¹Blood and Marrow Stem Cell Transplantation Programs at University of Michigan Medical Center, Ann Arbor, MI, USA

²Blood and Marrow Stem Cell Transplantation Programs at Comprehensive Cancer Center of the University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA

Correspondence to: Dr V Ratanatharathorn, B1-207 Cancer Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA

Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in long-term survivors of allogeneic stem cell transplantation. The immunopathogenesis of chronic GVHD is, in part, TH-2 mediated, resulting in a syndrome of immunodeficiency and an autoimmune disorder. The most important risk factor for chronic GVHD is prior history of acute GVHD and strategies that prevent acute GVHD also decrease the risk of chronic GVHD. Other important risk factors are the use of a non-T cell-depleted graft, and older age of donor and recipient. Whether recipients of peripheral blood stem cells are at increased risk of chronic GVHD remains unsettled. There are no known pharmacologic agents which can specifically prevent development of chronic GVHD. Agents which have efficacy in the treatment of autoimmune disorders have been utilized as therapy for established chronic GVHD and are associated with response rates of 20% to 80%. Most responses are confined to skin, soft tissue, oral mucosa and occasionally liver. Bronchiolitis obliterans responds infrequently to therapy and is associated with a dismal prognosis. Newer, promising therapeutic strategies under investigation include thalidomide, photopheresis therapy, anti-tumor necrosis factor and B cell depletion with anti-CD20 monoclonal antibody. Bone Marrow Transplantation (2001) 28, 121-129.

chronic graft-versus-host disease; immunosuppressive therapy; cyclosporine; tacrolimus; extracorporeal photochemotherapy; allogeneic stem cell transplantation

Chronic graft-versus-host disease (GVHD) occurs in approximately 60-80% of long-term survivors of allogeneic hematopoietic cell transplant (HCT).^1,2 This immunologic complication is a major cause of morbidity and mortality,³ accounting for about one-quarter of deaths in long-term survivors of transplants performed for leukemia and two-thirds of deaths in long-term survivors of allografts undertaken for severe aplastic anemia.⁴ The incidence of chronic GVHD is likely to rise due to the increasing availability and use of unrelated donors^5,6 as well as the inclusion of older recipients of non-myeloablative ('reduced conditioning') regimens. Chronic GVHD, as initially defined, resembled an autoimmune disorder occurring 100 days after allogeneic transplantation. The arbitrary day of onset, however, may not be as crucial in separating acute from chronic GVHD; rather, these two syndromes appear to result from different mechanisms.^7,8 The classification for severity of chronic GVHD is depicted in Table 1.

Immunology and pathology of chronic GVHD

Donor T cells play a central role in the immunologic attack on host tissues in both acute and chronic GVHD. While the cytokine production pattern of acute GVHD is mostly TH1 type, TH2 cytokines predominate in chronic GVHD.⁹ Furthermore, the elevation of TH2 cytokines is consistent with the clinical manifestations of chronic GVHD in both man and animal models (eg associations of elevated IL-5 with eosinophilia, IL-4 with gammopathy and possibly scleroderma).^10,11 Thus, chronic GVHD appears to be a syndrome of immune dysregulation resulting in immunodeficiency and autoimmunity - a TH2 disease.^12,13

Most patients with chronic GVHD have evidence of B cell dysregulation with a high prevalence of autoantibodies to several cell surface and intracellular antigens, although the role of these autoantibodies in the pathogenesis of chronic GVHD is unclear.^{14,15,16,17,18}

The pathogenetic role of autoantibodies in the autoimmune disease has been elusive for the past several decades, because of the difficulty in identifying the autoantibody-associated effector mechanisms. Plausible effector pathways have been proposed for the role of autoantibodies in various autoimmune diseases, such as rheumatoid arthritis (RA)¹⁹ and other autoimmune diseases.²⁰ In RA, IgG rheumatoid factor (RF) complexes may account for the articular and extra-articular features of RA,²⁰ ultimately through ligation of FcRIIIa by IgG RF with the subsequent generation of TNF, an inflammatory cytokine highly expressed on macrophages in synovium intima and other target tissues.^21,22 Similar mechanisms have been postulated for other autoimmune disorders, such as systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, and progressive systemic sclerosis,²⁰ which share similar clinical manifestations as chronic GVHD. Immune thrombocytopenia can also be associated with a number of autoimmune disorders.²³ In patients with extensive chronic GVHD, anti-platelet antibodies are frequently detected in chronic GVHD-associated thrombocytopenia.²⁴

Risk factors associated with chronic GVHD

The risk of acquiring chronic GVHD is increased with increasing HLA disparity between recipient and donor. Recipients of unrelated donor marrow have a higher incidence of chronic GVHD.^1,2 The most important risk factors for developing extensive chronic GVHD are a diagnosis of prior acute GVHD,^25,26 and the use of corticosteroids at day 100.²⁷ The probability of chronic GVHD ranges from 59% to 85% among those with prior grade II-IV acute GVHD, up to 49% with prior grade I acute GVHD, and up to 28% for those who developed de novo chronic GVHD.

