Rituximab is a chimeric monoclonal antibody reactive with CD20, found on the cell surface of B cells. Rituximab has been proposed as a treatment for cGVHD because of the suggested role of B cells and B cell–activating factor (BAFF) in cGVHD pathophysiology, the common finding of autoantibodies in patients with cGVHD, and the similarity between cGVHD manifestations and autoimmune conditions such as Sjögren’s syndrome and systemic sclerosis [18, 19]. Prospective studies have reported overall response rates (ORR) of 63–88 % [11, 20–24]. A meta-analysis of six studies reported a pooled proportion ORR of 60 % for cutaneous cGVHD; the skin was the organ with the highest response rate to rituximab therapy [25]. Regimens can vary, but patients usually receive a minimum of four weekly rituximab infusions of 375 mg/m². Additional infusions at intervals of 1 to 3 months have also been given. Van Dorp et al. [22] studied the immunologic phenotype of 18 patients with steroid-refractory or steroid-dependent cGVHD who were treated with rituximab to evaluate predictors of response to therapy. The ORR of rituximab for skin cGVHD was greater than 75 % regardless of the type of cutaneous involvement. About three fourths of the patients were able to decrease or discontinue corticosteroids. No correlation was seen between BAFF levels and rituximab response, but an elevated B-cell number prior to treatment correlated with response to therapy with rituximab [22].

The most common adverse events (AEs) in rituximab cGVHD trials were infusion reactions and infections [21, 26]. In a phase II prospective trial, infections and recurrent malignancy accounted for most of the treatment failures [21].

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that was first reported as a treatment for GVHD in the 1980s. Since then, ECP has become a widely used therapeutic modality for cGVHD of the skin and other organs (Fig. 10.6) [27–29]. As with other interventions, published reports are primarily retrospective in nature. One multicenter, randomized controlled trial compared standard treatment plus ECP (weekly on two consecutive days) to standard treatment alone over 12 weeks, for treatment of cutaneous cGVHD. The primary endpoint, a lower total skin score (TSS), had a positive trend, but it did not reach statistical significance. However, there was a steroid-sparing effect in the group that received ECP. Patients in the ECP arm were more likely to achieve both a reduction in steroid dose greater than 50 % and a total daily dose of 10 mg or less. The difference in the reduction of the steroid dose became apparent after week 8, though improvement in the TSS was noted earlier [30]. A steroid-sparing benefit of ECP also has been demonstrated in other studies [31–33].

As with other salvage therapies for cGVHD, comparison of the published literature for ECP is limited because of the heterogeneity of the disease and organ-specific outcome measures, as well as the variability in the schedule of ECP administration. Nonetheless, the skin appears to be among the organs most responsive to this treatment modality. A meta-analysis of ECP for steroid-refractory cGVHD found that ECP has the greatest benefit in skin, oral, liver, and musculoskeletal disease, with pooled response rates of 74 %, 72 %, 68 %, and 64 % respectively. Response rates were lower for other organs [32]. Similarly, a systematic review of ECP for acute or chronic steroid-refractory or steroid-dependent GVHD found a pooled ORR of 71 % for cutaneous chronic GVHD, which was higher than for other target organs with cGVHD [31].

ECP is generally a safe therapeutic option for cGVHD. The most commonly reported AEs are nausea, headache, and fever. Serious infections, including line infection, are rare, and relapse of malignancy has not been reported [27, 33, 34]. Both the U.K. Photopheresis Expert Group [33] and the Ontario Stem Cell Transplant Steering Committee [35] have developed consensus statements that recommend ECP as second-line therapy for cGVHD. The U.K. consensus statement recommends delivery of ECP on two consecutive days every other week, tapering to every 4 weeks once a response is seen. At this time, there is no biologic marker of disease response, so clinical assessment is the standard outcome measure. The clinical response of cGVHD to ECP is slow; 4 months is the recommended timeframe for response assessment [33].

Treatment of skin disease with ultraviolet (UV) radiation is commonly used for dermatologic conditions. As with many cGVHD therapies, high-quality trial data on the use of phototherapy is rare. In addition, different types of disease (e.g., lichenoid vs sclerotic) would be expected to have different responses, given the therapeutic penetration of UV light. No prospective studies have been carried out to provide recommendations for the type, dose, or schedule of UV therapy. Psoralen plus ultraviolet A (PUVA) is the best-studied phototherapy in cGVHD. In a retrospective analysis of 40 patients with cGVHD, 77 % had a local response (cutaneous or oral), with 40 % experiencing a complete response [36]. However, all but one of the patients included had concomitant systemic therapy. UVA1, a subset of the UVA wavelength (340–400 nm), has been evaluated in three small studies [37–39]. Overall, 24 of 25 total patients in the three studies responded, including those with both lichenoid and sclerotic cGVHD. Calzavara Pinton et al. [37] reported that all patients with lichenoid cGVHD relapsed within a month and required maintenance phototherapy. Only two studies have evaluated UVB (280–320 nm) as a local therapy for cGVHD [40, 41]. Brazzelli et al. [41] administered narrow band UVB (311–312 nm) to 10 pediatric patients, 5 with cGVHD and 5 with overlap GVHD. Of the 10 patients, 8 had a complete response, which was sustained in 71 % of the responders at 2 years.

