Latest Review Date: October 2024

Category: Therapy                                                                

POLICY:

Organ Rejection After Solid Organ Transplant

Extracorporeal photopheresis may be considered medically necessary to treat cardiac allograft rejection, including acute rejection, that is either recurrent or that is refractory to standard immunosuppressive drug treatment.

Extracorporeal photopheresis is considered investigational in all other situations related to treatment or prevention of rejection in solid organ transplantation.

Graft-Versus-Host Disease

Acute* (See Policy Guidelines)

Extracorporeal photopheresis may be considered medically necessary as a technique to treat acute graft-versus-host disease (GVHD) that is refractory to medical therapy.

Extracorporeal photopheresis is considered investigational as a technique to treat acute GVHD that is either previously untreated or is responding to established therapies.

Chronic** (See Policy Guidelines)

Extracorporeal photopheresis may be considered medically necessary as a technique to treat chronic GVHD that is refractory to medical therapy.

Extracorporeal photopheresis is considered investigational as a technique to treat chronic GVHD that is either previously untreated or is responding to established therapies.

Cutaneous T-Cell Lymphoma

Extracorporeal photopheresis may be considered medically necessary as a technique to treat late-stage (III or IV) cutaneous T-cell lymphoma.

Extracorporeal photopheresis may be considered medically necessary as a technique to treat early-stage (I or II) cutaneous T-cell lymphoma that is progressive and refractory to established nonsystemic therapies.

Extracorporeal photopheresis is considered investigational as a technique to treat early-stage (I or II) cutaneous T-cell lymphoma that is either previously untreated or responsive to established nonsystemic therapies.

Autoimmune Diseases

Extracorporeal photopheresis is considered not medically necessary and investigational for all other indications, including, but not limited to:

• Progressive systemic sclerosis (scleroderma)
• Pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, or other autoimmune bullous (blistering) diseases
• Systemic lupus erythematosus
• Multiple sclerosis
• Psoriatic arthritis or psoriasis vulgaris
• Rheumatoid arthritis
• Type I diabetes
• Atopic dermatitis
• Juvenile dermatomyositis
• Scleromyxedema
• Crohn’s Disease

Other

Extracorporeal photopheresis is considered investigational for all other indications.

For information regarding plasmapheresis, please refer to medical policy # 100 Plasma Exchange

For information regarding lipid apheresis, please refer to medical policy # 103 Lipid Apheresis

POLICY GUIDELINES:

Organ Rejection After Solid Organ Transplant

• A regimen of immunosuppressive therapy is standard of care for the treatment of solid organ rejection. Therefore, refractory rejection is defined as rejection that fails to respond adequately to a standard regimen of immunosuppressive therapy.
• Recurrent allograft rejection is defined as having at least 2 rejection episodes after standard immunosuppressive therapy.
• There is no standard schedule for extracorporeal photopheresis (ECP), and reported schedules vary by the organ type. However, most reported cardiac and lung schedules initiate therapy with 2 consecutive days of ECP in month 1, followed by biweekly therapy on 2 consecutive days in months 2 and 3, then monthly on 2 consecutive days in months 4 through 6.

Graft-Versus-Host Disease

*Methylprednisolone is considered first-line treatment of acute graft-versus-host disease (GVHD).

**For chronic GVHD, an alternating regimen of cyclosporine and prednisone is commonly used.

Other therapies for GVHD include antithymocyte globulin, corticosteroid monotherapy, and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide, or azathioprine.

Refractory disease is defined as GVHD that fails to respond adequately to a trial of any of these therapies.

Treatment schedule and duration of ECP for GVHD have not been optimally defined. Guidelines and consensus statements have generally recommended 1 cycle (i.e., ECP on 2 consecutive days) weekly for acute GVHD and every 2 weeks for chronic GVHD. Treatment duration is based on clinical response (see the Practice Guidelines and Position Statements section); discontinuation is generally recommended for no or minimal response.

Cutaneous T-Cell Lymphoma Staging

Cutaneous T-cell Lymphoma staging is based on the tumor, node, and metastases (TNM) classification system (see Table PG1).

Table PG1. Cutaneous T-cell Lymphoma Staging

Stage	Tumor T, N, and M Categories
IA	T1N0M0
IB	T2N0M0
IIA	T1-2N1M1
IIB	T3N0-1M0
III	T4N0-1M0
IVA	T1-4N2-3M0
IVB	T1-4N0-3M1

Sézary Syndrome

According to the World Health Organization-European Organization for Research and Treatment of Cancer, Sézary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T cells (Sézary cells) in the skin, lymph nodes, and peripheral blood. The International Society of Cutaneous Lymphomas recommends an absolute Sézary cell count of at least 1000 cells/ mm³, in the presence of immunophenotypical abnormalities (CD4/CD8 ratio >10; loss of any or all of the T-cell antigens CD2, CD3, CD4, and CD5; or both), or the demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods.