Other significant predictive factors for chronic GVHD are the use of non T cell-depleted bone marrow, male recipients of alloimmune female donors,²⁶ and older age of recipient or donor.^28,29 In unrelated donor transplantation, donor age is an independent predictor of acute and chronic GVHD.³⁰ The use of busulfan has been associated with increased risk of chronic GVHD in one study,³¹ but other studies have not found an increased incidence of chronic GVHD for busulfan-containing regimens.^32,33 Although there is general agreement that recipients of allogeneic peripheral blood stem cells (PBSC) do not develop more acute GVHD than those receiving marrow, whether the incidence of chronic GVHD is higher in PBSC recipients is controversial. Earlier studies reported the incidence of chronic GVHD to be higher,^34,35 however, the recent randomized trials comparing marrow and peripheral blood source of stem cells showed no difference in the rates of chronic GVHD.^36,37 Nonmyeloablative regimens that include CAMPATH-1H appear to have a low risk of acute and chronic GVHD, although longer follow-up is needed.³⁸

Clinical manifestations

Although the clinical manifestations of chronic GVHD differ from acute GVHD, concordance among clinicians in making the diagnosis, grading the disease, and deciding when to treat remains a challenge.³⁹ Practical problems encountered by clinicians caring for patients with chronic GVHD include the recognition of uncommon manifestations of the disease, interpretation of symptoms and signs of chronic GVHD appearing earlier than 2 months after transplant, and the determination whether to treat chronic GVHD limited to skin. The classification of chronic GVHD,⁷ which is based on clinical and pathologic findings, is helpful in categorizing the severity of chronic GVHD. Patients with extensive disease will invariably require systemic immunosuppressive therapy while most patients with limited disease do not (see Table 1). A more refined prognostic model for chronic GVHD was recently reported, and staging of chronic GVHD based on this model may provide greater accuracy in assessing the outcomes of various treatments.⁴⁰

Clinical manifestations of chronic GVHD are similar to autoimmune collagen vascular diseases,^41,42 such as oral ulcerations (lichen planus), keratoconjunctivitis sicca,⁴³ xerostomia,⁴⁴ polyserositis,⁴⁵ esophagitis and stricture,⁴⁶ vaginal ulceration and stricture,^47,48 intrahepatic obstructive liver disease, obstructive pulmonary disease, scleroderma, morphea, fasciitis⁴⁹ and myositis.^50,51

Oral mucosal involvement

The oral mucosa is most frequently involved by chronic GVHD. The clinical findings range from erythema, leukoplakia, lichenoid lesions, ulcers, mucosal atrophy, cicatricial changes and xerostomia.⁵² The mucosal appearance can be confused with oral candidiasis. The typical histologic findings of oral chronic GVHD consist of diffuse and periductal lymphocytic infiltration in labial salivary glands, subepithelial lymphocytic infiltration, and epithelial changes in buccal mucosa, similar to findings seen in patients with Sjögren's syndrome.^53,54,55 Involvement of major salivary glands invariably leads to severe xerostomia, rampant caries, periodontal disease, and occasionally sialadenitis.⁵⁶ Pilocarpine has been shown to relieve the symptoms of xerostomia.^57,58 Nystatin suspension and clotrimazole troches should not be used in patients with severe xerophthalmia because the high sugar content of nystatin suspension can exacerbate caries and troches are poorly dissolved in the absence of saliva.

