National Medical Policy

National Medical Policy Subject: Photopheresis (Extracorporeal Photochemotherapy) Policy Number NMP291 Effective Date*: September 2006 Updated: M...
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National Medical Policy Subject:

Photopheresis (Extracorporeal Photochemotherapy)

Policy Number


Effective Date*: September 2006 Updated:

March 2016

This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State's Medicaid manual(s), publication(s), citations(s) and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use X


Source National Coverage Determination (NCD)

National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other

Reference/Website Link

Extracorporeal Photopheresis (110.4):

MLM Matters, Extracorporeal Photopheresis: Provider Types Affected ads/MM5464.pdf MLM Matters, Extracorporeal Photopheresis, Revised. Effective Apr 2012: f


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Photopheresis (Extracorporeal Photochemotherapy) Mar 16


Instructions  Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions.  Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under “Reference/Website” and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2)

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Current Policy Statement Health Net, Inc. considers photopheresis (also known as extracorporeal photochemotherapy [ECP]) medically necessary for any of the following: 1. For treatment of advanced or refractory erythrodermic variants of cutaneous Tcell lymphoma (CTCL), e.g., mycosis fungoides, Sézary’s syndrome, etc. (see Scientific Rationale for more diseases); or 2. For treatment of acute or chronic graft-versus-host disease refractory to standard immunosuppressive therapy; or 3. For treatment of recurrent heart or heart-lung transplant rejection when rejection episodes are refractory to high-dose steroids plus two or more of the following, unless contraindicated:





Polyclonal and monoclonal antilymphocyte agents (e.g., antilymphocyte globulin [ALG], antithymocyte globulin [ATG], OKT3 [monoclonal T-cell antibody])

Treatment of lung transplant rejection in individuals who are refractory to or intolerant of standard therapy.

Note: The frequency of the treatments is determined by the clinical response. A typical photopheresis treatment schedule comprises two consecutive treatments every two weeks for three months, followed by two consecutive treatments every month until symptom resolution. Health Net, Inc. considers photopheresis investigational for the treatment of any of the following diseases. Although there are ongoing studies and clinical trials, the effectiveness of this treatment for these conditions has not been established. Such diagnoses include, but are not limited to:

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   

Solid organ graft rejection, except heart and heart/lung and lung Progressive systemic sclerosis (scleroderma) Pemphigus or other autoimmune bullous diseases Systemic lupus erythematosus AIDS-related complex Crohn's disease

Health Net, Inc. considers extracorporeal photopheresis not medically necessary for the treatment of any of the following diseases, as evidence in the peer review is lacking to support its efficacy: • • • • • • •

Autoimmune diseases Multiple sclerosis Chronic hepatitis C Psoriasis Psoriatic arthritis or psoriasis vulgaris Rheumatoid arthritis Type 1 diabetes mellitus

Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets.

ICD-9 Codes 202.10-202.18 202.20-202.28 996.83 996.84 996.85 996.84

Mycosis fungoides Sezary's disease Complications of transplanted organ; heart Complications of transplanted organ; lung Complications of transplanted organ; bone marrow; graft-versushost disease (acute) (chronic) Complications of transplanted lung 996.84 Complications of transplanted lung

ICD-10 Codes C84.0-C84.09 C84.1-C84.19 T86.810 T86.811 T86.812 T86.818 T86.819 V70.7 Z00.6

Mycosis fungoides Sezary disease Lung transplant rejection Lung transplant failure Lung transplant infection (not recommended for ECP coverage) Other complications of lung transplant Unspecified complication of lung transplant Examination of participant in clinical trial Encounter for examination for normal comparison and control in clinical research program (needed for CED)

CPT Codes

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Photopheresis, extracorporeal


Scientific Rationale – Update March 2016 Kitco et al (2015) reported reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graftversus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. The authors hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, they conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m2 + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). The authors concluded overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year survival, declining to 56%, reflecting a high incidence of chronic GVHD. Atzmony et al (2015) reported ECP is recommended for the erythrodermic mycosis fungoides (MF) and Sezary syndrome (SS) alone or in combination with other therapies. They sought to evaluate the clinical response rate of patients with erythrodermic MF and SS to ECP as part of a multimodality approach and to compare the kinetics of the blood and skin responses in the presence of leukaemic involvement. Twenty patients were treated with ECP and other modalities at a tertiary medical centre in 2003-2013. Ten patients had SS, 1 CD8-positive patchstage MF with leukaemic involvement and nine erythrodermic MF. Clinical and outcome data were collected retrospectively from the medical files. Response was evaluated overall and for blood and skin separately. Adjunctive therapies were interferon-α, narrow-band ultraviolet B, psoralen and ultraviolet A, isotretinoin, acitretin, methotrexate, prednisone, topical nitrogen mustard and total skin or localized hands/feet electron beam radiotherapy. Overall response was documented in 13 patients (65%) - complete 30%, partial 35% - and maintained for >2 years in 38.5%. In patients with leukaemic involvement (n = 11), the blood response occurred earlier than skin response (P = 0.008) and was maintained longer (P = 0.03). In three of the patients with a complete blood response, the skin response was partial (n = 2) or absent (n = 1). The authors concluded extracorporeal

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photopheresis as part of a multimodality approach yields a high durable clinical response in patients with erythrodremic MF and SS. The kinetics of the response differ between the blood and skin. The blood response occurs earlier and lasts longer; it does not necessarily predict the clinical skin response. Further studies are needed to determine if there is a survival advantage to a blood response in the absence of a skin response.

