Medicine Section - Photopheresis for the Treatment of Solid Organ Transplant Rejection

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

There are currently no ideal immunosuppressive therapies that will prevent organ rejection and promote graft survival without significant side effects. The currently available regimens can impair immune function in a nonspecific and toxic fashion, leaving the patient susceptible to increased risk of opportunistic infections and malignancies, in addition to the side effects of the drugs themselves. For example, the adverse effects of corticosteroid therapy, which have been reported to correlate with both long-term use and cumulative drug dose, include the following: osteoporosis, myopathy, increased susceptibility to infection, altered carbohydrate metabolism and cushingoid habitus. OKT3 limitations include increased rates of cytomegalovirus infection, increased incidence of lymphoproliferative disease, and the appearance of anti-mouse antibodies which either preclude repeat use of OKT3 or reduce drug efficacy. Methotrexate, another antirejection drug, may cause severe leukopenia, gastritis and pulmonary toxicity.

These severe treatment limitations have led to the investigation of alternative methods of immunosuppression in transplant recipients, one of which is extracorporeal photopheresis (ECP). ECP or photochemotherapy is a technique in which the patient’s peripheral blood mononuclear cells, in the presence of 8-methoxypsoralen (8-MOP), are exposed extracorporeally to ultraviolet A (UVA) light. 8-MOP is a compound that is only active when exposed to UVA light, thus there are no side effects or damage to non-exposed cells. The photoactivated 8-MOP covalently binds to DNA pyrimidine bases, cell surface molecules, and cytoplasmic components in the exposed white cells. These altered lymphocytes, when reinfused into the patient, produce a suppressor response that targets unirradiated T cells of similar clones via a mechanism which is not yet understood. The photopheresis process can be completed in approximately three to four hours in an outpatient setting.

Policy/Criteria

Extracorporeal photopheresis for the treatment of solid organ transplant rejection is considered investigational.

Position Summary

Most of the published literature to date focuses on ECP in the treatment of rejection in heart transplant patients. (3-5,7,9,10,11,13,18-19, 22) There is very little published about solid organ rejection in renal, liver and lung transplant patients. (8,12,14-16,21, 23,24)

Heart Transplant Rejection

Costanzo-Nordin and colleagues reported outcomes for 16 patients who were randomized to either ECP or pulse corticosteroid therapy.  (1) Photopheresis and corticosteroids successfully reversed 8 of 9 and 7 of 7 rejection episodes, respectively. Histopathological improvement was demonstrated within 5-20 days after treatment with photopheresis and within 3-13 days after corticosteroid treatment. Complete disappearance of mononuclear cell infiltration and myocyte necrosis was seen a median of 25 days (range, 6-67 days) after photopheresis and 17 days (range, 8-33 days) after corticosteroid therapy. The average follow-up period was 6.2 +/- 3.2 months.

At best, this study demonstrates that photopheresis may be as effective as corticosteroid therapy in the treatment of International Society for Heart and Lung Transplantation (ISHLT) grades 2, 3A and 3B rejection not associated with hemodynamic compromise. The small sample size and the wide disparity among times of entry into the study following transplant (0.2 - 69 months), in addition to other confounding factors such as previous treatment with horse antithymocyte globulin or OKT3, preclude meaningful statistical analysis of the results. The data do support the need for continued study of photopheresis in further clinical trials however.

One of the most significant studies of ECP treatment of heart transplant rejection was published by Barr and colleagues (14) This preliminary study was designed to investigate the effect of prophylactic photopheresis on the incidence of acute cellular rejection and infection in heart transplant recipients. In this multicenter study of 60 cardiac transplant recipients, 27 patients were randomized to standard triple-drug immunosuppressive therapy; 33 patients were randomized to standard triple drug therapy plus photopheresis. The study end-points were monitored for six months after transplantation, and safety and survival follow-up was continued for an additional six months. This study did demonstrate a statistically significant reduction in the number of acute rejection episodes in cardiac transplant recipients who received photopheresis in addition to standard immunosuppressive therapy. No significant differences were seen between the two groups in the time to a first rejection episode, the incidence of rejection associated with hemodynamic compromise, survival at both 6 and 12 months, or in the incidence of infection. Despite these promising results, the authors themselves consider this a preliminary study in evaluating the potential clinical value of photopheresis as an addition to standard immunosuppression. Additional studies with longer follow-up are still needed to evaluate the ultimate effect of photopheresis on graft and patient survival.

Liver, Lung and Kidney Transplant Rejection

As mentioned above, there is a paucity of published literature concerning ECP treatment of solid organ rejection in lung, liver and kidney transplant patients. Data from case reports and very small case series suggest similar promising outcomes, but meaningful conclusions cannot be reached about health outcomes. Again, the published authors call for further clinical trials.

