] The Japanese journal of clinical hematology.

[28]  S. Shamdani,et al.  Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies , 2020, Frontiers in Immunology.

[29]  V. Stonik,et al.  Fucosylated Chondroitin Sulfates from the Sea Cucumbers Paracaudina chilensis and Holothuria hilla: Structures and Anticoagulant Activity , 2020, Marine drugs.

[30]  M. Grce,et al.  New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions , 2020, Frontiers in Immunology.

[31]  G. Socié,et al.  The development of ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. , 2020, Blood advances.

[32]  Д. В. Шевцов,et al.  Chronic “graft versus host” disease after allogeneic hematopoietic stem cell transplantation: basic characteristics, pathogenetic mechanisms, treatment strategies and problems of clinical practice , 2020, Russian Journal of Pediatric Hematology and Oncology.

[33]  A. Buser,et al.  Extracorporeal Photopheresis in Graft-versus-Host Disease , 2020, Transfusion Medicine and Hemotherapy.

[34]  Xiao-jun Huang,et al.  Treatment and unmet needs in steroid-refractory acute graft-versus-host disease , 2020, Leukemia.

[35]  E. Surkova,et al.  Long-term outcomes of ruxolitinib therapy in steroid-refractory graft-versus-host disease in children and adults , 2020, Bone Marrow Transplantation.

[36]  M. Bilan,et al.  Fucosylated chondroitin sulfate from the sea cucumber Hemioedema spectabilis: Structure and influence on cell adhesion and tubulogenesis. , 2020, Carbohydrate polymers.

[37]  E. Lanino,et al.  Imatinib melylate as second‐line treatment of bronchiolitis obliterans after allogenic hematopoietic stem cell transplantation in children , 2020, Pediatric pulmonology.

[38]  G. Berlin,et al.  Extracorporeal photopheresis for graft‐vs‐host disease: A literature review and treatment guidelines proposed by the Nordic ECP Quality Group , 2020, European journal of haematology.

[39]  S. Farouk,et al.  The Many Faces of Calcineurin Inhibitor Toxicity-What the FK? , 2020, Advances in chronic kidney disease.

[40]  E. Shpall,et al.  A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease. , 2020, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[41]  B. Relja,et al.  Cytokines in Inflammatory Disease , 2019, International journal of molecular sciences.

[42]  N. Kröger,et al.  Allogeneic peripheral blood stem cell transplantation with anti-thymocyte globulin versus allogeneic bone marrow transplantation without anti-thymocyte globulin , 2019, Haematologica.

[43]  Heidi Chen,et al.  Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD. , 2019, Blood advances.

[44]  J. Ritz,et al.  Functional analysis of clinical response to low-dose IL-2 in patients with refractory chronic graft-versus-host disease. , 2019, Blood advances.

[45]  J. Ritz,et al.  Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease. , 2019, Blood advances.

[46]  M. Levings,et al.  Systematic testing and specificity mapping of alloantigen-specific chimeric antigen receptors in regulatory T cells. , 2019, JCI insight.

[47]  K. Sullivan,et al.  How I treat refractory chronic graft-versus-host disease. , 2019, Blood.

[48]  M. Bilan,et al.  New insight on the structural diversity of holothurian fucosylated chondroitin sulfates , 2019, Pure and Applied Chemistry.

[49]  M. Bilan,et al.  Influence of Modified Fucoidan and Related Sulfated Oligosaccharides on Hematopoiesis in Cyclophosphamide-Induced Mice , 2018, Marine drugs.

[50]  Wei Wei,et al.  Advance in Targeted Immunotherapy for Graft-Versus-Host Disease , 2018, Front. Immunol..

[51]  M. Murad,et al.  Steroid Refractory Chronic Graft-Versus-Host Disease: Cost-Effectiveness Analysis. , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[52]  I. Yakoub-Agha,et al.  Extracorporeal photopheresis for GVHD prophylaxis after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation: a prospective multicenter phase 2 study , 2018, Leukemia & lymphoma.

[53]  J. Dipersio,et al.  The Role of Janus Kinase Signaling in Graft-Versus-Host Disease and Graft Versus Leukemia. , 2017, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[54]  A. Babić,et al.  Graft-Versus-Host Disease (GvHD) -- The European Blood and Marrow Transplantation Textbook for Nurses: Under the Auspices of EBMT , 2018 .

[55]  Y. Skvortsova,et al.  New advances in pathogenesis, diagnostic and treatment of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation , 2018 .

[56]  D. Greenfield,et al.  Late Effects and Long-Term Follow-Up , 2018 .

