JOURNAL TRANSCRIPT
Bone Marrow Transplantation (2005) 35, 515–519 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00
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Graft-versus-host disease Medium dose long-wavelength ultraviolet A (UVA1) phototherapy for the treatment of acute and chronic graft-versus-host disease of the skin T Wetzig1, M Sticherling1, J-C Simon1, U Hegenbart2, D Niederwieser2 and HK Al-Ali2 1 Department of Dermatology, University of Leipzig, Germany; and 2Division of Hematology/Oncology, University of Leipzig, Germany
Summary: Long-wavelength ultraviolet A (340–400 nm UVA1) phototherapy has been reported to be effective in atopic dermatitis, localized scleroderma and other T-cell-derived skin diseases. UVA1 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 UVA1 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 UVA1. Two patients showed no response and systemic steroids had to be started. UVA1 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 UVA1 compared to other established treatment modalities. Bone Marrow Transplantation (2005) 35, 515–519. doi:10.1038/sj.bmt.1704804 Published online 24 January 2005 Keywords: UVA1; 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 HK Al-Ali, Division of Hematology, University of Leipzig, Johannesallee 32a, 04103 Leipzig, Germany; E-mail:
[email protected] 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 (340–400 nm UVA1) 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 UVA1 in a small number of patients with chronic cutaneous GVHD was reported.8–10 We present our pilot experience in seven patients treated with UVA1 as primary therapy for acute GVHD of the skin as well as the outcome of UVA1 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 UVA1 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/m2 once daily for 3 days (total dose 90 mg/m2) 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 110–400) 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
UVA1 phototherapy for GVHD of the skin T Wetzig et al
516 Table 1
Clinical characteristics and treatments of patients with chronic GVHD prior to UVA1
Pt. no.
Sex
1 2 3 4 5 6 7 8 9 10
Disease
M M F M M M M M M M
CML AA AML MDS CLL AML AML AML ALL MM
Type of GVHD
Affected body surface area (%)
Lichenoid Sclerodermoid Lichenoid Lichenoid Lichenoid Lichenoid Lichenoid Lichenoid Sclerodermoid Sclerodermoid
Treatment of GVHD
Response to treatment
a
55 90 60 50 70 35 30 30 85 55
CSA/steroids CSA/MMFb/steroidsa/ECP CSA/PUVA CSA/steroidsa CSA/steroidsa CSA CSA CSA CSA/steroidsa/MMFb CSA/steroidsa/ECP
PR NR NR PR PR NR NR NR PR 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; CLL ¼ 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 UVA1
Pt. no. 1 2 3 4 5 6 7
Sex F F F M F F M
Treatment for GVHD
Disease
Grading of GVHD
Interval SCT-GVHD (d)
AML CML CML MM AML AML CML
III III II II III III II
40 37 48 23 80 26 78
CSA/MMF CSA CSA CSA/MMF CSA/MMF CSA/MMF CSA/MMF
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 UVA1 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). UVA1 phototherapy was initiated after obtaining informed consent.
Phototherapy procedure For UVA1 irradiation (340–400 nm), a high dose-therapy system for whole-body treatment (Dermalights/medisuns 24000, Dr K Ho¨nle Medizintechnik GmbH, D-86916 Kaufering, Germany) was used. The starting test dose of UVA1 was 30 J/cm2. In the absence of adverse reaction, exposure was increased to 50 J/cm2 at the second session. If tolerated, the maximum dose of 60 J/cm2 was applied from the third session onward. Patients were initially treated 3–5 Bone Marrow Transplantation
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, UVA1 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, UVA1 was well tolerated without serious side effects. The median interval between SCT and UVA1 therapy was 414 days (range 110–2434). The median number of UVA1 therapies given was 30 (range 13–91) with a median total dose of 1330 J/cm2 (range 590–3500). 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
UVA1 phototherapy for GVHD of the skin T Wetzig et al
517 Table 3
Results of UVA1 therapy in patients with chronic GVHD of the skin
Pt. no.