Skin and soft tissues

There are two main forms of cutaneous chronic GVHD, namely, lichenoid and sclerodermatous types.⁵⁹ Early in the course of chronic GVHD, the lichenoid form predominates and typically involves the periorbital regions, ears, palms and soles. Rarely, lichenoid chronic GVHD may involve the glans penis and foreskin (causing phimosis),⁶⁰ and not infrequently involve the vaginal mucosa (resulting in stenosis).⁴⁷ Appearing later is the sclerodermatous form which may present as inflammatory plaques over the extremities. Frequently, the progression of sclerodermatous changes is insidious. Raynaud's phenomenon is rare in contrast to patients with progressive systemic sclerosis.⁴² Patchy areas of sclerotic plaques with bound-down consistency may occur on the trunk, especially over pressure surfaces (eg along the bra or waistline). Patients with truncal involvement by sclerodermatous GVHD may develop progressive restrictive lung disease due to diminished chest wall compliance. Skin sclerosis may be the product of excessive tissue repair resulting from immunologic injury by effector lymphocytes.⁶¹ Skin and subcutaneous involvement is often accompanied by dystrophic changes of the nails, including vertical ridges, onycholysis and telangiectasia of the nail fold.⁵⁹ Occasionally, fungal infection of the nail plate (onychomycosis) by dermatophytes and nondermatophytes may confound the clinical picture of chronic GVHD. Subungual accumulation of friable keratinous debris suggests the presence of onychomycosis.⁶²

Fasciitis is a rare presentation of chronic skin GVHD, involving the medial aspects of the proximal portion of extremities.⁴⁹ Inflammatory changes of the overlying skin and subcutaneous tissue simulating cellulitis may be pronounced. As the inflammation subsides, the skin and subcutaneous tissue is replaced with fibrotic tissue leading to dimpling appearance of the skin and contracture.⁵⁹

Xerophthalmia

Ocular involvement occurs in approximately 60% of patients with chronic GVHD. The most frequent ocular manifestations include keratoconjunctivitis sicca, cicatricial lagophthalmos, and sterile conjunctivitis and uveitis.⁶³ Xerophthalmia must be recognized early in order to avoid serious complications such as corneal epithelial defects and ulceration. The Schirmer's test should be routinely performed in all patients early in the onset of chronic GVHD. If xerophthalmia is present, aggressive use of topical lubricants should be initiated. Patients should be advised to wear protective eyewear outdoors especially on windy days. In more severe cases, punctal occlusion or cauterization, bandage soft contact lenses, and/or tarsorrhaphy may be needed.

Liver

Cholestasis predominates the clinical picture of chronic liver GVHD. However, isolated liver involvement by chronic GVHD, without the clinical signs and symptoms of other organ involvement, is uncommon. The severity of chronic liver disease correlates with the histopathologic findings on biopsy; namely, the presence of bridging necrosis indicates extensive chronic GVHD.^25,64 Hepatic failure resulting from progression of chronic GVHD is uncommon in long-term survivors. When hepatic failure occurs, the most frequent etiology is hepatitis C infection.⁶⁵

GI tract

Esophageal involvement in chronic GVHD results in dysphagia and retrosternal pain from mucosal desquamation with fibrosis, esophageal webs, distal peptic esophagitis, and stricture.⁶⁶ Gastrointestinal involvement is not usually a prominent manifestation of chronic GVHD, but occasionally may evolve from acute GVHD leading to gastrointestinal dysmotility and pseudo-obstruction.⁶⁷ In some patients, involvement of the small intestine by acute GVHD may lead to permanent damage, resulting in mechanical obstruction, diarrhea, stasis syndrome, and malabsorption.^46,68,69

Obstructive lung disease

Interstitial lung disease encompasses a broad range of etiologies, from regimen-related toxicity^70,71 to infection^72,73,74 and possibly to immunologic injury related to GVHD.⁷⁵ The occurrence of obliterative bronchiolitis, however, is limited to patients who develop chronic GVHD. Symptoms such as cough may begin 3 to 20 months after transplantation and then progress to dyspnea, progressive airflow obstruction, and finally respiratory failure.^76,77,78 A high-resolution CT scan may be normal or show hyperinflation, bronchial dilatation, consolidation, hypo-attenuated areas and vascular attenuation.⁷⁹ Patients with obstructive lung disease due to chronic GVHD infrequently respond to therapy, although some patients may survive long term.⁸⁰

Neuromuscular and CNS involvement

Neuromuscular involvement in chronic GVHD is uncommon.⁸¹ Sensory⁸² and motor neuropathy,⁸³ myositis,⁸⁴ dermatomyositis⁸⁵ and myasthenia gravis^86,87,88 have been reported to be associated with chronic GVHD. In most cases, neurologic complications after stem cell transplantation are the result of the toxicities of the preparative regimen.⁸¹ Neuropathy is frequently associated with treatment for GVHD, including thalidomide⁸⁹ and occasionally tacrolimus or cyclosporine.¹

