• WHAT IS THE PATHOGENESIS OF cGVHD?

    Chronic graft-versus-host disease is a complex multisystem disorder caused by an immune imbalance following an allogeneic HCT, which leads to serious and potentially life-threatening complications from both inflammatory and fibrotic processes. cGVHD is mediated by multiple immune pathways and is characterized by1

    Early inflammation due to tissue injury

    Chronic inflammation and a dysregulated adaptive immune system

    Tissue repair with fibrosis

    Although the understanding of the pathophysiology of cGVHD is improving, there is still much to be uncovered about the nature of the inflammatory cascade and the complex dynamics of the inflammatory and fibrotic processes.

    Improving comprehension of these manifestations could help in the development of more targeted treatments.

    What molecular pathways are implicated in cGVHD?

    Learn more about ROCK, BTK, JAK and IL-2

    BTK, Bruton’s tyrosine kinase; cGVHD, chronic graft-versus-host disease; HCT, hematopoietic cell transplant; IL-2, interleukin 2; JAK, Janus-associated kinase; ROCK, rho-associated coiled-coil–containing protein kinase.

      1. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579. doi:10.1056/NEJMra1703472

  • WHAT MOLECULAR PATHWAYS ARE IMPLICATED IN cGVHD?

    Several pathways have been shown to be key mediators of disease progression in chronic graft-versus-host disease.1



    ROCK
    The rho-associated coiled-coil–containing protein kinase (ROCK) molecular pathway plays a key role in immune and fibrotic disease.2,3 Additionally, ROCK is downstream of major profibrotic mediators and regulates multiple fibrotic processes, such as myofibroblast activation and profibrotic gene transcription.3
    ROCK2, specifically, is involved in both the inflammatory and fibrotic components of cGVHD and has been shown to play an important role in modulating immune homeostasis.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.2 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.3-5


    BTK
    Following HCT, B-cell homeostasis and tolerance mechanisms are disrupted, resulting in reduced memory B-cell formation.6 These host-reactive B cells are associated with the development of cGVHD.7
    BTK is a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways,8 which is expressed mainly in B cells and other hematopoietic tissues.9 Signaling via BTK results in the activation of pathways necessary for B-cell trafficking, chemotaxis and adhesion.8


    JAK
    JAK1 and JAK2 are signal mediators of several cytokines and growth factors that are necessary for hematopoiesis and immune function. STATs are recruited to cytokine receptors during JAK signaling, leading to modulation of gene expression.10
    In cGVHD pathogenesis, JAK-STAT molecular pathways regulate the development, proliferation and activation of various immune cell types.10


    IL-2
    IL-2, a cytokine signaling molecule, is essential for normal Treg cell development, expansion, activity and survival. CD4+ Treg cells play a role in immune tolerance and controlling immune responses. Impaired Treg cell function is characteristic of cGVHD and is associated with loss of tolerance and autoimmunity.11

    Research continues to uncover the role of these pathways.

    What manifestations are caused by the activation of these pathways?

    Learn more about inflammation and fibrosis

    BTK, Bruton’s tyrosine kinase; cGVHD, chronic graft-versus-host disease; HCT, hematopoietic cell transplant; IL-2, interleukin 2; JAK, Janus-associated kinase; LPA, lysophosphatidic acid; ROCK2, rho-associated coiled-coil–containing protein kinase 2; STAT, signal transducers and activators of transcription; TGF-β, transforming growth factor-beta.

      1. 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
      2. 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
      3. Riches DWH, Backos DS, Redente EF. ROCK and Rho: promising therapeutic targets to ameliorate pulmonary fifibrosis. Am J Pathol. 2015;185(4):909-912. doi:10.1016/j.ajpath.2015.01.005
      4. 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
      5. 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
      6. MacDonald KPA, Hill GR, Blazar BR. Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. Blood. 2017;129(1):13-21. doi:10.1182/blood-2016-06-686618
      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. Imbruvica. Package insert. Pharmacyclics LLC; 2022.
      9. 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
      10. Jakafi. Package insert. Incyte Corporation; 2021.
      11. 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

  • WHAT ROLES DO THE INFLAMMATORY AND FIBROTIC PROCESSES PLAY IN cGVHD?