Scientific Rationale – Update March 2015 Chronic allograft rejection has remained a major source of morbidity and mortality following lung transplantation. Transplanted lungs are susceptible to several different types of rejection including acute cellular rejection, humoral rejection, bronchiolitis obliterans (BO), bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome. BO is the predominant feature of chronic lung transplant rejection and is manifest pathologically as dense fibrous scar tissue affecting the small airways. Clinically, BO is associated with a progressive decline in forced expiratory volume in one second (FEV1). When a patient has airflow limitation in the absence of other etiologies, but not histopathology documenting BO, a diagnosis of BOS is made. A variety of therapies have been tried for BO/BOS, but there is no well-established protocol. Potential treatments include adding long-term azithromycin (if not already used for prevention), changing the maintenance immunosuppressive medications, extracorporeal photopheresis, total lymphoid irradiation, plasmapheresis, and other therapies to target antibodies to the allograft (immunoglobulin, rituximab, proteasome inhibitors), and inhaled cyclosporine. The decision among these choices depends on the severity of BOS, underlying immunosuppressive regimen, preferences of individual transplant centers, and response to treatment. Jaksch et al (2012) evaluated both the efficacy and safety of extracorporeal photopheresis (ECP) in patients with bronchiolitis obliterans syndrome (BOS) after lung transplantation and to identify factors predicting treatment response. This prospective study was performed at a single center and consisted of a cohort of 1,012 lung transplant recipients (November 1989-June 2010). A total of 194 patients developed BOS after a mean of 1,293 ± 1,008 days (range, 99-4,949 days) and received established treatment, and 51 patients received additional ECP. Thirty-one (61%) of the ECP-treated patients responded to the therapy and showed sustained stabilization (forced expiratory volume in 1 second range, -5% to 5% vs baseline at start of ECP) of lung function over 6 months. Responders to ECP showed significantly greater survival and less need for retransplantation (p = 0.001) than non-. Factors associated with an inferior treatment response were cystic fibrosis as underlying lung disease and a longer time between transplantation and development of BOS. No side effects were observed after ECP. Compared with BOS patients not treated with ECP, the ECP responders showed an improved graft survival (p = 0.05). The investigators concluded these results confirm and suggest that early use of ECP could be an effective adjunct treatment for patients who develop BOS after lung transplantation. Morrell et al (2010) analyzed the efficacy and safety of Extracorporeal photopheresis (ECP) for progressive BOS at a single institution. Between January 1, 2000, and December 31, 2007, 60 lung allograft recipients were treated with ECP for progressive bronchiolitis obliterans syndrome (BOS). During the 6-month period before the initiation of ECP, the average rate of decline in forced expiratory volume in 1 second (FEV(1)) was -116.0 ml/month, but the slope decreased to -28.9 ml/month during the 6-month period after the initiation of ECP, and the mean difference in the rate of decline was 87.1 ml/month (95% confidence interval, 57.3-

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116.9; p < 0.0001). The FEV(1) improved in 25.0% of patients after the initiation of ECP, with a mean increase of 20.1 ml/month. The authors concluded ECP is associated with a reduction in the rate of decline in lung function associated with progressive BOS. Benden et al (2008) reported single-center experience with ECP for BOS and recurrent acute rejection (AR) after lung transplantation. Lung transplant recipients undergoing ECP for BOS and recurrent AR were included (1997-2007). The rate of forced expiratory volume in 1 second (FEV1) decline was used as the primary measure and graft survival post-ECP as the secondary measure of efficacy. Twentyfour transplant recipients were included (BOS, n=12; recurrent AR, n=12). In recipients with BOS, decline in FEV1 was 112 mL/month before the start of ECP and 12 mL/month after 12 ECP cycles (P=0.011), mean (95% CI) change in rate of decline was 100 (28-171). Median patient survival was 7.0 (range, 3.0-13.6) years, median patient survival post-ECP 4.9 (range, 0.5-8.4) years. No ECP-related complications occurred. Extracorporeal photopheresis reduces the rate of lung function decline in recipients with BOS and is well tolerated. Furthermore, recipients with recurrent AR experience clinical stabilization. However, the underlying mechanism of ECP remains subject to further research.

Scientific Rationale – Update March 2014 Ussowicz et al (2013) evaluated the clinical effect of extracorporeal photopheresis (ECP), and its impact on intensivity of immunosuppresive therapy in allogeneic HSCT patients. In this study 443 Therakos ECP procedures were performed in 21 patients after allogeneic HSCT with acute (aGVHD, 8 patients) or chronic (cGVHD, 13 patients) therapy-refractory GVHD. The median age at ECP onset was 20.5 years (range, 10-55). Venous access was provided by a nontunelized central venous catheter (12 patients) or 9.6-French portacath (9 patients). In the cGVHD group 9/13 patients were improved with a 4-year overall survival rate of 67.7%. ECP led to steroid discontinuation in 6 and substantial dose reduction in 5 patients. The prednisone dose equivalent per kilogram body weight decreased from 0.32 mg to 0.07 mg after therapy. Therapy of aGVHD led to complete or partial symptom remission in 3/9 subjects. The change in steroid dose in the aGVHD group was not significant, there were no long-term survivors. Portacath access was well tolerated and provided adequate blood flow rates. Investigators concluded the ECP therapy significantly reduced the rates of remissions with steroid discontinuation among cGVHD but not aGVHD patients. Rare ECP-related complications were either catheter related or anticoagulation induced during ECP procedures. Photopheresis was a safe, effective method to treat steroid-resistant cGVHD. Bykova et al (2013) evaluated the efficiency of ECP in the treatment of patients with refractory chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The study included 49 patients aged 2 to 55 years. Allo-HSCT was carried out in 38 (79%) patients with acute leukemias, 5 (10%) with chronic leukemias, 4 (8%) with myelodysplastic syndrome/myeloproliferative disease, and 2 (3%) with other hematologic diseases. The patients included in the study had glucocorticosteroid (GCS)-refractory disseminated cGVHD or a history of severe complications from GCS therapy. When evaluating the efficiency of therapy, its response was recorded in 37 (77%) cases; the best results were obtained in patients with hepatic (82%), mucosal (76%), and skin (74%) lesions. The mean severity according to the cGVHD Working Group, National Institutes of Health, and a platelet level of more than 100.10(9)/1 were defined as factors improving a therapy response. In the patients receiving ECP,

