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Review

Therapeutic options for steroid-refractory acute and chronic GVHD: an evolving landscape

&
Pages 519-532 | Received 22 Feb 2020, Accepted 02 Apr 2020, Published online: 19 Apr 2020

References

  • Nassereddine S, Rafei H, Elbahesh E, et al. Acute graft versus host disease: a comprehensive review. Anticancer Res. 2017;37(4):1547–1555.
  • Zeiser R, Blazar BR. Acute graft-versus-host disease - biologic process, prevention, and therapy. N Engl J Med. 2017;377(22):2167–2179.
  • Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565–2579.
  • Lee SJ. Classification systems for chronic graft-versus-host disease. Blood. 2017;129(1):30–37.
  • Ruutu T, Gratwohl A, de Witte T, et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Transplant. 2014;49(2):168–173.
  • Gooptu M, Koreth J. Better acute graft-versus-host disease outcomes for allogeneic transplant recipients in the modern era: a tacrolimus effect? Haematologica. 2017;102(5):806–808.
  • Khoury HJ, Wang T, Hemmer MT, et al. Improved survival after acute graft- versus -host disease diagnosis in the modern era. Haematologica. 2017;102(5):958–966.
  • Choi SW, Reddy P. Current and emerging strategies for the prevention of graft-versus-host disease. Nat Rev Clin Oncol. 2014;11(9):536–547.
  • Jagasia MH, Greinix HT, Arora M, 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. Biol Blood Marrow Transplant. 2015;21(3):389–401.
  • Sarantopoulos S, Cardones AR, Sullivan KM. How I treat refractory chronic graft-versus-host disease. Blood. 2019;133(11):1191–1200.
  • Hill L, Alousi A, Kebriaei P, et al. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018;9(1):21–46.
  • Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2012;18(8):1150–1163.
  • Mielcarek M, Furlong T, Storer BE, et al. Effectiveness and safety of lower dose prednisone for initial treatment of acute graft-versus-host disease: a randomized controlled trial. Haematologica. 2015;100(6):842–848.
  • Mielcarek M, Storer BE, Boeckh M, et al. Initial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes. Blood. 2009;113(13):2888–2894.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT00929695, Low-dose prednisone or methylprednisolone in treating patients with newly diagnosed acute graft-versus-host disease; 2017 Aug 21 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT00929695
  • Levine JE, Braun TM, Harris AC, et al. A prognostic score for acute graft-versus-host disease based on biomarkers: a multicentre study. The Lancet Haematology. 2015;2(1):e21–e9.
  • Schoemans HM, Lee SJ, Ferrara JL, et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant. 2018;53(11):1401–1415.
  • MacMillan ML, Robin M, Harris AC, et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant. 2015;21(4):761–767.
  • Pidala J, Hamadani M, Dawson P, et al. Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial. Blood. 2020;135(2):97–107.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02806947, A study to evaluate steroid-free treatment for standard-risk aGVHD (BMT CTN 1501); 2019 Dec 30 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02806947
  • Chang Y-J, Xu L-P, Wang Y, et al. Controlled, randomized, open-label trial of risk-stratified corticosteroid prevention of acute graft-versus-host disease after haploidentical transplantation. J clin oncol. 2016;34(16):1855–1863.
  • Alousi AM, Weisdorf DJ, Logan BR, et al. Etanercept, mycophenolate, denileukin, or pentostatin plus corticosteroids for acute graft-versus-host disease: a randomized phase 2 trial from the Blood and Marrow Transplant Clinical Trials Network. Blood. 2009;114(3):511–517.
  • Bolanos-Meade J, Logan BR, Alousi AM, et al. Phase 3 clinical trial of steroids/mycophenolate mofetil vs steroids/placebo as therapy for acute GVHD: BMT CTN 0802. Blood. 2014;124(22):3221–3227.
  • Schroeder MA, Choi J, Staser K, et al. The role of Janus kinase signaling in graft-versus-host disease and graft versus leukemia. Biol Blood Marrow Transplant. 2018;24(6):1125–1134.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03139604, GRAVITAS-301: a study of itacitinib or placebo in combination with corticosteroids for treatment of acute graft-versus-host disease; 2020 Jan 18 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT03139604
  • Incyte announces results of phase 3 study of itacitinib in patients with treatment-naïve acute graft-versus-host disease. Business Wire. 2020 Feb 1 [cited 2020 Feb 1]. Available from: https://www.businesswire.com/news/home/20200102005480/en/
  • Pidala J, Anasetti C. Glucocorticoid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2010;16(11):1504–1518.
