Manifestations of cGVHD

woman sitting with her arms wrapped around her legs

The inflammatory and fibrotic manifestations of cGVHD have widespread clinical impacts

Patients who undergo an alloHCT can develop complications, such as debilitating and life-threatening cGVHD.1-3 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 cGVHD4-7

  • Prior aGVHD
  • Use of ATG
  • 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 cGVHD8

Organs affected by cGVHD at the time of diagnosis

bar graph showing percentage of patients with cGVHD with organ involvement in the skin, mouth, eyes, lower GI tract, upper GI tract, liver, lungs, esophagus and joints/fascia
bar graph showing percentage of patients with cGVHD with organ involvement in the skin, mouth, eyes, lower GI tract, upper GI tract, liver, lungs, esophagus and joints/fascia

Of patients who received 3 lines of systemic therapy, 42% had involvement of ≥4 organs at the time of diagnosis.8

According to a study of a prospectively assembled cohort of patients with cGVHD, approximately half of patients had lung manifestations.9

BOS, a severe life-threatening fibrotic manifestation of cGVHD, is difficult to treat and may be clinically underrecognized.10-13

Inflammation and fibrosis

The relationship between inflammation and fibrosis in cGVHD is complex and not fully understood.14,15 However, there is an association between chronic inflammatory changes in cGVHD and collagen-producing fibroblasts.16,17 This can lead to the development of fibrotic lesions across multiple organs.16,18

  • Significant morbidity and life-threatening complications are largely the result of fibrosis,19 which can affect extensive areas of the skin20 and involve other organs, such as the lungs15,18
  • Although some aspects of inflammation in cGVHD can be addressed, there is limited evidence regarding the effectiveness of current treatments on fibrosis21-26

REZUROCK is designed to restore immune homeostasis and to downregulate the fibrotic processes of cGVHD.27-29

Patients routinely require multiple lines of systemic therapy to address the ongoing burden of cGVHD

A prospective, multicenter, observational study, which included 250 adult patients who underwent an alloHCT and subsequently received treatment for cGVHD, demonstrated that30

  • Patients received a median of 3 lines of systemic therapy, and the median time to permanent discontinuation of IST was 69 months
  • Progressive disease or lack of improvement was the reason 86% of patients required the initiation of new treatments, indicating a lack of cGVHD control with previous lines of systemic therapy
  • More than half of patients who discontinued IST at least 1 time had to restart IST within a median of 3.4 months
  • Of the patients attempting a first-time discontinuation of IST, 23% did so only after
    3 lines of systemic therapy

of patients progress
beyond 2 lines of systemic therapy, emphasizing a clear unmet need in treatment.30

REZUROCK is an effective and innovative

dual inhibitor

for the treatment of cGVHD.27-29

Explore the rockstar study

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

References: 1. 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 2. 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 3. 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 4. 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 5. 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 6. 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 7. 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 8. Data on file. Kadmon Pharmaceuticals, LLC; 2018. 9. 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 10. 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 11. 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 12. 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 13. 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 14. 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 15. 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 16. 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 17. 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 18. 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 19. Henden AS, Hill GR. Cytokines in graft-versus-host disease. J Immunol. 2015;194(10):4604-4612. doi:10.4049/jimmunol.1500117 20. Chronic graft-vs-host disease of skin and connective tissues. BMT InfoNet. Accessed October 7, 2020. Bmtinfonet.org/video/chronic-graft-vs-host-disease-skin-and-connective-tissues 21. 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 22. Jakafi. Package insert. Incyte Corporation; September 2021. 23. 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 24. Imbruvica. Package insert. Pharmacyclics LLC; 2020. 25. 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 26. 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 27. REZUROCK. Package insert. Kadmon Pharmaceuticals, LLC; 2021. 28. 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 29. 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 30. 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