Acute graft-vs-host disease (aGVHD) is a serious and potentially life-threatening complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is characterized by the activation of innate immune cells during a cytokine storm, often triggered by tissue injury. aGVHD typically impacts the skin, liver, and gastrointestinal tract, resulting in a range of clinical manifestations that can hinder post-transplant recovery, increase risk of infection, and significantly affect patient survival. This review article integrates current knowledge on the prevalence, risk factors, pathophysiology, clinical presentation, and grading of aGVHD. Additionally, we explore existing strategies for prevention and treatment, including the use of immunosuppressive therapies and novel pharmacological agents. By synthesizing recent research findings and clinical insights, we aim to deepen the understanding of aGVHD and promote advancements in its management, ultimately enhancing the quality of life and survival outcomes for patients undergoing allo-HSCT.
FilipovichAHWeisdorfDPavleticS, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant2005; 11(12): 945–956.
JagasiaMAroraMFlowersME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood2012; 119(1): 296–307.
5.
Al MalkiMMLiMNishihoriT, et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch. Transplantation2020; 104(5): 1070–1080.
6.
HoltanSGPasquiniMWeisdorfDJ, et al. Disease progression, treatments, hospitalization, and clinical outcomes in acute GVHD: a multicenter chart review. Bone Marrow Transplant2022; 57(10): 1581–1585.
7.
Major-MonfriedHRenteriaASPawarodeA, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood2018; 131(25): 2846–2855.
8.
AxtLDoblerBHegenbartU, et al. Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant2019; 54(11): 1805–1814.
9.
LeeSEChoBSKimJH, et al. Risk and prognostic factors for acute GVHD based on NIH consensus criteria. Bone Marrow Transplant2013; 48(4): 587–592.
10.
BlazarBRMurphyWJAbediM.Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol2012; 12(6): 443–458.
11.
AkahoshiYKandaJIchinoheT, et al. Incidence, clinical presentation, risk factors, outcomes, and biomarkers in de novo late acute GVHD. Blood Adv2023; 7(16): 4479–4491.
12.
HoltickUAl-AliHBeelenD, et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev2014; 2014(4): CD010189.
13.
KieneSBethgeWABeelenDW, et al. Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults. Cochrane Database Syst Rev2024; 11(11): CD010189.
14.
ZeiserRBlazarBR.Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med2017; 377(22): 2167–2179.
15.
MurataM.Recent topics in graft-versus-host disease: from the perspectives of pathogenesis and treatment. Int J Hematol2015; 101(5): 426–427.
16.
HillGRFerraraJLAppelbaumFR, et al. Current concepts and advances in graft-versus-host disease immunology. Annu Rev Immunol2021; 39: 19–49.
17.
CourielDRSalibaRMGiraltS, et al. Acute and chronic graft-versus-host disease after ablative and nonmyeloablative conditioning for allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant2004; 10(3): 178–185.
18.
ChoiSWLevineJEFerraraJL.Pathogenesis and management of graft-versus-host disease. Immunol Allergy Clin North Am2010; 30(1): 75–101.
19.
MagenauJRunaasLReddyP.Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol2016; 173(2): 190–205.
20.
BrennanTVRendellVRYangY.Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation. Front Immunol2015; 6: 101.
21.
NakasoneHKakudaHYoshiharaS, et al. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation. Bone Marrow Transplant2015; 50(4): 559–565.
22.
OlivieriAManciniG.Current approaches for the prevention and treatment of acute and chronic GVHD. Cells2024; 13(18): 1524.
23.
GiacconeLDominiettoAGrecoR, et al. Biomarkers for acute and chronic graft versus host disease: state of the art. Expert Rev Hematol2021; 14(1): 79–96.
24.
KoyamaMHillGR.The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease. Blood2019; 134(24): 2139–2148.
25.
ChakravertyRSykesM.The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood2007; 110(1): 9–17.
26.
SckiselGDMirsoianAMinnarCM, et al. Out-of-sequence Signal 3 paralyzes primary CD4+ T-cell-dependent immunity. Immunity2015; 43(2): 240–250.
27.
