L. Geskin, MD
Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA
Extracorporeal photopheresis (ECP) and psoralen plus ultraviolet A therapy (PUVA) are widely accepted types of photochemotherapy used for the treatment of cutaneous T-cell lymphomas (CTCL). PUVA and ECP utilize a photosensitizing agent, that can be taken orally (PUVA) or added to the concentrated sample of white blood cells extracorporeally (ECP) prior to UVA exposure. Both therapies have been shown to be safe and effective for the treatment of CTCL. As a monotherapy, PUVA is preferentially used for treatment of patients at earlier stages with skin involvement alone (T1 and T2). ECP is usually used for patients with erythrodermic skin involvement (T4) in advanced stages (Stage III and IVA) with peripheral blood involvement as in Sézary syndrome (SzS). Use of ECP in earlier stages is controversial and is currently under investigation. Both PUVA and ECP are rarely used as monotherapy, though long-term remissions after PUVA monotherapy for early disease have been reported. CTCL is a rare disease and randomized prospective clinical trials are difficult. The best efficacy data derived from prospective case studies and meta-analysis are reviewed here.
ECP, PUVA, Extracorporeal Photopheresis, CTCL, Cutaneous T-cell Lymphoma, Psorlen + UVA Therapy
Cutaneous T-cell lymphomas (CTCL) are a group of skin homing non-Hodgkin’s lymphomas of T-cell origin. Mycosis fungoides (MF) and Sézary syndrome (SzS) are two of the most common variants. Survival of patients with MF is highly variable depending on the stage of the disease. Whereas life expectancy in the earliest stage (IA) is the same as age-matched controls, it is significantly reduced in advanced disease (1.5 years for Stage IV patients).1 Because of the rarity of MF/SzS, no prospective, placebo-controlled, randomized clinical trials have been performed to evaluate the impact of treatment on survival, and comparisons have usually been made with “historic controls”. Considering the good prognosis in earlier stages, and an assumption that “there is no cure”, choices of therapy are largely directed towards induction of long-term remissions and palliation in early, as well as in later, stages of the disease. Quality of life is of utmost importance when considering treatment options for CTCL. The choices of therapy in early stages are usually reflective of good prognosis with a low risk/benefit ratio. In general, skin directed therapies are used for early stage disease, and systemic therapies are reserved for advanced stages.
The mechanism of action for both skin-directed and extracorporeal photochemotherapies is thought to be related to the covalent photoadduction of methoxsalen molecules to pyrimidine bases in DNA, leading to impaired T-cell function or survival on the cellular level. PUVA has been shown to be highly effective in early CTCL (thin patches and plaques), with high levels of response rates and even complete clinical remissions (CCRs).2 However, PUVA’s effect on infiltrative thick lesions and tumors is controversial. Some studies assessing PUVA as monotherapy demonstrated residual malignant infiltrates in the deep dermis after complete epidermal and superficial dermal clearance,3 poor responses in erythrodermic patients,4 and the inability to clear in SzS patients.5 Another report showed significant and complete clearance of malignant infiltrates in over 40% of patients with tumors treated with PUVA as part of combination therapy with other agents.6 Long-term remissions in early disease patients have been reported,7 but, in general, maintenance therapy is required to sustain responses.
