Extracorporeal Photochemotherapy (ECP)

TRANSFUSION MEDICINE UPDATE

Issue #1 2010

Extracorporeal Photochemotherapy (ECP)

Anand Padmanabhan MD PhD, Transfusion Medicine Fellow, Institute for Transfusion Medicine & University of Pittsburgh School of Medicine, Department of Pathology and Joseph E. Kiss, MD, Medical Director, Hemapheresis & Blood Services, Institute for Transfusion Medicine & Associate Professor of Medicine, University of Pittsburgh

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INTRODUCTION

Photopheresis or extracorporeal photochemotherapy (ECP) is a leukocytapheresis-based therapy, in which leukocytes treated with 8-methoxypsoralen (8-MOP) are irradiated with ultraviolet-A light (UVA) ex vivo and re-infused into the patient. Notably, ECP was the first selective immunotherapy approved by the Food and Drug Administration (FDA) for the treatment of cancer. Edelson et al. performed studies that formed the basis for FDA approval for the use of ECP in the treatment of patients with cutaneous T-cell lymphoma (CTCL)1. In recent years, there has been a rapid broadening of interest in the use of ECP in transplant settings, both solid organ and hematopoietic stem cell transplantation utilizing both prophylactic and therapeutic approaches. This review briefly discusses various aspects of this treatment modality including mechanism of action, clinical applications, and technical specifications.

MECHANISM OF ACTION

Long wavelength UVA (320–400 nm) treatment of 8-MOP-exposed cells induces the formation of interstrand crosslinks in DNA and leads to T cell apoptosis2. A number of potential mechanisms by which apoptotic leukocytes induce immune tolerance have been proposed. They include generation of tolerogenic dendritic cells (DCs) after uptake of apoptotic bodies by antigen presenting cells (APCs); decreased production of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines; reduced ability of APCs to stimulate T-cell responses; enhanced production and function of regulatory T cells (Treg) and T suppressor cells; and peripheral clonal deletion of effector T cells by activation-induced cell death3. While the exact mechanism of action may not be completely understood, this has not hindered empiric use for various diseases and conditions discussed below.

CLINICAL APPLICATIONS

CTCL refers to a group of rare lymphoproliferative disorders such as Sezary syndrome, which are characterized by the accumulation of malignant T-cells that home to the skin. ECP is an established and effective therapy for CTCL. A meta-analysis of 19 studies in patients at all stages of CTCL reported a combined overall response rate of 55.5% with 17.6% achieving a complete response (CR)4.

Acute Graft Versus Host Disease (aGVHD), a serious and frequent complication of allogeneic hematopoietic stem cell transplantation contributes to post-transplant morbidity and mortality. Established therapy consists of corticosteroids and escalation to other immuno-suppressives. A major consequence of escalation of immunosuppressive treatment is infection and sepsis. In one study5, after a median of 4 cycles of ECP, 82% of patients with cutaneous involvement, 61% with liver involvement, and 61% with gut involvement achieved a complete resolution of aGVHD. CR rates were higher for patients with grade II and III disease (86% and 55%, respectively) than for grade IV disease (30%). In another recent retrospective analysis, ECP treatment was associated with a response rate of 61% in patients with severe chronic GVHD (cGVHD). Responses were seen in skin, liver, oral mucosa and eye cGVHD6. A recent multicenter prospective phase 2 randomized study of ECP for the treatment of cGVHD compared the safety and efficacy of ECP and standard therapy versus standard therapy alone in patients with cutaneous manifestations of cGVHD that were not adequately controlled by corticosteroid treatment7. While there were no differences in the percent change from baseline in total skin scores (TSS) at 12 weeks following treatment, there was a significant difference between the two groups in the percentage of patients whose steroid doses were decreased by at least 50% (ECP arm-8.3%; Standard treatment arm-0%). These results suggest that ECP may have a steroid sparing effect within 12 weeks of treatment. Progressive improvement in TSS and continued reduction of steroid dose was noted in patients in the ECP arm at 24 weeks, but most patients in the standard arm had either discontinued participation or had switched over to the ECP arm, precluding a meaningful statistical analysis.

