CAM 80136

Extracorporeal Photopheresis

Category:Therapy   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:August 2000    

Description
Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory procedure that involves the following 3 steps: (1) the patient’s blood is collected into a centrifuge system that separates the leukocyte-rich portion (buffy coat) from the rest of the blood; (2) the photosensitizer agent 8-methoxypsoralen is added to the lymphocyte fraction, which is then exposed to ultraviolet-A (320-400 nm wavelength) light at a dose of 1 to 2 J/cm2; and (3) the light-sensitized lymphocytes are reinfused into the patient. The use of ECP has been investigated for patients needing treatment for organ rejection after solid organ, transplant graft-versus-host disease (GVHD), autoimmune diseases, and T-cell lymphoma. 

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

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

For individuals who are heart transplant recipients who require prophylaxis to prevent graft rejection who receive ECP, the evidence includes a small RCT.  Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. The small randomized trial is insufficient to permit conclusions on the utility of ECP. Studies with more patients and longer follow-up are needed. The evidence is insufficient to determine the effects of the technology on health outcomes. 

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

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

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

Kidney Transplant
For individuals who are kidney transplant recipients who experience recurrent graft rejection who receive ECP, the evidence includes a small prospective study and numerous case reports. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. Current evidence does not permit conclusions on the effect of ECP on net health outcome. RCTs, comparing immunosuppressive therapy with immunosuppressive therapy using ECP and examining histologic confirmation of treatment response, are needed.The evidence is insufficient to determine the effects of the technology on health outcomes.

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

Clinical input obtained in 2014 supported the use of ECP in patients with refractory acute GVHD. 

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

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

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

Background 
ORGAN REJECTION TREATMENT AFTER SOLID ORGAN TRANSPLANT
The standard of care for treatment of organ transplant rejection is immunosuppression, with the particular regimen dictated by the organ being transplanted. As organ transplantation success rates have improved, more patients are facing the morbidity and mortality associated with immunosuppressive therapies developed to prevent rejection of the transplanted organ. Immunosuppressive therapies are used to lower the responsiveness of the recipient’s immune system, decreasing the chance of rejection. Unfortunately, portions of the immune system responsible for the prevention of viral, fungal, and bacterial infection also are affected. This can, in turn, lead to serious infections, including opportunistic infections.   

Although first approved for the treatment of cutaneous T-cell lymphoma (CTCL), extracorporeal photopheresis (ECP) has more recently been used as a supplement to conventional therapies in the area of solid organ transplantation.1 Reports of the successful use of ECP in human cardiac transplant recipients were published in 19922,3 and use in other transplant patients followed. Although the specific mechanism of action of ECP is unknown, the reinfusion of treated leukocytes seems to specifically suppress the patient’s immune response to the donor organ, although maintaining the body’s ability to respond to other antigens.4 The specificity of ECP to target the immune response to the transplanted organ allows ECP to decrease organ rejection without an increased risk of infection, common with immunosuppressive drugs.5

GRAFT-VERSUS-HOST DISEASE
Given that graft-versus-host disease (GVHD) is an immune mediated disease, ECP can be used to treat GVHD after a prior allogeneic cell transplant. In fact, GVHD can be categorized in 2 ways: (1) as an acute disease, occurring within the first 100 days after the infusion of allogeneic cells; or (2), as a chronic disease, which develops sometime after 100 days. Acute GVHD is commonly graded from I to IV, ranging from mild disease, which is characterized by a skin rash without involvement of the liver or gut, to grades III and IV, which are characterized by generalized erythroderma, elevated bilirubin levels, or diarrhea. Grade III acute GVHD is considered severe, and grade IV is considered life-threatening. Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such as progressive systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. Chronic GVHD may affect the mouth, eyes, respiratory tract, musculoskeletal system, and peripheral nerves, as well as the skin, liver, or gut—the usual sites of acute GVHD.

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

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

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

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

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

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

Peripheral T-Cell Lymphoma
Peripheral T-cell lymphoma is a group of rare and usually aggressive non-Hodgkin lymphomas that develop from mature T cells. This disease comprises approximately 10% to 15% of all cases of non-Hodgkin lymphoma in the United States and generally occurs in adults 60 years of age or older. Standards of care are evolving, including the use of hematopoietic cell transplantation.6    

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

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

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

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

Policy:
Organ Rejection after Solid Organ Transplant
Extracorporeal photopheresis may be considered MEDICALLY NECESSARY to treat cardiac allograft rejection, including acute rejection, that is either recurrent or that is refractory to standard immunosuppressive drug therapy.

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

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

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

Chronic GVHD
Extracorporeal photopheresis may be considered MEDICALLY NECESSARY as a technique to treat chronic GVHD that is refractory to medical therapy.

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

Automimmune Diseases:
Extracorporeal photopheresis is considered INVESTIGATIONAL as a technique to treat either the cutaneous or visceral manifestations of autoimmune diseases, including, but not limited to, scleroderma, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, multiple sclerosis or diabetes, or autoimmune bullous disorders, severe atopic dermatitiis or Crohn's disease.

Cutaneous T-cell lymphoma:
Extracorporeal photopheresis may be considered MEDICALLY NECESSARY as a technique to treat late-stage (III/IV) cutaneous T-cell lymphoma.