DESCRIPTION OF PROCEDURE OR SERVICE:

Organ Rejection Treatment After Solid Organ Transplant

The standard treatment for organ transplant rejection is immunosuppression, with the particular regimen dictated by the organ being transplanted. As organ transplantation success rates have improved, more patients are facing the morbidity and mortality associated with immunosuppressive treatments developed to prevent rejection of the transplanted organ. Immunosuppressive therapies are used to lower the responsiveness of the recipient’s immune system, decreasing the chance of rejection. Unfortunately, portions of the immune system responsible for the prevention of viral, fungal, and bacterial infections also are affected. Consequently, leading to serious infections, including opportunistic infections.

Although first approved for the treatment of cutaneous T-cell lymphoma (CTCL), extracorporeal photopheresis (ECP), in recent times has been used as a supplement to conventional treatments in the area of solid organ transplantation. Reports of the successful use of ECP in human cardiac transplant recipients were published in 1992 and use in other transplant patients followed. Although the specific mechanism of action of ECP is unknown, the reinfusion of treated leukocytes seems specifically to suppress the patient’s immune response to the donor organ, although maintaining the body’s ability to respond to other antigens. The specificity of ECP to target the immune response to the transplanted organ allows ECP to decrease organ rejection without an increased risk of infection, common with immunosuppressive drugs.

Graft-versus-Host Disease (GVHD)

ECP 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 immune mediated disease. GVHD can be categorized into acute disease, 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 from I to IV, ranging from mild disease, which is 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 life-threatening. Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such as progressive systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. Chronic GVHD may affect the mouth, eyes, respiratory tract, musculoskeletal system, and peripheral nerves, as well as the skin, liver, or gut—the usual sites of acute GVHD.

Autoimmune Disease

The use of ECP as a treatment of autoimmune disease is based on the premise that pathogenic lymphocytes form an expanded clone of cells, which are damaged when exposed to UV light in the presence of 8- methoxypsoralen (8-MOP). It is hypothesized that the resulting damage induces a population of circulating suppressor T- cells targeted against the light-damaged cells. It is further hypothesized that these suppressor T- cells are targeted at a component of the cell that is common to the entire clone of abnormal cells (i.e., not just the light-sensitized cells), thus inducing a systemic effect. However, although scleroderma and other autoimmune diseases are associated with the presence of circulating antibodies, it is not certain how these antibodies are related to the pathogenesis of the disease, and, as discussed in this policy, photopheresis is not associated with consistent changes in autoantibody levels.

T-Cell Lymphoma

Cutaneous T-Cell Lymphoma (CTCL)

According to the National Cancer Institute (NCI), cutaneous T-cell lymphoma (CTCL) is a neoplasia of malignant - lymphocytes that initially present as skin involvement. CTCL is extremely rare, with an estimated incidence of approximately 0.4 per 100,000 annually but, because most are low-grade malignancies with long survival, the overall prevalence is much higher. Two CTCL variants, mycosis fungoides and the Sézary syndrome, account for approximately 60% and 5% of new cases of CTCL, respectively.

CTCL is included in the Revised European-American Lymphoma classification as a group of low-grade T cell lymphomas, which should be distinguished from other T cell lymphomas that involve the skin, such as anaplastic large cell lymphoma, peripheral T cell lymphoma, adult T cell leukemia/lymphoma (usually with systemic involvement), or subcutaneous panniculitic T cell lymphoma. In addition, a number of benign or very indolent conditions can be confused with mycosis fungoides, further complicating diagnosis

Mycosis fungoides typically progress from an eczematous patch/plaque stage, covering less than 10% of the body surface (T1), to a plaque stage, covering 10% or more of the body surface (T2), and finally to tumors (T3) that frequently undergo necrotic ulceration. Sézary syndrome is an advanced form of mycosis fungoides with generalized erythroderma (T4) and peripheral blood involvement (B1) at presentation. Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma sometimes occurs during the course of these diseases and is associated with a poor prognosis. A common cause of death during the tumor phase is sepsis from Pseudomonas aeruginosa or Staphylococcus aureus caused by chronic skin infection with Staphylococcus species and subsequent systemic infections.

The natural history of mycosis fungoides is typically indolent. Symptoms may present for long periods (mean, 2-10 years) as waxing and waning cutaneous eruptions before biopsy confirmation. The prognosis of patients with mycosis fungoides/Sézary syndrome is based on the extent of disease at presentation and its stage. Lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. Median survival after diagnosis varies according to stage. Median survival in patients with stage IA disease exceeds 20 years, with most deaths in this group typically unrelated to mycosis fungoides. In contrast, median survival in patients with stage III or IV disease is less than 5 years; more than 50% of these patients die of their disease.