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the overall survival was 70%. The latter was higher in the group of patients who had responded to ECP therapy without involving the gastrointestinal tract in the cGVHD process and in those receiving a combination of ECP and other immunosuppressive drugs. Investigators concluded ECP is an effective treatment for patients with refractory cGVHD, it may be used in those with a history of severe complications from GCS therapy. ECP allows the dose of GCS to be reduced to the point of complete discontinuation. Bojanić et al (2013) evaluated the clinical and immunomodulatory effect of ECP procedures in patients with cGVHD. They analyzed 341 ECP procedures performed in 7 patients with cGVHD; median ECP per patient was 37 (range 13-131). All patients suffered from skin changes in combination with impaired joint mobility and symptoms of oral disease. ECP procedures were performed for two consecutive days: in initial phase weekly, followed by every two weeks and than monthly according to clinical response. Median of ECP treatment duration was 10 months (range 2-58). The effect of ECP in patients with cGVHD with skin and joint involvement was mostly beneficial: 6 patients experienced either improvement or stabilization in skin changes and joint mobility. In 2 patients who suffered from oral disease, the total recovery was observed. Clinical response was typically delayed until 2 to 3 months, and reduction in glucocorticoid dose was observed. Adverse reactions were observed in 4.9% procedures. The authors concluded in patients who responded to ECP treatment, CD4+/CD8+ ratio and number of NK cells were normalized. ECP proved to be an efficient and safe procedure that may be recommended for patients with cGVHD who do not respond to conventional therapy.

Scientific Rationale – Update March 2013 Extracorporeal photochemotherapy (with UVA and psoralen) has been used in localized scleroderma (LSc), but the evidence to support this modality is weak. Because of the risk of mutagenicity, the use of ultraviolet light is contraindicated in children.

Scientific Rationale - Update September 2009 Extracorporeal photochemotherapy (ECP), also called photopheresis, is a type of pheresis in which aliquots of the patient's blood are removed, treated with a photosensitizing agent, and subjected to ultraviolet A light. The treated cells are then re-infused into the patient. The mechanism of action has not been fully elucidated. It is likely that photopheresis activates antigen-presenting cells, such that tumorrelated antigens are more readily presented to cytoxic T cells. Despite a shift towards more potent immunosuppressive regimens, the development of chronic allograft rejection, as manifested by bronchiolitis obliterans syndrome continues to negatively impact on the long-term survival of lung transplant recipients. ECP has been utilized as a salvage therapy for the treatment of lung transplant rejection when conventional therapies do not produce an adequate response. National Institute for Health and Clinical Excellence (NICE) [2009]) states: "Current evidence on extracorporeal photopheresis (ECP) for Crohn’s disease is based on reports that include a very small number of patients. These reports describe no major safety issues but they provide little evidence of efficacy. Therefore, this procedure should not be used outside the context of research." Photopheresis (Extracorporeal Photochemotherapy) Mar 16


National Comprehensive Cancer Network (NCCN) [2009] notes: “Extracorporeal photopheresis is noted as a ‘Category A’ systemic therapy for mycosis fungoides, and Sézary’s syndrome.” Systemic therapies with extracorporeal photopheresis (ECP), interferons, systemic retinoids, denileukin diftitox, or vorinostat are preferred over traditional chemotherapy for patients who do not respond to initial skin-directed therapies. ECP is an immunomodulatory therapy using psoralen and UVA radiation extracorporally. It involves the removal of leukocytes by leukopheresis. The leukocytes are treated with 8-methoxypsoralen, exposed to UVA and returned to the patient. ECP is a long-standing treatment of mycosis fungoides (MF), and is particularly indicated in patients with or at risk of blood involvement (erythrodermic stage III disease or IVA with Sézary’s syndrome. National Cancer Institute (NCI) [2008] states: “Cutaneous T-cell lymphomas are any of a group of relatively uncommon Tcell non-Hodgkin lymphomas which begin in the skin as an itchy, red rash and can thicken or form tumors. Mycosis fungoides and Sézary syndrome are neoplasias of malignant T-lymphocytes and are the most common types of cutaneous T-cell lymphoma; Sézary syndrome is an advanced form of mycosis fungoides. Mycosis fungoides initially presents as skin involvement, with more frequent and extensive involvement of the peripheral blood, nodes and viscera as the disease progresses to Sézary syndrome.” Gandhi et al. (2008) performed a systematic review and meta-analysis to determine the efficacy of non-antigen based immunotherapies, including ECP, in the treatment of patients with DM1. Meta-analysis found a small-to-moderate improvement in beta-cell function with immunotherapy verses placebo. The authors noted that further research with larger randomized controlled trials is needed to determine the long-term safety and efficacy of extracorporeal photochemotherapy for individuals with type I diabetes.