HoltanSGPasquiniMWeisdorfDJ.Acute graft-versus-host disease: a bench-to-bedside update. Blood2014; 124(3): 363–373.
28.
AliAMDiPersioJFSchroederMA.The role of biomarkers in the diagnosis and risk stratification of acute graft-versus-host disease: a systematic review. Biol Blood Marrow Transplant2016; 22(9): 1552–1564.
29.
ToubaiTMathewsonNMagenauJ, et al. Role of cytokines in the pathophysiology of acute graft-versus-host disease (GVHD): are serum/plasma cytokines potential biomarkers for diagnosis of acute GVHD following allogeneic hematopoietic cell transplantation (allo-HCT)?Curr Stem Cell Res Ther2012; 7(3): 229–239.
30.
ZhaoXSHuangXJ.Seeking biomarkers for acute graft-versus-host disease: where we are and where we are heading?Biomark Res2019; 7: 17.
31.
HongJKangYJeonYW, et al. Understanding and treatment of cutaneous graft-versus-host disease. Bone Marrow Transplant2023; 58(12): 1298–1313.
32.
NaymagonSNaymagonLWongSY, et al. Acute graft-versus-host disease of the gut: considerations for the gastroenterologist. Nat Rev Gastroenterol Hepatol2017; 14(12): 711–726.
33.
CourielDCalderaHChamplinR, et al. Acute graft-versus-host disease: pathophysiology, clinical manifestations, and management. Cancer2004; 101(9): 1936–1946.
34.
ZeiserRTeshimaT.Nonclassical manifestations of acute GVHD. Blood2021; 138(22): 2165–2172.
35.
GlucksbergHStorbRFeferA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation1974; 18(4): 295–304.
36.
PrzepiorkaDWeisdorfDMartinP, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant1995; 15(6): 825–828.
37.
RowlingsPAPrzepiorkaDKleinJP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol1997; 97(4): 855–864.
38.
HarrisACYoungRDevineS, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: a report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant2016; 22(1): 4–10.
39.
KujawskaJZeiserRGilL.Recent advances in acute gastrointestinal graft versus host disease (aGVHD): aspects of steroid-resistant disease. Ann Hematol2024; 104(2): 855–865.
40.
PenackOAertsEFernandez-SojoJ, et al. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol2024; 11(2): e147–e159.
41.
DehnJSpellmanSHurleyCK, et al. Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR. Blood2019; 134(12): 924–934.
42.
TsamadouCAkyüzNBalduzziA, et al. HLA-DRB3/4/5 matching improves outcome of unrelated hematopoietic stem cell transplantation. Front Immunol2021; 12: 771449.
43.
PidalaJLeeSJAhnKW, et al. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood2014; 124(16): 2596–2606.
44.
KandaYYamamotoKChibaS, et al. A randomized controlled trial of cyclosporine and tacrolimus with strict control of blood concentrations after unrelated bone marrow transplantation. Bone Marrow Transplant2016; 51(1): 103–109.
45.
TörlénJRingdénOGarming-LegertK, et al. A prospective randomized trial comparing cyclosporine/methotrexate and tacrolimus/sirolimus as graft-versus-host disease prophylaxis after allogeneic hematopoietic stem cell transplantation. Haematologica2016; 101(11): 1417–1425.
46.
GooptuMAntinJH.GVHD prophylaxis 2020. Front Immunol2021; 12: 605726.
47.
PerkinsJFieldTKimJ, et al. A randomized phase II trial comparing tacrolimus and mycophenolate mofetil to tacrolimus and methotrexate for acute graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant2010; 16(7): 937–947.
48.
JamyOZeiserRChenYB.Novel developments in the prophylaxis and treatment of acute GVHD. Blood2023; 142(12): 1037–1046.
49.
HandgretingerR.Negative depletion of CD3(+) and TcRαβ(+) T cells. Curr Opin Hematol2012; 19(6): 434–439.
50.
RuggeriASanzGBittencourtH, et al. Timing of post-transplantation cyclophosphamide administration in haploidentical transplantation: a comparative study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant2020; 26(10): 1915–1922.
