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Aetna Aetna
Clinical Policy Bulletin:
Extracorporeal Photochemotherapy (Photopheresis)
Number: 0241


  1. Aetna considers extracorporeal photochemotherapy (ECP, photopheresis) medically necessary for erythrodermic variants of cutaneous T cell lymphoma (e.g., mycosis fungoides, Sézary syndrome).  

  2. Aetna considers ECP medically necessary in the treatment of acute cardiac allograft rejection that is refractory to standard immunosuppressive drug treatment (resistant or dependent to high-dose steroids plus refractory to 2 or more of the following, unless contraindicated: azathioprine, cyclosporine, methotrexate, and/or polyclonal and monoclonal antilymphocyte agents (e.g., anti-lymphocyte globulin (ALG) and anti-thymocyte globulin (ATG)).

  3. Aetna considers extracorporeal photochemotherapy medically necessary in the treatment of rejection (bronchiolitis obliterans) of lung transplants that are refractory to immunosuppressive drug treatment (resistant or dependent to high-dose steroids plus resistant to 2 or more of the following, unless contraindicated: azathioprine, cyclosporine, tacrolimus, and/or polyclonal and monoclonal antilymphocyte agents (e.g., ALG and ATG).

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

  5. Aetna considers the use of ECP experimental and investigational as a treatment for the following conditions because the effectiveness of this treatment for these diagnoses has not been established: s
  • Atopic dermatitis
  • Allograft rejection of solid organs other than the heart and lung 
  • Bullous pemphigoid
  • Crohn’s disease
  • Epidermolysis bullosa acquisita
  • Multiple sclerosis
  • Nephrogenic systemic fibrosis (previously known as nephrogenic fibrosing dermopathy)
  • Pemphigus vulgaris
  • Pityriasis rubra pilaris
  • Stage 0-p bronchiolitis obliterans syndrome
  • Systemic sclerosis (scleroderma)
  • Type 1 diabetes.


Photopheresis, also known as extracorporeal photochemotherapy (ECP), is an immunomodulatory technique based on pheresis of light-sensitive cells.  Whole blood is removed from patients who have previously ingested the photosensitizing agent 8-methoxypsoralen (8-MOP) followed by leukapheresis and exposure of the 8-MOP containing leukocytes extracorporeally to ultraviolet-A light before their return to the patient.  Two hours after an oral dose of photo-activatable drug, the patient undergoes leukopheresis.  The lymphocytes are then exposed to UVA light within the photopheresis device and the photo-irradiated cells are re-infused into the patient.

Photopheresis was approved by the Food and Drug Administration (FDA) in 1988 for treatment of cutaneous T-cell lymphoma, and is considered standard therapy for the early to moderately advanced (stage III) erythrodermic variants of cutaneous T-cell lymphoma (e.g., mycosis fungoides, Sézary's syndrome).  However, in a recent randomized controlled study, Child et al (2004) concluded that ECP is not effective in the treatment of plaque stage (1B/T2) mycosis fungoides even in patients with molecular evidence of a peripheral blood T-cell clone.  This is in agreement with the finings of Zackheim (2003) who stated the results of ECP for early to moderately advanced erythrodermic mycosis fungoides are favorable.  However, results in plaque and tumor stage disease are not impressive. 

The Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas recommended the use of ECP in patients with stage III mycosis fungoides/Sézary's syndrome.

Photopheresis is usually performed on 2 consecutive days at 4-week intervals with clinical evaluation at 6 months to determine response.  Those who show clinical improvement are maintained on this treatment schedule until maximum clearing.  An additional 6 months of treatment is typically given after which the patient is gradually weaned off therapy.

Photopheresis for the treatment of scleroderma and other autoimmune diseases is under investigation.  The safety and efficacy of this treatment for scleroderma has not been established.  Photopheresis, alone or in combination with immunosuppressive therapy, has also been used in the treatment of solid organ (e.g., heart, lung, and kidney) transplant rejection, graft-versus-host disease (GVHD), scleroderma, and other autoimmune diseases.  This form of photochemotherapy induces a selective inhibition of the host response to foreign histocompatibility antigens and reverses allograft rejection after organ transplantation.

An assessment conducted by the BlueCross BlueShield Association Technology Evaluation Center (2001) concluded that ECP does not meet TEC criteria for autoimmune diseases, including: 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; and other autoimmune diseases such as atopic dermatitis, juvenile dermatomyositis, or scleromyxedema.