Scientific Rationale - Initial Cutaneous T-cell lymphoma (CTCL) is a general name for a group of relatively uncommon disorders most often occurring in people between 40 and 60 years of age. It represents a heterogeneous group of cutaneous non-Hodgkin's lymphomas which include mycosis fungoides, Sézary’s syndrome, Woringer-Kolopp disease (pagetoid reticulosis), CD8+ (suppressor) T-cell lymphoma, granulomatous slack skin, peripheral T-cell lymphoma, angiocentric lymphoma, adult T-cell leukemia/ lymphoma, CD30+ (Ki-1+) large-cell, anaplastic lymphoma and lymphomatoid granulomatosis. CTCL occurs in slightly more than 2% of all lymphomas in the United States. Unlike other forms of non-Hodgkin lymphoma, CTCL mainly affects the skin. The most frequently diagnosed forms of CTCL are mycosis fungoides (MF) and its leukemic variant Sezary’s syndrome (SS). MF is the general name given to the other types of CTCL when the blood is not affected. MF has a frequency of 44% of all CTCL patients and the clinical course is unpredictable. Most patients will live normal lives and experience skin symptoms without serious complications. Approximately 10% of MF patients will experience progressive disease involving lymph nodes, peripheral blood, bone marrow and visceral organs.

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Sezary syndrome (SS) is a specific type of CTCL in which large areas of the skin may develop erythroderma, an intense and usually widespread reddening of the skin from dilation of blood vessels, often preceding or associated with exfoliation). Lymph glands may also be affected and abnormal T-lymphocytes may also be found circulating in the blood. SS has a frequency of 5-10% and a disease specific 5-year survival of 24%. Treatment goals in advanced stages of CTCL should be to reduce tumor burden, relieve symptoms, delay disease progression, and preserve quality of life. Approaches for advanced disease treatment include spot radiation for single or localized skin tumors, mono- or polychemotherapy, interferon-α, oral retinoids, monoclonal antibodies, recombinant toxins, and high-dose chemotherapy with allogeneic bone marrow transplant. Non-randomized clinical trials so far do not suggest any one treatment is preferable. Photopheresis (also known as extracorporeal photochemotherapy or ECP) is a medical treatment that is widely accepted as treatment for erythrodermic variants of cutaneous T-cell lymphoma involving the skin (e.g., mycosis fungoides, Sézary’s syndrome, etc.). Photopheresis is also an accepted treatment for graft-versus-host disease (GvHD). The latter condition is potentially life threatening and it has been shown to respond well to photopheresis treatments. Photopheresis therapy is a multi-step procedure. First, a photo-activated agent (psoralen) interacts with the blood cells. This is accomplished by the patient taking the agent by mouth prior to the light treatment or the agent is added directly to the cells after removal from the patient. The second step is exposing the cells that were treated with the photo-activated agent to ultraviolet A (UVA) light (PUVA). In preparation for the procedure, needles are placed in each of the patient's arms. Blood is drawn from the body from one needle and less than ten percent of the patient’s white blood cells are suspended in a sample of the patient’s plasma and exposed to UVA light using a photopheresis machine. The third step is returning the blood to the body through the other needle. The drug-sensitized T-cells will die and be removed from the blood stream when exposed to the UVA light. The entire process requires approximately 2.5 to 3.5 hours depending upon venous access flow rates. Photopheresis is usually performed on two consecutive days at 4-week intervals with clinical evaluation at 6 months to determine response. Patients who show clinical improvement are maintained on this treatment schedule until the physician feels that maximum benefit has been reached. An additional 6 months of treatment is typically given after which the patient is gradually weaned off therapy. Several clinical trials have illustrated that photopheresis decreases disease activity and improves related skin conditions significantly. In several cases, complete remission has been reported. The optimal management of MF is undetermined because of its low prevalence, and its highly variable natural history, with frequent spontaneous remissions and exacerbations and often prolonged survival. Non-aggressive approaches to therapy are usually warranted with treatment aimed at improving symptoms and physical appearance while limiting toxicity. Given that multiple skin sites are usually involved, the initial treatment choices are usually topical or intralesional corticosteroids or phototherapy using PUVA, a combination of psoralen (P) and long-wave ultraviolet radiation (UVA) psoralen. PUVA is not curative and its influence on disease progression remains uncertain. Repeated courses are usually required which may lead to an increased risk of both melanoma and nonmelanoma skin cancer. For thicker plaques, particularly if localized, radiotherapy with superficial electrons is an option. “Second line” therapy for early stage disease is often topical chemotherapy,