Immunodeficiency

The most important complication associated with chronic GVHD is immunodeficiency, leading to susceptibility to wide ranges of opportunistic infections and frequently to death.^{90,91,92,93,94} Antimicrobial prophylaxis against Pneumocystis carinii, cytomegalovirus (CMV),⁹⁵ and pneumococcus is crucial in the prevention of potentially fatal infections.⁹⁶ Late onset CMV infection also occurs preferentially in patients with chronic GVHD, especially in the setting of corticosteroid usage.⁹⁷ Long-term CMV prophylaxis may be needed in seropositive patients with chronic GVHD, especially those receiving immunosuppressive therapy. A comprehensive guideline for infectious prophylaxis in stem cell transplant recipients, including patients with chronic GVHD, has recently been published.⁹⁸

Prophylaxis of chronic GVHD

Although there is no specific prophylactic therapy for chronic GVHD, the most important risk factor for the development of chronic GVHD is a prior diagnosis of acute GVHD. Pharmacologic approaches to the prevention of chronic GVHD have been disappointing. One recent prospective randomized double-blind study using thalidomide, an agent shown to have activity in the treatment of chronic GVHD, resulted in a paradoxical outcome of a higher incidence of chronic GVHD and a lower overall survival for those receiving thalidomide.⁹⁹ Tacrolimus reduces the incidence of acute GVHD when used for GVHD prophylaxis, but does not influence the incidence of chronic GVHD.^1,2 T cell depletion of stem cell grafts reduces the risk of both acute and chronic GVHD.^26,100 Studies using Campath antibody have reported exceptionally low incidences of acute and chronic GVHD.^38,101,102 Other methods of T cell depletion also report low incidences of chronic GVHD.^100,103

Treatment

The diversity of organ involvement, the chronic nature of the illness, and the hematologic and immunologic dysfunction associated with the syndrome all contribute to the difficulties in successfully treating chronic GVHD. The 'progressive' form of chronic GVHD evolves without a hiatus from active acute GVHD. Patients with progressive chronic GVHD are more likely to receive corticosteroids and tacrolimus or cyclosporine at onset, but are less likely to respond to these and other immunosuppressive therapies.^3,40,104 By contrast, patients who develop chronic GVHD after an interval of response to treatment for acute GVHD (quiescent form) or patients who have never had acute GVHD (de novo form) are more likely to respond to therapy. In these latter situations, institution of tacrolimus or cyclosporine in combination with glucocorticoids is often effective.^90,104,105 Some patients failing on cyclosporine may achieve complete and durable remission with tacrolimus.¹⁰⁶

In patients with extensive chronic GVHD and a platelet count 100 ´ 10⁹/l, the addition of azathioprine to prednisone actually resulted in poorer survival than those treated with prednisone alone (5 year survivals of 47% and 61%, respectively).⁹⁰ Patients with extensive chronic GVHD who had platelet counts 100 000/l, most of whom had the 'progressive' form, had the poorest survival (5 year survival of 26%). A subsequent trial using alternate day cyclosporine and prednisone has shown improvement in this subset of patient with extensive chronic GVHD with thrombocytopenia.¹⁰⁵ Clinical trials using immunomodulatory approaches in the treatment of chronic GVHD are summarized in Table 2.

Despite the widely employed combination of steroids and cyclosporine or tacrolimus, the outcome of treatment in patients with extensive chronic GVHD remains unsatisfactory. Oral lichen planus often responds to immunosuppressive therapy. Involvement of limited scleroderma of the distal extremities is also more likely to respond to immunosuppressive therapy, but generalized scleroderma carries a poor prognosis.⁴⁰ Patients with bronchiolitis obliterans have an extremely poor prognosis independent of other clinical manifestations of chronic GVHD.^77,78,107 They respond poorly to corticosteroids and other immunosuppressive therapy and progress over months to years to become oxygen dependent, culminating in respiratory failure.

