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1 (2005) 35, & 2005 Nature Publishing Group All rights reserved /05 $ Graft-versus-host disease Medium dose long-wavelength ultraviolet A () phototherapy for the treatment of acute and chronic graft-versus-host disease of the skin T Wetzig 1, M Sticherling 1, J-C Simon 1, U Hegenbart 2, D Niederwieser 2 and HKAl-Ali 2 1 Department of Dermatology, University of Leipzig, Germany; and 2 Division of Hematology/Oncology, University of Leipzig, Germany Summary: Long-wavelength ultraviolet A ( nm ) phototherapy has been reported to be effective in atopic dermatitis, localized scleroderma and other T-cell-derived skin diseases. as an adjunct to systemic immunosuppressive treatment was found to be safe, and effective in 10 patients with chronic cutaneous (seven lichenoid and three sclerodermoid) graft-versus-host disease (GVHD) after stem cell transplantation. Complete and partial responses were achieved in six (60%), and in three (30%) patients, respectively. One patient had improvement of sclerotic skin lesions. At a median follow-up of 14 months, two patients with lichenoid lesions relapsed. Both responded to another treatment cycle. Furthermore, we treated seven patients with as primary therapy for acute cutaneous GVHD grades II and III in a pilot experience. Five patients had a complete response with no relapse at a median follow-up of 9 months after. Two patients showed no response and systemic steroids had to be started. therapy is feasible, well tolerated and can be effective in treating chronic as well as acute GVHD confined to the skin thereby avoiding systemic steroids. Our results should be confirmed in larger studies and the effectiveness of compared to other established treatment modalities. (2005) 35, doi: /sj.bmt Published online 24 January 2005 Keywords: ; graft-versus-host disease; phototherapy; stem cell transplantation Graft-versus-host disease (GVHD), acute and/or chronic, is still a major problem after allogeneic stem cell transplantation (SCT). GVHD occurs in 30 60% of patients after SCT from an HLA-identical related donor (MRD) and in 50 80% of patients receiving SCT from HLA-matched unrelated donors (MUD). 1 4 Cutaneous involvement is the Correspondence: Dr HKAl-Ali, Division of Hematology, University of Leipzig, Johannesallee 32a, Leipzig, Germany; alah@medizin.uni-leipzig.de Received 13 July 2004; accepted 22 October 2004 Published online 24 January 2005 most frequent manifestation of GVHD. Steroids are mostly used as initial therapy of GVHD. However, only 20 40% of patients show a durable response. 5 Long-wavelength ultraviolet A ( nm ) phototherapy has been reported to be successful in the treatment of atopic dermatitis, localized scleroderma and other T-cell-derived skin diseases. 6,7 Recently, the effectiveness of in a small number of patients with chronic cutaneous GVHD was reported We present our pilot experience in seven patients treated with as primary therapy for acute GVHD of the skin as well as the outcome of treatment in 10 patients with chronic GVHD treated at the University of Leipzig. Patients and methods Patients with chronic GVHD A total of 10 patients (nine male and one female) with chronic cutaneous GVHD were treated with at the University of Leipzig after obtaining informed consent. The characteristics of the patients are shown in Table 1. The median age was 49 years (range 23 61). Stem cell donors were matched related donor (MRD) in five, and matched unrelated donor (MUD) in the other five patients. Seven patients were conditioned with total body irradiation (TBI) 4 Gy in divided doses daily for 3 days (total dose 12 Gy)/cyclophosphamide (Cy) 60 mg/kg once daily i.v. on days 1 and 2 (total dose 120 mg/kg). Rabbit antithymocyte globulin (ATG) 15 mg/kg/day for 3 consecutive days was included in the regimen in two patients transplanted from MUD. In the remaining three patients conditioning consisted of fludarabine 30 mg/m 2 once daily for 3 days (total dose 90 mg/m 2 ) followed by TBI 2 Gy