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radiotherapy or total skin electron beam radiation (TSEB). Treatment of advanced stage (IIB-IV) MF usually consists of topical or systemic therapy in refractory or rapidly progressive SS. Bone marrow transplantation and peripheral blood stem cell transplantation have been used to treat many malignant hematologic disorders (e.g., leukemias) that are refractory to conventional treatment. Reports on the use of these procedures for the treatment of CTCL are limited and mostly consist of case reports or small case series. Allogeneic hematopoietic cell transplantation (HCT) is a treatment used for a variety of malignant and nonmalignant disease of the bone marrow and immune system. The procedure is often associated with serious immunological complications, particularly graft-versus-host disease (GvHD). A chronic form of GvHD afflicts many allogeneic HCT recipients which results in dysfunction of numerous organ systems or even a profound state of immunodeficiency. Chronic graft-versus-host disease (cGvHD) is a condition where the body rejects a newly transplanted marrow or organ, thus causing the immune system to attack the body. cGvHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors. Risk factors for cGvHD include older age of patient or donor, higher degree of histoincompatibility, unrelated versus related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GvHD. Chronic GvHD may occur by itself, evolve from acute GvHD, or occur after resolution of acute GvHD. The onset of the syndrome may be abrupt but is frequently insidious with manifestations evolving gradually for several weeks. Approximately 50% of patients with cGvHD have limited disease and a good prognosis. The remaining patients will develop opportunistic infection, or require prolonged treatment with immunosuppressive agents, which is the most frequent cause of poor long-term outcome and quality of life after allogeneic HCT. Of the patients with extensive disease, approximately 60% will respond to treatment with photopheresis therapy and eventually be able to discontinue immunosuppressive therapy. According to Bhushan and Collins (2003), the incidence of severe cGvHD has increased in recent years because of the use of more unrelated transplants, donor leukocyte infusions, nonmyeloablative transplants and stem cells obtained from the blood rather than the marrow. In several clinical trials, the use of photopheresis has been proven to significantly decrease rejection episode frequency and lesion severity. One study has reported a successful outcome of 84% of patients with Grade III disease. Two Ontario expert consultants (2006) jointly estimated that there may be approximately 30 new erythrodermic treatment resistant CTCL patients and 30 new treatment resistant cGvHD patients per year who are unresponsive to other forms of therapy and may be candidates for ECP. Photopheresis has been investigated as a treatment in other conditions, including type I diabetes, systemic sclerosis (scleroderma), hepatitis C infection and the prevention of restenosis following angioplasty. For Type 1 diabetes, a recent clinical trial demonstrated a small but significant effect on insulin requirements in some patients and resulted in temporary remission in one case. However, results need to be re-evaluated in further studies before this technique can be recommended. In relation to its application in systemic sclerosis, several clinical trials have found evidence that photopheresis had little to no effect on this condition. A small study in patients with hepatitis C virus (HCV) infection who had previously failed therapy with Interferon 2a, indicated that photopheresis completely removed all signs of serum

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HCV for a short period during treatment. The results were not universal in the study population and this may be an area, which requires further research. Finally, a study of photopheresis in patients with recent angioplasty, both with and without stent placement, demonstrated a small but significant reduction in restenosis. However, a recommendation cannot be based on the findings of this one trial.

Review History September 2006 September 2007 September 2009 April 2011 March 2012 June 2012 March 2013 March 2014 March 2015 March 2016

Medical Advisory Council initial approval Update - no revisions. Codes reviewed. Update - no revisions. Codes reviewed. Update – no revisions Update – no revisions Updated link to revised Medicare NCD and MLN. Update – no revisions. Codes updated. Update – no revision Update – Added as medically necessary, ECP for treatment of lung transplant rejection in individuals who are refractory to or intolerant of standard therapy. Update – no revisions

This policy is based on the following evidence-based guidelines: 1.

2. 3. 4. 5. 6. 7.

Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003 Dec;149(6):1095-107. Catalan Agency for Health Technology Assessment (CAHTA). Extracorporeal phototherapy (photopheresis) for the treatment of Sezary Syndrome and graft versus host disease. Barcelona, Spain: CAHTA; 2001. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Extracorporeal photopheresis for graft-versus-host disease. TEC Assessment Program. Chicago, IL: BCBSA; November 2001:16(9). BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Extracorporeal photopheresis for the treatment of autoimmune disease. TEC Assessment Program. Chicago IL: BCBSA; 2001;16(10). National Institute for Health and Clinical Excellence (NICE). Extracorporeal photopheresis for Crohn's disease. Interventional Procedure Guidance 288. London, UK: NICE; February 2009. National Comprehensive Cancer Network (NCCN). Non-Hodgkin’s Lymphoma. V.2.2009. Update Version 1. 2013. Update 1.2014. Update 1.2015 Update 1.2016 Hayes. Health Technology Brief. March 13, 2007. Updated March 24, 2009. Hayes. News Service. CMS Announces National Coverage Determination for Extracorporeal Photophoresis. August 5, 2011.

References – Update March 2016


Atzmony L, Amitay-Laish I, Gurion R, , et al. Erythrodermic mycosis fungoides and Sézary syndrome treated with extracorporeal photopheresis as part of a multimodality regimen: A single-centre experience. J Eur Acad Dermatol Venereol. 2015 Dec;29(12):2382-9.

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3. 4. 5. 6. 7.

8. 9.