Extracorporeal photopheresis may be considered MEDICALLY NECESSARY as a technique to treat early stage (I/II) cutaneous T-cell lymphoma that is progressive and refractoy to establish nonsystemic therapies.

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

Other indications
Extracorporeal Photophoresis is considered INVESTIGATIONAL for all other indications.

Policy Guidelines
Organ Rejection After Solid Organ Transplant
A regimen of immunosuppressive therapy is standard of care for the treatment of solid organ rejection. Therefore, refractory rejection is defined as rejection that fails to respond adequately to a standard regimen of immunosuppressive therapy.

Recurrent allograft rejection is defined as having at least 2 rejection episodes that recurred after standard immunosuppressive therapy.

There is no standard schedule for extracorporeal photopheresis, and reported schedules vary by the organ type. However, most reported cardiac and lung schedules initiate therapy with 2 consecutive days of extracorporeal photopheresis in month 1, followed by biweekly therapy on 2 consecutive days in months 2 and 3, then monthly on 2 consecutive days in months 4 through 6.

Graft-Versus-Host Disease
Methylprednisolone is considered first-line treatment of acute GVHD. For chronic GVHD, an alternating regimen of cyclosporine and prednisone is commonly used. Other therapies include antithymocyte globulin, corticosteroid monotherapy and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide or azathioprine. Therefore, refractory disease is defined as GVHD that fails to respond adequately to a trial of any of the above therapies.

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

Cutaneous T-Cell Lymphoma Staging (based on the TNM classification system)

IA: T1N0M0

IB: T2N0M0

IIA: T1-2N1M1

IIB: T3N0-1M0

III: T4N0-1M0

IVA: T1-4N2-3M0

IVB: T1-4N0-3M1

Sézary Syndrome
According to the World Health Organisation-European Organisation for Research and Treatment of Cancer (WHO-EORTC), Sézary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy and the presence of neoplastic T cells (Sézary cells) in skin, lymph nodes and peripheral blood. The International Society of Cutaneous Lymphomas recommends an absolute Sézary cell count of at least 1,000 cells per cubic mm, in the presence of immunophenotypical abnormalities (CD4/CD8 ratio greater than 10; loss of any or all of the T-cell antigens CD2, CD3, CD4 and CD5; or both) or the demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods.

Benefit Application
BlueCard®/National Account Issues
Plans may wish to negotiate a global payment for ECP for medically refractory chronic graft-versus-host disease.

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

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function---including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Graft Rejection After Solid Organ Transplant
Clinical Context and Therapy Purpose
The purpose of administering extracorporeal photopheresis (ECP) in patients are heart, lung, liver, or kidney transplant recipients who experience graft rejection (acute or recurrent) refractory to medical therapy or who require prophylaxis to avoid graft rejection is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of ECP in patients improve the net health outcome in those who are heart, lung, liver, or kidney transplant recipients who experience graft rejection?

The following PICOTS were used to select literature to inform this review.  

Patients
The relevant populations of interest include the following: 

  • heart transplant recipients who experience acute or recurrent graft rejection or receive preventive measure to avoid graft rejection; 
  • lung transplant recipients who experience acute graft rejection or have bronchiolitis obliterans syndrome (BOS); 
  • liver transplant recipients who experience graft rejection; and 
  • kidney transplant recipients who experience graft rejection.  

Interventions
The therapy being considered is ECP.
 

Comparators
The following practices are currently being used to treat transplant recipients: medical management, immunosuppression, and dialysis (for kidney only). 
 

Outcomes
The general outcomes of interest are overall survival, recurrence of graft failure, reduction in immunosuppressive agents, and treatment-related adverse events (eg, infections). 
 

Timing
Follow-up varies by treatment response and medical condition. Clinical follow-up to assess treatment response may take up to 6 months.
 

Setting
ECP would be administered in an outpatient setting. The number of treatments varies by medical condition and treatment response. Each procedure can take between 2 and 4 hours. 
 

Heart Transplant
Acute Graft Rejection
An RCT has compared the efficacy of extracorporeal photopheresis (ECP) with corticosteroids for the treatment of heart transplant rejection.2 Costanzo-Nordin et al (1992) enrolled 16 heart transplant patients and randomized to ECP (n=9) or corticosteroids (n=7). Recipients of orthotopically transplanted hearts who were eligible if an endomyocardial biopsy (EMB) showed moderate rejection (grades 2, 3A, 3B). Participants were excluded for leukopenia; hemodynamic compromise, manifested clinically or by a minimum 25% decrease in cardiac output and a minimum 25% increase in mean pulmonary artery wedge pressure; and/or allergy or intolerance to psoralen. Corticosteroids were dosed at oral prednisone 100 mg/d for 3 days or intravenous methylprednisolone 1 g/d for 3 days at the discretion of the managing physician. If on the seventh day EMB had not demonstrated improvement in rejection grade, treatment was repeated. If rejection grade persisted after retreatment, patients were given oral methotrexate 10-mg at weekly intervals for 8 weeks. Participants were followed for a mean of 6.2 months, and all participants completed the trial. Those who participated in ECP treatment generally only received the treatment once. The only reason for multiple treatments was if an inadequate number of cells hadbeen treated; in those cases, an additional treatment was given 48 hours later. Eight of 9 rejection episodes treated with ECP improved; all 7 rejection episodes treated with corticosteroid resolved. Improvement was seen a mean of 7 days (range, 5-20 days) after ECP and 8 days (range, 6-67 days) after corticosteroid treatment. Seven infections occurred during follow-up, five in the corticosteroid group, and two in the ECP group. No other adverse events were observed with ECP. The authors noted that major trial limitations included small sample size and a wide range in time from transplant to study entry. They concluded that ECP and corticosteroid in this small group with short-term follow-up appeared to have similar efficacies for the treatment of moderate heart transplant rejection. They also noted the reduced number of infections and no other observed harms associated with ECP.