applied once. GVHD prophylaxis consisted of either cyclosporine (CSA)/ methotrexate (MTX) (n ¼ 7) or CSA/mycophenolate mofetil (MMF) (n ¼ 3). All patients developed chronic GVHD of the skin at a median of 200 days (range ) after SCT. Skin lesions were lichenoid in seven and sclerodermoid in three patients. Skin biopsies to verify the diagnosis of GVHD were performed in all patients. No other organ involvement was present. All patients were treated with CSA (trough levels in whole blood were kept around 200 ng/ml). In six patients, methylprednisolone 2 mg/kg/ day was additionally needed. The various therapies for

2 516 Table 1 phototherapy for GVHD of the skin Clinical characteristics and treatments of patients with chronic GVHD prior to Pt. no. Sex Disease Type of GVHD Affected body surface area (%)Treatment of GVHD Response to treatment 1 M CML Lichenoid 55 CSA/steroids a PR 2 M AA Sclerodermoid 90 CSA/MMF b /steroids a /ECP NR 3 F AML Lichenoid 60 CSA/PUVA NR 4 M MDS Lichenoid 50 CSA/steroids a PR 5 M CLL Lichenoid 70 CSA/steroids a PR 6 M AML Lichenoid 35 CSA NR 7 M AML Lichenoid 30 CSA NR 8 M AML Lichenoid 30 CSA NR 9 M ALL Sclerodermoid 85 CSA/steroids a /MMF b PR 10 M MM Sclerodermoid 55 CSA/steroids a /ECP PR M ¼ male; F ¼ female; CML ¼ chronic myeloid leukaemia; AA ¼ aplastic anaemia; AML ¼ acute myeloid leukaemia; MDS ¼ myelodysplastic syndrome; CLL¼ chronic lymphatic leukaemia; ALL ¼ acute lymphatic leukaemia; MM ¼ multiple myeloma; PR ¼ partial response; NR ¼ no response. a Methylprednisolone 2 mg/kg/day. b MMF 2 g/day. Table 2 Clinical characteristics of patients with acute GVHD prior to Pt. no. Sex Treatment for GVHD Disease Grading of GVHD Interval SCT-GVHD (d) 1 F CSA/MMF AML III 40 2 F CSA CML III 37 3 F CSA CML II 48 4 M CSA/MMF MM II 23 5 F CSA/MMF AML III 80 6 F CSA/MMF AML III 26 7 M CSA/MMF CML II 78 M ¼ indicates male; F ¼ female; AML ¼ acute myeloid leukaemia; CML ¼ chronic myeloid leukaemia; MM ¼ multiple myeloma. GVHD and responses prior to therapy are presented in Table 1. Patients with acute GVHD Seven patients (five female and one male) at a median age of 44 years (range 22 65) were transplanted from MUD (n ¼ 6) and MRD (n ¼ 1) after conditioning with TBI 12 Gy/Cy/ATG (n ¼ 2) or TBI 2 Gy/fludarabine (n ¼ 5). GVHD prophylaxis consisted of CSA/MTX (n ¼ 2) or CSA/MMF (n ¼ 5). All developed histologically proven grade II (n ¼ 3) or grade III (n ¼ 4) acute GVHD of the skin after SCT. No other organ involvement was present. Grading of GVHD was according to the classic Glucksberg Seattle criteria. 11,12 All patients were treated with CSA (trough levels in whole blood were kept around 200 ng/ml). Five patients received MMF 2 g/day additionally (Table 2). phototherapy was initiated after obtaining informed consent. Phototherapy procedure For irradiation ( nm), a high dose-therapy system for whole-body treatment (Dermalight s /medisun s 24000, Dr KHo nle Medizintechnik GmbH, D Kaufering, Germany) was used. The starting test dose of was 30 J/cm 2. In the absence of adverse reaction, exposure was increased to 50 J/cm 2 at the second session. If tolerated, the maximum dose of 60 J/cm 2 was applied from the third session onward. Patients were initially treated 3 5 times per week. If patients showed response, the frequency of treatment was later tapered by one treatment session every week. After disappearance of cutaneous alterations, was given 1 2 times per week as maintenance therapy for further 4 weeks. Clinical response criteria A complete response (CR) was considered to be present if all skin lesions disappeared. Partial response (PR) was considered when a significant reduction of the intensity of cutaneous alterations (skin involvement less than 25%) was observed without new exacerbations. Results Patients with chronic GVHD Apart from reversible tanning in all patients and one case of mild erythema, was well tolerated without serious side effects. The median interval between SCT and therapy was 414 days (range ). The median number of therapies given was 30 (range 13 91) with a median total dose of 1330 J/cm 2 (range ). Six (60%) patients had a CR, three (30%) a PR and one patient showed improvement of sclerotic skin lesions and joint mobility. One patient with PR of lichenoid lesions relapsed on reduction of treatment frequency. Another patient with CR of lichenoid lesions relapsed 10 months after therapy. Both patients responded to another

