Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for a range of hematological and nonhematological diseases. The main obstacle to more widespread application of this technique is the problem of recognition of receptor tissue by immunity inherited from the donor, causing graft versus host disease (GVHD). Apart from tumor progression, this complication is the most common cause of morbidity and mortality associated with HSCT. However, the antitumor efficacy and potency of the technique also depend on the graft versus tumor effect mediated by T-lymphocytes of the donor, eradicating tumor cells.1,2

GVHD is classified as acute or chronic and these forms have different pathophysiological mechanisms and clinical presentation.3,4 In both cases, mucocutaneous involvement is the most common. Chronic GVHD usually presents in the first 100 days after HSCT and can affect almost any organ, leading initially to an underlying allogeneic autoimmune inflammatory process that progressively accumulates residual fibrotic changes. The cutaneous manifestations can be very varied and affect skin, mucosa, and skin appendages. Cutaneous manifestations can be divided into 2 groups: sclerotic (lichen sclerosus et atrophicus, morphea, and fascitis) and nonsclerotic (lichen planus and poikiloderma).5

There is no standard treatment and each patient is considered individually according to concurrent disease, affected organs, and the specific protocols for each center.5 The first-line treatment is high-dose corticosteroids (CS) alone or in combination with other immunosuppressants.5 More recently, new drugs and interventions have been introduced such as anti-tumor necrosis factor agents, imatinib, rituximab, and extracorporeal photoapheresis.6 All these treatments have side effects and increase the risk of infections and secondary neoplasms.

Phototherapy can thus play an important role in the management of both acute and chronic cutaneous GVHD as it is a therapy that targets the skin and has few side effects.7 UV-A light (320-400nm) has usually been used in combination with oral psoralen (PUVA), UV-A1 (340-400nm), and UV-B, which can be either broadband (280-320nm) or narrowband (311-312nm).

The present article describes the experience at our center in the treatment of patients with chronic cutaneous GVHD, covering all the clinical forms of presentation and the different types of phototherapy used (PUVA and narrowband UV-B).

Assessment of Response

We defined complete response (CR) as resolution of cutaneous GVHD and partial response as decrease in the clinical stage or clinical or symptomatic improvement (as measured by overall patient assessment and a pruritus scale).

Likewise, we noted the dose of prednisone and the number of immunosuppressants before and after treatment to assess possible reductions in usage (Figure 1).

Figure 1.

Chronic cutaneous lichenoid GVHD before (A) and after (B) phototherapy.

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The present study is, to the best of our knowledge, the first Spanish series published on the use of phototherapy for the treatment of patients with cutaneous GVHD. The main findings are as follows: a) treatment with phototherapy in cutaneous GVHD is safe; b) all patients showed clinical improvement with treatment; and c) phototherapy enabled a reduction in the CS dose administered.

Phototherapy may be a good therapeutic option for patients with chronic cutaneous GVHD who require systemic treatment to control their skin manifestations. The treatment targets the skin, and has few side effects. It has the advantage that it can enable CS sparing and reduction of the use of other immunosuppressants. The mechanism of action of phototherapy in GVHD is as yet unknown, but it appears that phenomena such as apoptosis, antiproliferative effects, and immunomodulatory effects (antigen presentation, cell activation, and cytokine release) may participate.8–10 It is still unclear whether phototherapy may have an impact on oral mucosa and other internal organs given its capacity to produce systemic immunomoduation.11,12

No randomized clinical trials have been conducted to compare phototherapy with other treatments. The evidence is based on case series that included a limited number of patients. Three studies have been published with at least 5 patients with chronic cutaneous GVHD treated with UV-A1.13–15 This type of phototherapy is not currently used in Spain. In these 3 published studies, doses of 50-60J/cm2 were used 3-5 times a week, with CR rates of 50%, although recurrences were common after stopping treatment. Five studies with at least 5 patients have also been published with oral or topical PUVA, with CR rates of 40% with both routes of administration.16–20 The authors reported some type of response in 70% of the patients and that treatment was more effective in the lichenoid forms. There are also 2 studies with UV-B (narrowband and broadband) in series of at least 5 patients,21,22 who were treated for 2-5 days a week, with symptomatic improvement and clearance of the lesions.

Our data show that phototherapy leads to clinical improvement in a high percentage of patients (100% in our series), also enabling a significant CS dose reduction (25%).