Recurrent and/or Refractory Graft Rejection
Carlo et al (2014) reported their experience with ECP in 20 pediatric heart transplant recipients between 1990 and 2012 at a U.S. university.6 Patients who had transplants at a median age of 12.7 years (range, 0.3-18.5) and received their first ECP treatment at a median age of 15.3 years (range, 7.3-31 years). Indications for ECP included rejection with hemodynamic compromise (HC rejection), rejection without HC, and prophylaxis. One- and 3-year survival rates after ECP were 84% and 53%, respectively. Survival outcomes were worse in noncompliant than compliant patients.  

Kirklin et al (2006) conducted a comparative study of 343 heart transplant recipients.7 Thirty-six patients were treated with ECP for rejection and formed the treatment group. Patients were 18 years of age or older, treated from 1990 to 1993, and followed to May 2004. Indications for ECP were episodes of rejection with HC rejection (n=12); recurrent (n=9), or persistent (n=11) rejection; or prophylaxis in the presence of antidonor antibodies (n=4). ECP consisted of psoralen in a 2-day treatment protocol every 3 to 6 weeks for 18 months; maintenance immunosuppression used cyclosporine- or tacrolimus-based therapy with prednisone for the first 4 to 6 months and azathioprine, which was replaced by mycophenolate mofetil during the later years of the study. The primary outcome was incidence of HC rejection or death from rejection (rejection death). Patients with at least 3 months of ECP were considered to have effective photopheresis treatment; patients who received less than 3 months of treatment were considered untreated but were analyzed as part of the photopheresis group. The period after 3 months of ECP was associated with a reduction in risk of HC rejection or rejection death (risk reduction, 0.29). A sustained decrease in the risk of HC rejection or HC death was observed for the photopheresis group through 2 years of follow-up. This study was not randomized; risk factor analysis showed that the ECP group had a higher baseline risk of HC rejection or rejection death. Changes in maintenance immunotherapy over time might have confounded the results because patients in the comparison group did not receive a consistent regimen. However, improvements in maintenance immunotherapy would tend to obscure any treatment effect of ECP compared with evolving immunotherapy regimens. This bias, therefore, strengthens the authors’ conclusion that ECP reduces the risk of subsequent HC rejection and/or death from rejection in patients at high risk of rejection.

Maccherini et al (2001) presented a case series of 12 patients treated with ECP for recurrent rejection.8 Inclusion criteria were recurrent rejection (n=5), recurrent infections associated with acute rejection (n=2), and a grade 3A acute rejection 2 years after transplantation (n=5). Mean post-ECP follow-up was 23.3 months. ECP was performed as 2 treatments weekly for 1 month, once weekly for 2 months, and then once monthly for 2 months. The total number of rejection episodes decreased from a mean of 3 per patient pre-ECP to 0.4 per patient post-ECP. All patients reduced immunosuppressive therapy. There were no adverse events or infections reported during follow-up. The authors concluded that ECP was safe and effective for heart transplant patients with recurrent rejection and reduced both rejection episodes and immunosuppressive therapy. 

Dall’Amico et al (2000) reported on a case series of 11 heart transplant recipients with recurrent rejection.9 Participants were eligible if they had acute rejection and at least 2 rejection episodes after standard immunosuppressive therapies in the 3 months before ECP. ECP was administered with ultraviolet-A radiation photopheresis instruments in 2 consecutive treatments at weekly intervals for 1 month, at 2-week intervals for 2 months, and then monthly for 3 months. One patient with grade 3B rejection received an intravenous pulse of corticosteroids during the first ECP cycle. Patients were followed for 60 months. During follow-up, 1 patient died from hepatitis C virus and another dropped out due to rejection unresponsive to ECP and high-dose corticosteroids; all others completed the study. All acute rejection episodes were successfully reversed after a mean of 14.2 days (range, 7-32 days). In terms of rejection relapse, the fraction of EMBs with grade 0/1A rejection increased during ECP from 46% to 72%, and those showing 3A/3B rejection decreased from 42% to 18%. One of 78 EMBs during ECP showed 3B rejection compared with 13 of 110 during the pre-ECP period. Six rejection relapses were observed during follow-up, two of which occurred during the tapering of oral corticosteroids. Four were reversed by ECP, one by intravenous corticosteroids, and one by methotrexate after the failure of both ECP and intravenous corticosteroids. The mean dose of immunosuppressive drugs (corticosteroids, cyclosporine, azathioprine) was reduced after 6 months of ECP therapy. One patient with anemia and low body weight experienced symptomatic hypotension during treatment, and another had interstitial pneumonia. The authors concluded that ECP was a well-tolerated treatment, which permitted better recurrent rejection control and reductions in immunosuppressive therapy. Follow-up time and patient population were adequate; however, the study was small and lacked a comparison group.  