3 Table 3 Results of therapy in patients with chronic GVHD of the skin phototherapy for GVHD of the skin 517 Pt. no. No. of treatments total dose (J/cm 2 ) Response to Remarks CR Off steroids. CSA being tapered Improvement Off steroids. MMF tapered to 1 g/day. CSA ongoing CR GVHD relapse after 10 months. CR after second treatment. CSA ongoing CR Off steroids. CSA being tapered PR GVHD relapse on reduction of. PR after second treatment. Off steroids. CSA ongoing CR CSA being tapered CR Off CSA CR Off CSA PR Off steroids. Off MMF. CSA ongoing PR Off steroids. CSA ongoing CR ¼ complete response; PR ¼ partial response. Table 4 Results of in patients with acute GVHD of the skin Pt. no. No. of treatments total dose (J/cm 2 ) Response to Remarks CR Alive. Off MMF. CSA being tapered CR Alive. Off CSA CR Alive. Off CSA NR Steroids a had to be added. Death (MOF) CR Alive. Off MMF. CSA being tapered NR Steroids a had to be added. Alive. CR. Now off steroids and MMF. CSA being tapered CR Alive. Off MMF. CSA being tapered CR ¼ complete response; PR ¼ partial response; NR ¼ no response; MOF ¼ multiorgan failure. a Methylprednisolone 2 mg/kg/day. treatment cycle of. All patients are alive after a median follow-up of 14 months (range 13 19). Steroids could be tapered and eventually withdrawn in six patients requiring steroids prior to treatment. The results of therapy and the systemic immunosuppressive treatments in patients with chronic cutaneous GVHD after treatment are shown in Table 3. Patients with acute GVHD Again, was well tolerated without serious side effects. Tanning which was reversible occurred in the responding patients. Five (71.4%) patients had a CR within 4 weeks. In responding patients, was applied for a median of 21 times (range 15 35). None of these patients relapsed over a median period of 9 months (range 5 15) after therapy. The median total dose of applied was 870 J/cm 2 (range ). The original immunosuppressive treatment with either CSA (n ¼ 2) or CSA and MMF (n ¼ 3) was continued in addition to therapy. No additional immunosuppressive treatment was needed. After treatment, MMF could be tapered and eventually withdrawn in all patients. The remaining two patients showed no response and systemic steroids had to be started after seven treatments. The results of therapy and the systemic immunosuppressive treatments in patients with acute GVHD of the skin after treatment are shown in Table 4. Figure 1 demonstrates the skin lesions in a patient with acute GVHD prior to therapy (patient number 3 in Table 4). Figure 2 shows the dramatic response to therapy in the same patient. Discussion At present, systemic steroids constitute the main therapy for GVHD, alone or in combination with other agents as ATG, CSA, tacrolimus (FK506), MMF or monoclonal antibodies. 5,13,14 As a major problem, systemic immunosuppressive treatment increases the risk of infectious diseases, especially in combined treatment modalities. For GVHD confined to the skin, several nonpharmacologic approaches have been tried. Photochemotherapy with 8-methoxypsoralen plus ultraviolet light (PUVA) can be an effective therapy for cutaneous chronic GVHD So far, published results of PUVA treatment for acute GVHD are very limited PUVA as first-line therapy for acute GVHD was described only once. 20 At our institution, PUVA was applied as first-line treatment in 28 patients with acute cutaneous GVHD. Complete and partial responses were achieved in 18 (64%) and three (11%) patients, respectively, without additional steroids. 21