Phototherapy is generally well tolerated. Photosensitizing medications (e.g., voriconazole, trimethoprim-sulfamethoxazole, and furosemide) should be discontinued prior to initiating phototherapy. Erythema is a common short-term AE. Oral psoralens may induce nausea, vomiting, dizziness, and hepatotoxicity, which can limit tolerability. Bath PUVA avoids the systemic side effects of psoralens, but is time-intensive. Strict sun protection (including eye protection) is required on the day psoralens are taken. Long-term phototherapy may cause accelerated photoaging and increase the risk of skin cancer, particularly with PUVA. Patients treated with PUVA develop squamous cell carcinoma more often than basal cell carcinoma or melanoma [42].

Imatinib is a tyrosine kinase inhibitor (TKI) that targets the platelet-derived growth factor receptor (PDGFR) among other tyrosine kinases [43]. Stimulatory autoantibodies to the PDGFR were reported in patients with sclerotic cGVHD and in patients with systemic sclerosis, suggesting a potential pathway of skin fibrosis targetable by this drug [44, 45]. In addition, in vitro studies have demonstrated that treatment of fibroblasts with imatinib inhibited proliferation [46]. Clinical studies have reported an ORR in sclerotic GVHD ranging from 26 % to 63 % [47–52]. Comparisons between studies is challenging because of the heterogeneous disease manifestations and the range of end points used to determine efficacy. Even within studies, the benefit of this antifibrotic therapy was not consistent among patients with sclerotic GVHD.

Imatinib appears to be less well tolerated in the cGVHD setting than in chronic myeloid leukemia (CML) and other indications. AEs have been reported at doses as low as 100 mg in sclerotic GVHD patients, despite dosing of 400 to 800 mg in the CML setting [51]. Hematologic AEs include neutropenia, thrombocytopenia, leukopenia, and anemia. Nonhematologic AEs include fatigue, nausea, diarrhea, electrolyte abnormalities, fluid retention (peripheral and periorbital), and muscular cramps. Sclerotic cGVHD patients are particularly sensitive to discomfort from fluid retention and muscular cramps, as they often experience these symptoms as part of their primary disease.

Dasatinib, a second-generation TKI, has been evaluated as an alternative agent in patients with sclerotic cGVHD who are resistant or intolerant to imatinib. Three patients with sclerotic cGVHD who could not take imatinib were treated with dasatinib [53]. All three achieved a partial response and corticosteroids were decreased in all patients. In contrast to imatinib, the patients did not experience dose-limiting toxicities from dasatinib. There is overlap in the observed AEs between imatinib and dasatinib, but it appears that individual patients develop differing AEs to the two different drugs [54]. This limited experience in cGVHD suggests that dasatinib warrants further investigation as a better-tolerated treatment for some patients with sclerotic cGVHD.

Sirolimus and its derivative everolimus are macrolide antibiotics that act through inhibition of the mTOR pathway. They act as immunosuppressive drugs and may also act via inhibition of proliferation of fibroblasts and smooth muscle cells. Additionally, they have a role in reconstitution of regulatory T cells in cGVHD [55]. mTOR inhibitors have been suggested as alternatives to CNIs for treatment of cGVHD because of the protective effect on skin cancer development that has been demonstrated in recipients of solid-organ transplants [56]. Data regarding the efficacy of mTOR inhibitors specifically for cutaneous cGVHD are scarce. One prospective study reported a response rate of 65 % in skin cGVHD, and one retrospective study of sclerotic cGVHD reported an ORR of 76 % [57, 58]. Additionally, mTOR inhibitors have demonstrated a steroid-sparing benefit.

The combination of CNIs and mTOR inhibitors is associated with increased risk of transplant-associated microangiopathy and renal toxicity [57]. Other toxicities seen with mTOR inhibitors include hyperlipidemia, infection, and cytopenias. mTOR inhibitors are substrates for cytochrome p450 3 A4, indicating that potential drug interactions may occur in GVHD patients, who often take multiple medications. Potential impairment of wound healing should also be considered for patients with skin breakdown or ulceration [59].