Prophylaxis to Prevent Graft Rejection
An RCT by Barr et al (1998) investigated ECP for the prevention of rejection after cardiac transplant.10 Sixty consecutive adult cardiac transplant recipients at 12 clinical sites (9 in U.S., 3 in Europe) were randomized to both immunosuppressive therapy plus ECP (n=33) or immunosuppressive therapy alone (n=27). Standard immunosuppressive therapy consisted of cyclosporine, azathioprine, and prednisone. Entry criteria included adequate peripheral venous access and residence less than 2 hours away from the transplant center. ECP treatment was delivered on days 1, 2, 5, 6, 10, 11, 17, 18, 27, and 28 in month 1; then for 2 consecutive days every 2 weeks in months 2 and 3; and then for 2 consecutive days every 4 weeks in months 4 to 6 for a total of 24 ECP procedures per patient. The primary end point was the number and frequency of histologic acute rejection episodes. Pathologists were blinded to treatment assignment. Follow-up for the primary end point was 6 months; an additional 6 months of follow-up was completed to assess safety and survival. 

After 6 months, the mean number of acute rejection episodes per patient was statistically greater in the standard therapy group (1.4) than in the ECP group (0.9). In the standard therapy group, 5 patients had no rejection episodes, 9 had 1, 9 had 2, and 4 had 3 or more. In the ECP group, 13 had none, 14 had 1, 3 had 2, and 3 had 3 or more. These differences were statistically significant. There were no differences in 6- or 12-month survival rates, number of infections, or time to first rejection between groups. During a subsequent 6 months of follow-up, there was no difference between groups in the number of acute rejection episodes; however, because of time management issues, institutions reverted to nonstandardized protocols during this interval. The authors concluded that ECP plus standard immunosuppressive therapy significantly reduced the risk of cardiac rejection without increasing the risk of infection. More long-term follow-up is necessary to assess the effects of a reduction of acute rejection on long-term graft function, survival of the transplant recipient, and development of graft vasculopathy. 

Section Summary: Graft Rejection After Heart Transplant
Acute Graft Rejection
For acute rejection, a 1992 randomized trial enrolled 16 heart transplant recipients. The use of ECP in combination with immunosuppressive therapy had efficacy similar to immunosuppressive therapy alone, with fewer infections in the ECP group. This trial was small, and time from transplantation to study entry varied. 

Recurrent and/or Refractory Graft Rejection
The use of ECP for recurrent and/or refractory cardiac allograft rejection has been the focus of most of the research on ECP. Although data are from nonrandomized studies, a comparative study of 343 cardiac transplant recipients in which 36 patients received ECP has been completed. The authors showed that at 3 months, ECP was related to a risk reduction of HC rejection or rejection death (relative risk, 0.29). A reduction in HC rejection or rejection death was observed through 2 years of follow-up. Although trial results might have been confounded by improvements in immunosuppressive therapy regimens over time, they are consistent with case series for this indication, which have suggested a benefit of ECP in patients with recurrent or refractory cardiac rejection. Thus, the evidence to date provides consistent evidence for a beneficial effect of ECP for cardiac transplant patients with rejection refractory to standard therapy.  

Prophylaxis to Prevent Graft Rejection
For prevention of rejection, a single trial from 12 clinical sites randomized 33 patients to immunosuppressive therapy plus ECP and 27 patients to immunosuppressive therapy alone. Differences between the numbers of acute rejection episodes were statistically significant; however, there was no difference in survival at 6 months. Thus, current evidence does not permit conclusions on the utility of ECP for the prevention of acute cardiac graft rejection. Studies with more patients and longer follow-up are needed. 

Lung Transplant
Acute Graft Rejection
Retrospective Studies
Villanueva et al (2000) retrospectively assessed 14 transplant recipients (7 bilateral lung, 6 single lung, 1 heart-lung) who received ECP for BOS.11 All patients were refractory to standard immunosuppressive therapy. ECP was administered every 2 weeks for 2 months and then monthly for 2 months (for a total of 6 treatments). Four of 8 patients with baseline grade of 0 or 1 BOS had improvement in BOS or stabilization after treatment. Mean survival after ECP was 14 months. Three of 4 patients received ECP during a concurrent episode of acute rejection; all 3 patients had complete resolution of acute rejection after treatment. 

Case Series
Benden et al (2008) published a single-center study of 24 patients treated with ECP, 12 for recurrent acute rejection and 12 for BOS (reviewed in the next section).12 The primary outcome measure was clinical stabilization of rejection after ECP. Twelve patients had biopsy-confirmed chronic acute rejection, defined as two or more biopsy-proven episodes of acute rejection before ECP. Of 11 patients who had follow-up biopsies during treatment, 2 patients had an episode of biopsy-proven acute rejection. All 12 patients experienced clinical stabilization after 12 ECP cycles; none experienced BOS. Treatment was well-tolerated with no ECP-related adverse events reported. Pooled median patient survival post-ECP treatment was 4.9 years (range, 0.5-8.4); however, these data were not specific to the group being treated for acute rejection. 
 

