New Investigational Drugs for Steroid-refractory Acute Graft-versus-host Disease: a Review of the Literature

Overview

Journal Expert Opin Investig Drugs

Specialty Pharmacology

Date 2024 Jul 8

PMID 38973782

Authors

Na Hyun Kim

Mehdi Hamadani

Sameem Abedin

Affiliations

Soon will be listed here.

Abstract

Introduction: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a formidable obstacle in the field of allogeneic hematopoietic cell transplantation (allo-HCT), significantly contributing to patient morbidity and mortality. The current therapeutic landscape for SR-aGVHD is limited, often yielding suboptimal results, thereby emphasizing the urgent need for innovative and effective treatments.

Areas Covered: In light of the pivotal REACH2 trial, ruxolitinib phosphate, a Janus kinase inhibitor, has gained prominence as the standard treatment for SR-aGVHD. Nevertheless, a considerable number of patients either do not respond to or cannot tolerate this therapy. This review delves into emerging treatments for SR-aGVHD, including mesenchymal stromal cells (MSCs), fecal microbiota transplantation (FMT), CD3/CD7 blockade, neihulizumab, begelomab, tocilizumab, and vedolizumab. While some of these agents have shown encouraging results in early-phase trials, issues such as treatment-related toxicities and inconsistent responses in larger studies highlight the necessity for ongoing research.

Expert Opinion: Current trials exploring new agents and combination therapies offer hope for fulfilling the unmet clinical needs in SR-aGVHD, potentially leading to more effective and precise treatment strategies.

References

Wang J, Liu K, Xu L, Liu D, Han W, Chen H . 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):1928-33. DOI: 10.1016/j.transproceed.2011.03.044. View

Jagasia M, Perales M, Schroeder M, Ali H, Shah N, Chen Y . Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020; 135(20):1739-1749. PMC: 7229262. DOI: 10.1182/blood.2020004823. View

van Oosterhout Y, van Emst L, Schattenberg A, Tax W, Ruiter D, Spits H . A combination of anti-CD3 and anti-CD7 ricin A-immunotoxins for the in vivo treatment of acute graft versus host disease. Blood. 2000; 95(12):3693-701. View

Ganetsky A, Frey N, Hexner E, Loren A, Gill S, Luger S . Tocilizumab for the treatment of severe steroid-refractory acute graft-versus-host disease of the lower gastrointestinal tract. Bone Marrow Transplant. 2018; 54(2):212-217. DOI: 10.1038/s41409-018-0236-z. View

Floisand Y, Lundin K, Lazarevic V, Kristiansen J, Osnes L, Tjonnfjord G . Targeting Integrin α4β7 in Steroid-Refractory Intestinal Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2016; 23(1):172-175. DOI: 10.1016/j.bbmt.2016.10.009. View

Ball L, Bernardo M, Roelofs H, Van Tol M, Contoli B, Zwaginga J . Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III-IV acute graft-versus-host disease. Br J Haematol. 2013; 163(4):501-9. DOI: 10.1111/bjh.12545. View

Hsu B, May R, Carrum G, Krance R, Przepiorka D . Use of antithymocyte globulin for treatment of steroid-refractory acute graft-versus-host disease: an international practice survey. Bone Marrow Transplant. 2001; 28(10):945-50. DOI: 10.1038/sj.bmt.1703269. View

Mohty M, Holler E, Jagasia M, Jenq R, Malard F, Martin P . Refractory acute graft-versus-host disease: a new working definition beyond corticosteroid refractoriness. Blood. 2020; 136(17):1903-1906. DOI: 10.1182/blood.2020007336. View

Floisand Y, Schroeder M, Chevallier P, Selleslag D, Devine S, Renteria A . A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease. Bone Marrow Transplant. 2021; 56(10):2477-2488. PMC: 8486663. DOI: 10.1038/s41409-021-01356-0. View

10.

Drobyski W, Pasquini M, Kovatovic K, Palmer J, Rizzo J, Saad A . Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transplant. 2011; 17(12):1862-8. PMC: 3716013. DOI: 10.1016/j.bbmt.2011.07.001. View

11.

Murray A, Linn S, Yu B, Novitzky-Basso I, Mattsson J, Kennah M . Real-world experience with ruxolitinib therapy for steroid-refractory acute graft versus host disease. Bone Marrow Transplant. 2024; 59(6):759-764. DOI: 10.1038/s41409-024-02249-8. View

12.

Zeiser R, Polverelli N, Ram R, Hashmi S, Chakraverty R, Middeke J . Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease. N Engl J Med. 2021; 385(3):228-238. DOI: 10.1056/NEJMoa2033122. View

13.

Uccelli A, Moretta L, Pistoia V . Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2009; 8(9):726-36. DOI: 10.1038/nri2395. View

14.

Mehta R, Saliba R, Jan A, Shigle T, Wang E, Nieto Y . Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft-Versus-Host Disease. Transplant Cell Ther. 2021; 27(3):272.e1-272.e5. DOI: 10.1016/j.jtct.2020.12.011. View

15.

Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder S . Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia. 2015; 29(10):2062-8. PMC: 4854652. DOI: 10.1038/leu.2015.212. View

16.

Zeiser R, Blazar B . Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy. N Engl J Med. 2017; 377(22):2167-2179. PMC: 6034180. DOI: 10.1056/NEJMra1609337. View

17.

Meyers G, Hamadani M, Martens M, Ali H, Chevallier P, Choe H . Anti-CD3/CD7 immunoconjugate (T-Guard) for severe, steroid-refractory GVHD: final report of BMT CTN 2002. Bone Marrow Transplant. 2023; 58(12):1416-1418. PMC: 11732251. DOI: 10.1038/s41409-023-02110-4. View

18.

Li A, Dong C, Tay S, Ananthakrishnan A, Ma K . Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis. Front Immunol. 2022; 13:1025350. PMC: 9692080. DOI: 10.3389/fimmu.2022.1025350. View

19.

Zhao K, Lin R, Fan Z, Chen X, Wang Y, Huang F . 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. J Hematol Oncol. 2022; 15(1):22. PMC: 8900437. DOI: 10.1186/s13045-022-01240-4. View

20.

Norona J, Apostolova P, Schmidt D, Ihlemann R, Reischmann N, Taylor G . Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans. Blood. 2020; 136(12):1442-1455. PMC: 7498363. DOI: 10.1182/blood.2020005957. View