While PUVA has been clearly demonstrated to be effective in the treatment of CTCL, its efficiency is further improved and toxicity minimized by combining it with other therapies, such as retinoids and interferons (IFNs). Retinoids (acitretin and isotretinoin) and rexinoid (bexarotene) are photosensitizing agents and may reduce the total cumulative UVA dose needed to induce and sustain remission (RePUVA therapy).8,9 In addition, bexarotene is an effective agent in the treatment of early and advanced disease with overall response rates of more than 50% in therapeutic doses.10 Maintenance therapy with retinoids/rexinoids may prolong remissions. IFNs have been shown to be highly effective in the treatment of CTCL with response rates of up to 80% at higher doses, even in advanced disease.11 IFNs may potentiate effects of PUVA and result in remission in previously refractive patients.12 In addition, the use of both retinoids/rexinoids and IFNs is not immunosuppressive and does not result in increased cutaneous malignancies. Studies evaluating secondary cutaneous malignancies in CTCL patients after PUVA therapy are lacking; however, inferring from studies conducted with other patients treated with long-term PUVA or patients on long-term immunosuppressive therapies, the use of retinoids may be protective in CTCL patients from a skin carcinogenesis standpoint.13
Safety and Side-Effects
PUVA is a well established first-line therapy for selected patients with CTCL. However, it has several disadvantages and side-effects when compared with other skin directed therapies. The short-term side-effects of therapy are mostly associated with oral psoralen intake and include nausea, vomiting, inconsistent GI absorption, and consecutive variability in dosing. This in turn results in variable dosing of UVA that increases the potential for burning. Additionally, patients receiving PUVA treatment require periodic monitoring of hepatic function because PUVA is metabolized by the liver. This can become a serious problem, especially if patients are on other hepatotoxic drugs, such as retinoids and lipid lowering agents, among many others. As poly-pharmacy is common among elderly patients, additional oral medication may be perceived as a disadvantage in this context. In younger patients, the inconvenience of frequent (though brief) office visits may preclude some from using this modality.
A significant issue for PUVA is extended photosensitivity.
Patients are advised to wear protective eyewear, avoid sunlight, apply sunscreens, and have regular full body dermatological assessments for skin cancer surveillance. Photosensitivity may be further increased by commonly used medications, such as antibiotics and diuretics; this underscores the need for thorough history taking before initiating PUVA therapy to ensure its safe administration and to avoid PUVA burns.
Skin cancers are significant long-term side-effects of PUVA therapy. Indirect evidence from psoriasis studies shows substantially increased risk for nonmelanoma skin cancers, most significantly dose dependent squamous cell carcinoma (SCC) and (potentially) melanoma.1 The risk of skin cancers has not been systematically studied in CTCL patients, but may be higher than in psoriasis patients due to immunosuppression associated with the disease, which approaches 30%.13 Some patients who develop leukoderma on long-term PUVA therapy have a very high rate of SCCs and require frequent monitoring (see Figure 1).
Elderly African-American man with more than a 20-year history of PUVA therapy for MF, who developed leukoderma (left), and numerous SCCs on his arm (right)
Due to valid concerns with the safety and side-effects of PUVA, as well as with its limitation in the treatment of predominantly early disease, an attempt was made to improve its safety profile while extending its efficacy. It was hypothesized that if patients’ leukopheresed blood were exposed extracorporeally to UVA in the presence of a photosensitizing agent (8-MOP), the benefits of the therapy might be extended to a more advanced patient population with a circulating malignant clone in their peripheral blood.
At the same time, the side-effects associated with skin UV irradiation would be eliminated. In 1987, a new medical device (UVAR® Instrument, Therakos) was approved by the US FDA for the treatment of CTCL.14
This is a leukopheresis-based procedure in which the patient’s whole blood is processed extracorporeally: the white blood cells (WBC) are separated from the red blood cells (RBC) by centrifugation, exposed to UVA light, and then returned to the patient (hence the name “extracorporeal photopheresis” or ECP). Initially, induction of photosensitivity of WBCs was achieved by oral administration of 8-MOP prior to therapy. However, the oral route of administration is associated with the same side-effects discussed above for PUVA (i.e., nausea, vomiting, diarrhea, inconsistent blood levels of 8-MOP and photosensitivity). To avoid these, the procedure was further modified to use liquid psoralen (methoxsalen) at a concentration of 340ng/mL (Uvadex®, Therakos) added directly into the treatment bag after collection of the buffy coat by leukopheresis. Similar to the initial procedure, the WBCs are then exposed to ultraviolet A light in a photoactivation chamber. This is a clear plastic plate with a 1mm thin zigzagging pathway that allows for greater surface area of the WBC exposure to the UVA during their recirculation through the plate. The UVA lamps on both sides of the plate achieve cell exposure energy up to 2J/cm2 of UVA, which is enough energy to induce apoptosis of all cells in the chamber.15
The RBCs and plasma are returned to the patient after each collection cycle and WBCs are returned to the patient at the end of the overall treatment. Each treatment lasts about 3 hours, depending on the technical aspects of the procedure. Usually, the therapy is administered for 2 days in a row, once per month, though other (accelerated) regimens have been used under certain circumstances. For patients sustaining clinical remission, the treatment interval may be slowly increased to two treatments every 6-8 weeks. If no evidence of active disease is present, the treatment may be discontinued with established close clinical follow-up.