Appropriate therapy of CTCL depends on a variety of factors, including stage, the patient's overall health, and the presence of symptoms. In general, therapies can be categorized into topical and systemic treatments that include ECP. In contrast to more conventional lymphomas, CTCL is possibly not curable except ones in the earliest stages. Thus, systemic cytotoxic chemotherapy is avoided except for advanced-stages. Partial or complete remission is achievable, although the majority of patients require lifelong treatment and monitoring.

KEY POINTS:

The most recent literature update was performed on August 27, 2024. The following is a summary of the key literature to date.

Summary of Evidence

Graft Rejection after Solid Organ Transplant

Heart Transplant

For individuals who are heart transplant recipients who experience acute graft rejection refractory to immunosuppression who receive extracorporeal photopheresis (ECP), the evidence includes a small randomized controlled trial (RCT). The relevant outcomes are overall survival (OS), change in disease status, and treatment-related mortality and morbidity. The small RCT, while suggesting similar outcomes for ECP and corticosteroids, is insufficient to permit conclusions on the utility of ECP. Studies with more patients and longer follow-up are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are heart transplant recipients who experience recurrent and/or refractory graft rejection who receive ECP, the evidence includes a comparative study and small case series. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Current evidence is consistent on the beneficial effect of ECP for cardiac transplant patients with graft rejection refractory to standard therapy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are heart transplant recipients who require prophylaxis to prevent graft rejection who receive ECP, the evidence includes a small RCT and a prospective pilot study. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. The small randomized trial is insufficient to permit conclusions on the utility of ECP. The pilot study was non-comparative and evaluated outcomes in high-risk cardiac transplant patients. Studies with more patients and longer follow-up are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Lung Transplant

For individuals who are lung transplant recipients who experience acute graft rejection who receive ECP, the evidence includes a small retrospective study and small case series. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Current evidence is very limited and any conclusions drawn lack certainty. A prospective, randomized trial is needed specifically evaluating the treatment of patients with acute graft rejection. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are lung transplant recipients with bronchiolitis obliterans syndrome (BOS) refractory to corticosteroids who receive ECP, the evidence includes a prospective study and numerous retrospective analyses. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Studies have shown inconsistent results across bronchiolitis obliterans syndrome (BOS) grades. Prospective, RCTs are necessary with analyses stratified by syndrome grade. The evidence is insufficient to determine the effects of the technology on health outcomes

Liver Transplant

For individuals who are liver transplant recipients who experience graft rejection and receive ECP, the evidence includes a small nonrandomized study, a retrospective study, and a case series. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Current evidence does not permit conclusions on the utility of ECP in this population. There is a need for RCTs comparing immunosuppressive therapy alone with immunosuppressive therapy with ECP. The evidence is insufficient to determine the effects of the technology on health outcomes.

Kidney Transplant

For individuals who are kidney transplant recipients who experience recurrent graft rejection who receive ECP, the evidence includes a small prospective study and numerous case reports. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Current evidence does not permit conclusions on the effect of ECP on net health outcome. There is a need for RCTs comparing immunosuppressive therapy with and without the use of ECP and examining histologic confirmation of treatment response. The evidence is insufficient to determine the effects of the technology on health outcomes.

Graft-Versus-Host Disease

For individuals who have acute or chronic graft-versus-host disease (GVHD) refractory to medical treatment who receive ECP, the evidence includes systematic reviews, retrospective studies, and case series. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Current evidence has consistently shown that ECP reduces the incidence of GVHD that is unresponsive to standard therapy. Additionally, there is a lack of other treatment options for these patients; adverse events related to ECP are minimal; and, if there is a response to ECP, patients may be able to reduce or discontinue treatment with corticosteroids and other immunosuppressive agents. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Other Indications, Not Related To Solid Organ Transplant

Autoimmune Disease

For individuals who have autoimmune diseases (e.g., cutaneous or visceral manifestations of autoimmune diseases including but not limited to scleroderma, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, multiple sclerosis, diabetes, autoimmune bullous disorders, severe atopic dermatitis, and Crohn disease) who receive ECP, the evidence includes isolated RCTs, small prospective and retrospective studies, and case reports. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. The current literature assessing the various autoimmune diseases is not sufficiently robust to support conclusions. The evidence is insufficient to determine the effects of the technology on health outcomes.