Extracorporeal photopheresis is also being evaluated as a treatment for Crohn’s disease.  Available evidence is limited to case reports and small uncontrolled case series (Reinisch et al, 2001; Guariso et al, 2003).  An assessment by the National Institute for Health and Clinical Excellence (2009) concluded: "[c]urrent 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."

Based upon an evidence review, the Centers for Medicare and Medicaid Services (CMS, 2006) concluded that ECP is reasonable and necessary for persons with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment.  Centers for Medicare and Medicaid Services also concluded that ECP is reasonable and necessary for persons with chronic GVHD whose disease is refractory to standard immunosuppressive drug treatment.  There is evidence that photopheresis is effective in the treatment of heart, bone marrow and stem cell transplant rejection.  Photopheresis has been reported to be as effective as conventional immunosuppressive agents in reducing rejection episodes in heart transplant recipients.  It has also been demonstrated to be effective in treating steroid-resistant chronic GVHD following bone marrow or stem cell transplantation (Foss et al, 2005; Couriel et al, 2006; Bisaccia et al, 2006).  By contrast, there is limited scientific evidence to determine the effectiveness of photopheresis in treating rejection of lung or kidney transplants .

Morrell et al (2010) reported that ECP is associated with a reduction in the rate of decline in lung function associated with progressive bronchiolitis obliterans syndrome (BOS).  The authors retrospectively analyzed the efficacy and safety of ECP in 60 lung transplant recipients treated for progressive BOS at a single institution between 2000 and 2007.  They reported that 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 [CI]: 57.3 to 116.9; p < 0.0001).  The authors noted that FEV(1) improved in 25.0 % of patients after the initiation of ECP with a mean increase of 20.1 ml/month.

Haenssle and colleagues (2004) noted that pityriasis rubra pilaris (PRP) is a rare papulosquamous skin disease of unknown etiology that has been categorized into 5 clinical types based on age at onset, cutaneous features and prognosis.  These investigators presented a patient with chronic exanthematic type II atypical adult PRP, whose skin status was significantly improved with monthly ECP.  Various therapeutic regimens including narrow-band UV-B, bath PUVA therapy, systemic fumaric acid esters and systemic cyclosporin had failed.  Oral retinoids could not be administered due to a type IIa hyper-lipoproteinemia with profound hepatic steatosis and elevated liver transaminases.  The observed clinical benefit may encourage future clinical studies analyzing the clinical value of ECP in otherwise unresponsive cases of type II PRP.

Dall'Amico and Messina (2002) stated that ECP is a new type of photochemotherapy used for the treatment of oncological and autoimmune diseases.  Additionally, recent reports indicated that this therapy is promising in both pediatric and adult patients who develop GVHD resistant to conventional protocols after bone marrow transplantation.  These researchers reviewed 31 studies where ECP was used in the treatment of acute and chronic GVHD.  A total of 76 (32 % female) acute GVHD patients have been considered in 11 series; 59 patients presented with skin involvement; 47 had liver involvement, and 28 had gastro-intestinal manifestations.  Treatment duration ranged from 1 to 24 months.  A regression of skin manifestations was observed in 83 % of the patients with a complete response in 67 %.  A complete regression of liver and gut manifestations was reported in 38 % and 54 % of the patients, respectively.  The overall patient survival was 53 %.  Of the 43 patients alive, 8 developed chronic GVHD manifestations.  The immunosuppressive therapy was discontinued in 28 % of cases and reduced in 46 %.  A total of 204 (45 % female) chronic GVHD patients treated with ECP 1 to 110 months from transplantation have been considered in 20 series.  A total of 128 patients presented with skin involvement; 84 with liver, 31 with lung, and 59 with oral manifestations.  Treatment duration ranged from 3 to 40 months.  A regression of skin manifestations was observed in 76 % of patients with a complete response in 38 %.  An improvement of liver and lung involvement was reported in 48 % and 39 % of the patients, respectively.  Of the 59 patients with oral manifestations, an improvement was obtained in 63 % of cases.  The overall patient survival was 79 %.  Extracorporeal photopheresis is a non-aggressive treatment that may benefit patients with both acute and chronic GVHD who do not respond to standard immunosuppressive therapy.