[57]  M. Solh,et al.  Donor Type and Disease Risk Predict the Success of Allogeneic Hematopoietic Cell Transplantation: A Single-Center Analysis of 613 Adult Hematopoietic Cell Transplantation Recipients Using a Modified Composite Endpoint. , 2017, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[58]  A. Logan,et al.  Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. , 2017, Blood.

[59]  J. Colombel,et al.  Acute graft-versus-host disease of the gut: considerations for the gastroenterologist , 2017, Nature Reviews Gastroenterology & Hepatology.

[60]  V. Stonik,et al.  A highly regular fucosylated chondroitin sulfate from the sea cucumber Massinium magnum: Structure and effects on coagulation. , 2017, Carbohydrate polymers.

[61]  M. Bilan,et al.  The structure of a fucosylated chondroitin sulfate from the sea cucumber Cucumaria frondosa. , 2017, Carbohydrate polymers.

[62]  D. Covas,et al.  Mesenchymal stromal cell infusion to treat steroid-refractory acute GvHD III/IV after hematopoietic stem cell transplantation , 2017, Bone Marrow Transplantation.

[63]  S. Nikiforow,et al.  Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation , 2017, Haematologica.

[64]  J. Ritz,et al.  The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. , 2017, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[65]  Jeffrey A Jones,et al.  Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma , 2017, Clinical Cancer Research.

[66]  G. Hill,et al.  Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. , 2017, Blood.

[67]  R. Presland Biology of chronic graft-vs-host disease: Immune mechanisms and progress in biomarker discovery , 2016, World journal of transplantation.

[68]  A. Aiuti,et al.  Bone marrow-derived CD34- fraction: A rich source of mesenchymal stromal cells for clinical application. , 2016, Cytotherapy.

[69]  V. Stonik,et al.  Structural characterization of fucosylated chondroitin sulfates from sea cucumbers Apostichopus japonicus and Actinopyga mauritiana. , 2016, Carbohydrate polymers.

[70]  E. Holler,et al.  Risk Factors and Outcome of Chronic Graft-versus-Host Disease after Allogeneic Stem Cell Transplantation-Results from a Single-Center Observational Study. , 2016, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[71]  A. Rudensky,et al.  An essential role for IL-2 receptor in regulatory T cell function , 2016, Nature Immunology.

[72]  J. Weiss,et al.  Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. , 2016, Blood.

[73]  S. Scheding,et al.  Isolation and characterization of primary bone marrow mesenchymal stromal cells , 2016, Annals of the New York Academy of Sciences.

[74]  A. Dmitrenok,et al.  The synthesis of heterosaccharides related to the fucoidan from Chordaria flagelliformis bearing an α-L-fucofuranosyl unit. , 2016, Organic & biomolecular chemistry.

[75]  K. Ozawa,et al.  Bone marrow-derived mesenchymal stem cells (JR-031) for steroid-refractory grade III or IV acute graft-versus-host disease: a phase II/III study , 2016, International Journal of Hematology.

[76]  S. Choi,et al.  Approaches for the prevention of graft-versus-host disease following hematopoietic cell transplantation. , 2015, International journal of hematologic oncology.

[77]  M. Mohty,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[78]  A. Greinacher CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia. , 2015, The New England journal of medicine.

[79]  H. Greinix,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease , 2015 .

[80]  A. Ho,et al.  Modulation of lymphocyte subpopulations by extracorporeal photopheresis in patients with acute graft-versus-host disease or graft rejection , 2015, Leukemia & lymphoma.

[81]  J. Goldberg,et al.  Sirolimus, tacrolimus and low-dose methotrexate based graft-versus-host disease prophylaxis after non-ablative or reduced intensity conditioning in related and unrelated donor allogeneic hematopoietic cell transplant , 2015, Leukemia & lymphoma.

[82]  A. Dmitrenok,et al.  Synthesis of the Oligosaccharides Related to Branching Sites of Fucosylated Chondroitin Sulfates from Sea Cucumbers , 2015, Marine drugs.

[83]  Paul J Martin,et al.  How we treat chronic graft-versus-host disease. , 2015, Blood.

[84]  Daniel Wolff,et al.  National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[85]  J. Weiss,et al.  Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism , 2014, Proceedings of the National Academy of Sciences.

[86]  N. V. Krukovskaya,et al.  Fucoidans as a platform for new anticoagulant drugs discovery , 2014 .

[87]  S. Devine,et al.  Graft-versus-host disease: why have we not made more progress? , 2014, Current opinion in hematology.

[88]  M. Suthanthiran,et al.  Immunosuppressive drug therapy. , 2013, Cold Spring Harbor perspectives in medicine.

