Effective Date:

a)    This policy will apply to all services performed on or after the above revision date which will become the new effective date.

b)    For all services referred to in this policy that were performed before the revision date, contact customer service for the rules that would apply.

Extracorporeal photopheresis is covered for the treatment of cutaneous T-cell lymphoma, bronchiolitis obliterans (lung transplant rejection), acute heart transplant rejection refractory to standard treatment, and chronic graft-versus-host disease (GVHD) after a prior allogeneic stem cell transplant. 

1)    Extracorporeal photochemotherapy (photopheresis) is considered medically necessary for erythrodermic variants of cutaneous T cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).  

2)    Extracorporeal photochemotherapy is considered medically necessary in the treatment of acute cardiac allograft rejection that is refractory to standard immunosuppressive drug treatment (high-dose steroids plus 2 or more of the following, unless contraindicated: azathioprine, cyclosporine, methotrexate, and/or polyclonal and monoclonal antilymphocyte agents (e.g., anti-lymphocyte globulin (ALG), anti-thymocyte globulin (ATG), and OKT3 [monoclonal T-cell antibody]).

3)    Extracorporeal photochemotherapy is considered medically necessary in the treatment of lung transplant rejection (bronchiolitis obliterans syndrome)

4)    Extracorporeal photochemotherapy is considered medically necessary for the treatment of graft-versus-host disease of an allogeneic bone marrow or stem cell transplant when the disease is refractory to standard immunosuppressive drug treatment.

Codes Used In This BI:

36522             Photopheresis

Extracorporeal photochemotherapy is considered experimental and investigational as a treatment for the following conditions because the effectiveness of this treatment for these diagnoses has not been established: 

• Allograft rejection of solid organs other than the heart and lung
• Bullous pemphigoid
• Crohn’s disease
• Multiple sclerosis
• Nephrogenic systemic fibrosis (previously known as nephrogenic fibrosing dermopathy)
• Pemphigus vulgaris
• Pityriasis rubra pilaris
• Systemic sclerosis (scleroderma)
• Type 1 diabetes.

Extracorporeal photopheresis has been shown in prospective case studies to be effective in the treatment of T-Cell Lymphoma.  Evidence suggests that it prolongs life and induces 50-75% response rates.

The use of photopheresis as a treatment of graft-versus-host disease (GVHD) after a prior allogeneic stem cell transplant is based on the fact that GVHD is an immunologically mediated disease.  GVHD can be categorized into acute, occurring within the first 100 days after infusion of allogeneic cells, or chronic disease, which develops sometime after 100 days.  Acute GVHD is commonly graded I-IV, ranging from mild disease characterized by a skin rash without involvement of the liver or gut, to grades III and IV, which are characterized by generalized erythroderma, elevated bilirubin levels, or diarrhea.  Grade III acute GVHD is considered severe, while Grade IV is considered threatening.  Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such a progressive systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis.  It may affect the mouth, eyes, respiratory tract, musculoskeletal system, peripheral nerves, as well as the skin, liver, or gut - the usual sites of acute GVHD.

An alternating regimen of cyclosporine and prednisone are commonly used to treat chronic GVHD.  Other therapies include antithymocyte globulin, corticosteroid monotherapy, and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide, or azathioprine.  Therefore, refractory disease is defined as chronic GVHD that fails to respond adequately to a trial of any of the above therapies.  

There is no standard schedule for photopheresis therapy.  However, most reported schedules initiate therapy with 1-3 days of photopheresis at 1-3 week intervals, followed by a tapering of therapy.

In 2006, the Ontario Health Technology Advisory Committee (OHTAC) published results of a systematic review of ECP for the treatment of refractory chronic GVHD.  In summary, OHTAC reported that there is low quality evidence that ECP improves response rates and survival in patients with chronic GVHD who are unresponsive to other forms of therapy. Limitations in the literature related to ECP for the treatment of refractory GVHD mostly pertained to the quality, size, and heterogeneity in treatment regimens and diagnostic criteria of available clinical studies. The Committee did, however, recommend a 2-year duration field evaluation of ECP for chronic GVHD, using standardized inclusion criteria and definitions to measure disease outcomes including response rates, quality of life, and morbidity.

