• HOW CAN THE TREATMENT PARADIGM OF cGVHD BE OPTIMIZED?

    The lack of standardized treatment and response biomarkers, as well as the variability of the disease from person to person, impedes the goals of extending survival and improving QOL.1

    First-line therapy
    with systemic corticosteroids, with or without CNIs, is well established in patients with chronic graft-versus-host disease.2-4    		 Second-line therapy
    may be required for approximately
    70%
    of patients with cGVHD.5    		 Third-line therapy
    may be required for approximately
    50%
    of those patients, with many progressing to later lines of therapy.5

    Both corticosteroids and CNIs may provide effective initial therapy for cGVHD. However, prolonged systemic use of either can cause significant toxicities.2

    Toxicities associated with prolonged corticosteroid use include2

    • Weight gain
    • Bone loss 
    • Myopathy
    • Diabetes 
    • Hypertension
    • Mood swings
    • Cataract formation
    • Increased risk of infection

    Toxicities associated with prolonged CNI use include6

    • Nephrotoxicity
    • Neurotoxicity
    • Metabolic abnormalities

    Corticosteroids should be tapered to allow for the lowest dose that adequately controls cGVHD. Once cGVHD is controlled, corticosteroids should be withdrawn, followed by withdrawal of CNIs.2 For these patients who are unable to tolerate prolonged exposure, a more targeted approach may be required.3,4,6,7

    As patients progress to later lines of therapy, the focus of treatment becomes stabilizing the condition while limiting AEs and maintaining QOL.6,8

    A treatment paradigm that allows for the right treatment for the right patient at the right time may better address the manifestations of cGVHD.

    If initial therapy is not enough, what is the next step?

    Learn more about other treatment options

    AE, adverse event; cGVHD, chronic graft-versus-host disease; CNI, calcineurin inhibitor; QOL, quality of life.

      1. Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021;2021(1):648-654. doi:10.1182/hematology.2021000301
      2. Flowers MED, Martin PJ. How we treat chronic graft-versus-host disease. Blood. 2015;125(4):606-615. doi:10.1182/blood-2014-08-551994
      3. Mawardi H, Hashmi SK, Elad S, Aljurf M, Treister N. Chronic graft-versus-host disease: current management paradigm and future perspectives. Oral Dis. 2019;25(4):931-948. doi:10.1111/odi.12936
      4. Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood. 2017;129(1):22-29. doi:10.1182/blood-2016-08-686659
      5. Lee SJ, Nguyen TD, Onstad L, et al. Success of immunosuppressive treatments in patients with chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2018;24(3):555-562. doi:10.1016/j.bbmt.2017.10.042
      6. Dignan FL, Amrolia P, Clark A, et al; on behalf of the Haemato-oncology Task Force of the British Committee for Standards in Haematology and the British Society for Blood and Marrow Transplantation. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol. 2012;158(1):46-61. doi:10.1111/j.1365-2141.2012.09128.x
      7. Hill L, Alousi A, Kebriaei P, Mehta R, Rezvani K, Shpall E. New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. 2018;9(1):21-46. doi:10.1177/2040620717741860
      8. 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.e1. doi:10.1016/j.bbmt.2014.12.001

  • WHAT ARE OTHER TREATMENT OPTIONS?

    There are several adjunctive options for the treatment of patients with chronic graft-versus-host disease, including targeted therapies and ECP. However, there is currently limited guidance regarding when each should be considered and for which patients these treatments will be most effective.1-4



    ECP
    ECP is a nonpharmacologic immunomodulatory therapy that involves leukapheresis of patient peripheral blood mononuclear cells, exposure of the cellular product to UV-A light in the presence of 8-methoxypsoralen and reinfusion of the ex vivo–treated cells.1
    The mechanisms of ECP are not completely understood, although it is believed that ECP suppresses alloimmune responses by altering the maturation and function of dendritic cells, as well as through the induction of Treg cells.1 The procedure has shown benefit in patients with steroid-refractory cGVHD,1 as well as in those with skin, oral, and liver cGVHD.5
    ECP requires venous or central access and involves a variety of treatment schedules to identify the appropriate dose intensity and length of treatment.6


    BTK inhibitors
    BTK inhibitors form a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. Nonclinical studies have shown that this class of drug inhibits the proliferation and survival of malignant B cells in vivo, as well as cell migration and substrate adhesion in vitro.3 Some BTK inhibitors also inhibit IL-2–ITK, which is highly expressed in T cells and is closely related to BTK.1
    Both B and T cells play important roles in the pathogenesis of cGVHD,7 and the inhibition of BTK and ITK has shown clinical benefit.1,7
    Warnings and precautions associated with BTK inhibitors include infections and cytopenias, which include thrombocytopenia, neutropenia and anemia.3


    JAK inhibitors
    JAK1 and JAK2 mediate receptor signaling for a variety of pro-inflammatory cytokines, which are elevated in cGVHD.1
    Inhibitors of this pathway have been shown to decrease expression of inflammatory cytokines and reduce GVHD in murine models,1,2 as well as suppress activation and differentiation of dendritic cells and T cells.1 This approach has shown promising results in patients with steroid-refractory cGVHD.1,8
    Safety considerations associated with JAK inhibitors include monitoring for pruritus, infections, thrombocytopenia and leukopenia.8

    A greater number of treatments that address both the inflammatory and fibrotic processes of cGVHD are needed.

    Are there new approaches to the treatment of cGVHD under clinical development?