    Chronic graft-versus-host disease is characterized by a combination of tissue inflammation and fibrosis, which manifest across multiple organ systems.1-4
    The relationship between these 2 processes in cGVHD is complex and not fully understood.3 Fibrosis may be viewed as a natural consequence of inflammation, as an independent process or as interrelated with inflammation in some ways but not completely dependent on it.5

    Because of chronic inflammatory changes, cGVHD can present with collagen-producing fibroblasts,2 resulting in fibrotic lesions.2,4

    Fibrotic lesions can develop across multiple organs4

    SKIN MOUTH JOINTS EYES
    GI TRACT ESOPHAGUS    LIVER LUNGS


    Fibrosis is a major contributor to life-threatening complications and significant morbidity.6

    Patients develop multiorgan manifestations, including skin, mouth, joint/fascia, eye, upper and lower GI tract, esophagus, liver, genitourinary and/or lung manifestations.4,7,8

    Skin manifestations are the most common, occurring in

    Approximately half of patients have lung involvement,

    which can manifest as bronchiolitis obliterans, a fibrotic manifestation that can be especially difficult to treat.

    Although the inflammation associated with cGVHD can be addressed, there is limited evidence regarding the impact of current treatments on
    fibrosis.10-15

    How do inflammation and fibrosis affect patients’ lives?

    Learn more about patient quality of life

    What treatments are currently available for cGVHD?

    Learn more about current treatment options

    cGVHD, chronic graft-versus-host disease; GI, gastrointestinal.

      1. Fall-Dickson JM, Pavletic SZ, Mays JW, Schubert MM. Oral complications of chronic graft-versus-host disease. J Natl Cancer Inst Monogr. 2019;2019(53):lgz007. doi:10.1093/jncimonographs/lgz007
      2. MacDonald KPA, Hill GR, Blazar BR. Chronic graft-versus-host disease: biological insights from preclinical and clinical studies. Blood. 2017;129(1):13-21. doi:10.1182/blood-2016-06-686618
      3. Kitko CL, White ES, Baird K. Fibrotic and sclerotic manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012;18(1 suppl):S46-S52. doi:10.1016/j.bbmt.2011.10.021
      4. Fiuza-Luces C, Simpson RJ, Ramírez M, Lucia A, Berger NA. Physical function and quality of life in patients with chronic GvHD: a summary of preclinical and clinical studies and a call for exercise intervention trials in patients. Bone Marrow Transplant. 2016;51(1):13-26. doi:10.1038/bmt.2015.195
      5. Cooke KR, Luznik L, Sarantopoulos S, et al. The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2017;23(2):211-234. doi:10.1016/j.bbmt.2016.09.023
      6. Henden AS, Hill GR. Cytokines in graft-versus-host disease. J Immunol. 2015;194(10):4604-4612. doi:10.4049/jimmunol.1500117
      7. Jacobsohn DA, Kurland BF, Pidala J, et al. Correlation between NIH composite skin score, patient-reported skin score, and outcome: results from the Chronic GVHD Consortium. Blood. 2012;120(13):2545-2552. doi:10.1182/blood-2012-04-424135
      8. Inamoto Y, Martin PJ, Chai X, et al; on behalf of the Chronic GVHD Consortium. The clinical benefit of response in chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2012;18(10):1517-1524. doi:10.1016/j.bbmt.2012.05.016
      9. Chronic graft-vs-host disease of skin and connective tissues. BMT InfoNet. Accessed January 4, 2023. https://www.bmtinfonet.org/video/ chronic-graft-vs-host-disease-skin-and-connective-tissues
      10. 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
      11. Jakafi. Package insert. Inctye Corporation; 2021.
      12. 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
      13. Imbruvica. Package insert. Pharmacyclics LLC; 2022.
      14. 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
      15. 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

Chronic graft-versus-host disease presents multiple challenges for both clinicians and patients, specifically through manifestations of inflammation and fibrosis.

Although advances have been made in the understanding of cGVHD, many questions still remain.


What roles do the inflammatory and fibrotic processes play in cGVHD?
Understanding the manifestations of cGVHD



What is the full impact of cGVHD on patients' lives?
cGVHD is a significant burden on patients, affecting them physically, mentally, emotionally and financial



What is under clinical development?
How targeting alternative molecular pathways may offer a different treatment approach

cGVHD,chronicgraft-versus-hostdisease.

Tissue repair with fibrosis

Although the understanding of the pathophysiology of cGVHD is improving, there is still much to be uncovered about the nature of the inflammatory cascade and the complex dynamics of the inflammatory and fibrotic processes.

Improving comprehension of these manifestations could help in the development of more targeted treatments.

What molecular pathways are implicated in cGVHD?

Learn more about ROCK, BTK, JAK and IL-2

BTK, Bruton’s tyrosine kinase; cGVHD, chronic graft-versus-host disease; HCT, hematopoietic cell transplant; IL-2, interleukin 2; JAK, Janus-associated kinase; ROCK, rho-associated coiled-coil–containing protein kinase.

    1. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377(26):2565-2579. doi:10.1056/NEJMra1703472

MAT-SA-2300860/v2/March2024