Extracorporeal Photopheresis as a Treatment of Graft-versus-Host Disease, Autoimmune Disease, and Cutaneous T-Cell Lymphoma
DESCRIPTIONExtracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory procedure that involves the following steps:
ECP has been investigated for the treatment of patients with a variety of autoimmune diseases, graft-versus-host disease (GVHD), and cutaneous T-cell lymphoma (CTCL).
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 some time 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. 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.
The use of photopheresis 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 antibodies, it is not certain how these antibodies are related to the pathogenesis of the disease. Photopheresis is not associated with consistent changes in autoantibodylevels.
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 Sezary 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 plaque stage covering 10% or more of the body surface (T2), and finally to tumors (T3) that frequently undergo necrotic ulceration. Sezary 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, an average of 2 to 10 years, as waxing and waning cutaneous eruptions prior to biopsy confirmation. The prognosis of patients with mycosis fungoides/Sezary 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.
In the United States, the UVAR® XTS Photopheresis System was approved via premarket application (PMA) by the U.S. Food and Drug Administration (FDA) for use in the ultraviolet-A (UVA) irradiation (in the presence of the photoactive drug, methoxsalen) of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) in persons who have not been responsive to other therapy.
8-MOP (UVADEX®) is approved by the FDA for use in conjunction with UVAR XTS Photopheresis System for use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood 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 the UVAR XTS photopheresis system or UVADEX for other conditions is an off-label use of a FDA-approved device/drug.
POLICYExtracorporeal 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.
POLICY EXCEPTIONSFederal 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.
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 the above 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)
According to the WHO-EORTC, Sezary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T-cells (Sezary cells) in skin, lymph nodes, and peripheral blood. The International Society of Cutaneous Lymphomas recommends an absolute Sezary 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.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY5/2001: 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.
SOURCE(S)Blue Cross Blue Shield Association policy # 8.01.36
CODE REFERENCEThis 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.