Another series published by Salerno et al (1999) reported on 2 patients with histologic reversal of concurrent acute rejection after treatment with ECP.13  

BOS Refractory to Corticosteroids
Prospective Studies
Jaksch et al (2012) reported on a prospective study of 194 patients who developed BOS and received standard treatment (n=143) or standard treatment plus ECP (n=51).14 Patients who did not respond to standard immunosuppressive therapy and showed further decline of lung function received ECP when reaching BOS stage 1 or higher. ECP was administered on 2 successive days every 2 weeks during the first 3 months and then every 4 weeks until the end of therapy. The use of ECP was discontinued after a minimum of 3 months if lung function decreased significantly. If forced expiratory volume in 1 second (FEV1)improved or stabilized, ECP was continued for a minimum of 6 months. Change in FEVat 3, 6, and 12 months after ECP initiation was used as a surrogate for treatment response. The primary end pointwas change in lung function before and after ECP. Eighteen percent of patients receiving ECP experienced an improvement in FEVfor more than 1 year after initiation of ECP, and 12% showed improvement for only 3 to 6 months. FEVstabilized in 31% of patients and declined in 39%. Kaplan-Meier method analysis showed a significant difference in responders and nonresponders in survival and the need for a transplant. Compared with patients who had BOS and did not receive ECP but were similar in demographics and treatment history, the ECP group had longer survival (p=0.046) and underwent fewer transplantations (18 vs 21; p=0.04). Mean time to transplant also was twice as long in the ECP group (1839 days vs 947 days; p=0.006). No ECP-related adverse events were reported. Although this study was not randomized, a group with similar demographics and treatment history was available for comparison. 

Retrospective Studies
Greer et al (2013) retrospectively analyzed 65 patients treated at a single institution with ECP for chronic lung allograft dysfunction, defined as deteriorating FEVdue to BOS, as well as reduced total lung capacity and broncho-alveolar lavage neutrophilia.15 Fifty-one (78%) patients had undergone double lung transplant, 9 (14%) patients had undergone a single-lung transplant, and 5 (8%) patients had undergone a heart-lung transplant. The median time to chronic lung allograft dysfunction diagnosis was 3 years (interquartile range, 2-5 years). Patients had progressed (≥10% decline in FEV1) on first-line azithromycin. At ECP initiation, 35 (54%) patients were graded BOS stage 3; 21 (32%) patients were BOS stage 2; and 9 (14%) patients were BOS stage 1 or 0p (potential BOS). ECP was administered every 2 weeks for 3 months; subsequent treatments were administered not more than 8 weeks apart to maintain stabilized graft function. The medianfollow-up time was 17 months; 44 patients who continued treatment beyond 3 months received a median of 15 ECP treatments. Eight (12%) patients achieved a 10% or greater improvement in FEV1, considered a treatment response; 27 (42%) patients experienced no change in FEV1; and 30 (46%) patients experienced a 10% or greater decline in FEV1, considered progressive disease. Median progression-free survival was 13 months (interquartile range, 10-19 months) among responders and 4 months (interquartile range, 3-6 months) among those who did not respond. This study was retrospective and lacked a control group. 

Jaksch et al (2012) reported on a prospective series of 194 patients who developed BOS and received standard treatment (n=143) or standard treatment plus ECP (n=51).14 Patients who did not respond to standard immunosuppressive therapy and showed a further decline of lung function received ECP when reaching BOS stage 1 or higher. ECP was administered on 2 successive days every 2 weeks during the first 3 months and then every 4 weeks until the end of therapy. ECP was discontinued after a minimum of 3 months if lung function decreased significantly. If FEV1improved or stabilized, ECP was continued for a minimum of 6 months. Change in FEVat 3, 6, and 12 months after ECP initiation was used as a surrogate for treatment response. The primary end pointwas change in lung function before and after ECP. Eighteen percent of patients receiving ECP experienced an improvement in FEVfor more than 1 year after initiation of ECP, and 12% showed improvement for 3 to 6 months. FEVstabilized in 31% of patients and declined in 39%. Kaplan-Meier method analysis showed a significant difference in responders and nonresponders in survival and the need for a transplant. Compared with patients who had BOS and did not receive ECP but were similar in demographics and treatment history, the ECP group had longer survival (p=0.046) and underwent fewer transplantations (18 vs 21; p=0.04). Mean time to transplant also was twice as long in the ECP group (1839 days vs 947 days; p=0.006). No ECP-related adverse events were reported. Although this study was not randomized, a group with similar demographics and treatment history was available for comparison. 

Lucid et al (2011) retrospectively evaluated 9 patients treated with ECP between 2008 and 2009.16 Median follow-up was 23 months posttransplant (range, 9-93 months), and the median age was 38 years (range, 21-54 years). The primary indication for ECP was symptomatic progressive BOS that failed previous therapy. Patients were treated weekly with 2 sessions of ECP for 3 to 4 weeks. Treatment frequency then decreased to every 2 to 3 weeks, with the goal of reducing treatment to every 4 weeks. Clinical response was defined as symptomatic improvement, decreased dependency on supplemental oxygen, and improved pulmonary function tests. Six (67%) of 9 patients responded to ECP after a median of 25 days. No ECP-related complications occurred in this series. As in several previous studies, this report lacked a control group for comparison.  

