cGvHD

Chronic GvHD: management and future perspectives

Chronic graft-versus-host disease (cGvHD) can be active for decades and requires years of treatments including immunosuppressive therapies that can lead to many late complications.

Hani Mawardi, from the Faculty of Dentistry at King AdbulAziz University, Jeddah, SA, and colleagues discussed an overview of cGvHD1, its pathophysiology, management paradigms and what the future holds for the treatment of the condition.

Acute GvHD

Acute GvHD (aGvHD) is categorized as early-onset or late disease. This is then divided into three types: de novo, recurrent, or persistent, and graded on a scale of 0—IV depending on the number of organs involved. Typically, aGvHD affects only the skin, liver, and gastrointestinal tract (table 1). However, in severe cases of aGvHD, mortality rates can approach 90%.2

Chronic GvHD

cGvHD is classified as either classic or overlap disease.3 Classic GvHD often involves organs such as the nails, lungs, genitals, muscles, kidneys, and the heart3 (table 1). A mixture of the features of both aGvHD and cGvHD is considered ‘overlap disease’, and is associated with adverse prognosis and increased disease burden. Classic GvHD can be defined as the presence of cGvHD clinical features, without the presence of aGvHD features. A prior history of aGvHD increases the risk of developing cGvHD.4

Epidemiology

The incidence of cGvHD depends on a number of factors, such as the source of HCT, type of donor, and post-HCT immunosuppressive therapy. It is lower in matched unrelated (MUD) donor-umbilical cord transplantation, compared with MUD-peripheral blood stem cell transplantations (PBSCT).5 The 5-year mortality rate overall, including deaths due to infections, is between 30% and 50%.6

Pathophysiology

Two proposed theories of pathogenesis for cGvHD exist:

  1. Includes a focus on the role of differentiated donor Th2 cells in association with activated B cells and antibody production in tissue destruction.7
  2. Suggests an impaired immunological tolerance and differentiation of autoreactive T cells, resulting in the release of cytokines and thus cytolytic activity.6

In both theories, donor dendritic cells (DCs) help to mature the peripheral tissues and is followed by antigen presentation to CD4+ and CD8+ T cells. B cells also have a role in cGvHD, with rituximab, a B cell depleting anti-CD20 monoclonal antibody, demonstrating efficacy as a second-line therapy for cGvHD.8 Some studies have highlighted the potential impact neutrophils may have in cGvHD pathogenesis, as they have the ability to facilitate T cell activation.9

Clinical features

The condition has a number of clinical features, with huge impacts on the patients’ quality of life.

 

aGvHD

cGvHD

Skin

Maculopapular rash

Depigmentation, poikiloderma, sclera-derma-like features

Liver

Cholestatic hyperbilirubinemia

Jaundice, elevated LFTs

Upper gastrointestinal tract

Nausea, anorexia

Anorexia, weight loss

Lower gastrointestinal tract

Diarrhea (bloody), severe abdominal pain

 

Mouth

Ulcerative and erythematous changes, lip crusting

Xerostomia, lichen planus-like features, SICCA syndrome-like features, trismus, mucoceles

Nails

n/a

Nail dystrophy, longitudinal ridging, onycholysis

Eyes

n/a

Dry eyes, sicca syndrome, conjunctivitis, panuveitis

Muscles/Joints

n/a

Myositis, fasciitis

Female genitalia

n/a

Vaginal sclerosis/stenosis, ulceration, lichen planus-like features

Male genitalia

n/a

Lichen planus-like features, phimosis, scarring/stenosis

Lungs

n/a

Pleural effusion, bronchiolitis obliterans, obstructive pulmonary disease

Kidneys

n/a

Nephrotic syndrome

Heart

n/a

Pericarditis

Table 1: Clinical characteristics of aGvHD and cGvHD

Diagnosis and scoring

Primarily, the diagnosis of cGvHD is based on patient history and clinical presentation. According to the NIH criteria, cGvHD is diagnosed when at least one diagnostic manifestation or a distinctive manifestation along with a pertinent biopsy, laboratory test or radiographic imaging, of cGvHD is present.

cGvHD is classified into mild, moderate and severe by the NIH (table 2).