Perfetti and associates (2008) examined the effects of ECP for the treatment of steroid refractory acute GVHD.  Extracorporeal photopheresis was given to 23 patients with steroid-refractory acute GVHD (aGVHD, grade II (n = 10), III (n = 7) or IV (n = 6)).  The median duration of ECP was 7 months (1 to 33) and the median number of ECP cycles in each patient was 10.  Twelve patients (52 %) had complete responses.  Eleven patients (48 %) survived and 12 died, 10 of GVHD with or without infections and 2 of leukemia relapse.  The average grade of GVHD was reduced from 2.8 (on the first day of ECP) to 1.4 (on day +90 from ECP) (p = 0.08), and the average dose of intravenous methylprednisolone from 2.17 to 0.2 mg/kg/day (p = 0.004).  Complete responses were obtained in 70, 42 and 0 % of patients, respectively, with grades II, III and IV aGVHD; complete responses in the skin, liver and gut were 66, 27 and 40 %.  Patients treated within 35 days from onset of aGVHD had higher responses (83 versus 47 %; p = 0.1).  A trend for improved survival was seen in grade III-IV aGVHD treated with ECP as compared to matched controls (38 versus 16 %; p =  0.08).  The authors concluded that ECP is a treatment option for patients withsteroid refractory aGVHD and should be considered early in the course of the disease.  Moreover, the authors stated that "[t]he good results in patients receiving ECP, within 1 month from the onset of GVHD and when the severity does not exceed grade II-III may warrant a prospective trial to explore the role of photochemotherapy as upfront treatment of aGVHD".

A decision memorandum from the CMS concluded that there is insufficient evidence to support the use of ECP in pemphigus vulgaris and bullous pemphigoid (CMS, 2006).

Richmond and colleagues (2007) stated that nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition observed in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, functional disability, and systemic complications.  Recent reports have suggested a possible link with exposure to gadolinium.  No current therapy has clearly demonstrated effectiveness for NSF, although case reports suggested that ECP may be of benefit.  These researchers explored the plausibility of a gadolinium linkage with NSF and evaluated the effectiveness of ECP in the treatment of a cohort of patients with NSF (n = 8).  Of the 8 patients, 6 had a history of arterial or venous thrombotic disease, and 7 had a documented exposure to gadolinium within 1 week to several months before onset of NSF.  Specifically, all patients were exposed to gadodiamide.  These investigators treated 5 of the patients with ECP.  After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.  The authors concluded that their findings support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF.  They noted that larger epidemiologic studies will be needed to confirm this association.  Furthermore, their experience suggest that, if used for extended periods, ECP might have some mild benefit for patients with NSF.  They stated that larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.

Regarding the appropriate duration of ECP, an article from eMedicine recommends ECP weekly for 2 consecutive days each week, tapering to every other week until rejection resolves (Introcaso et al, 2007).  A systematic review (Dall'Amico and Messina, 2002) assessed 31 studies of ECP for GVHD, and noted that treatment duration ranged from 3 to 40 months.

Shaughnessy et al (2010) stated that GVHD is partly mediated by host antigen-presenting cells (APCs) that activate donor T cells.  Extracorporeal photopheresis can modulate APC function and benefit some patients with GVHD.  These investigatros reported the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD.  Grades II to IV acute GVHD developed in 9 (30 %) of 30 recipients of HLA-matched related transplants and 13 (41 %) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants.  Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89 % (95 % CI: 78 to 94 %) and 77 % (95 % CI: 64 to 86 %), respectively.  There were no unexpected adverse effects of ECP.  Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multi-variate analysis indicated a lower risk of grades II to IV acute GVHD in patients receiving ECP (p = 0.04).  Adjusted OS at 1 year was 83 % in the ECP study group and 67 % in the historical control group (relative risk 0.44; 95 % CI: 0.24 to 0.80) (p = 0.007).  The authors concluded that these preliminary findings may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.  Moreover, they stated that longer follow-up, larger sample sizes, and randomized comparisons to standard approaches are needed.

