Graft-versus-host disease chronic L99.2-

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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cGVHD; Chronic graft-versus-host disease; Chronic graft-versus-host reaction

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Barnes and Loutit, 1957

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Complex multi-organ disease that occurs 3-5 months or later after allogeneic hematopoietic stem cell transplantation (see below Graft-versus-Host Disease) The skin is the most frequently affected organ. Clinical morphology shows an overlap between systemic scleroderma, lichen sclerosus, systemic lupus erythematosus and Sjögren's syndrome. The cGVHD can affect different compartments of the skin (epidermis, corium) as well as the subcutaneous fatty tissue. Epidermal or dermal or subcutaneous changes, or a combination of both, may be the main cause. The 2 most frequent manifestations are lichenoid and sclerodermiform cGVHD (Ziemer M 2013).

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Classification of chronic GvHD

  • Progressive form (about 32% of cases), which directly follows an acute form with the worst prognosis
  • Delayed form (quiescent onset; about 36% of cases) occurring after a disease-free interval after acute GvHD
  • De novo form (about 30% of cases), without previous acute GvHD, with the best prognosis.

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Since allogeneic stem cell transplantations (aSZT) are becoming more and more important therapeutically (expansion of indications), cGVHD will gain in importance in the future. About 50% of patients who survive allogeneic stem cell transplantation in the long term develop cGVHD.

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Clinical features
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A generalized form must be distinguished from a localized form.

  • Generalized cGVHD: Beginning with lichenoid exanthema and hyperpigmentation in the facial area; erosive cheilitis, as well as extracutaneous manifestations such as sicca symptoms, keratoconjunctivitis, buccal mucositis, esophageal and vaginal strictures, intestinal infestation, lupoid hepatitis, general physical deterioration and pulmonary insufficiency. Risk of opportunistic infections. The lichenoid exanthema may develop into manifestations similar (or identical) to systemic scleroderma.
  • Late cGVHD shows poikilodermatic conditions with extensive skin sclerosis and contractures.
  • Localized cGVHD: Clinical features of lichen sclerosus et atrophicus, also genital lichen sclerosus (w>m) or lichen planus, circumscribed scleroderma ( Morphea), eosinophilic fasciitis ( analogous to Shulman's syndrome) or septal panniculitis.
  • Images of pityriasis rosea have also been described. The changes can also spread linearly along the Blaschko lines.
  • Nail alterations show as nail fold hyperkeratosis, onycholysis, transverse furrows, splinter hemorrhages, hyperpigmentation (melanonychia).

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There is no specific pattern of chronic GvHD. Rather, there is a morphological substrate that corresponds to the clinical picture (lichenoid pattern, scleroderma-like pattern, etc.). In the papillary dermis, accumulations of melanophages occur during prolonged persistence of the skin lesions. Often there is a compact hyperkeratosis and hypergranulosis. There is a pronounced vacuum degeneration along the basal cell layer as well as keratinocyte apoptosis mainly in the lower epidermal layers and along the pelvic epithelium. Lymphocytic inflammation is usually subepithelial in the form of a band and is accentuated under the image of an interfacedermatitis. In the poicilodermal courses, an atrophy of the epidermis is noticeable in dermal sclerosis, melanin incontinence and telangiectasia. Sclerosing changes reach deep into the subcutaneous fatty tissue and remind of morphea. The extent of interface dermatitis decreases with increasing sclerosis.

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In the area of the ulcers, it cleans wounds, promotes granulation and is antiseptic, see below wound treatment.

The indication for systemic immunosuppression depends on the extent of organ involvement. At the latest when two organ systems are affected (e.g. skin and liver, skin and intestine, skin and mucous membrane), an immunosuppressive therapy is useful. The therapy belongs in the hands of experienced colleagues.

The chronic GVH reaction is also directed against residual leukemia cells. The aim of therapeutic efforts is therefore not the complete suppression of the GVHR.

In addition to systemic immunosuppressive treatment, the following therapies can be attempted in the treatment of scleroderma, erythematous and/or lichenoid skin changes:

  • PUVA therapy, systemic: initial 0.5-0.25 J/cm2 at 0.6 mg/kg bw/day of methoxsalene (e.g. meladinine), dose increase up to 8 J/cm2 over several sessions. Maintenance therapy 1-2 times/week over 1-2 years.
  • Thalidomide: Briefly 200-400 mg/day p.o., then reduction to 100 mg/day. Cave! Off-Label-Use! Strictest indication for women of childbearing age.
  • Extracorporeal photopheresis: Every 4 weeks, good results are reported. Due to its good tolerability, it is an increasing supplement to systemic steropid therapy, especially since ECP does not negatively influence the graft-versus-leukemia effect and does not increase the risk of infection. In a larger retrospective study of 71 patients with steroid-refractory cGvHD the response rate of cutaneous manifestations was >50% (Flowers ME et al. 2008).
  • Regarding the success of TNF alpha antagonists, the results of the study are awaited.

General therapy
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Regular intensive physiotherapy exercises are necessary to improve joint mobility.

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Chronic GvHD is the main risk factor for significant morbidity and mortality after allogeneic stem cell transplantation. Approximately 15% of patients die as a result. A further 25% suffer significant impairment of their quality of life. The main risk factor for the occurrence of chronic GvHD is a previous acute GvHD and a high recipient age.

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Last updated on: 29.10.2020