A retrospective case series published in 2007 reported results of ECP for steroid-resistant GVHD in pediatric (aged 6–18 years) patients who had undergone hematopoietic stem-cell transplantation to treat a variety of cancers (Massimo et al, 2007).  Patients had acute GVHD (aGVHD, n=15, stages II-IV) or chronic GVHD (cGVHD, n=10, 7 deemed extensive) that did not respond to at least 7 days of methylprednisolone therapy. Patients received ECP on 2 consecutive days at weekly intervals for the first month, every 2 weeks during the second and third months, and then at monthly intervals for a further 3 months. ECP was progressively tapered and discontinued based on individual patient response. Response to ECP was assessed 3 months after ECP ended or after 6 months if the ECP protocol was prolonged. Among patients with aGVHD, a CR was observed in 7 of 7 (100%) with Grade II and 2 of 4 (50%) with Grade III illness, whereas none with Grade IV responded to ECP. In the group with cGVHD, 3 of 3 (100%) with limited disease had CR, compared to 1 of 7 (14%) with extensive disease who had a CR; 5 of 7 (71%) of patients with extensive cGVHD had no response to ECP. Adverse effects of ECP were generally mild in all cases.

Bronchiolitis obliterans syndrome (BOS), a manifestation of chronic allograft rejection, has become the leading obstacle to long-term success in patients who have received lung transplantation.  BOS is usually an irreversible and inexorably progressive complication that responds poorly to treatment.  A retrospective analysis published in 2010 of all patients with progressive BOS treated at Barnes-Jewish Hospital demonstrated significant reduction in the decline of lung function in a pre/post treatment analysis (Morrell et al 2010).  The average rate of decline of FEV1 during the six months prior to photopheresis was 116.0 ml/month, with the slope decreasing to -28.9 ml/month during the six months after initiation of photopheresis.  The FEV1 improved in 25% of the treated patients.

Cavaletti G, Perseghin P, Dassi M et al.(2006) Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol Sci 2006; 27(1):24-32.

Cribier B, Faradji T, Le Coz C, et al.(1995) Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Derm 1995; 191:25-31.

Enomoto DNH, Meekes JR, Bossuyt PMM, et al.(1999) Treatment of patients with systemic sclerosis with extracorporeal photochemotherapy (photopheresis). J Am Acad Derm 1999; 41:915-922.

Extracorporeal photopheresis for treatment of graft versus host disease or autoimmune disease. 2001 Blue Cross Blue Shield Association Technology Evaluation Center Assessment.

Fries JF, Seibold JR, Medsger TA.(1992) Photopheresis for scleroderma. J Rheum 1992; 19:1011-1013;.

Knobler RM, Grainger W, Grainger W, et al.(1992) Extracorporeal photochemotherapy for the treatment of systemic lupus erythematosus. A pilot study. Arthrit Rheum 1992; 35:319-324.

Mayes MD.(2000) Photopheresis and autoimmune disease. Rheum Dis Clin N Am 2000; 26; 75-81.

Melski JW.(1992) Price of technology: A blind spot. JAMA 1992; 267:1516-17.

Rook AH, Freundlich B, Jegasothy BV, et al.(1992) Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Derm 1992; 128:337-346.

Rostami A, Sater R, Bird S, et al.(1999) A double blind, placebo controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis. Multi Scler 1999; 5:198-203.

Schwwartz J, Gonzalez J, Palangio M, et al.(1997) Extracorporeal photochemotherapy in progressive systemic sclerosis: A follow-up study. Int J Derm 1997; 36:380-385.

Trentham DE.(1992) Photochemotherapy in systemic sclerosis. Arch Dermatol 1992;128:389-90.

Vhalquist C, Larsson M, Ernerudh J, et al.(1996) Treatment of psoriatic arthritis with extracorporeal photo chemotherapy and conventional psoralen-ultraviolet A irradiation. Arthrit Rheum 1996; 39:1519-1523.

Wollina U, Lange D, Looks A.(1999) Short-time extracorporeal photochemotherapy in the treatment of drug-resistant autoimmune bullous disease. Derm 1999; 198:140-144.

Alcindor T, Gorgun G, Miller KB, et al.(2001) Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease. Blood 2001; 98:1622-5.

Arai S, Vogelsang GB.(2000) Management of graft-versus-host disease. Blood Rev 2000; 14:190-204.

Besnier DP, Chabannes D, Mahe B, et al.(1997) Treatment of graft-versus-host disease by extracorporeal photochemotherapy: a pilot study. Transplantation 1997; 64:49-54.

Chao NJ, Parker PM, Niland JC, et al.(1996) Paradoxical effect of thalidomide prophylaxis on chronic graft-versus-host disease. Biol Blood Marrow Transplant 1996; 2:86-92.

Child FJ, Ratnavel R, Watkins P, et al.(1999) Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). BMT 1999; 23:881-7.

Dall`Amico R, Zacchello G.(1998) Treatment of graft-versus-host disease with photopheresis. Transplantation 1998; 65:1283-4.

Extracorporeal photopheresis for treatment of graft versus host disease or autoimmune disease. 2001 Blue Cross Blue Shield Association Technology Evaluation Center Assessment.