Kusztal et al (2011) stated that ECP is considered a promising immunomodulatory therapy of acute allograft rejection in organ transplantation and GVHD.  These researchers investigated the biological responses of 10 patients who underwent kidney transplantation with ECP as prophylactic treatment.  They received conventional immunosuppressive therapy plus ECP immediately after transplantation: 12 to 16 applications over the course of 2.5 months.  ECP procedures were performed using an automated system for leukocyte separation and photo-activation with methoxsalen.  All recipients were followed by estimated glomerular filtration rate (eGFR) and peripheral T, B, natural killer, T-regulatory (Treg) and dendritic cells (DC) counts and phenotypes.  An acute rejection episode appeared in one control group recipient.  The ECP group showed a positive trend to an higher GFR at months 3 (53 ± 11 versus 47.1 ± 9; p = 0.17) and 6 (67.5 ± 10 versus 53.6 ± 3; p = 0.03, Wilcoxon test).  An increased percentage of Treg (CD3+ CD4+ CD25+) among the total CD3 cell count (4.9 % ± 1 % to 9.4 % ± 15 %) as well as inducible Treg (CD3+ CD8+ CD28-) was observed among CD3 cells (3.3 % ± 3 % to 11.8 % ± 8 %, p = 0.025) within 3 months of ECP treatment.  A significant difference in the percentage of Treg was noted at month 3 (completed ECP) between the ECP and the control groups (9.4 % ± 15 % versus 3 % ± 1 %; p = 0.01).  Addition of ECP to standard immunosuppression was associated with a significantly higher GFR at 6 months and with a significant increase in natural Treg among CD3 cells.  The authors stated that these preliminary results are promising.

Gurcan and Ahmed (2011) noted that long-term remission in epidermolysis bullosa acquisita (EBA) patients is difficult to achieve.  Patients who are resistant or develop side effects to conventional immunosuppressive therapy (CIST) have been treated with several other agents.  These researchers reviewed the clinical outcome in patients treated with a single drug or combination, and determined if long-term remission can be induced.  Data on 71 patients were analyzed.  There are no controlled trials.  The regimens used included dapsone, colchicine, mesalazine, cyclosporine, mycophenolic acid, intravenous immunoglobulin, rituximab, daclizumab, extracorporeal photochemotherapy, and plasmapheresis.  The use of CIST, especially in wide spread and recalcitrant patients, usually does not produce a prolonged clinical remission and can have hazardous side effects.  Intravenous immunoglobulin, rituximab and immunoadsorption have been successfully used in some, but the benefits from their use may require additional studies.

Lucid et al (2011) stated that ECP has been shown to be a promising treatment for chronic GVHD; however, only a few case reports are available that examine the effectiveness of ECP for bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT).  Because of the poor response to traditional therapies, ECP has been explored as a possible therapeutic option for severe BO after allo-SCT.  A total of 9 patients received ECP between July 2008 and August 2009 after a median follow-up of 23 months (range of 9 to 93 months) post-transplant.  The primary indication for ECP was the development of BO in patients who had failed prior multi-drug regimens.  The median number of drugs used for BO management before ECP was 5 (range of 2 to 7); this included immunosuppressive therapy.  Six of 9 (67 %) patients responded to ECP after a median of 25 days (range of 20 to 958 days).  No ECP-related complications occurred.  ECP seemed to stabilize rapidly declining pulmonary function tests in about 2/3 of patients with severe and heavily pre-treated BO that developed after allo-SCT.  The authors concluded that these findings support the need for a larger prospective study to confirm the impact of ECP on BO, and to consider earlier intervention with ECP to improve the outcome of BO after allo-SCT.  Limitations of this study included its retrospective nature, small sample size, and short follow-up.

In a prospective study, Wolf et al (2012) examined the effect of a defined 20-week ECP protocol in patients with severe, refractory atopic dermatitis.  The patient inclusion criteria included (i) disease duration of at least 1 year, (ii) “SCORing Atopic Dermatitis" (SCORAD; an objective clinical tool for assessing the severity (i.e., extent, intensity) of atopic dermatitis) greater than 45, and (iii) resistance to first-line therapy, including topical steroids, topical calcineurin inhibitors, and 1 form of phototherapy (UVA, UVB, or PUVA) or 1 second-line therapy, including systemic steroids or cyclosporine.  A total of 10 patients (4 women and 6 men; age range of 29 to 61 years) were enrolled and treated with 2 sessions of standard ECP in 2-week intervals for 12 weeks and 4-week intervals thereafter until week 20.  The patients' clinical status and response was determined by SCORAD at baseline and every 2 weeks, and quality of life was assessed every 4 weeks using SKINDEX, SF-36, and FACT scores.  There was a statistically significant (p = 0.015) reduction of the mean SCORAD by 10.3 (95 % CI: 2.5 to 18.0) from 64.8 at baseline to 54.5 (i.e., 15.9 % reduction) at week 20.  In a subset of patients (all of female sex), the relative reduction in SCORAD after ECP was more than 25 % at week 20.  Improvement in quality of life measured by SKINDEX, SF-36, and FACT did not reach statistical significance.  The authors concluded that they detected a small but significant therapeutic effect of ECP in patients with severe, refractory atopic dermatitis.  The findings of this small study need to be validated by well-designed studies with larger sample size and longer follow-up.