Score

Symptoms

0

No symptoms

1

Mild symptoms with disease signs but not limiting oral intake significantly

2

Moderate symptoms with disease signs and partial limitation of oral intake

3

Severe symptoms, disease signs and major limitations on oral intake.

Table 2: NIH severity staging system for oral cGvHD

 

GvHD management
  1. Systemic therapies
Systemic therapy

 

Corticosteroids (CSs)

Considered first-line therapy and the backbone for cGvHD treatment, fast mechanism of action compared with other systemic immunosuppressive agents. For around 50% of those diagnosed and treated with corticosteroids, disease control is inadequate and so second-line systemic therapies are required.

Calcineurin inhibitors

These include cyclosporine and tacrolimus. They block the nuclear factor of activated T cells (NFAT), and weaken the expression of IL-2 which leads to the inhibition of donor T cell proliferation. However, calcineurin inhibitors often come with side effects such as hyperlipidemia, hirsutism, neurotoxicity and renal toxicity, with prolonged use possible leading to gingival hyperplasia.  

mTOR inhibitors

Mammalian target of rapamycin (mTOR) inhibitors have an inhibitory effect on T cell activation, by forming a complex that results in a G1 cycle cell arrest through the inhibition of DNA transcription, translation, and protein synthesis. Examples of mTOR inhibitors are sirolimus and everolimus, with side effects including renal failure, hyperlipidemia, cytopenia and aphthous-like oral ulcerations.

Antimetabolites

Mycophenolate mofetil (MMF)

This antimetabolite functions through the inhibition of purine synthesis in lymphocytes with a potent cytostatic effect on both T and B cells. This has a response of between 45% and 75%.10 Side effects associated with MMF include diarrhea, infections and thrombocytopenia.

Azathioprine (AZP)

AZP is an antimetabolite immunosuppressive agent that has a limited benefit. A double-blind, placebo-controlled study found, that in comparison with prednisone alone, AZD with prednisone resulted in an increase in non-relapse mortality (NRM) (40% vs 21%) and a decrease in overall survival (47% vs 61%).13 Pancreatitis and bone marrow suppression are two serious side effects of AZP.

Rituximab

This monoclonal IgG1 anti-CD20 antibody that targets B cells has been used to treat multiple immune-mediated conditions. A meta-analysis, which included 111 patients, found that the cumulative response rate to rituximab was 66%, with the best responses in patients with  musculoskeletal and cutaneous manifestations.14

Extracorporeal photopheresis

Approved by the FDA in the 1980s, the actions of this drug are complex, and include the apoptosis of leukocytes, increased production of anti-inflammatory cytokines and the inhibition of pro-inflammatory cytokines. Response rates ranged between 50% and 63%, with greater efficacy in patients with cutaneous disease.15 Despite this being considered relatively safe, it still carries an increased risk of infection.

Tyrosine kinase inhibitors (TKI)

Imatinib

This potential treatment for sclerodermatous cGvHD involves a mechanism using platelet-derived growth factor-driven fibrosis reduction. In a phase I/II study using 19 patients, imatinib 100mg/day, was associated with an overall response rate of 79% at six months. Of the 19, seven patients achieved complete remission.16 Side effects of imatinib include fluid retention and myelosuppression.

Ibrutinib

Approved by the FDA as a second-line treatment for cGvHD in 2017, this treatment involves Th2 and B cells, and was found to have a 67% response rate in multiple organs in a study that enrolled 42 patients with cGvHD resistant to CS (NCT 02195869). Known side effects of ibrutinib are infection and hemmorhage.

Low-dose IL-2

The cytokine interleukin IL-2 was administered to 35 patients. Of these patients, 61% demonstrated a clinical response in multiple organs and 20 achieved a reduction in CS.10

 

  1. Ancillary therapies

Localized ancillary therapies can provide additional benefit, sometimes allowing for the tapering or discontinuation of systemic therapy. These treatments are targeted to specific organs, and may even be sufficient alone in patients with limited involvement. They should be maximized in order to reduce the need for systemic immunosuppressive therapies.