FDA.(2001) FDA Summary of Safety and Effectiveness. www.fda.gov/cdrh/pdf/p0100156.pdf; 2001.

Flowers ME, Kansu E, Sullivan KM.(1999) Pathophysiology and treatment of graft-versus-host disease. Hematol Oncol Clin North Am 1999; 13:1091-112, viii-ix.

Fries JF, Seibold JR, Medsger TA.(1992) Photopheresis for scleroderma? No!. J Rheumatol 1992; 19:1011-13.

Gaziev D, Galimberti M, Lucarelli G, et al.(2000) Chronic graft-versus-host disease: is there an alternative to the conventional treatment. BMT 2000; 25:689-96.

Greinix HT, Knobler RM, Worel N et al.(2005) Prospective study of extracorporeal photopheresis in steroid refractory or steroid-resistant extensive chronic graft-versus-host disease. Haematologica 2006; 91(3):405-408.

Greinix HT, Volc-Platzer B, Rabitsch W, et al.(1998) Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood 1998; 92:3098-104.

Halle P, Paillard C, D`Incan M et al.(2002) Successful extracorporeal photochemotherapy for chronic graft versus-host disease in pediatric patients. J Hematothera Stem Cell Res 2002; 11(3):501-512.

Hiraoka A, Ohashi Y, Okamoto S, et al.(2001) Phase III study comparing tacrolimus (FK 506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. BMT 2001; 28:181-5.
Knobler RM, Trautinger F, Graninger W, et al.(1993) Parenteral administration of 8-methoxypsoralen in photopheresis. J Am Acad Derm 1993; 28:580-4.

Massimo B, Rosanna P, Roberto A et al.(2007) Extracorporeal photopheresis for steroid resistant graft-versus-host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007; 29(10):678-687.

Melski JW.(1992) Price of technology. A blind spot. JAMA 1992; 267:1516-8.

Melski JW.(1992) Price of technology: A blind spot. JAMA 1992; 267:1516-17.

OHTAC Recommendation: Extracorporeal Photopheresis. March 28, 2006. http://www.health.gov.on.ca/english/providers/program/ohtac/tech/recommend/rec_ecp_032806.pdf

Ratanatharathorn V, Ayash L, Lazarus HM, et al.(2001) Chronic graft-versus-host disease: clinical manifestation and therapy. BMT 2001; 28:121-9.

Rook AH, Freundlich B, Jegasothy BV, et al.(1992) Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Derm 1992;128:337-46.

Russell-Jones R.(2001) Shedding light on photopheresis. Lancet 2001; 357:820-1.

Salvaneschi L, Perotti C, Zecca M et al.(2001) Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001; 41(10):1299-1305.

Shephard SE, Nestle FO, Panizzon R.(1999) Pharmacokinetics of 8-methoxypsoralen during extracorporeal photopheresis. Photodermatol Photoimmunol Photomed 1999; 15:64-74.

Smith EP, Sniecinski I, Dagis AC, et al.(1998) Extracorporeal photochemotherapy for treatment of drug resistant graft vs-host disease. Biol Blood Marrow Transplant 1998; 4:27-37.

Trentham DE.(1992) Photochemotherapy in systemic sclerosis. Arch Dermatol 1992;128:389-90.

Vogelsang GB.(2000) Advances in the treatment of graft-versus-host disease. Leukemia 2000; 14:509-10.

Vogelsang GB.(2001) How I treat chronic graft-versus-host disease. Blood 2001; 97:1196-201.

Wagner JL, Flowers ME, Longton G, et al.(1998) The development of chronic graft-versus-host disease: an analysis of screening studies and the impact of corticosteroid use at 100 days after transplantation. BMT 1998; 22:139-46.

Fraser-Andrews E, Seed P, Whittaker S, et al.(1998) Extracorporeal photopheresis in Sézary syndrome: no significant effect in the survival of 44 patients with a peripheral blood T cell clone. Arch Derm 1998; 134:1001-05.

Heald P, Rook A, Perez M, et al.(1992) Treatment of erythrodermic cutaneous T cell Lymphoma with extracorporeal photochemotherapy. J Am Acad Derm 1992; 27:427-433.

Lim HW, Edelson Rl.(1995) Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin N Am 1995; 9:1117-26.

Zackheim HS.(1999) Cutaneous T cell Lymphoma: Update of treatment. Derm 1999; 199:102-5.

Morrell MR, et al. (2010) The Efficacy of Photopheresis for Bronchiolitis Obliterans Syndrome After Lung Transplantation.  Jnl Heart Lung Trans 2010 Apr; 29(4):424-31