Stage 0-p BOS (i.e., an average decline in FEV1 of 10 to 19 % of the basal value of 2 measurements at least 3 weeks apart) refers to a decline in lung function that is thought to be predictive of BOS, but does not establish the diagnosis of BOS (Riise et al, 2011).

Russo et al (2012) noted that since 1960, different classes of immunosuppressive drugs have been used in the post-transplant follow-up.  Each is assessed for its effectiveness in preventing rejection but also on the basis of the many side effects induced by prolonged treatment.  To reduce these side effects, continuous development of knowledge and medical technology to create cutting-edge therapies in the field is necessary.  One of these is ECP, which is a useful therapeutic tool for the development of immunomodulation supported by CD8+ clone-specific cytotoxic lymphocytes.  The T cells targeted by ECP are modified by photo-activation and seem to develop marked immunogenicity with no suppression of the immune response.  Recent studies suggested the possible utility of ECP in the treatment of glomerulonephritis and in countering rejection after transplantation of organs including the kidney.

Lai et al (2012) stated that the fundamental role of antibodies in the development of acute graft rejection has been established recently.  Antibody-mediated acute rejection may develop at any time during the post-renal transplant period.  Several therapeutic approaches have been proposed in the last decades.  However, there is no standardized therapy.  These researchers reported the Sapienza University experience of combined plasma treatment and high-dose intravenous immunoglobulin ± ECP.  From January 2006 to September 2009, 6 patients were treated at Sapienza University.  In 5 cases (83 %) complete regression of the acute rejection was observed, followed by stable renal function (median creatinine value at 1-year follow-up: 1.5 mg/dL).  No adverse events were reported.  The authors concluded that this approach seems to give good results in terms of graft survival and procedure safety.  Moreover, they stated that further studies on a larger number of patients are needed to confirm the validity of these findings.  Furthermore, comparison between the authors' protocol and other treatments is necessary.

Benden et al (2012) noted that lung transplantation has evolved as an accepted therapy in selected adults and children with end-stage lung diseases.  Outcomes following lung transplantation have improved in the recent era with a 5-year survival of greater than 70 % and an overall good functional status of surviving recipients.  Many of the advances have been achieved by the use of modern immunosuppressive agents.  To date, multiple strategies exist that may be employed when utilizing immunosuppression.  These agents can be used in a variety of roles that may include induction, maintenance or rescue therapy, many of which are illustrated in this review including the current evidence to support their use.  Infections in lung transplant recipients remain a significant cause of morbidity and mortality.  Special considerations are required with the substantial burden of chronic infection in candidates with cystic fibrosis lung disease before transplantation.  Furthermore, recent progress and advances in prevention and treatment of post-transplantation infectious complications were detailed.  Chronic lung allograft dysfunction remains to be the burden of lung transplantation in the long-term.  Unfortunately, there is no well-established therapy to address it.  However, therapy attempts include change/augmentation of immunosuppression, use of neomacrolides and ECP, all of which were reviewed in detail.

Kaloyannidis and Mallouri (2012) noted that over the last decades significant advances have been made in the field of donor selection, alternative transplant sources, immunosuppressive treatment and supportive care, as well as in the better understanding of the immunobiology of allogeneic hematopoietic stem cell transplantation (alloTx).  Nevertheless, several factors still affect unfavorably the outcome of the procedure.  Graft-versus-host disease remains the leading cause of morbidity, non-relapse mortality and treatment failure post alloTx.  So far, steroids are the widely used 1st-line treatment for GVHD achieving considerable response rate however, patients who fail to respond to the initial therapy have a dismal prognosis and no standard treatment is well-established for them to date.  In recent years, ECP has been proposed as a safe and effective treatment for steroid-refractory GVHD.  Overall responses of 75 % have been reported in the cutaneous and mucosal involvement and 45 to 65 % in other organ manifestations (e.g., lung, liver and intestinal), allowing reduction and even discontinuation of steroids, thus contributing towards a significant reduction of morbidity.  Although the mechanism of action of ECP is not fully understood, it seems that it has an immunomodulatory rather than an immunosuppression effect and induces immunotolerance, preserving the beneficial graft-versus-tumor effect.  Given these very promising results in steroid-refractory or steroid-depended GVHD, currently, ECPis being investigated as both first-line and prevention therapy also.

