Print Extracorporeal Photopheresis

Extracorporeal Photopheresis






Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory procedure that involves the following steps:

  1. Patient blood is collected into a centrifuge system that separates the leukocyte-rich portion (buffy coat) from the rest of the blood.
  2. The photosensitizer agent 8-methoxypsoralen (8-MOP) is added to the lymphocyte fraction, which is then exposed to ultraviolet (UV) A (320-400 nm wavelength) light at a dose of 1-2 J/cm².
  3. The light-sensitized lymphocytes are reinfused into the patient.

ECP has been investigated for the treatment of patients with a variety of autoimmune diseases, graft-versus-host disease (GVHD), T-cell lymphoma (TCL), treatment for and prevention of organ rejection after solid organ transplant, and other miscellaneous conditions.

Treatment for and Prevention of Organ Rejection After Solid Organ Transplant

The standard of care for treatment of 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 therapies 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 infection also are affected. This can, in turn, lead to serious infections, including opportunistic infections.

Although first approved for the treatment of CTCL, ECP has more recently been used as a supplement to conventional therapies 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 to specifically 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.

Treatment of Graft-versus-Host Disease (GVHD)

ECP as a treatment of 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 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–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, peripheral nerves, as well as the skin, liver, or gut—the usual sites of acute GVHD.

Treatment of Autoimmune Disease

The use of ECP as a treatment of autoimmune disease is based on the premise that the pathogenic lymphocytes form an expanded clone of cells, which are damaged when exposed to UV light in the presence of 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 autoantibodies, it is unknown how these antibodies are related to the pathogenesis of the disease. Photopheresis is not associated with consistent changes in autoantibody levels.

Treatment of T-Cell Lymphoma

Cutaneous T-Cell Lymphoma
According to the National Cancer Institute, cutaneous T-cell lymphoma (CTCL) is a neoplasia of malignant T-lymphocytes that initially presents as skin involvement. CTCL is extremely rare, with an estimated incidence of about 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 about 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. See the Policy Guidelines for the current staging classification of CTCL using the TNM (tumor, node, metastasis) classification system.

Mycosis fungoides typically progresses 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 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, an average of 2 to 10 years, as waxing and waning cutaneous eruptions prior to 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. The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 or more years, with the majority of deaths for this group typically unrelated to mycosis fungoides. In contrast, more than 50% of patients with stage III through stage IV disease die of their disease, with a median survival of less than 5 years.

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, possibly excepting ones in the earliest stages, is not curable. Thus, systemic cytotoxic chemotherapy is avoided except for advanced-stage cases. Partial or complete remission is achievable, although the majority of patients require lifelong treatment and monitoring.

Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a group of rare and usually aggressive non-Hodgkin lymphomas that develop from mature T cells. PTCL comprises approximately 10% to 15% of all cases of non-Hodgkin lymphoma in the U.S. and generally occurs in adults 60 years of age or older. Standards of care are evolving, including the use of hematopoietic stem cell transplantation.

FDA has approved via premarket application for two photopheresis systems manufactured by Therakos™ Inc. (West Chester, PA). Both systems are approved for use in ultraviolet A (UVA) irradiation treatment, in the presence of the photoactive drug 8-MOP, of extracorporeally circulating leukocyte-enriched blood, in the palliative treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL), in persons who have not been responsive to other forms of treatment. The two systems are:

  • UVAR® XTS Photopheresis System, FDA approved in 1987.
  • CELLEX®, FDA approved in 2009.

8-MOP (UVADEX®) is approved by the FDA for extracorporeal administration with the UVAR XTS or CELLEX Photopheresis System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma in persons who have not been responsive to other therapy.

The use of either Therakos Photopheresis System or UVADEX® for other conditions is an off-label use of an FDA-approved device/drug.



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.

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

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

Extracorporeal photopheresis may be considered medically necessary as a technique to treat early stage (I/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/II) cutaneous T-cell lymphoma that is either previously untreated or is responding to established nonsystemic therapies.

Extracorporeal photopheresis is considered investigational as a technique to treat either the 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, or Crohn disease.

Extracorporeal photopheresis is considered investigational as a technique to treat acute graft-versus-host disease or chronic graft-versus-host disease that is either previously untreated or is responding to established therapies.



Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity. 



The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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 that recurred after standard immunosuppressive therapy.

There is no standard schedule for extracorporeal photopheresis, and reported schedules vary by the organ type. However, most reported cardiac and lung schedules initiate therapy with 2 consecutive days of extracorporeal photopheresis 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 GVHD. For chronic GVHD, an alternating regimen of cyclosporine and prednisone is commonly used; other therapies include antithymocyte globulin, corticosteroid monotherapy, and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide, or azathioprine. Therefore, refractory disease is defined as graft-versus-host disease 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 generally recommend 1 cycle (ie, ECP on 2 consecutive days) weekly for acute GVHD and every 2 weeks for chronic GVHD. Treatment duration is based on clinical response; discontinuation is generally recommended for no or minimal response.