Other agents that have been studied in the past decade are etritrenate,¹⁰⁸ thalidomide,^89,109,110 hydroxychloroquine,¹¹¹ extracorporeal photopheresis,^112,113 UVB,¹¹⁴ and PUVA.¹¹⁵ Cutaneous involvement most frequently responds while pulmonary disease rarely responds to any of these treatments. The difficulty of conducting clinical trials in patients with chronic GVHD has been illustrated in a recent randomized double-blind study comparing thalidomide to placebo.¹¹⁶ Contrary to earlier reports,^89,110 thalidomide was poorly tolerated, leading to early discontinuation of this agent in most patients. Furthermore, frequently reported side-effects in the placebo arm underscore the problem of interpretation of signs and symptoms not truly related to drug therapy but rather to chronic GVHD or other concurrent treatments. Heterogeneity of patient populations in these clinical trials also complicates the comparison of treatment outcomes across various series. The recent development of a prognostic model of chronic GVHD may help investigators improve future clinical trials in patients with extensive chronic GVHD.⁴⁰

The recent recognition of tumor necrosis factor (TNF) as an effector molecule in GVHD has drawn attention to the use of monoclonal antibodies and receptor antagonists for the treatment of GVHD.^75,117 Both a humanized chimeric antibody against TNF (infliximab) and a TNF antagonist (etanercept) have been studied in patients with chronic GVHD. Preliminary reports reveal high response rates even for lung involvement.^118,119 Further studies of TNF blockade to treat chronic GVHD are warranted.

The recognition of a possible pathogenetic link between autoantibodies and various autoimmune disorders has unveiled a new paradigm for the treatment of chronic GVHD.²⁰ A recent study designed to deplete B lymphocytes with an anti-CD20 monoclonal antibody has reported sustained improvement for patients with rheumatoid arthritis.¹²⁰ We had the opportunity to test this hypothesis by administering the anti-CD20 chimeric monoclonal antibody (rituximab) in a patient with severe chronic GVHD-associated thrombocytopenia.¹²¹ This patient had a dramatic response with complete recovery of her platelet count and concurrent improvement of other clinical signs of chronic GVHD, despite discontinuation of all other immunosuppressive agents. Improvement of myasthenia gravis associated with extensive chronic GVHD has also been reported.¹²² Further study of this innovative approach is underway.

In conclusion, chronic GVHD remains one of the most important challenges in allogeneic transplantation. Survival and quality of life in long-term survivors of allogeneic stem cell recipients depend on new innovative approaches to treat this chronic debilitating condition. Modulation of cytokines, depletion of autoantibody-producing B cells with monoclonal antibody, and other immunomodulatory agents are being investigated for their role in the treatment of chronic GVHD. Other supportive care measures such as antimicrobial prophylaxis, symptomatic control of sicca syndrome, skin care, psychological support, and physical rehabilitation are equally important in minimizing catastrophic infectious complications and improving the quality of life.

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67 Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-obstruction. New Engl J Med 1999; 341: 137-141, MEDLINE

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77 Epler GR. Bronchiolitis obliterans and airways obstruction associated with graft-versus-host disease. Clin Chest Med 1988; 9: 551-556, MEDLINE

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88 Smith CI, Aarli JA, Biberfeld P et al. Myasthenia gravis after bone-marrow transplantation. Evidence for a donor origin. New Engl J Med 1983; 309: 1565-1568, MEDLINE

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90 Sullivan KM, Witherspoon RP, Storb R 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; 72: 546-554, MEDLINE

91 Atkinson K, Farewell V, Storb R et al. Analysis of late infections after human bone marrow transplantation: role of genotypic nonidentity between marrow donor and recipient and of nonspecific suppressor cells in patients with chronic graft-versus-host disease. Blood 1982; 60: 714-720, MEDLINE

92 Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol 1983; 12: 791-811, MEDLINE

93 Meyers JD. Infection in bone marrow transplant recipients. Am J Med 1986; 81: 27-38, MEDLINE

94 Lum LG. The kinetics of immune reconstitution after human marrow transplantation. Blood 1987; 69: 369-380, MEDLINE

95 Sullivan KM, Meyers JD, Flournoy N et al. Early and late interstitial pneumonia following human bone marrow transplantation. Int J Cell Cloning 1986; 4: (Suppl. 1) 107-121, MEDLINE

96 Kulkarni S, Powles R, Treleaven J et al. Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood 2000; 95: 3683-3686, MEDLINE

97 Einsele H, Hebart H, Kauffmann-Schneider C et al. Risk factors for treatment failures in patients receiving PCR-based preemptive therapy for CMV infection. Bone Marrow Transplant 2000; 25: 757-763, MEDLINE

98 Anonymous. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2000; 6: 7-75,

99 Chao NJ, Parker PM, Niland JC et al. Paradoxical effect of thalidomide prophylaxis on chronic graft-vs.-host disease. Biol Blood Marrow Transplant 1996; 2: 86-92, MEDLINE

100 Papadopoulos EB, Carabasi MH, Castro-Malaspina H et al. T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease. Blood 1998; 91: 1083-1090, MEDLINE