  • Toubai T, Rossi C, Tawara I, et al. Murine models of steroid refractory graft-versus-host disease. Sci Rep. 2018;8(1):12475.
  • Murata M, Nakasone H, Kanda J, et al. Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2013;19(8):1183–1189.
  • Thangavelu G, Blazar BR. Achievement of tolerance induction to prevent acute graft-vs.-host disease. Front Immunol. 2019;10:309. Available from: https://www.frontiersin.org/article/10.3389/fimmu.2019.00309
  • Marty FM, Lee SJ, Fahey MM, et al. Infliximab use in patients with severe graft-versus-host disease and other emerging risk factors of non-Candida invasive fungal infections in allogeneic hematopoietic stem cell transplant recipients: a cohort study. Blood. 2003;102(8):2768–2776.
  • Pavletic SZ. Response as an end point in treatment trials for acute GVHD. Bone Marrow Transplant. 2012;47(2):161–163.
  • Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018;131(25):2846–2855.
  • Choi J, Cooper ML, Alahmari B, et al. Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PLoS One. 2014;9(10):e109799.
  • Spoerl S, Mathew NR, Bscheider M, et al. Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014;123(24):3832–3842.
  • Koreth J, Matsuoka K-I, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055–2066.
  • Zeiser R, Burchert A, Lengerke C, et al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015;29(10):2062–2068.
  • Jagasia M, Ali H, Schroeder MA, et al. Ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute graft-vs-host disease: results from the phase 2 REACH1 trial. Biol Blood Marrow Transplant. 2019;25(3):S52.
  • Rafei H, Kharfan-Dabaja MA, Nishihori T. A critical appraisal of extracorporeal photopheresis as a treatment modality for acute and chronic graft-versus-host disease. Biomedicines. 2017;5(4):60.
  • Malagola M, Cancelli V, Skert C, et al. Extracorporeal photopheresis for treatment of acute and chronic graft versus host disease: an Italian multicentric retrospective analysis on 94 patients on behalf of the Gruppo Italiano Trapianto di Midollo Osseo. Transplantation. 2016;100(12):e147–e55.
  • Schneiderman J. Extracorporeal photopheresis: cellular therapy for the treatment of acute and chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2017;2017(1):639–644.
  • Belizaire R, Kim HT, Poryanda SJ, et al. Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease. Blood Adv. 2019;3(7):969–979.
  • Couriel DR, Saliba R, de Lima M, et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15(12):1555–1562.
  • Yalniz FF, Hefazi M, McCullough K, et al. Safety and efficacy of infliximab therapy in the setting of steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2017;23(9):1478–1484.
  • Pidala J, Kim J, Field T, et al. Infliximab for managing steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant. 2009;15(9):1116–1121.
  • Nygaard M, Andersen NS, Moser CE, et al. Evaluation of infliximab as second-line treatment of acute graft versus host disease -validating response on day 7 and 28 as predictors of survival. Bone Marrow Transplant. 2018;53(7):844–851.
  • De Jong CN, Saes L, Klerk CPW, et al. Etanercept for steroid-refractory acute graft-versus-host disease: a single center experience. PLoS One. 2017;12(10):e0187184.
  • Lee SJ, Zahrieh D, Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood. 2004;104(5):1559–1564.
  • Wang JZ, Liu KY, Xu LP, et al. Basiliximab for the treatment of steroid-refractory acute graft-versus-host disease after unmanipulated HLA-mismatched/haploidentical hematopoietic stem cell transplantation. Transplant Proc. 2011;43(5):1928–1933.
  • Zeiser R, Blazar BR. Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood. 2016;127(25):3117–3126.
  • Tan Y, Xiao H, Wu D, et al. Combining therapeutic antibodies using basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease: a multi-center prospective study. OncoImmunology. 2017;6(3):e1277307.
  • Zeiser R. Advances in understanding the pathogenesis of graft-versus-host disease. Br J Haematol. 2019;187(5):563–572.
