Itacitinib
A selective Janus kinase-1 (JAK-1) inhibitor. One phase 3 trial of patients with grades II to IV acute GVHD failed to demonstrate a significant difference in overall response rate between itacitinib plus systemic corticosteroids versus placebo (standard treatment with systemic corticosteroids only).[154]Zeiser R, Socié G, Schroeder MA, et al. Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial. Lancet Haematol. 2022 Jan;9(1):e14-25.
http://www.ncbi.nlm.nih.gov/pubmed/34971577?tool=bestpractice.com
Vorinostat
A histone deacetylase (HDAC) inhibitor, vorinostat has been studied in combination with tacrolimus and methotrexate for the prevention of GVHD in patients undergoing HCT.[155]Choi SW, Braun T, Chang L, et al. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial. Lancet Oncol. 2014 Jan;15(1):87-95.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103793
http://www.ncbi.nlm.nih.gov/pubmed/24295572?tool=bestpractice.com
[156]Choi SW, Braun T, Henig I, et al. Vorinostat plus tacrolimus/methotrexate to prevent GVHD after myeloablative conditioning, unrelated donor HCT. Blood. 2017 Oct 12;130(15):1760-7.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5639486
http://www.ncbi.nlm.nih.gov/pubmed/28784598?tool=bestpractice.com
A phase 1/2 multicenter trial of vorinostat for GVHD prevention in children, adolescents, and young adults undergoing allogeneic blood and marrow transplantation is recruiting.[157]ClinicalTrails.gov. Vorinostat for graft vs host disease prevention in children, adolescents and young adults undergoing allogeneic blood and marrow transplantation. 2024 [internet publication].
https://clinicaltrials.gov/study/NCT03842696?cond=GVHD&intr=vorinostat&rank=1
Corticosteroid prophylaxis
One randomized open-label trial found that low-dose corticosteroid prophylaxis effectively reduced acute GVHD in high-risk patients (based on bone marrow allogeneic graft CD4:CD8 ratio).[158]Chang YJ, Xu LP, 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 Jun 1;34(16):1855-63.
http://jco.ascopubs.org/content/34/16/1855.long
http://www.ncbi.nlm.nih.gov/pubmed/27091717?tool=bestpractice.com
More evidence is required on the role of corticosteroids for GVHD prophylaxis.
Basiliximab
A chimeric murine/human monoclonal antibody specific for the alpha subunit (CD 25) interleukin-2-alpha receptor.[159]Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005 Aug;130(4):568-74.
http://www.ncbi.nlm.nih.gov/pubmed/16098072?tool=bestpractice.com
Basiliximab, in conjunction with a corticosteroid, may be considered as an alternative to ruxolitinib for corticosteroid-refractory GVHD.[92]National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: hematopoietic cell transplantation [internet publication].
https://www.nccn.org/guidelines/category_3
[159]Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease. Br J Haematol. 2005 Aug;130(4):568-74.
http://www.ncbi.nlm.nih.gov/pubmed/16098072?tool=bestpractice.com
The role of basiliximab in the management of GVHD continues to be explored.[160]Podichetty JT, Brinda BJ, Nelson RP, et al. Pharmacokinetics of basiliximab for the prevention of graft-versus-host disease in patients undergoing hematopoietic cell transplantation with minimal-intensity cyclophosphamide and fludarabine. Pharmacotherapy. 2020 Jan;40(1):26-32.
http://www.ncbi.nlm.nih.gov/pubmed/31742732?tool=bestpractice.com
[161]Freyer CW, Gier S, Carulli A, et al. Salvage therapy with basiliximab and etanercept for severe steroid-refractory acute graft-versus-host disease. Am J Hematol. 2022 Jul;97(7):E273-6.
https://onlinelibrary.wiley.com/doi/10.1002/ajh.26568
http://www.ncbi.nlm.nih.gov/pubmed/35413140?tool=bestpractice.com
[162]Mo XD, Hong SD, Zhao YL, et al. Basiliximab for steroid-refractory acute graft-versus-host disease: a real-world analysis. Am J Hematol. 2022 Apr;97(4):458-69.
http://www.ncbi.nlm.nih.gov/pubmed/35064928?tool=bestpractice.com
Further studies are required.
Itolizumab
Itolizumab, a monoclonal antibody that selectively targets CD6, is under investigation as a first-line treatment for acute GVHD in combination with corticosteroids.[163]Koreth J, Chhabra S, Pidala J, et al. Equate, a phase 1b/2 study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of a novel targeted anti-CD6 therapy, itolizumab, in subjects with newly diagnosed acute graft versus host disease. Blood. 2019;134:4516.
https://ashpublications.org/blood/article/134/Supplement_1/4516/424498/Equate-a-Phase-1b-2-Study-Evaluating-the-Safety
[164]Nagai H, Shimizu K, Shikata J, et al. Chylous leakage after circumferential thoracolumbar fusion for correction of kyphosis resulting from fracture. Report of three cases. Spine (Phila Pa 1976). 1997 Dec 1;22(23):2766-9.
http://www.ncbi.nlm.nih.gov/pubmed/9431612?tool=bestpractice.com
It has been granted orphan drug designation by the European Medicines Agency (EMA) and fast track designation by the Food and Drug Administration (FDA).
Remestemcel-L
The European Medicines Agency (EMA) has granted orphan drug designation to the mesenchymal stem cell (MSC) product remestemcel-L for acute GVHD. Remestemcel-L is currently approved in Canada and New Zealand for the management of acute GVHD in children and is available for adults and children in eight countries including the US, under an Expanded Access Program. It has also been granted approval by the FDA for use in children with corticosteroid-refractory acute GVHD.
BPX-501
BPX-501, a T-cell therapy using donor-derived T cells transduced with an iC9 suicide gene, attempts to improve upon the delayed recovery of adaptive T-cell immunity that occurs post HCT. Clinical studies are ongoing.[165]ClinicalTrials.gov. Safety study of gene modified donor T-cells following TCRαβ+ depleted stem cell transplant. Jan 2023 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT02065869
[166]ClinicalTrials.gov. Long term follow-up study for patients enrolled on the BP-004 clinical study. Jul 2022 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT03733249
The FDA has granted orphan drug designation to BPX-501 for the treatment of immunodeficiency and GVHD following stem cell transplant.
LP-310
A proprietary liposomal tacrolimus oral rinse formulation, LP-310 has received orphan drug designation by the FDA for the treatment of oral GVHD.