In a review on "Bronchiolitis obliterans after allo-SCT: Clinical criteria and treatment options", Uhlving and colleagues (2012) stated  that "though several studies have been performed in patients with BO after HSCT and lung transplantation, the studies are difficult to interpret because of the heterogeneity in the treatment schedules, diagnostic criteria and response assessment criteria.  A prospective study randomized study of extracorporeal photophoresis treatment performed by Flower et al revealed a significant improvement of cGVHD in the skin, and indicated a steroid sparing effect on cGVHD in general.  No effect on lung function parameters was noted .... Solid evidence regarding the efficacy of the various available treatment modalities in BO is still sparse".

On April 30, 2012, a National Coverage Determination (NCD) by the Centers for Medicare & Medicaid Services stated that ECP for the treatment of bronchiolitis obliterans syndrome (BOS) following lung allograft transplantation will be covered only when ECP is provided under a clinical research study that meets criteria. An accompanying decision memorandum (CMS, 2012) stated that the evidence is insufficient to conclude that, in Medicare beneficiaries with BOS developing after lung allograft transplantation refractory to standard immunosuppressive therapy, ECP will improve patient centered health outcomes. However, based on its previously published criteria for considering CED, CMS concluded that evidence of basic safety, potential for patient-centered health outcome improvement, and demonstrated difficulty of conducting appropriate clinical trials are sufficient in combination to persuade CMS to propose coverage for ECP therapy for BOS after lung allograft transplantation within approved clinical research studies.

CPT Codes / HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
ICD-9 codes covered if selection criteria are met:
202.10 - 202.18 Mycosis fungoides
202.20 - 202.28 Sezary's disease
279.50 - 279.53 Graft-versus-host disease
996.83 Complications of transplanted organ; heart
996.84 Complication of transplanted organ; lung
996.85     bone marrow
V42.1 Organ or tissue replaced by transplant; heart
V42.81     other specified organ or tissue, bone marrow
V42.82     other specified organ or tissue, peripheral stem cells
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
242.00 - 242.01 Toxic diffuse goiter
245.2 Chronic lymphocytic thyroiditis
250.00 - 250.93 Diabetes mellitus
255.41 - 255.42 Corticoadrenal insufficiency
281.0 Pernicious anemia
283.0 Autoimmune hemolytic anemias
287.0 Allergic purpura
340 Multiple sclerosis
358.00 - 358.01 Myasthenia gravis
446.21 Goodpasture's syndrome
555.0 - 555.9 Regional enteritis [Crohn's]
691.8 Other atopic dermatitis and related conditions
694.4 Pemphigus
694.5 Pemphigoid
696.4 Pityriasis rubra pilaris
710.0 Systemic lupus erythematosus
710.1 Systemic sclerosis [scleroderma]
710.2 Sicca syndrome
710.4 Polymyositis
714.0 - 714.9 Rheumatoid arthritis and other inflammatory polyarthropathies
757.39 Other specified congenital anomaly of skin [epidermolysis bullosa acquisita]
996.81 Complications of transplanted organ, kidney
996.82 Complications of transplanted organ, liver
996.86 Complications of transplanted organ, pancreas
996.87 Complications of transplanted organ, intestine
V42.0 Organ or tissue replaced by transplant, kidney
V42.6 Organ or tissue replaced by transplant, lung
V42.7 Organ or tissue replaced by transplant, liver
V42.83 Organ or tissue replaced by transplant, pancreas
V42.84 Organ or tissue replaced by transplant, intestines

The above policy is based on the following references:
  1. 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.  
  2. 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.  
  3. 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.  
  4. 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.  
  5. 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.  
  6. 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.  
  7. 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.  
  8. Kirklin JK, Bourge RC, McGiffin DC. Recurrent or persistent cardiac allograft rejection: Therapeutic options and recommendations. Transplantation Proc. 1997;29( 8A):40S-44S.  
  9. 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.  
  10. 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.  
  11. 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.  
  12. Giunti G, Schurfeld K, Maccherini M, et al. Photopheresis for recurrent acute rejection in cardiac transplantation. Transplantation Proc. 1999;31(1-2):128-129.  
  13. Zic JA, Miller JL, Stricklin GP, King LE Jr. The North American experience with photopheresis. Ther Apher. 1999;3(1):50-62.  
  14. 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.  
  15. 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.  
  16. 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.  
  17. 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.  
  18. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Arch Dermatol. 1992;128(3):337-346.  
  19. Trentham DE. Photochemotherapy in systemic sclerosis: The stage is set. Arch Dermatol. 1992;128:389-390.  
  20. Cribier B, Faradji T, Le Coz C, et al. Extracorporeal photochemotherapy in systemic sclerosis and severe morphea. Dermatology. 1995;191(1):25-31.  
  21. 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.  
  22. Lim HW, Edelson RL. Photopheresis for the treatment of cutaneous T-cell lymphoma. Hematol Oncol Clin North Am. 1995;9(5):1117-1126.  
  23. 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.  
  24. Mielke V, Staib G, Sterry W. Systemic treatment for cutaneous lymphomas. Recent Results Cancer Res. 1995;139:403-408.  
  25. 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.  
  26. Kahari VM. Activation of dermal connective tissue in scleroderma. Ann Med. 1993;25(6):511-518.  
  27. Pope J. Treatment of systemic sclerosis. Curr Opin Rheumatol. 1993;5(6):792-801.  
  28. Kaplan EH, Leslie WT. Cutaneous T-cell lymphomas. Curr Opin Oncol. 1993;5(5):812-818.  
  29. Oliven A, Shechter Y. Extracorporeal photopheresis: A review. Blood Rev. 2001;15(2):103-108.  
  30. 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.
  31. Stummvoll GH. Current treatment options in systemic sclerosis (scleroderma). Acta Med Austriaca. 2002;29(1):14-19.
  32. Wiendl H, Hohlfeld R. Therapeutic approaches in multiple sclerosis: Lessons from failed and interrupted treatment trials. BioDrugs. 2002;16(3):183-200.
  33. 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. 
  34. 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. 
  35. 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. 
  36. Almazán C, Espallargues M. Extracorporeal phototherapy (photopheresis) for the treatment of Sezary Syndrome and graft versus host disease [summary]. Barcelona, Spain: Catalan Agency for Health Technology Assessment (CAHTA); July 2001. Available at: Accessed June 18, 2003. 
  37. Gorgun G, Miller KB, Foss FM. Immunologic mechanisms of extracorporeal photochemotherapy in chronic graft-versus-host disease. Blood. 2002;100(3):941-947. 
  38. Foss FM, Gorgun G, Miller KB. Extracorporeal photopheresis in chronic graft-versus-host disease. Bone Marrow Transplant. 2002;29(9):719-725. 
  39. 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. 
  40. 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. 
  41. 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. 
  42. Russell-Jones R. Extracorporeal photophoresis in chronic cutaneous graft-versus-host disease. Bone Marrow Transplant. 1998;22(7):621-623. 
  43. Greinix HT, Volc-Platzer B, Rabitsch W, et al. Successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease. Blood. 1998;92(9):3098-3104. 
  44. 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. 
  45. 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). Available at: Accessed September 30, 2003.
  46. 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). Available at: Accessed April 23, 2004.
  47. Zackheim HS. Treatment of mycosis fungoides/Sezary syndrome: The University of California, San Francisco (UCSF) approach. Int J Dermatol. 2003;42(1):53-56.
  48. 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.
  49. Srinivasan R, Lichtenstein GR. Recent developments in the pharmacological treatment of Crohn's disease. Expert Opin Investig Drugs. 2004;13(4):373-391.
  50. 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.
  51. 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.