Cutaneous T-Cell Lymphoma

For individuals who have advanced-stage (stage III or IV) cutaneous T-cell lymphoma (CTCL) who receive ECP, the evidence includes a systematic review and numerous small case series. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Evidence from these small case series has shown a favorable response to ECP treatment and an increase in survival in a proportion of these patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have refractory or progressive early-stage (stage I or II) CTCL who receive ECP, the evidence includes a systematic review. The relevant outcomes are OS, change in disease status, and treatment-related mortality and morbidity. Given the unfavorable prognosis for patients with early-stage CTCL that progresses on nonsystemic therapies, the relative lack of adverse events with ECP compared with other systemic treatments, and the good response rates often observed with ECP, this therapy is an option for those with refractory or progressive early-stage CTCL. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

Transplant

Lung Transplant

International Society for Heart and Lung Transplantation

A 2019 document from the International Society for Heart and Lung Transplantation addressed the use of ECP in patients with chronic lung allograft dysfunction/bronchiolitis obliterans syndrome. The guideline listed ECP as a therapeutic option and stated that ECP may be most beneficial in patients with a slow decline in forced expiratory volume in 1 second (FEV1) and increased neutrophilia on bronchoalveolar lavage. Patients with rapidly declining FEV1, lack of significant neutrophilia, or restrictive allograft syndrome.

Acute GVHD

American Society of Blood and Marrow Transplantation

Evidence-based recommendations from the American Society of Blood and Marrow Transplantation (2012) (now the American Society for Transplantation and Cellular Therapy) advised that extracorporeal photopheresis (ECP) cannot be considered superior to horse antithymocyte globulin for the treatment of acute GVHD. This conclusion was based on older studies.

Acute and Chronic GVHD

European Society for Blood and Marrow Transplantation

In 2024, the European Society for Blood and Marrow Transplantation published updated prophylaxis and management guidelines for acute and chronic GVHD. The guidelines state that while there is no standard second-line treatment for both acute and chronic GVHD, ECP is listed as therapy for use for second-line treatment. The guideline does comment that not enough data exists to compare the efficacy of different second-line treatments.

Cutaneous T-Cell Lymphoma

National Comprehensive Cancer Network

National Comprehensive Cancer Network guidelines on primary cutaneous lymphomas (v.3.2024) list the use of ECP as a category 2A treatment alone or in combination with other agents as first-line systemic therapy for advanced (stages III-IV) disease, as well as for patients with earlier stage mycosis fungoides with Sézary syndrome involvement. The guidelines add that ECP may be more appropriate as systemic therapy in patients with or at risk of blood involvement (B1 or B2; erythrodermic stage III disease or IVA with Sézary syndrome).

National Cancer Institute

The National Cancer Institute lists ECP (alone or in combination with total-skin electron-beam radiation) as a phototherapeutic option for patients with stage III or IV Sezary syndrome or erythrodermic mycosis fungoides.

U.S. Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

Extracorporeal photopheresis, ECP, graft vs host disease, GVHD, GvHD, acute GVHD, aGVHD, chronic GVHD, cGVHD, ECP, 8- methoxypsoralen, 8-MOP, UVADEX, UVAR XTS, CELLEX Photopheresis System, transplant rejection, hemodynamic compromise rejection, HC rejection, cutaneous t-cell lymphoma, CTCL, transplant rejection

APPROVED BY GOVERNING BODIES:

Two photopheresis systems (Therakos; now Mallinckrodt) were approved by the U.S. Food and Drug Administration (FDA) through the premarket approval process. Both systems are approved for use in ultraviolet-A irradiation treatment, in the presence of the photoactive drug 8-methoxypsoralen, of extracorporeally circulating leukocyte-enriched blood, in the palliative treatment of skin manifestations of CTCL, in persons who have not been responsive to other forms of treatment. The 2 systems are:

• UVAR® XTS Photopheresis System (FDA approved in 1987).

• CELLEX® (FDA approved in 2009).

Photoactive 8-methoxypsoralen (UVADEX®; Therakos; now Mallinckrodt) is FDA approved for extracorporeal administration with the UVAR® XTS or CELLEX® Photopheresis System in the palliative treatment of the skin manifestations of CTCL unresponsive to other forms of treatment.

The use of either photopheresis system or UVADEX® for other conditions is off-label. FDA product code: LNR.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply. Refer to member’s benefit plan.