An updated search of the MEDLINE database through July 14, 2008 identified no new data which alters the conclusions reached above.

References

1. Barr ML. Immunomodulation in transplantation with photopheresis. Artificial Organs 1996;20(8):971-973
2. Christensen I, Heald P. Photopheresis in the 1990s. Journal of Clinical Apheresis 1991;6:216-220
3. Costanzo-Nordin MR, et al. Photopheresis versus corticosteroids in the therapy of heart transplant rejection: preliminary clinical report. Circulation 1992;86(Suppl II, No. 5):242-50
4. Costanzo-Nordin MR, et al. Efficacy of photopheresis in the rescue therapy of acute cellular rejection in human heart allografts: a preliminary clinical and immunopathologic report. Transplantation Proceedings 1993;25(1):881-883
5. Dall'Amico R, et al. Benefits of photopheresis in the treatment of heart transplant patients with multiple/refractory rejection. Transplantation Proceedings 1997;29(1-2):609-11
6. Dall'Amico R, et al. Applications of extracorporeal photochemotherapy in "non-oncological" diseases. International Journal of Artificial Organs 1993;16(Suppl 5):168-72
7. Dall'Amico R, et al. Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation 1995;60:45-49
8. Dall'Amico R, et al. Successful treatment of recurrent rejection in renal transplant patient with photopheresis. Journal of the American Society of Nephrology 1998;9(1):121-7
9. Kirklin, J.K. Recurrent or persistent cardiac rejection: therapeutic options and recommendations. Transplantation Proceedings 1997;29(8A):40S-44S
10. Meiser BM, et al. Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation. Transplantation 1994;57(4):563-8
11. Wieland M, et al. Treatment of severe cardiac allograft rejection with extracorporeal photochemotherapy. Journal of Clinical Apheresis 1994;9:171-175
12. Wolfe J, et al. Reversal of acute renal allograft rejection by extracorporeal photopheresis: a case presentation and review of the literature. Journal of Clinical Apheresis 1996;11:36-41
13. Barr M, et al. Photopheresis for the prevention of rejection in cardiac transplantation. NEJM 1998;339(24):1744-1751
14. Salerno CT, Park SJ, Kreykes NS, Kulick DM, Savik K, Hertz MI, Bolman RM III. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 1999;117(6):1063-9
15. O'Hagen AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999;115(5):1459-62
16. Lehrer MS, Ruchelli E, Olthoff KM, French LE, Rook AH. Successful reversal of recalcitrant hepatic allograft rejection by photopheresis. Liver Transpl 2000;6(5):644-7
17. Rook AH, Suchin KR, Kao DM, Yoo EK, Macey WH, DeNardo BJ, Bromley PG, Geng Y, Junkins-Hopkins JM, Lessin SR. Photopheresis: clinical applications and mechanism of action. J Investig Dermatol Symp Proc 1999;4(1):85-90
18. Giunti G, Schurfeld K, Maccherrini M, Tanganelli P, Rubegni P, Alfani D, D'Ascenzo G, Diciolla F, Bernazzali S, Fimiani M, Toscana M, Sani G. Photopheresis for recurrent acute rejection in cardiac transplantation. Transplant Proc 1999;31(1-2):128-9
19. Barr ML, Baker CJ, Schenkel FA, McLaughlin SN, Stouch BC, Starnes VA, Rose EA. Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac transplantation.. Clin Transplant 2000;14(2):162-6
20. Zic JA, Miller JL, Stricklin GP, King LE Jr. The North American experience with photopheresis. Ther Apher 1999;3(1):50-62
21. Kumlien G, Genberg H, Shanwell A, Tyden G. Photopheresis for the treatment of refractory renal graft rejection. Transplantation 2005;79(1):123-5
22. Kirklin JK, Brown RN, Huang ST et al. Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant. 2006;25(3):283-8
23. Urbani L, Mazzoni A, De Simone P et al. Avoiding calcineurin inhibitors in the early post-operative course in high-risk liver transplant recipients: The role of extracorporeal photopheresis. J Clin Apher. 2007;22(4):187-94
24. Meloni F, Cascina A, Miserere S et al. Peripheral CD4(+)CD25(+) TREG cell counts and the response to extracorporeal photopheresis in lung transplant recipients. Transplant Proc. 2007;39(1):213-7

Cross References

Photopheresis as a Treatment of Autoimmune Disease and Graft-versus-Host Disease, Regence Medical Policy Manual, Medicine, Policy No. 84

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