CTCL Staging (based on the TNM classification system)

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 (WHO-EORTC), Sézary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T-cells (Sézary cells) in skin, lymph nodes, and peripheral blood. The International Society of Cutaneous Lymphomas recommends an absolute Sézary cell count of at least 1,000 cells per cubic mm, in the presence of immunophenotypical abnormalities (CD4/CD8 ratio greater than 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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.



5/2001: Approved by Medical Policy Advisory Committee (MPAC)

2/14/2002: Investigational definition added

5/2/2002: Type of Service and Place of Service deleted

5/29/2002: Code Reference section updated

1/27/2004: Literature search 2001-2003, remains investigational, pemphigus, psoriasis, multiple sclerosis or diabetes added, CPT codes 96900, 96912 deleted, ICD-9 diagnosis codes 701.1, 710.0, 710.1, 714.0-714.9 deleted

10/23/2006: Policy reviewed, graft-versus-host disease section added to policy section

1/14/2008: Policy reviewed, no changes

06/22/2010:  Policy title changed from “Photopheresis as a Treatment of Autoimmune Disease” to “Extracorporeal Photopheresis as a Treatment of Graft-versus-Host Disease, Autoimmune Disease, and Cutaneous T-Cell Lymphoma” to reflect the conditions addressed.  Policy description updated to address graft-versus-host disease (GVHD) and cutaneous T-cell lymphoma (CTCL) and to add FDA information. Three new policy statements regarding T-cell lymphoma (CTCL) added, including two medically necessary statements. Intent of other policy statements unchanged.  Supporting explanations added to the policy guidelines.  FEP verbiage added to the Policy Exceptions section. Added ICD-9 codes 202.10-202.18, 202.20-202.28, 202.70-202.78, 279.50-279.53, 710.1, 710.0, 714.0-714.9, and 996.85.

04/25/2011: Policy statement revised to add autoimmune bullous disorders as investigational.

03/27/2012: Policy reviewed; no changes.

07/18/2013: Policy reviewed; no changes to policy statement. Removed non-covered diagnosis codes 710.1, 710.0, and 714.0-714.9 from the Code Reference section.

10/30/2014: Policy reviewed; description updated regarding peripheral T-cell lymphoma. Medically necessary policy statement regarding chronic GVHD revised to state that extracorporeal photopheresis may be medically necessary as a technique to treat acute graft-versus-host disease or chronic graft-versus-host disease that is refractory to medical therapy. Investigational policy statement for autoimmune diseases updated to add "severe atopic dermatitis or Chrohn disease." Policy guidelines updated regarding acute GVHD and recommendations regarding the treatment schedule and duration of ECP for GVHD.

08/27/2015: Code Reference section updated for ICD-10.

03/04/2016: Policy description updated regarding photopheresis systems. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.

06/09/2016: Policy number A.8.01.36 added. The Extracorporeal Photopheresis as Treatment for and Prevention of Organ Rejection after Solid Organ Transplant medical policy was combined with this policy. Policy title changed from "Extracorporeal Photopheresis as a Treatment of Graft-versus-Host Disease, Autoimmune Disease, and Cutaneous T-Cell Lymphoma" to "Extracorporeal Photopheresis" to reflect combined policies. Policy description, policy statement, and policy guidelines updated regarding treatment for and prevention of organ rejection after solid organ transplant. Code Reference section updated to add ICD-9 code 996.83 and ICD-10 code T86.21.

07/25/2016: Code Reference section updated to make the following correction: ICD-10 diagnosis code range T84.00 - T84.09 should be C84.00 - C84.09.



Blue Cross Blue Shield Association policy # 8.01.36



This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Code Number




Photopheresis, extracorporeal



ICD-9 Procedure

ICD-10 Procedure


Therapeutic photopheresis

6A650ZZ, 6A651ZZ

Phototherapy, Circulatory, Single or Multiple

ICD-9 Diagnosis

ICD-10 Diagnosis


C84.A0 - C84.A9

Cutaneous T-cell lymphoma code range


Mycosis fungoides

C84.00 - C84.09

Mycosis fungoides code range


Sezary’s disease

C84.10 - C84.19

Sezary’s disease code, range


Peripheral T-cell lymphoma

C84.40 - C84.49

Peripheral T-cell lymphoma code range


Graft-versus-host disease code range

D89.810 - D89.813

Graft-versus-host disease code range

996.83Complications of transplanted heartT86.21Heart transplant rejection


Bone marrow graft versus host disease (chronic)

T86.00 - T86.09

Complications of bone marrow transplant code range

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