CURRENT CODING: 

CPT code:

36522

Photopheresis, extracorporeal

REFERENCES:

1. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marrow Transplant. Nov 2014; 20(11):1677-1686.
2. Baron ED, Heeger PS, et al. Immunomodulatory effect of extracorporeal photopheresis after successful treatment of resistant renal allograft rejection. Photodermatol Photoimmunol Photomed, April 2001; 17(2): 79-82.
3. Barr, M.L. Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. New Engl J Med Dec 10 1998; 339:24; 1744-1751.
4. Batgi H, Dal MS, Erkurt MA, et al. Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: A multicenter experience. Transfus Apher Sci. Oct 2021; 60(5): 103242.
5. Benden C, Haughton M, Leonard S, et al. Therapy options for chronic lung allograft dysfunction-bronchiolitis obliterans syndrome following first-line immunosuppressive strategies: A systematic review. J Heart Lung Transplant. Sep 2017;36(9): 921-933.
6. Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation: A 10-year single-center experience. Transplantation, December 15 2008; 86(11): 1625-1627.
7. Berger M, Pessolano R, Albiani R et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol Oct 2007; 29(10):678-687.
8. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Extracorporeal photopheresis for autoimmune disease. TEC Assessments 2001; Volume 16, Tab 10.
9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Extracorporeal photopheresis for graft-versus-host disease. TEC Assessments 2001; Volume 16, Tab 9.
10. Bredeson C, Rumble RB, Varela NP, et al. Extracorporeal photopheresis in the management of graft-versus-host disease. Curr Oncol. Apr 2014; 21(2):e310-325.
11. Buder K, Zirngibl M, Bapistella S, et al. Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents. Cochrane Database Syst Rev. Jun 09 2022; 6(6): CD009898.
12. Carlo WF, Pearce FB, George JF, et al. Single-center experience with extracorporeal photopheresis in pediatric heart transplantation. J Heart Lung Transplant. Jun 2014; 33(6):624-628.
13. Cavaletti G, Perseghin P, Dassi M, Cavarretta R, et al. Extracorporeal photochemotherapy:  A safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol Sci, Apr 2006; 27(1): 24-32.
14. Costanzo-Nordin MR, Hubbell EA, et al. Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report. Circulation, November 1992; 86(5 Suppl): II242-II250.
15. Dal MS, Batgi H, Erkurt MA, et al. Extracorporeal photopheresis in steroid-refractory chronic graft-versus-host disease: A retrospective multicenter study. Transfus Apher Sci. Oct 2021; 60(5): 103243.
16. Dall’Amico R, Murer L, et al. Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol Jan 1998; 9(1): 121-127.
17. Dall’Amico R and Murer L. Extracorporeal photochemotherapy after cardiac transplantation: A new therapeutic approach for allograft rejection. Int J Artif Organs. Jan 2000; 23(1): 49-54.
18. Dall'Amico R, Murer L. Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection. Transfus Apher Sci. Jun 2002; 26(3): 197-204.
19. Das-Gupta E, Dignan F, Shaw B, et al. Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature. Bone Marrow Transplant. Oct 2014; 49(10):1251-1258.
20. Del Fante C, Scudeller L, Oggionni T, et al. Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre Analysis. Respiration. 2015; 90(2): 118-28.
21. Dignan FL, Aguilar S, Scarisbrick JJ et al. Impact of extracorporeal photopheresis on skin scores and quality of life in patients with steroid-refractory chronic GVHD. Bone Marrow Transplant May 2014; 49(5):704-708.
22. Edelson R, Berger C, Gasparro F et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med Feb 05 1987; 316(6):297-303.
23. Foss FM, DiVenuti GM, Chin K et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant Jun 2005; 35(12):1187-1193.
24. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. Oct 1 2008; 112(7):2667-2674.
25. Freiman A, Sasseville D. Treatment of mycosis fungoides: overview. J Cutan Med Surg 2006; 10(5):228-233.
26. Fries JF, Seibold JR, Medsger TA, Jr. Photopheresis for scleroderma? No! J Rheumatol Jul 1992; 19(7):1011-1013.
27. Gao C, McCormack C, van der Weyden C, et al. Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome. Blood. Oct 17 2019; 134(16): 1346-1350.
28. Gokler J, Aliabadi-Zuckermann A, Zuckermann A, et al. Extracorporeal Photopheresis With Low-Dose Immunosuppression in High-Risk Heart Transplant Patients-A Pilot Study. Transpl Int. 2022; 35: 10320.
29. Greer M, Dierich M, De Wall C et al. Phenotyping established chronic lung allograft dysfunction predicts extracorporeal photopheresis response in lung transplant patients. Am J Transplant Apr 2013; 13(4):911-918.
30. Greinix HT, Knobler RM, Worel N et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica Mar 2006; 91(3):405-408.
31. Greinix HT, Volc-Platzer B, Knobler R. Criteria for assessing chronic GVHD. Bone Marrow Transplant Mar 2000; 25(5):575.
32. Halle P, Paillard C, D'Incan M et al. Successful extracorporeal photochemotherapy for chronic graft-versus-host disease in pediatric patients. J Hematother Stem Cell Res Jun 2002; 11(3):501-512.