51.
ChenYBKimHTMcDonoughS, et al. Vedolizumab for the prevention of intestinal acute GVHD after allogeneic hematopoietic stem cell transplantation: a randomized phase 3 trial. Nat Med2024; 30(8): 2277–2287.
52.
KornblitBMasmasTNPetersenSL, et al. Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors. Blood2020; 136(13): 1499–1506.
53.
KeanLSKennedy-NasserAARondonG, et al. Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation. Blood2024; 144(17): 1834–1845.
54.
WatkinsBQayedMMcCrackenC, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol2021; 39(17): 1865–1877.
55.
KorethJStevensonKEKimHT, et al. A bortezomib-based regimen offers promising survival and graft-versus-host disease prophylaxis in myeloablative HLA-mismatched and unrelated donor transplantation: a phase II trial. Biol Blood Marrow Transplant2015; 21(11): 1907–1913.
56.
DrobyskiWRHariPNArmitageJO, et al. Tocilizumab, tacrolimus and methotrexate for the prevention of acute graft-versus-host disease: low incidence of lower gastrointestinal tract disease. Haematologica2018; 103(4): 717–727.
57.
PenackOMarchettiMRuutuT, et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol2020; 7(2): e157–e167.
58.
IbrahimRBHessDALutzRJ, et al. Nonabsorbable corticosteroids use in the treatment of gastrointestinal graft-versus-host disease. Biol Blood Marrow Transplant2009; 15(4): 395–405.
59.
MacMillanMLDeForTEWeisdorfDJ.The best endpoint for acute GVHD treatment trials. Blood2010; 115(26): 5412–5417.
60.
SpyrouNSaitoBGloudeNJ, et al. A day 14 endpoint for acute GVHD clinical trials. Transplant Cell Ther2024; 30(4): 421–432.
61.
MacMillanMLWeisdorfDJDaviesSM, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant2002; 8(7): 387–394.
62.
WaisVFigueiredoIGreinixHT, et al. Treatment of steroid-refractory acute/chronic graft-versus-host disease: a single-center real-world experience of ruxolitinib in combination with extracorporeal photopheresis in a high-risk population. Leuk Res2024; 147: 107611.
63.
ZeiserRBurchertALengerkeC, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia2015; 29(10): 2062–2068.
64.
Asensi CantóPPerez SimonJACarrerasE, et al. Extracorporeal photopheresis in graft-versus-host disease. Transplant Cell Ther2023; 29(9): 556–566.
65.
GreinixHTAyukFZeiserR.Extracorporeal photopheresis in acute and chronic steroid-refractory graft-versus-host disease: an evolving treatment landscape. Leukemia2022; 36(11): 2558–2566.
66.
AliMMMacMillanMLWeisdorfDJ, et al. Extracorporeal photopheresis as graft-versus-host disease prophylaxis: a randomized controlled trial. Transplant Cell Ther2023; 29(6): 364.e1–364.e11.
67.
DöringMCabanillas StanchiKMMezgerM, et al. Long-term follow-up after the application of mesenchymal stromal cells in children and adolescents with steroid-refractory graft-versus-host disease. Stem Cells Dev2021; 30(5): 234–246.
68.
FisherSACutlerADoreeC, et al. Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition. Cochrane Database Syst Rev2019; 2019(1): CD009768.
69.
StaffasABurgosdaSilvaMvan den BrinkMR.The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood2017; 129(8): 927–933.
70.
BilinskiJGrzesiowskiPSorensenN, et al. Fecal microbiota transplantation in patients with acute and chronic graft-versus-host disease—spectrum of responses and safety profile. Results from a prospective, multicenter study. Am J Hematol2021; 96(3): E88–E91.
71.
KimNHHamadaniMAbedinS.New investigational drugs for steroid-refractory acute graft-versus-host disease: a review of the literature. Expert Opin Investig Drugs2024; 33(8): 791–799.
72.
GaoZFanXZhouH, et al. Vedolizumab plus basiliximab as second-line therapy for steroid-refractory lower gastrointestinal acute graft-versus-host disease. Front Immunol2024; 15: 1408211.