[89]  K. Ozawa,et al.  Unrelated allogeneic bone marrow-derived mesenchymal stem cells for steroid-refractory acute graft-versus-host disease: a phase I/II study , 2013, International Journal of Hematology.

[90]  M. Bilan,et al.  Influence of Fucoidans on Hemostatic System , 2013, Marine drugs.

[91]  J. S. San Miguel,et al.  Analysis of incidence, risk factors and clinical outcome of thromboembolic and bleeding events in 431 allogeneic hematopoietic stem cell transplantation recipients , 2013, Haematologica.

[92]  M. Danhof,et al.  Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[93]  Bruce R. Blazar,et al.  Advances in graft-versus-host disease biology and therapy , 2012, Nature Reviews Immunology.

[94]  H. Stark,et al.  Inhibitors of specific ceramide synthases. , 2012, Biochimie.

[95]  J. S. San Miguel,et al.  Chronic Graft-Versus-Host Disease , 2012, Drugs.

[96]  D. Parenti,et al.  Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresis--results of a crossover randomized study. , 2011, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[97]  J. Rozmus,et al.  Biomarkers in chronic graft-versus-host disease , 2011, Expert review of hematology.

[98]  Z. M. Kaskova,et al.  Acid-promoted synthesis of per-O-sulfated fucooligosaccharides related to fucoidan fragments. , 2011, Carbohydrate research.

[99]  J. Wagner,et al.  Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. , 2011, Blood.

[100]  A. Zenclussen,et al.  REVIEW ARTICLE: Regulatory T Cells and Their Role in Pregnancy , 2010, American journal of reproductive immunology.

[101]  D. Pulanić,et al.  Thrombocytopenia and hemostatic disorders in chronic graft versus host disease , 2009, Bone Marrow Transplantation.

[102]  A. Morita,et al.  Experimental Extracorporeal Photopheresis Inhibits the Sensitization and Effector Phases of Contact Hypersensitivity via Two Mechanisms: Generation of IL-10 and Induction of Regulatory T Cells1 , 2008, The Journal of Immunology.

[103]  M. Bilan,et al.  A sulfated glucuronofucan containing both fucofuranose and fucopyranose residues from the brown alga Chordaria flagelliformis. , 2008, Carbohydrate research.

[104]  L. Bouzas,et al.  A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. , 2008, Blood.

[105]  E. Colado,et al.  Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the national institutes health scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[106]  A. McKenzie,et al.  Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease. , 2008, Experimental hematology.

[107]  J. Segal,et al.  The incidence of and risk factors for venous thromboembolism (VTE) and bleeding among 1514 patients undergoing hematopoietic stem cell transplantation: implications for VTE prevention. , 2008, Blood.

[108]  Paul J. Martin,et al.  Study design and endpoints in graft-versus-host disease. , 2008, Best practice & research. Clinical haematology.

[109]  A. Al Haj Zen,et al.  Effect of Low Molecular Weight Fucoidan and Low Molecular Weight Heparin in a Rabbit Model of Arterial Thrombosis , 2008, Journal of Vascular Research.

[110]  Allen R. Chen,et al.  Phase II study of pentostatin in patients with corticosteroid-refractory chronic graft-versus-host disease. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[111]  A. Balduzzi,et al.  Extracorporeal Photochemotherapy Is Accompanied by Increasing Levels of Circulating CD4+CD25+GITR+Foxp3+CD62L+ Functional Regulatory T-Cells in Patients With Graft-Versus-Host Disease , 2007, Transplantation.

[112]  M. Sykes,et al.  The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. , 2007, Blood.

[113]  Maeve Kelly,et al.  A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. , 2007, Glycobiology.

[114]  J. Kari,et al.  What is the calcineurin inhibitor of choice for pediatric renal transplantation? , 2004, Pediatric transplantation.

[115]  P. Frenette,et al.  The integrin αMβ2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization , 2004 .

[116]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[117]  J. Lee,et al.  Failure of trilineage blood cell reconstitution after initial neutrophil engraftment in patients undergoing allogeneic hematopoietic cell transplantation – frequency and outcomes , 2004, Bone Marrow Transplantation.

[118]  F. Aubin,et al.  Ultraviolet light-induced regulatory (suppressor) T cells: an approach for promoting induction of operational allograft tolerance? , 2004, Transplantation.

[119]  P. Frenette,et al.  The integrin alphaMbeta2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization. , 2004, Blood.

[120]  B. Blazar,et al.  The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. , 2002, Blood.

[121]  P. Frenette,et al.  Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms. , 2000, Blood.

[122]  H. Deeg Graft-Versus-Host Disease (GVHD) , 1999 .