33. Hautmann AH, Wolff D, Hahn J et al. Extracorporeal photopheresis in 62 patients with acute and chronic GVHD: results of treatment with the COBE Spectra System. Bone Marrow Transplant Mar 2013; 48(3):439-445.
34. Hivelin M, Siemionow M, et al. Extracorporeal photopheresis: From solid organs to face transplantation. Transpl Immunol, July 2009; 21(3): 117-128.
35. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
36. Jacob MC, Manches O, Drillat P et.al. Quality control for the validation of extracorporeal photopheresis process using the Vilbert-Lourmat UV-A irradiation’s system. Transfus Apher Sci 2003; 28(1):63-70.
37. Jagasia M, Greinix H, Robin M et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant Jul 2013; 19(7):1129-1133.
38. Jaksch P, Scheed A, Keplinger M et al. A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant Sep 2012; 31(9):950-957.
39. Jardine MJ, Bhandari S, Syburn KR, et al. Photopheresis therapy for problematic renal allograft rejection. J Clin Apher 2009; 24(4): 161-169.
40. Kansu E, Ward D, Sanchez AP, et al. Extracorporeal photopheresis for the treatment of chronic graft versus host disease. Hematology. Dec 2022; 27(1): 785-794.
41. Keehn CA, Belongie IP, Shistik G et al. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control Apr 2007; 14(2):102-111.
42. Kirklin JK, Brown RN, Huang ST, et al. Rejection with hemodynamic compromise:  Objective evidence for efficacy of photopheresis. J Heart Lung Transplant, March 2006; 25(3): 283-288.
43. Kitko CL, Abdel-Azim H, Carpenter PA, et al. A Prospective, Multicenter Study of Closed-System Extracorporeal Photopheresis for Children with Steroid-Refractory Acute Graft-versus-Host Disease. Transplant Cell Ther. May 2022; 28(5): 261.e1-261.e7
44. Knobler E. Current management strategies for cutaneous T-cell lymphoma. Clin Dermatol 2004; 22(3):197-208.
45. Knobler R, Berlin G, Calzavara-Pinton P et al. Guidelines on the use of extracorporeal photopheresis. J Eur Acad Dermatol Venereol 2014; 28 Suppl 1:1-37.
46. Knobler R, Duvic M, Querfeld C et al. Long-term follow-up and survival of cutaneous T-cell lymphoma patients treated with extracorporeal photopheresis. Photodermatol Photoimmunol Photomed Oct 2012; 28(5):250-257.
47. Kozlov A, Estrina M, Paina O, et al. Extracorporeal Photopheresis in Children with Chronic Graft-Versus-Host Disease. Pharmaceuticals (Basel). Aug 17 2021; 14(8).
48. Kumlien G, Genberg H, et al. Photopheresis for the treatment of refractory renal graft rejection. Transplantation, Jan 15 2005; 79(1): 123-125.
49. Leroux J, Hirschi S, Essaydi A, et al. Initiation of extracorporeal photopheresis in lung transplant patients with mild to moderate refractory BOS: A single-center real-life experience. Respir Med Res. May 2022; 81: 100913
50. Lucid CE, Savani BN, Engelhardt BG et al. Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transplant 2011; 46(3):426-429.
51. Ludvigsson J, Samuelsson U, Ernerudh J et al. Photopheresis at onset of type I diabetes: a randomised, double blind, placebo controlled trial. Arch Dis Child Aug 2001; 85(2):149-54.
52. Maccherini M, Diciolla F, et al. Photopheresis immunomodulation after heart transplantation. Transplant Proc 2001; 33(1-2): 1591-1594.
53. Malik MI, Litzow M, Hogan W, et al. Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis. Blood Res. Jun 2014; 49(2):100-106.
54. Marques MB and Tuncer HH. Photopheresis in solid organ transplant rejection. J Clin Apher, April 2006; 21(1): 72-77.
55. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Aug 2012; 18(8): 1150-63.
56. Mehta RS, Bassett R, Rondon G, et al. Randomized phase II trial of extracorporeal phototherapy and steroids vs. steroids alone for newly diagnosed acute GVHD. Bone Marrow Transplant. Jun 2021; 56(6): 1316-1324.
57. Melski JW. Price of technology. A blind spot. JAMA Mar 18 1992; 267(11):1516-1518.
58. Morrell MR, Despotis GJ, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant, April 2010; 29(4): 424-431.
59. National Cancer Institute. Mycosis Fungoides (Including Sezary Syndrome) Treatment (PDQ) Health Professional Version. August 16, 2024; www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq.
60. National Cancer Institute. Childhood Hematopoietic Cell Transplantation (PDQ) Health Professional Version. June 13, 2024; www.cancer.gov/types/childhood-cancers/hp-stem-cell-transplant#_5.
61. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice Guidelines in Oncology: Primary Cutaneous Lymphomas. Version 3.2024. www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf. 
62. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines on B-Cell Lymphomas: v.3.2024. www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. 
63. Ontario Health Technology Assessment Committee (OHTAC) Recommendation: Extracorporeal Photopheresis. 2006. www.hqontario.ca/english/providers/program/ohtac/tech/recommend/rec_ecp_032806.pdf. 
64. Papp G, Horvath IF, Barath S et al. Immunomodulatory effects of extracorporeal photochemotherapy in systemic sclerosis. Clin Immunol Feb 2012; 142(2):150-159.
65. Penack O, Marchetti M, Aljurf M, et al. Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haematol. Feb 2024; 11(2): e147-e159.