  • Chen Y-B, McDonough S, Chen H, et al. Expression of α4β7 integrin on memory CD8+ T cells at the presentation of acute intestinal GVHD. Bone Marrow Transplant. 2013;48(4):598–603.
  • Fløisand Y, Lazarevic VL, Maertens J, et al. Safety and effectiveness of vedolizumab in patients with steroid-refractory gastrointestinal acute graft-versus-host disease: a retrospective record review. Biol Blood Marrow Transplant. 2019;25(4):720–727.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02993783, A dose-finding study of vedolizumab for treatment of steroid-refractory acute intestinal graft-versus-host disease (GvHD) in participants who have undergone allogeneic hematopoietic stem cell transplantation (Allo-HSCT); 2019 May 24 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02993783
  • Chen Y-B, Shah NN, Renteria AS, et al. Vedolizumab for prevention of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Blood Adv. 2019;3(23):4136–4146.
  • Magenau JM, Goldstein SC, Peltier D, et al. α1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood. 2018;131(12):1372–1379.
  • Rodriguez-Otero P, Porcher R, APeffault de Latour R, et al. Fecal calprotectin and alpha-1 antitrypsin predict severity and response to corticosteroids in gastrointestinal graft-versus-host disease. Blood. 2012;119(24):5909–5917.
  • Marcondes AM, Hockenbery D, Lesnikova M, et al. Response of steroid-refractory acute GVHD to α 1 -antitrypsin. Biol Blood Marrow Transplant. 2016;22(9):1596–1601.
  • Elgaz S, Kuçi Z, Kuçi S, et al. Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfusion Med Hemotherapy. 2019;46(1):27–34.
  • Dunavin N, Dias A, Li M, et al. Mesenchymal stromal cells: what is the mechanism in acute graft-versus-host disease? Biomedicines. 2017;5(4):39.
  • Chen X, Wang C, Yin J, et al. Efficacy of mesenchymal stem cell therapy for steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis. PLoS One. 2015;10(8):e0136991.
  • Kebriaei P, Hayes J, Daly A, 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. Biol Blood Marrow Transplant. 2019;S1083-8791(19):30573–30577.
  • Martin PJ, Uberti JP, Soiffer RJ, et al. Prochymal improves response rates in patients with steroid-refractory acute graft versus host disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant. 2010;16(2):S169–S170.
  • Roddy JVF, Haverkos BM, McBride A, et al. Tocilizumab for steroid refractory acute graft-versus-host disease. Leuk Lymphoma. 2016;57(1):81–85.
  • Chang Y-J, Zhao X-Y, Huang X-J. Strategies for enhancing and preserving anti-leukemia effects without aggravating graft-versus-host disease. Front Immunol. 2018;9:3041. DOI:10.3389/fimmu.2018.03041
  • Das-Gupta E, Greinix H, Jacobs R, et al. Extracorporeal photopheresis as second-line treatment for acute graft-versus-host disease: impact on six-month freedom from treatment failure. Haematologica. 2014;99(11):1746–1752.
  • Jagasia M, Greinix H, Robin M, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant. 2013;19(7):1129–1133.
  • Ragon BK, Mehta RS, Gulbis AM, et al. Pentostatin therapy for steroid-refractory acute graft versus host disease: identifying those who may benefit. Bone Marrow Transplant. 2018;53(3):315–325.
  • Tey S-K, Hill GR. Chronic graft-versus-host disease: therapeutics at last? Hematologist. 2019;16(3). https://pub.hematology.org/Thehematologist/Mini-Review/9583.aspx
  • Jaglowski SM, Blazar BR. How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD. Blood Adv. 2018;2(15):2012–2019.
  • Waller EK, Miklos D, Cutler C, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy: 1-year update of a phase 1b/2 study. Biol Blood Marrow Transplant. 2019;25(10):2002–2007.
  • Kim SJ, Lee JW, Jung CW, et al. Weekly rituximab followed by monthly rituximab treatment for steroid-refractory chronic graft-versus-host disease: results from a prospective, multicenter, phase II study. Haematologica. 2010;95(11):1935–1942.
  • Kharfan-Dabaja MA, Mhaskar AR, Djulbegovic B, et al. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009;15(9):1005–1013.
  • van der Wagen L, Te Boome L, Schiffler M, et al. Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib. Bone Marrow Transplant. 2018;53(10):1255–1262.