Morrell et al (2010) published a retrospective case series of all lung transplant recipients (n=60) who received ECP for progressive BOS at a university-based hospital.17 Ninety-five percent of patients had received a bilateral lung transplant, and 58% had grade 3 BOS. The indication for ECP was a progressive decline in lung function that was refractory to standard immunosuppressive therapy. The primary end point was the rate of change in lung function before and after the initiation of ECP. ECP was delivered as 2 cycles on days 1, 2, 5, 6, 10, 11, 17, 18, 27, and 28 during the first month (10 treatments); biweekly for the next 2 months (8 treatments); and then monthly for the following 3 months (6 treatments), for a total of 24 treatments. Sixty patients were followed from the time of lung transplantation to death or the end of the study (July 2008). Median follow-up was 5.4 years (range, 1.0-16.6 years). At the end of the study, 33 patients were still alive; 4 deaths occurred early in the study. Most deaths were due to the progression of respiratory failure, except for one due to sepsis and another to graft failure. In the 6 months before ECP, the mean rate of decline in FEV1 was -116.0 mL/mo; after ECP, the mean rate of decline was -28.9 mL/mo (mean difference, 87.1 mL; 95% confidence interval, 57.3 to 116.9 mL). The rate of decline in lung function slowed in 44 (79%) patients, and lung function improved (increase in FEV1 above pretreatment values) in 14 (25%) patients. Through 12 months of follow-up, mean improvement in FEVwas 145.2 mL. Ten (17%) of 60 patients experienced adverse events. Eight were hospitalized for catheter-related bacteremia; 1 case resulted in death. All cases resulted from indwelling pheresis catheters. The authors concluded that ECP was associated with a significant reduction in the rate of decline in lung function. This reduction was sustained through 12 months of follow-up. The major study limitations were its retrospective design and lack of a control group. Most patients had grade 3 BOS and, therefore, may differ from patients with other grades. Statistical analyses were robust. 

As noted, Benden et al (2008) published a single-center study of 24 patients treated with ECP (12 for BOS and 12 for recurrent acute rejection).12 ECP was delivered when BOS grade worsened despite standard therapy. At the start of therapy, 5 patients had BOS grade 1; 2 patients had BOS grade 2; and 5 patients had BOS grade 3. Before ECP, the rate of decline in FEV1 was 112 mL/mo compared with 12 mL/mo after ECP (mean difference, 100 mL/mo; range, 28-171 mL/mo). However, ECP did not seem to affect absolute FEV1. Treatment was well-tolerated, with no ECP-related adverse events reported. Median patient survival was 7.0 years (range, 3.0-13.6 years); median patient survival post-ECP was 4.9 years (range, 0.5-8.4 years). However, results were pooled and not specific to the 12 patients with BOS. 

Also as noted, Villanueva et al (2000) retrospectively reviewed outcomes of 14 transplant recipients (7 bilateral lung, 6 single lung, 1 heart-lung) who received ECP for BOS.11 All patients were refractory to standard immunosuppressive therapy. ECP was administered every 2 weeks for 2 months and then once monthly for 2 months (for a total of 6 treatments). In 4 of 8 patients with grade 0 or 1 BOS, BOS improved or stabilized after treatment. Mean survival after ECP was 14 months. Six patients with initial BOS grade 2 or higher suffered progression of their BOS after ECP. Mean survival after ECP was 14 months. Four of these patients died of chronic rejection, and one of lung cancer. The remaining patient survived to retransplantation. Two of the 14 patients developed line-related sepsis, which cleared with antibiotic therapy and catheter removal. 

Section Summary: Organ Rejection After Lung Transplant
Acute Graft Rejection
Data on acute graft rejection are very limited and do not permit any conclusions on the utility of ECP for this indication. Use of ECP in this population needs a prospective, randomized trial focused specifically on the treatment for acute rejection. 

BOS Refractory to Corticosteroids
The bulk of the evidence for ECP in lung transplantation focuses on treatment of refractory BOS. The primary limitations of these data are they derive from nonrandomized and uncontrolled studies. Further, the evidence is inconsistent, with some studies reporting ECP to be beneficial in those with early refractory BOS but not in those with grade 2 or higher BOS, which contrasts with a retrospective series of 60 patients who responded well to ECP (nearly 60% of these patients were BOS grade 3). Prospective, RCTs are necessary, and analyses should be stratified by BOS grade because there is some evidence that ECP efficacy may vary by BOS grade. 

Liver
The published evidence on the use of ECP in liver recipients derives from a group in Italy. Urbani et al (2004-2008) published a series of articles on various potential applications of ECP for liver transplant recipients.18-20 The first, from 2004, retrospectively reviewed 5 patients who received liver transplantation and ECP for biopsy-proven allograft rejection. Indications for ECP were recalcitrant ductopenic rejection with hepatitis C virus recurrence; corticosteroid-resistant acute rejection (2 patients); severe acute rejection in a major ABO-incompatible liver graft; and severe acute rejection in a patient with a proven corticosteroid allergy.18 ECP was performed twice weekly for 4 weeks, then every 2 weeks for 2 months, and then once monthly. ECP was discontinued when indicated by biopsy-proven reversal of rejection or the absence of clinically evident rejection relapse. Liver function tests improved to baseline in all but 1 patient, and no procedure-related complications were reported. At a median follow-up of 7.9 months, 3 patients were off ECP treatment with normal liver function tests and low-level immunosuppressive therapy, and 2 patients continued ECP treatments with full-dose immunosuppressive therapy. 