Brownback KR, Simpson SQ, Pitts LR, Polineni D, et al. Effect of extracorporeal photopheresis on lung function decline for severe bronchiolitis obliterans syndrome following allogeneic stem cell transplantation. J Clin Apher. 2015 May 29. Fowler S, Jones J, Hull PR, Ghosh S. Extracorporeal photopheresis for the treatment of Crohn's disease. Transfus Apher Sci. 2015 Apr;52(2):183-6. Kitko CL, Braun T, Couriel DR, et al. Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial. Biol Blood Marrow Transplant. 2015 Nov 6. Kitko CL, Levine JE. Extracorporeal photopheresis in prevention and treatment of acute GVHD. Transfus Apher Sci. 2015 Apr;52(2):151-6. Patel J, Klapper E, Shafi H, Kobashigawa JA. Extracorporeal photopheresis in heart transplant rejection. Transfus Apher Sci. 2015 Apr;52(2):167-70. 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. 2015 Dec 15;12:CD009898. Yung GL, Craig V. Lung transplantation and extracorporeal photopheresis: The answer to bronchiolitis obliterans? Transfus Apher Sci. 2015 Apr;52(2):162-6. Zhu L, Couriel DR, Chang CH. The effect of extracorporeal photopheresis on T cell response in chronic graft-versus-host disease. Leuk Lymphoma. 2015 Jul 18:1-9.

References – Update March 2015 1. 2. 3.

4. 5. 6. 7. 8.

Andreu-Ullrich H. Miscellaneous indications for extracorporeal photochemotherapy (ECP). Transfus Apher Sci. 2014 Jun;50(3):363-9 Benden C, Speich R, Hofbauer GF, et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation. 2008 Dec 15;86(11):1625-7 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. 2.J Heart Lung Transplant. 2012 Sep;31(9):950-7 Jaksch P, Knobler R. ECP and solid organ transplantation. Transfus Apher Sci. 2014 Jun;50(3):358-62. Marques MB, Adamski J. Extracorporeal photopheresis: technique, established and novel indications. J Clin Apher. 2014 Aug;29(4):228-34. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010 Apr;29(4):424-31. Villanueva J, Bhorade SM, Robinson JA, et al. Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant. 2000;5(3):44-7. Whitson BA. Lung Transplantation Treatment & Management. eMedicine. Updated Jan 2015. Available at:

References – Update March 2014 1. 2.

Bojanić I, Seiwerth RS, Mazić S, et al. Extracorporeal photopheresis in treatment of chronic graft versus host disease. Lijec Vjesn. 2013 MayJun;135(5-6):139-44. Bykova TA, Kozlov AV, Stancheva NV, et al. Extracorporeal photopheresis in the treatment of patients with refractory chronic graft-versus-host disease after allogeneic bone marrow transplantation. Ter Arkh. 2013;85(8):60-8.

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3. 4.

5. 6.


Dieterlen MT, Bittner HB, Pierzchalski A, et al. Immunological monitoring of extracorporeal photopheresis after heart transplantation. Clin Exp Immunol. 2013 Dec 12. Quaglino P, Knobler R, Fierro MT, et al. Extracorporeal photopheresis for the treatment of erythrodermic cutaneous T-cell lymphoma: a single center clinical experience with long-term follow-up data and a brief overview of the literature. Int J Dermatol. 2013 Nov;52(11):1308-18. Rieber N, Wecker I, Neri D, et al. Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD. Bone Marrow Transplant. 2014 Jan 27. 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. 2013 Aug;169(2):450-7. Ussowicz M, Musiał 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. 2013 Nov;45(9):3375-80.

References – Update March 2013 1. 2.

Chao NJ. Treatment of chronic graft-versus-host disease. UpToDate. January 7, 2013. National Cancer Institute (NCI). Mycosis fungoides and the Sézary syndrome treatment. Updated Feb 17, 2012. Available at: fessional

References – Update April 2011 1. 2.


Chiesa-Fuxench ZC, González-Chávez J. Extracorporeal photopheresis: a review on the immunological aspects and clinical applications. P R Health Sci J. 2010 Dec;29(4):337-47 González Vicent M, Ramirez M, Sevilla J, Abad L, Díaz MA. Analysis of clinical outcome and survival in pediatric patients undergoing extracorporeal photopheresis for the treatment of steroid-refractory GVHD. J Pediatr Hematol Oncol. 2010 Nov;32(8):589-93 Pothiawala SZ, Baldwin BT, Cherpelis BS, et al. The role of phototherapy in cutaneous T-cell lymphoma. J Drugs Dermatol. 2010 Jul;9(7):764-72.

References – Update September 2009 1. 2. 3.

4. 5.

Bhorade SM, Stern E. Immunosupression for lung transplantation. Proc Am Thorac Soc. 2009 Jan 15;6 (1)47-53 Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. 2008;42(9):609-617. Scarisbrick JJ, Taylor P, Holtick U, et al., for the Photopheresis Expert Group. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. British J Derm. 2008; 158: 659-678. Centers for Medicare and Medicaid Services (CMS). Decision memo for extracorporeal photopheresis (CAG 00324R). Updated Jan 2008. National Cancer Institute (NCI). Mycosis fungoides and the Sézary syndrome. Updated May 2008. Available at:

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6. 7. 8. fessional ECRI Institute. Hotline Response. Plymouth Meeting (PA): ECRI Institute; Applications of Extracorporeal Photopheresis. 2008 Apr 10. Gandhi GY, Murad MH, Flynn DN, et al. Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials. Clin Endocrinol (Oxf). 2008 Jan 10. 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. 2008 Jan 30.

References – Initial 1. 2. 3. 4. 5.

6. 7.

8. 9. 10. 11. 12. 13. 14. 15.

