Novel Agents for the Treatment of Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation
Maxwell A. Brown, PharmD
Clinical Pharmacy Manager, Bone Marrow Transplantation
New York–Presbyterian, Weill Cornell Medical Center
New York, NY
Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for a variety of malignant and nonmalignant hematologic disorders, but its efficacy is often limited by transplant-related complications. Graft-versus-host disease (GVHD) is one such complication. For the past 60 years, GVHD has remained a major cause of morbidity and mortality following allogeneic HSCT, with acute GVHD affecting 20%–80% of patients and chronic GVHD affecting 25%–80% of patients.1,2 Despite the prevalence of GVHD after HSCT, the overall severity of GVHD has been decreasing over time, primarily because of increased use of reduced-intensity conditioning regimens prior to HSCT and the development of novel regimens for prophylaxis and treatment of GVHD.3,4
Acute Graft-Versus-Host Disease
Acute GVHD develops through a series of complex immunological steps. Damage from HSCT conditioning chemotherapy causes activation of antigen-presenting cells, which release inflammatory cytokines to recruit immune effector cells to the area of injury. As a result of exposure to these cytokines, T cells from the HSCT donor become activated and erroneously recognize recipient tissue as foreign. This leads to a profound activation of the donor’s immune system against recipient tissues. The skin, liver, and gastrointestinal (GI) tract are the most common organ systems affected, and the development of acute GVHD in any of these organ systems can result in severe dysfunction and damage.5 Corticosteroids remain the first-line agents used in the treatment of acute GVHD, but response rates are suboptimal at 40%–50%.6,7 In addition, no second-line agent has proven superior to another, highlighting the need for more effective therapeutic modalities.
Janus Kinase Inhibition
The Janus kinase (JAK) family of tyrosine kinases are signal transducers that activate intracellular transcription factors of the signal transducer and activator of transcription (STAT) protein family. Activation of the JAK/STAT pathway is essential for numerous cellular processes, including cytokine-mediated intracellular signaling of lymphocytes.8 Given the role of cytokines in the activation and proliferation of T cells, inhibition of the JAK/STAT pathway has been heavily investigated as a potential treatment option for acute GVHD.
Ruxolitinib is an oral selective JAK1/JAK2 inhibitor recently approved by the U.S. Food and Drug Administration (FDA) for acute steroid-refractory GVHD. Preclinical studies demonstrated that ruxolitinib suppresses several aspects of the immune response, including reducing T-cell proliferation and inhibiting cytokine production.9 The phase 2 REACH1 trial investigated the use of ruxolitinib in combination with corticosteroids for the treatment of steroid-refractory acute GVHD. Patients received ruxolitinib 5 mg twice daily orally plus methylprednisolone 2 mg/kg/day (or equivalent). The overall response rate (ORR) at day 28 was 54.9%, with a complete response (CR) rate of 26.8%. Ruxolitinib also allowed for rapid tapering of the corticosteroid dose, with 55.8% of patients having a ≥50% reduction in their corticosteroid dose at day 28. Two additional clinical trials, REACH2 and REACH3, are ongoing and will determine the utility of ruxolitinib alone versus best available therapy in acute and chronic GVHD, respectively.8 In addition, two large ongoing phase 3 trials, GRAVITAS 301 and GRAVITAS 309, are investigating a selective JAK1 inhibitor, itacitinib, for the treatment of acute and chronic GVHD, respectively.
The integrins are a family of cell-surface proteins consisting of alpha and beta subunits that are widely expressed on leukocytes, including lymphocytes. These proteins are heavily involved in the trafficking of lymphocytes from the circulation into sites of inflammation.10 For patients with inflammatory bowel disease, integrin antagonists have been used to block integrin adhesion molecules, preventing lymphocyte migration into the intestinal mucosa.11 Given that acute GVHD of the GI tract results from profound inflammation in the intestinal mucosa, integrin inhibitors have also been investigated as a treatment modality for acute GI GVHD.
Natalizumab is a humanized monoclonal antibody directed against the alpha 4 subunit of integrin molecules and is currently FDA approved for treatment of multiple sclerosis and Crohn’s disease. A small phase 2 study of 18 patients investigated natalizumab and corticosteroids for the treatment of newly diagnosed acute GI GVHD. The ORR at day 28 was 75% and at day 56 was 62.5%. Natalizumab has been associated with progressive multifocal leukoencephalopathy (PML), a potentially life-threatening demyelinating neurologic disease, but it is important to note that none of the patients in this study developed PML.12
Vedolizumab is a humanized monoclonal antibody directed against the alpha 4/beta 7 subunit of integrin molecules and is currently FDA approved for the treatment of Crohn’s disease and ulcerative colitis. A small retrospective analysis investigated off-label use of vedolizumab for the treatment of 29 patients with steroid-refractory acute GI GVHD. The ORR at 2 months was 64%, with 28% of patients achieving a CR. However, 25 (86%) of the 29 patients developed infections, 12 of which were considered severe adverse effects.13
Sirtuin 1 (Sirt-1) is a member of a family of proteins that belong to the class 3 histone deacetylases. Sirt-1 regulates various biological processes, including inflammatory responses and immune cell activation. Preclinical data have demonstrated that Sirt-1-deficient mice experience diminished T-cell activation and reduced severity of acute GVHD.14 Although pharmacologic inhibitors of Sirt-1 do exist, the only data available on their use are in mouse models. Nonetheless, inhibition of Sirt-1 may be a promising therapeutic target for controlling acute GVHD.
Despite improvements in the understanding of the pathophysiology of GVHD, treatment of this complication remains a challenge. Corticosteroids remain the standard of care today, and no clearly superior agent for managing corticosteroid-refractory GVHD has been identified. Nonetheless, numerous new and promising therapeutic targets exist for the treatment of GVHD that are not mentioned in this article. As these therapeutic modalities are further developed, we can be hopeful that the improvement in treatment outcomes for patients suffering from GVHD seen over the past 2 decades will continue.
- 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.
- Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol. 2012;158(1):46-61.
- Aoudjhane M, Labopin M, Gorin NC, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19(12):2304-2312.
- 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.
- Ghimire S, Weber D, Mavin E, et al. Pathophysiology of GvHD and other HSCT-related major complications. Front Immunol. 2017;8:79.
- MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transplant. 2002;8(7):387-394.
- 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.
- Mannina D, Kröger N. Janus kinase inhibition for graft-versus-host disease: current status and future prospects. Drugs. 2019;79(14):1499-1509.
- 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.
- Beniwal-Patel P, Saha S. The role of integrin antagonists in the treatment of inflammatory bowel disease. Expert Opin Biol Ther. 2014;14(12):1815-1823.
- 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.
- Kekre N, Kim HT, Ho VT, et al. Phase II trial of natalizumab (Tysabri®) with corticosteroids as initial treatment of gastrointestinal acute graft versus host disease. Blood. 2017;130:3252.
- 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.
- Daenthanasanmak A, Iamsawat S, Chakraborty P, et al. Targeting Sirt-1 controls GVHD by inhibiting T-cell allo-response and promoting Treg stability in mice. Blood. 2019;133(3):266-279.