No. of UVA1 treatments
UVA1 total dose (J/cm2)
1 2 3 4 5
13 37 31 29 36
6 7 8 9 10
25 31 29 91 28
Response to UVA1
Remarks
590 1750 1310 850 1680
CR Improvement CR CR PR
1165 850 1350 3500 1600
CR CR CR PR PR
Off steroids. CSA being tapered Off steroids. MMF tapered to 1 g/day. CSA ongoing GVHD relapse after 10 months. CR after second UVA1 treatment. CSA ongoing Off steroids. CSA being tapered GVHD relapse on reduction of UVA1. PR after second UVA1 treatment. Off steroids. CSA ongoing CSA being tapered Off CSA Off CSA Off steroids. Off MMF. CSA ongoing Off steroids. CSA ongoing
CR ¼ complete response; PR ¼ partial response.
Table 4
Results of UVA1 in patients with acute GVHD of the skin
Pt. no.
No. of UVA1 treatments
UVA1 total dose (J/cm2)
Response to UVA1
21 23 19 7 35 7 15
940 765 870 240 2645 340 825
CR CR CR NR CR NR CR
1 2 3 4 5 6 7
Remarks
Alive. Off MMF. CSA being tapered Alive. Off CSA Alive. Off CSA Steroidsa had to be added. Death (MOF) Alive. Off MMF. CSA being tapered Steroidsa had to be added. Alive. CR. Now off steroids and MMF. CSA being tapered 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 UVA1. 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 UVA1 treatment. The results of UVA1 therapy and the systemic immunosuppressive treatments in patients with chronic cutaneous GVHD after UVA1 treatment are shown in Table 3.
with acute GVHD of the skin after UVA1 treatment are shown in Table 4. Figure 1 demonstrates the skin lesions in a patient with acute GVHD prior to UVA1 therapy (patient number 3 in Table 4). Figure 2 shows the dramatic response to UVA1 therapy in the same patient.
Discussion Patients with acute GVHD Again, UVA1 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, UVA1 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 UVA1 applied was 870 J/cm2 (range 765–940). The original immunosuppressive treatment with either CSA (n ¼ 2) or CSA and MMF (n ¼ 3) was continued in addition to UVA1 therapy. No additional immunosuppressive treatment was needed. After UVA1 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 UVA1 treatments. The results of UVA1 therapy and the systemic immunosuppressive treatments in patients
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.15–17 So far, published results of PUVA treatment for acute GVHD are very limited.18–20 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 Bone Marrow Transplantation
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Figure 1
Skin lesions in a patient with acute GVHD prior to UVA1
therapy.
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 UVA1 phototherapy has become recently a potent treatment modality for inflammatory skin diseases.7 Studies in atopic dermatitis indicate that UVA1 therapy is capable of downregulating in situ expression of interferon-g in lesional skin. UVA1 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 UVA1 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 UVA1 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 UVA1 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 UVA1 therapy because of steroid-resistant sclerodermatous GVHD. All patients Bone Marrow Transplantation
Figure 2 The same patient with acute GVHD after UVA1 therapy.
showed remarkable improvement.8,9 In addition, UVA1 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 UVA1 in our 10 patients with chronic GVHD, UVA1 therapy was initiated as primary therapy for acute GVHD of the skin in seven patients to avoid the addition of systemic steroids. Again, UVA1 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/cm2/UVA1, initially five times a week, with a reduction to three times weekly after 2 months.9 The doses of UVA1 used for our patients with acute GVHD were based on our experience in the treatment of chronic GVHD with medium dose UVA1 (50–60 J/cm2/treatment). Optimal dosing and schedule of UVA1 treatment remain to be determined. Second, our
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results should be confirmed in larger studies and the effectiveness of UVA1 compared to other established treatment modalities. Thirdly, the incidence of chronic GVHD in patients treated with UVA1 for acute GVHD needs to be evaluated. Fourthly, skin carcinogenesis after UVA1 therapy as a potential long-term adverse effect has to be discussed. Experiments in hairless mice clearly established UVA1 radiation as a complete carcinogen.28 A case report of cutaneous melanoma 18 months after UVA1 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, UVA1 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, UVA1 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.
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