Treatment of MF and SzS with ECP was thoroughly analyzed through a meta-analysis of 19 studies reporting the use of ECP as a monotherapy (5 studies), or as part of combination therapy (14 studies) in more than 400 patients.16 The authors report that the combined overall response rate (OR) for all stages of CTCL was 55.7% (244 out of 438), with 17.6% (77 out of 438) achieving a complete response (CR). Analysis of data where ECP was used as a monotherapy revealed similar results with 55.5% OR and 14.8% CR.16 Similarly, for erythrodermic disease (T4) the OR was 57.6% and CR was 15.3%. Notably, combined analysis of responses to ECP by SzS patients revealed an OR of 42.9% and CR of 9.5% (see Table 1).
Use of ECP in early stages of CTCL is controversial. There are some reports of significant efficacy of ECP in stage IB patients with wide-spread skin disease, where response rates of 64% OR and 28% CR were cited.16 Recently, a clinical trial was initiated to definitively address the use of ECP in early MF with minimal blood involvement.
The mechanism of action of ECP is not known. However, because only a small fraction of lymphocytes (up to 5%) is undergoing the process, the effects are thought to be better explained by induced immune responses resulting from the procedure. Several different mechanisms have been proposed to play a role, including dendritic cell activation, and loading by apoptotic lymphocytes as a result of UVA induced apoptosis.17 The usual time to response may approach 6 months and an appropriate therapeutic trial is necessary before the therapy may be considered ineffective.
Safety and Side-Effects
The current ECP procedure using direct administration of psoralen into the photopheresis bag, bypassing oral administration, has significantly improved its safety profile. This technique can be safely administered in broad age groups from children (over 40kg) to the extremely elderly. The procedure has been performed safely by highly trained photopheresis personnel in children under 40kg. However, technical treatment modifications are required. The procedure is contraindicated in patients with serious comorbid conditions where fluid shifts may not be well tolerated, including severe heart, liver or kidney failure.
Anemia with low hematocrit or conditions that may change the color or density of blood (such as extreme hypertriglyceridemia) may interfere with the proper collection of the WBC due to incorrect triggering of the light sensor separating these fractions during centrifugation of the blood. This is especially important for patients on concurrent retinoids or rexinoid (bexarotene).
Venous access may be a rate limiting step for some patients, because peripheral access is the preferred way of therapy delivery. Central catheters have been used in patients whose access was problematic, but this route should be carefully considered due to a high risk of sepsis from indwelling catheters and an even higher risk of infection in erythrodermic patients. Ports may also be used for treatment delivery, with variable success, and may be safer in these patients.
Side-effects of the procedure include pain associated with needle insertion; inconvenience of the procedure itself; hypotension (rare); anemia due to incomplete return of the RBC after the procedure; low grade fevers (very rare); and temporary increase in erythroderma.
Therapy for MF and SzS is based on the clinical stage of the patients. In early or localized patch stage MF (Stage IA-IIA), PUVA treatment alone or in combination with other skin-directed therapies may result in long-term clinical remission. In order to achieve and maintain clinical remission and to improve quality of life, systemic therapy may be necessary in more advanced disease. Combination therapies, including IFN plus PUVA, and bexarotene with PUVA may be more effective than PUVA alone for treatment of the recalcitrant disease.
ECP is a first-choice treatment of erythrodermic CTCL.18 Similarly, the combination of ECP with other treatment modalities, including low-dose bexarotene, interferon, and total and localized skin electron beam have been shown to be superior to monotherapy. Though the mechanism of action of ECP is not completely understood, immunological factors are thought to play a role. As such, some argue that immunosuppressive agents (such as prednisone and chemotherapeutic agents) should be avoided during therapy. Investigations into the mechanism of action of ECP and potential combination therapies are ongoing.