The inflammatory and fibrotic manifestations of cGVHD have widespread clinical impacts1

Patients who undergo an alloHCT can develop complications, such as debilitating and life-threatening cGVHD.2-4 In fact, cGVHD is the leading cause of nonrelapse mortality in patients surviving >2 years post alloHCT.3

Risk factors for identifying patients who are more likely to develop cGVHD5-8

  • Prior aGVHD
  • No ATG use
  • Older age
  • Bone marrow source
  • RIC
  • HLA mismatch
  • Female donor to male recipient
  • Peripheral blood stem cell source
  • High numbers of infused T cells
  • Positive CMV serology

Multiple organs can be affected by cGVHD9


Bar graph showing percentage of patients with cGVHD with organ involvement in the skin (55%), mouth (47%), eyes (34%), lower GI tract (22%), upper GI tract (24%), liver (22%), lungs (20%), esophagus (17%) and joints/fascia (17%)
Of patients who received ≥3 lines of systemic therapy, 42% had involvement of ≥4 organs at the time of diagnosis.9
icon of lungs showing approximately 50% of capacity filled

According to a study of a prospectively assembled cohort of patients with cGVHD, approximately half of patients had lung manifestations.10

Treatment of fibrosis in the lungs is a critical unmet need.11-14

Inflammation and fibrosis

The relationship between inflammation and fibrosis in cGVHD is complex and not fully understood.15,16 However, there is an association between chronic inflammatory changes in cGVHD and collagen-producing fibroblasts.17,18 This can lead to the development of fibrotic lesions across multiple organs.17,19

  • Significant morbidity and life-threatening complications are largely the result of fibrosis,20 which can affect extensive areas of the skin21 and involve other organs, such as the lungs16,19
  • Although some aspects of inflammation in cGVHD can be addressed, there is limited evidence regarding the effectiveness of current treatments on fibrosis22-27

designed for the treatment of cGVHD.28-30

aGVHD, acute graft-versus-host disease; alloHCT, allogeneic hematopoietic cell transplant; ATG, antithymocyte globulin; cGVHD, chronic graft-versus-host disease; CMV, cytomegalovirus; GI, gastrointestinal; HLA, human leukocyte antigen; MOA, mechanism of action; RIC, reduced-intensity conditioning.

References: 1. 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 2. Arora M, Pidala J, Cutler CS, et al. Impact of prior acute GVHD on chronic GVHD outcomes: a Chronic Graft-versus-Host Disease Consortium study. Leukemia. 2013:27(5):1196-1201. doi:10.1038/leu.2012.292 3. Wingard JR, Majhail NS, Brazauskas R, et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011;29(16):2230-2239. doi:10.1200/JCO.2010.33.7212 4. Arai S, Arora M, Wang T, et al; for the Graft-vs-Host Disease Working Committee of the CIBMTR. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266-274. doi:10.1016/j.bbmt.2014.10.021 5. Afram G, Pérez Simón JA, Remberger M, et al. Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting. Med Oncol. 2018;35(6):79. doi:10.1007/s12032-018-1127-2 6. Chen Y-B, Wang T, Hemmer MT, et al. GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes. Bone Marrow Transplant. 2017;52(3):400-408. doi:10.1038/bmt.2016.265 7. Lazaryan A, Weisdorf DJ, DeFor T, et al. Risk factors for acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched sibling donors. Biol Blood Marrow Transplant. 2016;22(1):134-140. doi:10.1016/j.bbmt.2015.09.008 8. Kok LMC, Bungener L, de Bock GH, et al. Risk factors associated with the development of moderate to severe chronic graft-versus-host disease after non-myeloablative conditioning allogeneic stem cell transplantation in patients with AML or MDS. Hum Cell. 2020;33(1):243-251. doi:10.1007/s13577-019-00297-7 9. Data on file. Kadmon Pharmaceuticals, LLC; 2018. 10. 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 11. Arora M, Cutler CS, Jagasia MH, et al. Late acute and chronic graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):449-455. doi:10.1016/j.bbmt.2015.10.018 12. Inagaki J, Moritake H, Nishikawa T, et al. Long-term morbidity and mortality in children with chronic graft-versus-host disease classified by National Institutes of Health Consensus Criteria after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2015;21(11):1973-1980. doi:10.1016/j.bbmt.2015.07.025 13. Inamoto Y, Martin PJ, Chai X, et al; on behalf of the Chronic GVHD Consortium. 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 14. Gazourian L, Spring L, Meserve E, et al. Pulmonary clinicopathological correlation after allogeneic hematopoietic stem cell transplantation: an autopsy series. Biol Blood Marrow Transplant. 2017;23(10):1767-1772. doi:10.1016/j.bbmt.2017.06.009 15. 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 16. 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 17. 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 18. 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 19. 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 20. Henden AS, Hill GR. Cytokines in graft-versus-host disease. J Immunol. 2015;194(10):4604-4612. doi:10.4049/jimmunol.1500117 21. Chronic graft-vs-host disease of skin and connective tissues. BMT InfoNet. Accessed June 2, 2023. 22. 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 23. Jakafi. Package insert. Incyte Corporation; 2023. 24. 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 25. Imbruvica. Package insert. Pharmacyclics LLC; 2022. 26. 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 27. 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 28. REZUROCK. Package insert. Kadmon Pharmaceuticals, LLC. 29. 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 30. 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