    Learn more about potential targeted options

    BTK, Bruton's tyrosine kinase; cGVHD, chronic graft-versus-host disease; ECP, extracorporeal photopheresis; IL-2, interleukin 2; ITK, inducible kinase; JAK, Janus-associated kinase.

      1. Cutler CS, Koreth J, Ritz J. Mechanistic approaches for the prevention and treatment of chronic GVHD. Blood. 2017;129(1):22-29. doi:10.1182/blood-2016-08-686659
      2. Jakafi. Package insert. Incyte Corporation; 2021.
      3. Imbruvica. Package insert. Pharmacyclics LLC; 2022.
      4. Hamilton BK. Updates in chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program. 2021;2021(1):648-654. doi:10.1182/hematology.2021000301
      5. Afram G, Watz E, Remberger M, et al. Higher response rates in patients with severe chronic skin graft-versus-host disease treated with extracorporeal photopheresis. Cent Eur J Immunol. 2019;44(1):84-91. doi:10.5114/ceji.2018.75831
      6. Wolff D, Schleuning M, von Harsdorf S, et al. Consensus Conference on Clinical Practice in Chronic GVHD: second-line treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2011;17(1):1-17. doi:10.1016/j.bbmt.2010.05.011
      7. 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. doi:10.1182/blood-2017-07-793786
      8. Modi B, Hernandez-Henderson M, Yang D, et al. Ruxolitinib as salvage therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2019;25(2):265-269. doi:10.1016/j.bbmt.2018.09.003

  • WHAT TREATMENTS ARE UNDER CLINICAL DEVELOPMENT?

    There are multiple novel therapies currently being investigated for the treatment of chronic graft-versus-host disease with the hopes of improving patient outcomes.



    Selective ROCK2 inhibitors
    Selective rho-associated coiled-coil–containing protein kinase (ROCK) 2 inhibitors have been studied as a potential treatment option for cGVHD, given that this molecular pathway mediates both the inflammatory and fibrotic components of the disease.1,2
    Selective ROCK2 inhibition has been shown to help resolve immune dysregulation by downregulating pro-inflammatory T helper (Th) 17 cells and increasing regulatory T (Treg) cells. Furthermore, selective ROCK2 inhibition has been shown to downregulate key fibrotic processes, such as TGF-β and LPA, leading to a decrease in fibrosis and collagen deposition.1-4
    Clinical studies are currently ongoing to evaluate the potential benefifits of selective ROCK2 inhibition in cGVHD.


    Selective JAK1 inhibitors5
    The involvement of JAKs in the signaling of pro-inflammatory cytokines involved in cGVHD pathogenesis has been a large area of interest. The potential use of JAK1 selective inhibitors in the treatment of cGVHD is currently being explored.


    IL-26
    The important role that IL-2 plays in Treg cell development, expansion, activity and survival has led to interest in its use for the treatment of cGVHD. Clinical studies in patients with cGVHD have shown that low-dose subcutaneous IL-2 has increased Treg cells, with minimal effect on CD4+ T cells. Clinical studies are currently ongoing to explore the potential benefits of IL-2 therapy.


    Combination therapy7
    Combination therapy that is intended to disrupt each phase of the GVHD cascade is another area in which research is underway. This approach to therapy would ideally use synergistic agents with different mechanisms of action and nonoverlapping toxicities

    As research continues, promising targets in cGVHD are being uncovered, with the possibility of offering patients more comprehensive and optimized treatments in the near future.

    What are the manifestations of cGVHD that need to be addressed?

    Learn more about inflammation and fibrosis

    cGVHD, chronic graft-versus-host disease; IL-2, interleukin 2; JAK, Janus-associated kinase; LPA, lysophosphatidic acid; ROCK, rho-associated coiled-coil–containing protein kinase; TGF-β, transforming growth factor-beta.

      1. Zanin-Zhorov A, Weiss JM, Nyuydzefe MS, et al. Selective oral ROCK2 inhibitor down-regulates IL-21 and IL-17 secretion in human T cells via STAT3-dependent mechanism. Proc Natl Acad Sci USA. 2014;111(47):16814-16819. doi:10.1073/pnas.1414189111
      2. Riches DWH, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fibrosis. Am J Pathol. 2015;185(4):909-912. doi:10.1016/j.ajpath.2015.01.005
      3. Flynn R, Paz K, Du J, et al. Targeted Rho-associated kinase 2 inhibition suppresses murine and human chronic GVHD through a Stat3-dependent mechanism. Blood. 2016;127(17):2144-2154. doi:10.1182/blood-2015-10-678706
      4. Takeda Y, Matoba K, Kawanami D, et al. ROCK2 regulates monocyte migration and cell to cell adhesion in vascular endothelial cells. Int J Mol Sci. 2019;20(6):1331. doi:10.3390/ijms20061331
      5. Im A, Morariu-Zamfir R, Bleam M, Yan Y, Pavletic SZ. Trial in progress: a phase 3 study of itacitinib or placebo in combination with corticosteroids as initial treatment for chronic graft-versus-host disease (GRAVITAS-309). Blood. 2019;134(suppl 1):3277. doi:10.1182/blood-2019-128586
      6. 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. doi:10.1182/blood-2016-02-702852
      7. Jacobsohn DA. Emerging therapies for graft-versus-host disease. Expert Opin Emerg Drugs. 2003;8(2):323-338. doi:10.1517/14728214.8.2.323

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