The second study, from 2007, was a nonrandomized comparative assessment of 36 patients (18 active treatment, 18 historical matched controls) who received ECP to delay the introduction of calcineurin inhibitors (CNI) to avoid CNI toxicity.19 Patients were included if they were at risk of postliver transplant renal impairment and neurologic complications, defined as having at least one of the following risk factors: a calculated glomerular filtration rate of 50 mL/min or less at transplantation; severe ascites; history of more than 1 hospitalization for encephalopathy within 1 year of transplant and/or 1 hospitalization within 1 month of transplantation; or age 65 years or older. Outcome measures were treatment success rate, defined as the ratio of patients with full CNI-sparing or delayed immunosuppression; interval from liver transplantation to CNI introduction; safety of ECP; and the need for biopsy. ECP was initiated during the first week posttransplant; 2 different systems (Therakos, PIT) for photopheresis were used, and treatment was given as scheduled for the system used. All 18 patients tolerated and completed ECP therapy. For 17 patients, CNI was introduced at a mean of 8 days; 1 patient remained CNI-free for 22 months. Acute rejection occurred in 5 (28%) of 18 patients in the ECP group and in 3 (17%) of 18 historical controls. One-, 6-, and 12-month survival rates were 94.4%, 88.1%, and 88.1%, respectively, for ECP recipients vs 94.4%, 77.7%, and 72.2%, respectively, for controls. The authors concluded that the addition of ECP improved management of liver transplant patients in the early transplant phase,  delayed CNI introduction, and lower CNI-related mortality. This study was not randomized and assessed a small number of patients.  

The third case series (2008) reported on 3 fields of interest for ECP as prophylaxis of allograft rejection in liver transplant patients20:  

  • Use of ECP to delay CNI among high-risk liver transplant recipients to avoid toxicity (previously discussed); 
  • Use of ECP for prophylaxis of acute cellular rejection among ABO-incompatible liver transplant recipients (11 consecutive patients received ECP plus immunosuppressive therapy with no evidence of acute rejection through 568 days of follow-up); and 
  • Use of ECP in hepatitis C virus-positive patients (which is beyond the scope of this evidence review).  

Except for the first area, these studies were small and lacked comparison groups; RCTs are needed for the proper assessment of outcomes.  

Section Summary: Organ Rejection After Liver Transplant
In liver transplantation, evidence for the use of ECP is limited, and research to date has been generated by a single group. Although there is a comparative (nonrandomized) study, it involved only 18 cases and 18 historical controls. The focus in liver transplantation has been on prevention of rejection with ECP; this would be best addressed by an RCT comparing immunosuppressive therapy alone with immunosuppressive therapy plus ECP. Current evidence does not permit conclusions on the utility of ECP for liver transplant patients experience graft rejection. 
 

Kidney Transplant
The largest reported group of renal patients to receive ECP was at a hospital in Australia. Jardine et al (2009) published a prospective case series of 10 patients treated with ECP for recurrent and/or refractory rejection after renal transplantation.21 ECP was delivered weekly for 4 weeks, then every 2 weeks. Total number of treatments ranged from 2 to 12 treatments for more than 5 to 20 weeks. Median follow-up was 66.7 months after transplant and 65.0 months from initiation of ECP. Indication for ECP was acute resistant or recurrent rejection in 9 patients and the need to avoid high-dose corticosteroids in another. Refractory rejection resolved in all patients through the stabilization of renal function. The authors concluded that ECP might have a role as an adjunct to current therapies in patients with refractory rejection. Although this is the largest series of renal patients, it was small and lacked a comparison group. Renal biopsies were not used to document therapeutic response. 
 

Additional evidence comes from case reports on 32 patients with renal transplants. Twenty-six of these patients had refractory rejection. After ECP, renal function improved in 19 (73%) of 26 patients, 3 patients were stable, and 4 patients returned to dialysis because of deteriorating function. Reports of long-term outcomes varied. Among 22 patients who showed initial improvement and/or stabilization of renal function, 5 had improved function at 1 year,22 1 was stable at 25 months,23 5 were stable at 1 year,22,24 7 were rejection-free at 2 to 5 years,23 and one graft was lost.24 Long-term outcomes were not reported for three patients.25,26 

Section Summary: Graft Rejection After Kidney Transplant
For renal transplant recipients, the evidence base on the use of ECP to treat graft rejection is sparse. While studies have consistently reported evidence of benefit from ECP for those with refractory graft rejection, there are no comparative studies, and current numbers are too small to permit conclusions. A prospective, randomized trial, with histologic confirmation of treatment  response is needed. This trial would randomize patients to immunosuppressive therapy or immunosuppressive therapy plus ECP to address whether there is an additional benefit from ECP for patients with refractory graft rejection after renal transplantation. 
 

Graft-Versus-Host Disease
Clinical Context and Therapy Purpose
The purpose of administering ECP in patients who acute or chronic graft-versus-host-disease (GVHD) refractory to medical therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies. 

The question addressed in this evidence review is: Does the use of ECP in patients improve the net health outcome in those who have acute or chronic GVHD? 