4 518 phototherapy for GVHD of the skin Figure 1 therapy. Skin lesions in a patient with acute GVHD prior to Extracorporeal photochemotherapy (ECP), which often requires a central venous catheter implantation, has also been shown to be effective in steroid-refractory acute and chronic GVHD. 22,23 phototherapy has become recently a potent treatment modality for inflammatory skin diseases. 7 Studies in atopic dermatitis indicate that therapy is capable of downregulating in situ expression of interferon-g in lesional skin. phototherapy induces apoptosis of skin infiltrating T cells and thereby causes a gradual reduction of the inflammatory infiltrate. 24,25 In addition, in vitro experiments showed that radiation is a potent inducer of the immunosuppressive cytokine interleukin 10 in human keratinocytes. 26 Previous reports showed a dose-dependent upregulation of collagenase activity, which could be responsible for the clinical improvement seen in patients with scleroderma. 27 is usually well tolerated with very few side effects. Erythema, tanning, polymorphic light eruptions, itching and recrudescence of herpes simplex infection are the main acute adverse effects. 7 The effectiveness of in a few patients with chronic GVHD was reported. The patient described by Grundmann-Kollmann et al and the six patients described by Staender et al received therapy because of steroid-resistant sclerodermatous GVHD. All patients Figure 2 The same patient with acute GVHD after therapy. showed remarkable improvement. 8,9 In addition, has significant advantages over PUVA as nausea, vomiting, long-lasting skin photosensitivity and the need for eye protection are avoided. Furthermore, PUVA therapy often fails and is not well tolerated by the patients as it can cause local pain and blistering. Based on the satisfactory responses obtained with in our 10 patients with chronic GVHD, therapy was initiated as primary therapy for acute GVHD of the skin in seven patients to avoid the addition of systemic steroids. Again, was highly effective in this group of patients with five of seven patients achieving a dramatic CR without serious side effects. None of these patients relapsed now 9 months after therapy. Nevertheless, some points need to be addressed. First, Staender et al treated five patients with 50 J/cm 2 /, initially five times a week, with a reduction to three times weekly after 2 months. 9 The doses of used for our patients with acute GVHD were based on our experience in the treatment of chronic GVHD with medium dose (50 60 J/cm 2 /treatment). Optimal dosing and schedule of treatment remain to be determined. Second, our

5 results should be confirmed in larger studies and the effectiveness of compared to other established treatment modalities. Thirdly, the incidence of chronic GVHD in patients treated with for acute GVHD needs to be evaluated. Fourthly, skin carcinogenesis after therapy as a potential long-term adverse effect has to be discussed. Experiments in hairless mice clearly established radiation as a complete carcinogen. 28 A case report of cutaneous melanoma 18 months after and PUVA for urticaria pigmentosa has been described, but it is unclear whether or not the melanoma was caused by phototherapy. 29 In most patients with GVHD, therapy is usually applied in combination with systemic immunosuppressive treatment, which may increase the risk of developing cutaneous malignancies. The benefits and risks of such a combined treatment modality must therefore be carefully considered. We did not observe any cutaneous malignancies, but the follow-up period is too short and the number of patients treated too small for a final assessment. In conclusion, appears to be a promising therapeutic option for both acute and chronic cutaneous GVHD as an adjunct to other immunosuppressive therapies or even as first-line treatment. Consequently, systemic steroids can be avoided in a substantial proportion of patients. Larger studies are required to answer the still open questions. References 1 Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: Beatty PG, Hanson JA, Longton GM et al. Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies. Transplantation 1991; 51: Ringden O, Backman L, Lonnqvist B et al. A randomized trial comparing use of cyclosporin and methtrexate for prophylaxis of graft-versus-host disease in bone marrow transplant recipients with hematological malignancies. Bone Marrow Transplant 1986; 1: Sullivan K, Agura E, Anasetti C. Chronic graft versus host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: Vogelsang GB, Lee L, Bensen-Kennedy DM. Pathogenesis and treatment of graft-versus-host-disease after bone marrow transplant. Annu Rev Med 2003; 54: Simon JC, Pfleger D, Schopf E. Recent advances in phototherapy. Eur J Dermatol 2000; 10: Dawe RS. Ultraviolet A1 phototherapy. Topical review. Br J Dermatol 2003; 148: Grundmann-Kollmann M, Behrens S, Gruss C et al. Chronic sclerodermic graft-versus-host disease refractory to immunosuppressive treatment responds to phototherapy. JAm Acad Dermatol 2000; 42: Staender H, Schiller M, Schwarz T. therapy for sclerodermic graft-versus-host disease of the skin. J Am Acad Dermatol 2002; 46: Calzavara Pinton P, Porta F, Izzi T et al. Prospects for ultraviolet A1 phototherapy as a treatment for chronic phototherapy for GVHD of the skin cutaneous graft-versus-host disease. Haematologica 2003; 88: Glucksberg H, Storb R, Fever A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA matched sibling donors. Transplantation 1974; 18: Thomas ED, Storb R, Clift RA et al. Bone marrow transplantation. N Engl J Med 1975; 292: Doney KC, Weiden PL, Storb R et al. Treatment of graftversus-host disease in human allogeneic marrow graft recipients: a randomized trial comparing antithymocyte globulin and corticosteroids. Am J Hematol 1981; 11: Arai S, Vogelsang GB. Management of graft-versus-host disease. Blood Rev 2000; 14: Aubin F, Brion A, Deconinck E et al. Phototherapy in the treatment of cutaneous graft-versus-host disease. Our preliminary experience in resistant patients. Transplantation 1995; 59: Eppinger T, Ehninger G, Steinert M et al. 8-Methoxypsoralen and ultraviolet A therapy for cutaneous manifestations of graft-versus-host disease. Transplantation 1990; 50: Leiter U, Kaskel P, Kraehn G et al. Psoralen plus ultraviolet- A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease. Photodermatol Photoimmunol Photomed 2002; 18: Furlong T, Leisenring W, Storb R et al. Psoralen and ultraviolet A irradiation (PUVA) as therapy for steroidresistant cutaneous acute graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8: Wiesmann A, Weller A, Lischka G et al. Treatment of acute graft-versus-host disease with PUVA (psoralen and ultraviolet irradiation): results of a pilot study. Bone Marrow Transplant 1999; 23: Reinauer S, Lehmann P, Plewig G et al. Photochemotherapy (PUVA) of acute graft-versus-host disease. Hautarzt 1993; 44: Wetzig T, Al-Ali HK, Kirstner S et al. Primary PUVA phototherapy can be effective for acute graft-versus-host disease of the skin. Bone Marrow Transplant 2004; 33: 183 (Abstract). 22 Greinix HT, Volc-Platzer B, Kahls P et al. Extracorporeal photochemotherapy in the treatment of severe steroid-refractory acute graft-versus-host disease: a pilot study. Blood 2000; 96: 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: Morita A, Werfel T, Stege H et al. Evidence that singlet oxygen-induced human T helper cell apoptosis is the basic mechanism of ultraviolet-a radiation phototherapy. J Exp Med 1997; 186: Grewe M, Gyufko K, Schopf E et al. Lesional expression of interferon-a in atopic eczema. Lancet 1994; 343: Krutmann J. Ultraviolet A radiation-induced immunomodulation: molecular and photobiological mechanisms. Eur J Dermatol 1998; 8: Petersen MJ, Hansen C, Craig S. Ultraviolet A irradiation stimulates collagenase production in cultured human fibroblasts. J Invest Dermatol 1992; 99: van Kranen HJ, de Laat A, van de Ven J et al. Low incidence of p53 mutations in UVA (365-nm)-induced skin tumors in hairless mice. Cancer Res 1997; 57: Wallenfang K, Stadler R. Assoziation zwischen bzw. Bade-PUVA-Bestrahlung und Melanomentwicklung? Hautarzt 2001; 52: