Extracorporeal Photopheresis 

Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory therapy that has been approved by the US Food and Drug Administration for the treatment of cutaneous T-cell lymphoma (CTCL) (see the images below) since 1988. Extracorporeal photopheresis, also known as extracorporeal photochemotherapy, is performed at more than 150 centers worldwide for multiple indications.^[1] Long-term follow-up data are available from many investigators that indicate extracorporeal photopheresis produces disease remission and improved survival for CTCL patients.

In addition to CTCL, extracorporeal photopheresis has been shown to have efficacy in the treatment of other T-cell mediated disorders, including chronic graft versus host disease (GVHD) and solid organ transplant rejection.^{[2, 3]} Extracorporeal photopheresis use for the treatment of autoimmune disease, such as systemic sclerosis^[4] and rheumatoid arthritis, is also being explored.

Extracorporeal photopheresis (ECP)is performed using the UVAR XTS Photopheresis System developed by Therakos, Inc (Exton, Pa). The process is performed through one intravenous access port and has 3 basic stages: (1) leukapheresis, (2) photoactivation, and (3) reinfusion. The process takes 3-4 hours to complete.

• One 16-gauge peripheral intravenous line or central venous access is established in the patient.
• Blood (225 mL) is passed through 3 cycles of leukapheresis, or 125 mL of blood is passed through 6 cycles, depending on the patient's hematocrit value and body size. At the end of each leukapheresis cycle, the red blood cells and plasma are returned to the patient.
• The collected WBCs (including approximately 5% of the peripheral blood mononuclear cells) are mixed with heparin, saline, and 8-methoxypsoralen (8-MOP), which intercalates into the DNA of the lymphocytes upon exposure to UVA light and makes them more susceptible to apoptosis when exposed to UVA radiation.
• The mixture is passed as a 1-mm film through a sterile cassette surrounded by UVA bulbs for 180 minutes, resulting in an average UVA exposure of 2 J/cm² per lymphocyte.
• The treated WBC mixture is returned to the patient.

Over the past 20 years, on-going research has explored the mechanism of action of extracorporeal photopheresis (ECP). The combination of 8-MOP and UVA radiation causes apoptosis of the treated T cells and may cause preferential apoptosis of activated or abnormal T cells, thus targeting the pathogenic cells of cutaneous T-cell lymphoma (CTCL) or graft versus host disease (GVHD). However, given that only a small percentage of the body's lymphocytes are treated, this seems unlikely to be the only mechanism of action.

Other evidence suggests that extracorporeal photopheresis also induces monocytes to differentiate into dendritic cells capable of phagocytosing and processing the apoptotic T-cell antigens. When these activated dendritic cells are reinfused into the systemic circulation, they may cause a systemic cytotoxic CD8⁺ T-lymphocyte–mediated immune response to the processed apoptotic T-cell antigens.

Finally, evidence from animal models also indicates that photopheresis may induce antigen-specific regulatory T cells, which may lead to suppression of allograft rejection or GVHD.

Extracorporeal photopheresis (ECP) is a very well-tolerated procedure. Transient hypotension may occur in some patients during the collection phase of the treatment, but this is asymptomatic in most and usually resolves with reinfusion of the blood products. Occasionally, saline must be given during extracorporeal photopheresis to maintain blood pressure, and patients taking antihypertensives are asked to withhold these medications until after the procedure.

Two to 12 hours after extracorporeal photopheresis, some patients experience low-grade fevers, likely due to the release of cytokines. Over the same time course, some patients with cutaneous T-cell lymphoma (CTCL) may experience an increase in pruritus or redness.

Finally, although patients with hypertriglyceridemia do not experience any further adverse events during extracorporeal photopheresis, they may have a less efficacious treatment because of the inability of the UVAR machine to separate the WBCs from the lipid-rich blood. Because of this, patients should have triglyceride levels of less than 300 mg/dL and should fast (except for fluid intake) before the procedure.

In all of the various patient groups treated, no immunosuppression, opportunistic infections, or neoplasia has been associated with extracorporeal photopheresis. Although 8-MOP is rapidly cleared from the blood, levels in the eyes have not been measured. The risk of cataract formation is minimal if the patient protects the eyes using UVA-blocking sunglasses the day of the procedure.

Cutaneous T-cell lymphoma (CTCL) is the name for a group of lymphoproliferative disorders caused by clonally derived, skin-homing, malignant T cells. The most common of these disorders is mycosis fungoides and its leukemic variant, Sézary syndrome, which has peripheral blood, lymph node, and, sometimes, organ involvement. A variety of skin-directed treatments exist for CTCL, which have little effect on the extracutaneous disease of Sézary syndrome.

The initial indication for extracorporeal photopheresis (ECP) was based on the results of a trial performed with a cohort of 37 CTCL patients in whom 73% had some improvement in skin and/or extracutaneous disease with extracorporeal photopheresis alone.^[5] Since that time, multiple retrospective and prospective studies have indicated that when extracorporeal photopheresis is used as a single agent, most often with treatments given on 2 consecutive days every 3-4 weeks, overall response rates are 50-80% and complete response rates are 10-25%.^[6] More recently, extracorporeal photopheresis has been used in combination with other immunomodulatory therapies, such as interferons alpha and gamma or oral retinoids, to achieve even higher response rates. In addition to the improvement in cutaneous manifestations of CTCL, extracorporeal photopheresis has been demonstrated to cause a decrease in the burden of peripheral blood disease and lymphadenopathy.^{[7, 8, 9]}

A clinical profile of patients who are more likely to respond to extracorporeal photopheresis has been developed over the past 20 years of experience. The presence of circulating Sézary cells, identified by abnormal flow cytometry results or histology findings, appears to be necessary for a response. Normal or near-normal numbers of CD8⁺ cytotoxic lymphocytes, indicating an adequate cell-mediated immunity, also makes a response more likely. Therefore, patients who have had the disease for 2 years or less and who have not undergone systemic cytotoxic chemotherapy are more likely to gain benefit from extracorporeal photopheresis compared with patients with prolonged disease or those who have been heavily pretreated.

Well-supported evidence indicates that extracorporeal photopheresis (ECP) is effective for treating acute and chronic cardiac rejection, and studies have suggested that extracorporeal photopheresis may be beneficial for treating lung, liver, and renal transplant rejection, as well as for preventing episodes of acute rejection.^[10] According to the authors' experience, acute or symptomatic rejection should be treated aggressively, with treatments on 2 consecutive days, weekly for the first 2 weeks, and then on alternating weeks until rejection has resolved. Although extracorporeal photopheresis treatment immediately following lymphocytolytic therapy may be less effective, immunosuppression should be continued.

Graft versus host disease (GVHD) (see the image below) complicates the course of many patients after undergoing allogeneic stem cell transplantation and limits the use of this potentially life-saving therapy.^{[11, 12]} It affects various organ systems and is conventionally divided into acute and chronic GVHD, depending on whether it occurs within the first 100 days posttransplant or beyond that time.

Extracorporeal photopheresis (ECP) has been used for the treatment of immunosuppressive-resistant chronic GVHD for at least 12 years and has been shown to improve skin manifestations, joint mobility, xerostomia, and xerophthalmia. Extracorporeal photopheresis may also improve liver enzyme abnormalities and diarrhea associated with gastrointestinal GVHD, and further studies are currently being conducted to determine the effect of extracorporeal photopheresis on bronchiolitis obliterans observed in association with GVHD. Studies are also currently underway exploring conditioning with extracorporeal photopheresis prior to allogeneic stem cell transplantation for preventing GVHD. Early studies seem to indicate that extracorporeal photopheresis may exert some of its effects on GVHD through modulation of T-regulatory cells.^[13]

Extracorporeal photopheresis (ECP) has also been explored as therapy for a variety of autoimmune diseases, including systemic sclerosis. In a study of 79 patients with severe skin involvement, significant improvement of skin softening was demonstrated with extracorporeal photopheresis compared with D-penicillamine. In a randomized, double-blinded, placebo-controlled trial of 64 patients (ECP vs sham ECP), extracorporeal photopheresis again had some clinical effects, but statistical significance was not achieved because of the small number of subjects.^[14]

Similar reports of success in individual cases and small case series have been described and suggest efficacy of extracorporeal photopheresis treatment in type 1 diabetes mellitus, pemphigus vulgaris, epidermolysis bullosa acquisita, atopic dermatitis, and inflammatory bowel disease. Several case series suggest the potential efficacy of extracorporeal photopheresis for systemic lupus erythematosus, morphea,^[15] and scleromyxedema. Other reports also suggest the potential efficacy for nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy.^[16] Other possible clinical indications studied in which extracorporeal photopheresis has not shown benefit include multiple sclerosis, chronic hepatitis C, andpsoriasis.