Ancillary therapy

 

Cutaneous cGvHD

Topical treatment is considered first-line because of better accessibility. Even when systemic therapy is used, the topical treatment is usually combined to maximize efficacy.

Oral cGvHD

Mild oral cGvHD can be managed using topical treatments alone, with some severe cases responding better to topical treatments than systemic therapies.

Ocular cGvHD

The application of artificial tears is usually the first step for ocular cGvHD, however topical CS and cyclosporine can also be used to reduce inflammation.

Genital cGvHD

Vulvovaginal mucosa can be treated with topical CS and estrogens. Systemic therapies include dilation therapy, systemic estrogen and even surgical intervention in severe cases.

 

  1. Future directions

Despite advances in clinical achievements for patients with cGvHD involving long-term survival outcomes, the condition continues to be a challenge and is still one of the leading causes of non-relapse mortality. Therapies, such as ruxolitinib, pacritinib, abatacept, natalizumab, ixazomib, carfilzomib, IL-2, IL-22 and maraviroc, that are currently in early-phase trials are showing promise for the future.

Summary

The complex condition, cGvHD, is an immune-mediated disease with a range of manifestations, with patients being at risk of a number of other late complications that require coordinated follow-up. There is still an unmet need for the development of effective therapies – especially for more severe cases.

References
  1. Mawardi, H., et al. Chronic graft‐versus‐host disease: Current management paradigm and future perspectives. Oral diseases. 2019 Jul 9. 25(4):931—948. DOI: 1111/odi.12936
  2. Gratwohl, A., et al. Acute graft-versus-host disease: grade and outcome in patients with chronic myelogenous leukemia. Working Party Chronic Leukemia of the European Group for Blood and Marrow Transplantation. Blood. 1995 Jul 15. 86 (2): 813-818.
  3. Jagasia M.H., 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 Mar 1. 21(3):389-401. DOI: 1016/j.bbmt.2014.12.001
  4. Ferrara J.L. & Reddy P. Pathophysiology of graft-versus-host disease. Seminars in hematology. 2006 Jan 1 43(1):3—10. DOI: 1053/j.seminhematol.2005.09.001
  5. Ponce D.M., et al. Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match. Biol blood marrow transplant. 2013 Jun 1. 19(6):904-11. DOI: 1016/j.bbmt.2013.02.008
  6. Blazar B.R., et al. Advances in graft-versus-host disease biology and therapy. Nature reviews Immunology. 2012 May 11. 12(6):443. DOI: 1038/nri3212
  7. Kataoka Y. et al. The role of donor T cells for target organ injuries in acute and chronic graft‐versus‐host disease. Immunology. 2001 Dec 21. 103(3):310—8. DOI: 1046/j.1365-2567.2001.01240.x
  8. Cutler C. et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006 Jul 15. 108(2):756—62. DOI: 10.1182/blood-2006-01-0233
  9. Schwab L. et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nature medicine. 2014 May 18. 20(6):648. DOI: 1038/nm.3517
  10. Koreth J. & Antin J.H. Current and future approaches for control of graft-versus-host disease. Expert review of hematology. 2008 Oct 1. 1(1):111—28. DOI: 1586/17474086.1.1.111
  11. Sullivan K.M. et al. Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation. Blood. 1988 Aug 1. 72(2):546—54.
  12. Kharfan-Dabaja M.A. et al. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2009 Sep 1. 15(9):1005—13. DOI: 1016/j.bbmt.2009.04.003
  13. Kanold J. et al. Update on extracorporeal photochemotherapy for graft-versus-host disease treatment. Bone marrow transplantation. 2005 Mar 1. 35(S1):S69. DOI: 1038/sj.bmt.1704851
  14. Kim H. et al. Successful long‐term use of imatinib mesylate in pediatric patients with sclerodermatous chronic GVHD. Pediatric transplantation. 2012 Oct 11. 16(8):910—2. DOI: 1111/petr.12004

 

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