The successful use of photopheresis in human cardiac transplant recipients was first published in 19928. Less than a decade later, results from a multicenter, international, randomized, double-blind study were published9. In this study, a total of 60 recipients of primary cardiac transplants were randomly assigned to standard medical immunosuppressive therapy alone or standard therapy in conjunction with photopheresis. Significantly more patients in the photopheresis group had no rejection or one rejection episode compared to the standard-therapy group, and significantly fewer patients in the photopheresis group had two or more rejection episodes compared to the standard-therapy group. In addition, although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group. Several subsequent reports show beneficial effects of ECP in the management of heart transplant recipients, including its use in the prevention of coronary allograft vasculopathy, a leading cause of mortality in cardiac transplant patients10-12.

Groups have reported successful experience utilizing ECP in lung transplant patients with bronchiolitis obliterans (BOS), a manifestation of chronic lung rejection that constitutes a major hurdle to long-term survival13-15. In a recent large retrospective analysis, outcomes were reported for 60 lung allograft recipients treated with ECP for progressive BOS16. This analysis showed that ECP was associated with a significant reduction in the rate of decline in lung function associated with progressive BOS. Very limited data exists at this time for the use of this treatment modality in other transplant areas including kidney, liver and pancreas17. Interestingly ECP has also been introduced in the treatment of rejection in the area of composite organ transplantation with its use in two patients with face transplants18,19.

TECHNICAL SPECIFICATIONS

Photopheresis is now generally performed using the UVAR-XTS second-generation photopheresis system (Therakos, Exton, PA). In the first step of ECP, whole blood is drawn from the patient via a large-caliber needle/catheter into the centrifugation bowl of the instrument where cellular components are separated. This is repeated three to six times depending on patient size and level of hemoglobin. At the end of each cycle, the white blood cells (buffy coat) are added to a bag, while plasma and red cells are returned to the patient. The second step of ECP involves exposure of the leukocytes to UVA in the presence of 8-MOP injected into the bag. In general, adverse effects from ECP have been minor and are typically related to volume shifts during the procedure, however fatigue, low-grade fever and abdominal discomfort have been reported20. Patients are also counseled about the use of sunscreen/protective clothing and dark glasses for 24 hours after the procedure given the risk of photosensitivity. Risks related to maintenance of vascular access include bleeding, infection, thrombus formation and venous sclerosis21. The typical schedule for ECP involves multiple cycles of treatment on two consecutive days separated by one or more weeks. These protocols vary from institution to institution and also depend upon the severity and nature of the disease process. Recent FDA approval for a third generation device (Cell Ex Photopheresis System, Therakos, Exton, PA) will permit continuous separation of blood components with the use of double needle access, and result in abbreviated treatment times, treatment of a greater number of leukocytes, and offer the capability to treat younger and smaller patients by use of a RBC prime in the set.

CONCLUSION

ECP is showing promising efficacy in a number of disease states. It is expected that its use will expand and that optimal treatment protocols will be developed.

Increasing our understanding of the mechanisms of action of ECP should facilitate improvements in the use of this therapy.

REFERENCES

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15.Villanueva J, Bhorade SM, Robinson JA, et al. Ann Transplant 2000;5: 44-7.

16.Morrell MR, Despotis GJ, Lublin DM, et al. J Heart Lung Transplant 2009.

17.Hivelin M, Siemionow M, Grimbert P, Lantieri L.. Transpl Immunol 2009;21: 117-28.

18.Dubernard JM, Lengele B, Morelon E, et al.. N Engl J Med 2007;357: 2451-60.

19.Lantieri L, Meningaud JP, Grimbert P, et al.Lancet 2008;372: 639-45.

20.Zackheim HS. Dermatology 1999;199: 102-5.

21.Bambauer R, Schneidewind-Muller JM, Schiel R, Latza R. Ther Apher Dial 2003;7: 221-4.

Editor: Donald L. Kelley, MD, MBA: .

For questions about this TMU, please contact:

Joseph E. Kiss, MD at: 412-209-7320.

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