  52. Guariso G, D'Inca R, Sturniolo GC, et al. Photopheresis treatment in severe Crohn disease. J Pediatr Gastroenterol Nutr. 2003;37(4):517-520.
  53. 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.
  54. 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.
  55. 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.
  56. 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.
  57. 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. 2005;35(12):1187-1193.
  58. Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood. 2006;107(8):3074-3080.
  59. Bisaccia E, Palangio M, Gonzalez J, et al. Treatment of extensive chronic graft-versus-host disease with extracorporeal photochemotherapy. J Clin Apher. 2006;21(3):181-187.
  60. Centers for Medicare and Medicaid Services (CMS). Decision memo for extracorporeal photopheresis (CAG-00324R). Medicare Coverage Database. Rockville, MD: CMS; December 19, 2006. Available at: Accessed March 9, 2007.
  61. Ontario Ministry of Health and Long-Term Care, Medical Advisory Secretariat (MAS). Extracorporeal photopheresis (ECP). Health Technology Policy Assessment. Toronto, ON: MAS; March 2006. Available at: Accessed March 17, 2007.
  62. Lamioni A, Carsetti R, Legato A, et al. Induction of regulatory T cells after prophylactic treatment with photopheresis in renal transplant recipients. Transplantation. 2007;83(10):1393-1396.
  63. Urbani L, Mazzoni A, De Simone P, 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.
  64. Sand M, Bechara FG, Sand D, et al. Extracorporeal photopheresis as a treatment for patients with severe, refractory atopic dermatitis. Dermatology. 2007;215(2):134-138.
  65. Richmond H, Zwerner J, Kim Y, Fiorentino D. Nephrogenic systemic fibrosis: Relationship to gadolinium and response to photopheresis. Arch Dermatol. 2007;143(8):1025-1030.
  66. Introcaso CE, Rook A. Extracorporeal photopheresis. eMedicine Dermatology Topic 566. Omaha, NE:; updated March 8, 2007. Available at: Accessed January 23, 2008.
  67. Dall'Amico R; Messina C. Extracorporeal photochemotherapy for the treatment of graft-versus-host disease. Ther Apher. 2002;6(4):296-304.
  68. Haenssle HA, Bertsch HP, Emmert S, Extracorporeal photochemotherapy for the treatment of exanthematic pityriasis rubra pilaris. Clin Exp Dermatol. 2004;29(3):244-246.
  69. 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.
  70. National Institute for Health and Clinical Excellence (NICE). Extracorporeal photopheresis for Crohn's disease. Interventional Procedure Guidance 288. London, UK: NICE; February 2009.
  71. Morrell MR, Despotis GJ, Lublin DM, et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant. 2010;29(4):424-431.
  72. Szodoray P, Kiss E. Progressive Systemic Sclerosis - from the molecular background to innovative therapies. Front Biosci (Elite Ed). 2010;2:521-525.
  73. 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. 2010;45(6):1068-1076.
  74. Kusztal M, KoĊ›cielska-Kasprzak K, Gdowska W, et al. Extracorporeal photopheresis as an antirejection prophylaxis in kidney transplant recipients: Preliminary results. Transplant Proc. 2011;43(8):2938-2940.
  75. Gurcan HM, Ahmed AR. Current concepts in the treatment of epidermolysis bullosa acquisita. Expert Opin Pharmacother. 2011;12(8):1259-1268.
  76. 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.
  77. 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. 2012;12(1):174-181.
  78. Riise GC, Martensson G, Houltz B, Bake B. Prediction of BOS by the single-breath nitrogen test in double lung transplant recipients. BMC Research Notes. 2011, 4:515.
  79. Russo GE, D'Angelo AR, Testorio M, et al. New therapeutic prospects for renal transplant: extracorporeal photochemotherapy. G Ital Nefrol. 2012;29 Suppl 54:S36-S39.
  80. Lai Q, Pretagostini R, Gozzer M, et al. Multimodal treatment for acute antibody-mediated renal transplant rejection: Successful rescue therapy with combined plasmapheresis, photopheresis and intravenous immunoglobulin. G Ital Nefrol. 2012;29 Suppl 54:S31-S5.
  81. Benden C, Danziger-Isakov L, Faro A. New developments in treatment after lung transplantation. Curr Pharm Des. 2012;18(5):737-746.
  82. Kaloyannidis P, Mallouri D. The role of the extracorporeal photopheresis in the management of the graft-versus-host disease. Transfus Apher Sci. 2012;46(2):211-219.
  83. Uhlving HH, Buchvald F, Heilmann CJ, et al, Bronchiolitis obliterans after allo-SCT: Clinical criteria and treatment options. Bone Marrow Transplant, 2012;47(8):1020-1029.
  84. Centers for Medicare & Medicaid Services (CMS). National coverage determination (NCD) for extracorporeal photopheresis (110.4). Baltimore, MD: CMS; April 30, 2012.
  85. Centers for Medicare & Medicaid Services (CMS). Decision Memo for Extracorporeal Photopheresis (ECP) (CAG-00324R2). Baltimore, MD: CMS; April 30, 2012.
  86. Dignan FL, Greenblatt D, Cox M, et al. Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD. Bone Marrow Transplant. 2012;47(6):824-830.

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