Given the lack of phototherapy protocols for a specific disease, psoriasis protocols are usually used, choosing the starting dose according to the minimum phototoxic dose, the minimum erythemogenic dose, and the phototype.23 Our patients were treated according to the psoriasis protocol, but we quickly realized that these patients displayed generalized erythema at lower doses. We therefore started treatment at lower doses than those corresponding to the skin phototype and escalated the dose with greater care, increasing 0.5J/cm2 every 2-3 sessions and performing a close follow-up of the patients (once weekly). In the case of PUVA, we found it difficult to increase the dose above 4J/cm2, as erythema occurred in most of our patients at this dose.

Given the special characteristics of these patients, they need tailored treatments, and it is not possible, in our experience, to apply rigid and fixed protocols. We can, however, point out the differences between phototherapy in patients with GVHD and phototherapy in other diseases12: lower starting doses are used, with slower dose escalation, more sessions, and lower cumulative doses. Improvement begins to become apparent from the tenth session, and the maximum response usually occurs after between 15 and 30 sessions.12 In addition, burns usually occur more easily (more erythema at lower doses), probably because of the disease itself and because many of the phototoxic agents cannot be discontinued or switched because they are essential for controlling the disease. One possible approach for setting the initial dose is to phototest the patients prior to starting treatment. This would probably not, however, avoid burns, which usually present during treatment and not during the first session.

Several considerations need to be taken into account before starting treatment. The immunosuppressive agents should not be withdrawn before, during, or after phototherapy. These are long-term treatments and often require the patient to attend the hospital, so it is necessary to take into account the distance from home and the dates of appointments with other specialists. Patients have several underlying diseases and will likely be taking multiple medications and possibly phototoxic drugs as well. After HSCT, patients often take voriconazole, an antifungal agent known to be an important phototoxic agent and photocarcinogen in immunosuppressed patients.24,25 When choosing between PUVA and UV-B, it is important to assess whether the patient has liver failure (due to GVHD or associated with drugs, infection, or other causes), ocular involvement (GVHD or cataracts), low phototypes, or a history of melanoma or nonmelanoma skin cancer. Narrowband UV-B is more comfortable for the patient and easier to manage for the dermatologist, and has fewer side effects and a lower long-term carcinogenic effect. Therefore, whenever possible, for superficial lesions, this should be the preferred type of phototherapy. For deeper lesions, as mentioned earlier, it will be necessary to use PUVA given that it penetrates further into the dermis and so is more effective.

Patients with GVHD are immunosuppressed patients who in their own right have a higher risk of melanoma and nonmelanoma skin cancer.26 This risk may be augmented by phototherapy even though the cumulative doses are lower. In any case, skin cancer should be ruled out before starting treatment, and follow-up is necessary. For patients with low phototypes and a history of skin cancer who are receiving immunosuppressive and/or phototoxic treatment (assessment in the event of withdrawal), the risk and benefit of phototherapy should be assessed individually.7

The present study has certain limitations. First, a limited number of patients are included, even though our center is a reference center for HSCT with many patients requiring management for GVHD. Nevertheless, we have collected data on our extensive experience in the management of these specific types of patients. Second, the clinical characteristics of the patients are heterogenous, probably because the disease is also very varied in its clinical manifestations. Therefore individually tailored treatment regimens need to be considered. Third, the study lacks a control group and so we are unable to draw definitive conclusions about CS and immunosuppressant sparring with phototherapy. Finally, the assessment of clinical response to treatment of the sclerodermiform lesions is complex given the difficulty of differentiating between active and inactive lesions.

The results are, therefore, difficult to interpret and compare with other therapies although, currently, these are the only information available given the lack of clinical trials.

Phototherapy may be a good therapeutic option for patients with extensive (lichenoid) or limited but deep (sclerodermiform) chronic cutaneous GVHD. The technique would also be valid for patients who do not respond to topical treatment or in patients in whom increased immunosuppressant doses would be associated with an increased risk of infections or interfere with the graft-versus-tumor response. The main advantage is that it is a targeted, safe, and effective treatment that enables sparing of CS doses.

To choose the best type of phototherapy (PUVA or narrowband UV-B) in each patient, we should bear in mind the following variables: phototype; type, extension, and depth of the lesions; possible involvement of other organs; and concurrent medication. The regimen will be individually tailored, generally with starting doses, intervals, and maximum and cumulative doses that are lower than for other diseases.

The authors declare that they have no conflicts of interest.