  • Pidala JA, Bhatt VR, Hamilton BK, et al. Ixazomib for treatment of refractory chronic graft vs. host disease: a chronic GVHD consortium phase II trial. Biol Blood Marrow Transplant. 2019;25(3):S28.
  • Pidala J, Jaglowski S, Im A, et al. Carfilzomib for treatment of refractory chronic graft-versus-host disease: a chronic GVHD consortium pilot phase II trial. Biol Blood Marrow Transplant. 2020;26(2):278–284.
  • Schwartz J, Padmanabhan A, Aqui N, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the seventh special issue. J Clin Apher. 2016;31(3):149–162.
  • Gandelman JS, Song DJ, Chen H, et al. A prospective trial of extracorporeal photopheresis for chronic graft-versus-host disease reveals significant disease response and no association with frequency of regulatory T cells. Biol Blood Marrow Transplant. 2018;24(12):2373–2380.
  • Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft-versus-host disease. Blood. 2016;128(1):130–137.
  • Nahas MR, Soiffer RJ, Kim HT, et al. Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease. Blood. 2018;131(25):2836–2845.
  • Lazaryan A, Lee SJ, Salhotra A, et al. Initial results of KD025-208: a phase 2a open-label clinical trial of KD025 for steroid-dependent chronic graft versus host disease (cGVHD). Biol Blood Marrow Transplant. 2018;24(3):S70.
  • Jagasia M, Salhotra A, Bachier CR, et al. KD025-208: a phase 2a study of KD025 for patients with chronic graft versus host disease (cGVHD) - pharmacodynamics (PD) and updated results. Biol Blood Marrow Transplant. 2019;25(3):S28–S9.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02913261, Safety and efficacy of ruxolitinib versus best available therapy in patients with corticosteroid-refractory acute graft vs. host disease after allogeneic stem cell transplantation (REACH2); 2019 Nov 22 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02913261
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03112603, A study of ruxolitinib vs best available therapy (BAT) in patients with steroid-refractory chronic graft vs. host disease (GvHD) after bone marrow transplantation (REACH3); 2020 Jan 21 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT03112603
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04070781, Itacitinib and tocilizumab for steroid refractory acute graft versus host disease (GVHD); 2020 Jan [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT04070781
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02027805, Safety and efficacy study of T-guard to treat steroid-resistant acute GVHD; 2020 Jan [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02027805
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02759731, Study of baricitinib, a JAK1/2 inhibitor, in chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation; [ cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02759731
  • Miklos D, Cutler CS, Arora M, et al. Ibrutinib for chronic graft-versus-host disease after failure of prior therapy. Blood. 2017;130(21):2243–2250.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04198922, Acalabrutinib for the treatment of chronic graft versus host disease; 2020 Feb 5 [cited 2020 Feb 9]. Available from: https://clinicaltrials.gov/ct2/show/NCT04198922
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02923375, A study of CYP-001 for the treatment of steroid-resistant acute graft versus host disease; 2019 Jan 30 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02923375
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03327857, Neihulizumab (AbGn-168H) in patients with steroid-refractory acute graft-versus-host disease; 2019 Aug 28 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT03327857
  • van Lier YF, Davids M, Haverkate NJE, et al. Fecal microbiota transplantation can cure steroid-refractory intestinal graft-versus-host disease. Biol Blood Marrow Transplant. 2019;25(3):S241.
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04059757, Fecal microbiota transplantation for the treatment of gastro-intestinal acute GVHD; 2019 Nov 12 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT04059757
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT04189432, Efficacy and safety of SCM-CGH in patients with steroid-refractory or dependent chronic graft-versus-host disease; 2019 Dec 6 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT04189432
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT03422627, Safety and efficacy of amg 592 in subjects with steroid refractory chronic graft versus host disease; 2019 Nov 29 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT03422627
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT02385019, A phase 1/2 trial of donor regulatory T-cells for steroid-refractory chronic graft-versus-host-disease (TREGeneration); 2018 Mar 6 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT02385019
  • ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT01937468, Trial of regulatory T-cells plus low-dose interleukin-2 for steroid-refractory chronic graft-versus-host-disease; 2018 Mar 6 [cited 2020 Jan 31]. Available from: https://clinicaltrials.gov/ct2/show/NCT01937468

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