66. Perfetti P, Carlier P, Strada P et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant Nov 2008; 42(9):609-617.
67. Perotti C, Del Fante C, Tinelli C et al. Extracorporeal photochemotherapy in graft-versus-host disease: a longitudinal study on factors influencing the response and survival in pediatric patients. Transfusion Jun 2010; 50(6):1359-1369.
68. Pierelli L, Perseghin P, Marchetti M et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfusion 2013; 53(10):2340-2352.
69. Reinisch W, Knobler R, Rutgeerts PJ, et al. Extracorporeal photopheresis (ECP) in patients with steroid-dependent Crohn's disease: an open-label, multicenter, prospective trial. Inflamm Bowel Dis. Feb 2013; 19(2):293-300.
70. Rook AH, Freundlich B, Jegasothy BV et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol Mar 1992; 128(3):337-346.
71. Rose EA, Barr ML, Xu H, et al. Photochemotherapy in human heart transplant recipients at high risk for fatal rejection. J Heart Lung Transplant 1992; 11(4 Pt 1): 746-750.
72. Rubegni P, Cuccia A, Sbano P et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. Br J Haematol Jul 2005; 130(2):271-275.
73. Rubegni P, Feci L, Poggiali S et al. Extracorporeal photopheresis: a useful therapy for patients with steroid-refractory acute graft-versus-host disease but not for the prevention of the chronic form. Br J Dermatol Aug 2013; 169(2):450-457.
74. Rubegni P, Poggiali S, Cevenini G et al. Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal photochemotherapy. J Eur Acad Dermatol Venereol Apr 2013; 27(4):523-526.
75. Salerno CT, Park SJ, Kreykes NS, et al. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg, June 1999; 117(6): 1063-1069.
76. Salvaneschi L, Perotti C, Zecca M et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion Oct 2001; 41(10):1299-1305.
77. Sanli H, Akay BN, Ayyildiz E et al. Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy. Transfus Apher Dec Sci 2010; 43(3):353-359.
78. Scarisbrick JJ. Staging and management of cutaneous T-cell lymphoma. Clin Exp Dermatol Mar 2006; 31(2):181-186.
79. Scarisbrick JJ, Taylor P, Holtick U et al. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol Apr 2008; 158(4):659-678.
80. Shaughnessy PJ, Bolwell BJ, van Besien K et al. Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant Jun 2010; 45(6):1068-1076.
81. Solh MM, Farnham C, Solomon SR, et al. Extracorporeal photopheresis (ECP) improves overall survival in the treatment of steroid refractory acute graft-versus-host disease (SR aGvHD). Bone Marrow Transplant. Feb 2023; 58(2): 168-174.
82. Szczepiorkowski ZM, Bandarenko N, Kim HC, et al. Guidelines on the use of therapeutic apheresis in clinical practice: Evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher, June 2007; 22(3): 106-175.
83. Sunder-Plassman G, Druml W, et al. Renal allograft rejection controlled by photopheresis. Lancet, Aug 19 1995; 346(8973): 506.
84. Therakos, Inc. US FDA approves new THERAKOS™ CELLEX™ Photopheresis system. News Release, March 23, 2009. www.biospace.com/article/releases/u-s-fda-approves-therakos-inc-s-new-therakos-tm-cellex-tm-photopheresis-system-/. 
85. Trautinger F, Knobler R, Willemze R et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer May 2006; 42(8):1014-1030.
86. Trentham DE. Photochemotherapy in systemic sclerosis. The stage is set. Arch Dermatol Mar 1992; 128(3):389-390.
87. Urbani L, Mazzoni A, Catalano G, et al. The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients. Transplant Proc, Dec 2004; 36(10): 3068-3070.
88. Urbani L, Mazzoni A, 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): 187-194.
89. Urbani L, Mazzonie A, Colombatto P, et al. Potential applications of extracorporeal photopheresis in liver transplantation. Transplant Proc, May 2008; 40(4): 1175-1178.
90. Ussowicz M, Musial J, Mielcarek M et al. Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Transplant Proc Nov 2013; 45(9):3375-3380.
91. Villanueva J, Bhorade SM, Robinson JA, et al. Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 2000; 5(3): 44-47.
92. Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. May2019; 38(5): 493-503.
93. Weitz M, Strahm B, Meerpohl JJ et al. Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients. Cochrane Database Syst Rev Feb 25 2014; 2:CD009898.
94. Weitz M, Strahm B, Meerpohl JJ et al. Extracorporeal photopheresis versus standard treatment for acute graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients. Cochrane Database Syst Rev Feb 25 2014; 2:CD009759.
95. Whittaker SJ, Foss FM. Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sézary syndrome variants of cutaneous T-cell lymphoma. Cancer Treat Rev Apr 2007; 33(2):146-160.
96. Wolf P, Georgas D, Tomi NS et al. Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from a prospective trial. Photochem Photobiol Sci Jan 2013; 12(1):174-181.
97. Zhang H, Chen R, Cheng J, et al. Systematic review and meta-analysis of prospective studies for ECP treatment in patients with steroid-refractory acute GVHD. Patient Prefer Adherence 2015; 9:105-111.