101 Hale G, Zhang MJ, Bunjes D et al. Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood 1998; 92: 4581-4590, MEDLINE

102 Hale G, Jacobs P, Wood L et al. CD52 antibodies for prevention of graft-versus-host disease and graft rejection following transplantation of allogeneic peripheral blood stem cells. Bone Marrow Transplantation 2000; 26: 69-76, MEDLINE

103 Marmont AM, Horowitz MM, Gale RP et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120-2130, MEDLINE

104 Sullivan KM, Shulman HM, Storb R et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57: 267-276, MEDLINE

105 Sullivan KM, Witherspoon RP, Storb R et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood 1988; 72: 555-561, MEDLINE

106 Carnevale-Schianca F, Martin P, Sullivan K et al. Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000; 6: 613-620, MEDLINE

107 Rosenberg ME, Vercellotti GM, Snover DC et al. Bronchiolitis obliterans after bone marrow transplantation. Am J Hematol 1985; 18: 325-328, MEDLINE

108 Marcellus DC, Altomonte VL, Farmer ER et al. Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease. Blood 1999; 93: 66-70, MEDLINE

109 Rovelli A, Arrigo C, Nesi F et al. The role of thalidomide in the treatment of refractory chronic graft-versus-host disease following bone marrow transplantation in children. Bone Marrow Transplant 1998; 21: 577-581, MEDLINE

110 Vogelsang GB, Farmer ER, Hess AD et al. Thalidomide for the treatment of chronic graft-versus-host disease. New Engl J Med 1992; 326: 1055-1058, MEDLINE

111 Gilman AL, Chan KW, Mogul A et al. Hydroxychloroquine for the treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2000; 6: 327-334, MEDLINE

112 Greinix HT, Volc-Platzer B, Rabitsch W et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 1998; 92: 3098-3104, MEDLINE

113 Child FJ, Ratnavel R, Watkins P et al. Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 1999; 23: 881-887, MEDLINE

114 Enk CD, Elad S, Vexler A et al. Chronic graft-versus-host disease treated with UVB phototherapy. Bone Marrow Transplant 1998; 22: 1179-1183, MEDLINE

115 Vogelsang GB, Wolff D, Altomonte V et al. Treatment of chronic graft-versus-host disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant 1996; 17: 1061-1067, MEDLINE

116 Koc S, Leisenring W, Flowers ME et al. Thalidomide for treatment of patients with chronic graft-versus-host disease. Blood 2000; 96: 3995-3996, MEDLINE

117 Krijanovski OI, Hill GR, Cooke KR et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999; 94: 825-831, MEDLINE

118 Couriel DR, Hicks K, Ippoliti C et al. Infliximab for the treatment of graft-versus-host disease in allogeneic transplant recipients: an update. Blood 2001; 96: 400a Abstr. 1724,

119 Chiang KY, Marshall C, Abhyankar S et al. Recombinant human soluble tumor necrosis factor receptor fusion protein (Enbrel) as a treatment for chronic graft-versus-host disease (CGvHD) following allogeneic bone marrow transplantation. Blood 2001; 96: 401a,

120 Edwards JCW, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatol 2001; 40: 205-211,

121 Ratanatharathorn V, Carson E, Reynolds C et al. Anti-CD20 chimeric monoclonal antibody treatment of refractory immune-mediated thrombocytopenia in a patient with chronic graft-versus-host disease. Ann Int Med 2000; 133: 275-279,

122 Zaja F, Russo D, Fuga G, et al. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology 2000; 55: 1062-1063, MEDLINE

123 Browne PV, Weisdorf DJ, DeFor T et al. Response to thalidomide therapy in refractory chronic graft-versus-host disease. Bone Marrow Transplant 2000; 26: 865-869, MEDLINE

124 Gaziev D, Lucarelli G, Polchi P et al. A three or more drug combination as effective therapy for moderate or severe chronic graft-versus-host disease. Bone Marrow Transplant 2001; 27: 45-51, MEDLINE

125 Lee SJ, Wegner SA, McGarigle CJ et al. Treatment of chronic graft-versus-host disease with clofazimine. Blood 1997; 89: 2298-2302, MEDLINE

126 Mookerjee B, Altomonte V, Vogelsang G. Salvage therapy for refractory chronic graft-versus-host disease with mycophenolate mofetil and tacrolimus. Bone Marrow Transplant 1999; 24: 517-520, MEDLINE

Table 1 Classification of chronic GVHD⁷

Table 2 Agents used in the treatment of chronic GVHD