Faresjo MK, Ernerudh J, Berlin G, et al. The immunological effect of photopheresis in children with newly diagnosed type 1 diabetes. Pediatr Res. 2005;58(3):459-466. Kanold J, Messina C, Halle P, et al. Update on extracorporeal photochemotherapy for graft-versus-host disease treatment. Bone Marrow Transplant. 2005;35 Suppl 1:S69-S71. Rubegni P, Cuccia A, Sbano P, et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. Br J Haematol. 2005;130(2):271-275. Srinivasan R, Lichtenstein GR. Recent developments in the pharmacological treatment of Crohn's disease. Expert Opin Investig Drugs. 2004;13(4):373-391. Quaglino P, Fierro MT, Rossotto GL, et al. Treatment of advanced mycosis fungoides/Sezary syndrome with fludarabine and potential adjunctive benefit to subsequent extracorporeal photochemotherapy. Br J Dermatol. 2004;150(2):327-336. Child FJ, Mitchell TJ, Whittaker SJ, et al. A randomized cross-over study to compare PUVA and extracorporeal photopheresis in the treatment of plaque stage (T2) mycosis fungoides. Clin Exp Dermatol. 2004;29(3):231-236. Whittaker SJ, Marsden JR, Spittle M, et al. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol. 2003;149(6):1095-1107. Zackheim HS. Treatment of mycosis fungoides/Sezary syndrome: The University of California, San Francisco (UCSF) approach. Int J Dermatol. 2003;42(1):53-56. Guariso G, D'Inca R, Sturniolo GC, et al. Photopheresis treatment in severe Crohn disease. J Pediatr Gastroenterol Nutr. 2003;37(4):517-520. Apisarnthanarax N, Talpur R, Duvic M. Treatment of cutaneous T cell lymphoma: Current status and future directions. Am J Clin Dermatol. 2002;3(3):193-215. Stummvoll GH. Current treatment options in systemic sclerosis (scleroderma). Acta Med Austriaca. 2002;29(1):14-19. Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: Lessons from failed and interrupted treatment trials. BioDrugs. 2002;16(3):183-200. Besnier DP, Chabannes D, Mussini JM, et al. Extracorporeal photochemotherapy for secondary chronic progressive multiple sclerosis: A pilot study. Photodermatol Photoimmunol Photomed. 2002;18(1):36-41. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100(3):941-947. Foss FM, Gorgun G, Miller KB. Extracorporeal photopheresis in chronic graftversus-host disease. Bone Marrow Transplant. 2002;29(9):719-725.

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16. Perutelli P, Rivabella L, Lanino E, et al. ATP downregulation in mononuclear cells from children with graft-versus-host disease following extracorporeal photochemotherapy. Haematologica. 2002;87(3):335-336. 17. Oliven A, Shechter Y. Extracorporeal photopheresis: A review. Blood Rev. 2001;15(2):103-108. 18. Ratanatharathorn V, Ayash L, Lazarus HM, et al. Chronic graft-versus-host disease: clinical manifestation and therapy. Bone Marrow Transplant. 2001;28(2):121-129. 19. Reinisch W, Nahavandi H, Santella R, et al. Extracorporeal photochemotherapy in patients with steroid-dependent Crohn's disease: A prospective pilot study. Aliment Pharmacol Ther. 2001;15(9):1313-1322. 20. Barr ML, Baker CJ, Schenkel FA, et al. Prophylactic photopheresis and chronic rejection: Effects on graft intimal hyperplasia in cardiac transplantation. Clin Transplant. 2000;14(2):162-166. 21. Wiendl H, Neuhaus O, Kappos L, Hohlfeld R. [Multiple sclerosis. Current review of failed and discontinued clinical trials of drug treatment.] Nervenarzt. 2000;71(8):597-610. 22. Giunti G, Schurfeld K, Maccherini M, et al. Photopheresis for recurrent acute rejection in cardiac transplantation. Transplantation Proc. 1999;31(1-2):128129. 23. Zic JA, Miller JL, Stricklin GP, King LE Jr. The North American experience with photopheresis. Ther Apher. 1999;3(1):50-62. 24. O'Hagan AR, Stillwell PC, Arroliga A, Koo A. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest. 1999;115(5):1459-1462. 25. Schoch OD, Boehler A, Speich R, Nestle FO. Extracorporeal photochemotherapy for Epstein-Barr virus-associated lymphoma after lung transplantation. Transplantation. 1999;68(7):1056-1058. 26. Salerno CT, Park SJ, Kreykes NS, et al. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg. 1999;117(6):1063-1069. 27. Rostami AM, Sater RA, Bird SJ, et al. A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis. Mult Scler. 1999;5(3):198-203. 28. Child FJ, Ratnavel R, Watkins P, et al. Extracorporeal photopheresis (ECP) in the treatment of chronic graft-versus-host disease (GVHD). Bone Marrow Transplant. 1999;23(9):881-887. 29. Dall'Amico R, Murer L, Montini G, et al. Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol. 1998;9(1):121-127. 30. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. N Engl J Med. 1998;339(24):1744-1751. 31. Russell-Jones R. Extracorporeal photophoresis in chronic cutaneous graft-versushost disease. Bone Marrow Transplant. 1998;22(7):621-623. 32. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versushost disease. Blood. 1998;92(9):3098-3104. 33. Dall'Amico R, Montini G, Murer L, et al. Benefits of photopheresis in the treatment of heart transplant patients with multiple/refractory rejection. Transplantation Proc. 1997;29(1-2):609-611. 34. Kirklin JK, Bourge RC, McGiffin DC. Recurrent or persistent cardiac allograft rejection: Therapeutic options and recommendations. Transplantation Proc. 1997;29( 8A):40S-44S.