POLICY HISTORY:

Medical Policy Group, 1991

Medical Policy Group, 1996

TEC Medical Policy Reference Manual, August 8, 2000

Medical Policy Group, July 2001

Medical Review Committee, September 26, 2001

TEC Medical Policy Reference Manual, October 4, 2001

Medical Policy Administration Team, November 8, 2001

Medical Policy Group, October 2003 (1)

Medical Policy Group, October 2004 (1)

Medical Policy Group, October 2005 (1)

Medical Policy Group, October 2006 (1)

Medical Policy Group, June 2007 (1)

Medical Policy Group, April, 2010 (1): Added new coverage statement, Key Points, References, 

Medical Policy Administration Committee, April 2010

Available for comment April 8-May 23, 2010

Medical Policy Group, November 2012 (1): Update to Key Points and References related to MPP update; no change in policy statement

Medical Policy Panel, February 2013

Medical Policy Group, September 2013 (1): Added verbiage to noncoverage statement for clarification purposes, ECP is investigational for “all other indications, including, but not limited to:” no change in coverage; update to Description, Key Points, Governing Bodies and References

Medical Policy Administration Committee, September 2013

Medical Policy Panel, May 2014

Medical Policy Group, June 2014 (1): Update to Policy statement, Key Points, Governing Bodies and References related to addition of coverage criteria for refractory acute GVHD; no other changes to policy

Medical Policy Administration Committee, July 2014

Available for comment June 30 through August 13, 2014

Medical Policy Panel, April 2015

Medical Policy Group, April 2015 (3): 2015 Updates to Key Points and References, no change to policy statement.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (7): 2017 Updates to Key Points and References. No change to Policy Statement.

Medical Policy Panel, October 2018

Medical Policy Group, October 2018 (3): Updates to Description, Key Points, References and Key Words: added: ECP, 8- methoxypsoralen, 8-MOP, UVADEX®, UVAR XTS®, CELLEX™ Photopheresis System, transplant rejection, hemodynamic compromise rejection, HC rejection, acute GVHD, aGVHD, chronic GVHD, and cGVHD. No changes to policy statement or intent.

Medical Policy Panel, October 2019

Medical Policy Group, November 2019 (3): 2019 Updates to Key Points, and Practice Guidelines and Position Statements. No changes to policy statement or intent.

Medical Policy Panel, October 2020

Medical Policy Group, November 2020 (3): 2020 Updates to Key Points, Practice Guidelines and Position Statements and References. Added the diagnosis Crohn’s Disease as not medically necessary and investigational to the list of autoimmune diseases. No other changes to policy statement or intent.  

Medical Policy Panel, October 2021

Medical Policy Group, November 2021(3): 2021 Updates to Key Points, Practice Guidelines and Position Statements and References. No other changes to policy statement or intent. 

Medical Policy Panel, October 2022

Medical Policy Group, October 2022 (3): 2022 Updates Key Points, Approved By Governing Bodies, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent. 

Medical Policy Panel, October 2023

Medical Policy Group, October 2023 (11): Minor update to policy guidelines, Key Points, Benefit Application, and References. No changes to policy intent.

Medical Policy Panel, October 2024

Medical Policy Group, October 2024 (11): Updates to Key Points, Benefit Application, and References. No changes to policy intent. 

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.