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35. Hausen B, Morris RE. Review of immunosuppression for lung transplantation. Novel drugs, new uses for conventional immunosuppressants, and alternative strategies. Clin Chest Med. 1997;18(2):353-366. 36. Rook AH, Gottlieb SL, Wolfe JT, et al. Pathogenesis of cutaneous T-cell lymphoma: Implications for the use of recombinant cytokines and photopheresis. Clin Exp Immunol. 1997;107 Suppl 1:16-20. 37. Dall'Amico R, Rossetti F, Zulian F, et al. Photopheresis in paediatric patients with drug-resistant chronic graft-versus-host disease. Br J Haematol. 1997;97(4):848-854. 38. Wolfe JT, Tomaszewski JE, Grossman RA, et al. Reversal of acute renal allograft rejection by extracorporeal photopheresis: A case presentation and review of literature. J Clin Apheresis. 1996;11(1):36-41. 39. Dall'Amico R, Livi U, Milano A, et al. Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation. 1995;60(1):45-49. 40. Barr ML, McLaughlin SN, Murphy MP, et al. Prophylactic photopheresis and effect on graft atherosclerosis in cardiac transplantation. Transplant Proc. 1995;27(3):1993-1994. 41. Cribier B, Faradji T, Le Coz C, et al. Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology. 1995;191(1):25-31. 42. Lim HW, Edelson RL. Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9(5):1117-1126. 43. Gollnick HP, Owsianowski M, Ramaker J, et al. Extracorporeal photopheresis--a new approach for the treatment of cutaneous T cell lymphomas. Recent Results Cancer Res. 1995;139:409-415. 44. Mielke V, Staib G, Sterry W. Systemic treatment for cutaneous lymphomas. Recent Results Cancer Res. 1995;139:403-408. 45. Meiser BM, Kur F, Reichenspurner H, et al. Reduction of the incidence of rejection by adjunct immunosuppression with photochemotherapy after heart transplantation. Transplantation. 1994;57(4):563-568. 46. Bunn PA Jr, Hoffman SJ, Norris D, et al. Systemic therapy of cutaneous T-cell lymphomas (mycosis fungoides and the Sezary syndrome). Ann Intern Med. 1994;121(8):592-602. 47. Costanzo-Nordin MR, Cooper DK, Jessup M, et al. 24th Bethesda conference: Cardiac transplantation. Task Force 6: Future developments. J Am Coll Cardiol. 1993;22(1):54-64. 48. Kahari VM. Activation of dermal connective tissue in scleroderma. Ann Med. 1993;25(6):511-518. 49. Pope J. Treatment of systemic sclerosis. Curr Opin Rheumatol. 1993;5(6):792801. 50. Kaplan EH, Leslie WT. Cutaneous T-cell lymphomas. Curr Opin Oncol. 1993;5(5):812-818. 51. 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. 52. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Arch Dermatol. 1992;128(3):337-346. 53. Trentham DE. Photochemotherapy in systemic sclerosis: The stage is set. Arch Dermatol. 1992; 128:389-390. Important Notice General Purpose. Health Net's National Medical Policies (the "Policies") are developed to assist Health Net in administering plan benefits and determining whether a particular procedure, drug, service or supply is medically

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necessary. The Policies are based upon a review of the available clinical information including clinical outcome studies in the peer-reviewed published medical literature, regulatory status of the drug or device, evidence-based guidelines of governmental bodies, and evidence-based guidelines and positions of select national health professional organizations. Coverage determinations are made on a case-by-case basis and are subject to all of the terms, conditions, limitations, and exclusions of the member's contract, including medical necessity requirements. Health Net may use the Policies to determine whether under the facts and circumstances of a particular case, the proposed procedure, drug, service or supply is medically necessary. The conclusion that a procedure, drug, service or supply is medically necessary does not constitute coverage. The member's contract defines which procedure, drug, service or supply is covered, excluded, limited, or subject to dollar caps. The policy provides for clearly written, reasonable and current criteria that have been approved by Health Net’s National Medical Advisory Council (MAC). The clinical criteria and medical policies provide guidelines for determining the medical necessity criteria for specific procedures, equipment, and services. In order to be eligible, all services must be medically necessary and otherwise defined in the member's benefits contract as described this "Important Notice" disclaimer. In all cases, final benefit determinations are based on the applicable contract language. To the extent there are any conflicts between medical policy guidelines and applicable contract language, the contract language prevails. Medical policy is not intended to override the policy that defines the member’s benefits, nor is it intended to dictate to providers how to practice medicine. Policy Effective Date and Defined Terms. The date of posting is not the effective date of the Policy. The Policy is effective as of the date determined by Health Net. All policies are subject to applicable legal and regulatory mandates and requirements for prior notification. If there is a discrepancy between the policy effective date and legal mandates and regulatory requirements, the requirements of law and regulation shall govern. * In some states, prior notice or posting on the website is required before a policy is deemed effective. For information regarding the effective dates of Policies, contact your provider representative. The Policies do not include definitions. All terms are defined by Health Net. For information regarding the definitions of terms used in the Policies, contact your provider representative. Policy Amendment without Notice. Health Net reserves the right to amend the Policies without notice to providers or Members. states, prior notice or website posting is required before an amendment is deemed effective.

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