The following PICOTS were used to select literature to inform this review.  

Patients
The relevant populations of interest are adults and children with acute or chronic GVHD refractory to medical therapy. 
 

Interventions
The therapy being considered is ECP. 
 

Comparators
The following practices are currently being used to treat GVHD: medical management and immunosuppression. 
 

Outcomes
The general outcomes of interest are overall survival, recurrence of GVHD, reduction in immunosuppressive agents, and treatment-related adverse events (eg, infections). 
 

Timing
Follow-up varies by treatment response and medical condition. Clinical follow-up to assess treatment response may take up to 6 months. 
 

Setting
ECP would be administered in an outpatient setting. The number of treatments varies by medical condition and treatment response. Each procedure can take between 2 and 4 hours.
 

Acute GVHD and Chronic GVHD
Systematic Reviews
Abu-Dalle et al (2014) published a systematic review of prospective studies in patients with steroid-refractory acute or chronic GVHD.27 Relevant literature was searched through February 2013, and the following items were identified: 1 RCT in patients with chronic GVHD28; and 8 cohort studies in patients with acute and/or chronic GVHD (total N=323 patients). In meta-analyses, the overall response rates for acute and chronic GVHD were 69% and 64%, respectively. In both acute GVHD and chronic GVHD, the overall response rates were highest in cutaneous disease (84% and 71%, respectively) followed by gastrointestinal disease (65% and 62%, respectively). Rates of immunosuppression discontinuation were 55% and 23% for acute GVHD and chronic GVHD, respectively. Statistical heterogeneity for most meta-analyses was high (I2>60%).

ECP for the treatment of acute and chronic GVHD was addressed in a TEC Assessment (2001) that offered the following observations and conclusions29: For acute GVHD or chronic GVHD in previously untreated patients or in those responding to conventional therapy, no studies met selection criteria and reported results of ECP, alone or in combination with other therapies. Therefore, ECP failed to meet TEC criteria for these indications. Studies focusing on patients with chronic GVHD unresponsive to other therapies reported resolution or marked improvement of lesions in approximately 50% of patients. Finally, studies of patients with acute GVHD also reported successful outcomes in 67% to 84% of patients with grade 3 disease, but patients with grade 4 disease rarely responded.

Case Series
Hautmann et al (2013) reported on a cohort of 62 patients with acute GVHD (n=30) or chronic GVHD (n=32) at a single institution in Germany.30 For acute GVHD, ECP was administered 2 or 3 times weekly on consecutive days until clinical improvement, then 2 treatments on consecutive days biweekly, reducing to monthly, if tolerated. At 3 months, 15 (50%) patients achieved complete response (CR) or partial response (PR) (9 [30%] complete). Ten (83%) of 12 patients who continued ECP beyond 3 months and had data available decreased steroid dose by 50% or more. For chronic GVHD, ECP was administered on 2 consecutive days weekly until improvement, then biweekly for 3 to 4 weeks, and then monthly. At 3 months, 14 (44%) patients achieved CR or PR (2 [6%] complete). Five (29%) of 17 patients who continued ECP beyond 3 months had data available and were taking steroids at baseline, decreased steroid dose by 50% or more.

Ussowicz et al (2013) reported on 21 patients with steroid-refractory or steroid-dependent, grade 3 or 4 acute (n=8) or chronic (n=13) GVHD in Poland.31 For acute GVHD, ECP was administered on 2 consecutive days weekly for up to 4 weeks. Although clinical response was noted in 3 (37.5%) patients, there were no long-term (>18 months after ECP) survivors. For  chronic GVHD, ECP was administered on 2 consecutive days every 2 weeks for 14 weeks and then monthly for up to 8 weeks. The 4-year overall survival rate was 67.7%. 

Treatment in Pediatrics
Acute and Chronic GVHD
Systematic Reviews
Two Cochrane reviews, both by Weiss et al (2014), assessed acute GVHD32 and chronic GVHD33 in pediatric patients. Literature searches were performed in September 2012, and no RCTs were found. Reviewers cited the need for RCTs but stated that “performing RCTs in this patient population will be challenging because of the limited number of patients, the variable disease presentation, and the lack of well-defined response criteria.”33

Retrospective Studies
A retrospective review by Perotti et al (2010) assessed 73 pediatric patients (age, <18 years) with acute or chronic GVHD after an allogeneic cell transplant unresponsive to 1 week of steroid treatment.34 Patients received ECP for a minimum of 10 treatments. ECP was administered 2 to 3 times weekly on alternating days until clinical improvement. Treatment was then reduced to 2 procedures per week for 2 weeks, then 2 procedures every other week for 3 weeks, ending with 2 procedures per month until maximum response as clinically indicated. ECP was discontinued if no improvement (≥50% clinical and laboratory response) was seen after 4 weeks. Of 47 patients with acute GVHD, 39 (83%) patients with skin involvement improved, and 7 (87.5%) of 8 patients with mucosal involvement improved. Among patients with chronic GVHD, all 4 (100%) patients with liver involvement improved, and 22 (95.6%) of 23 patients with skin involvement improved. 
 

The literature also includes small studies that have focused on ECP for treatment of acute and chronic GVHD in children 35,36 and a larger retrospective study. The retrospective study by Berger et al (2007) reported results of ECP for steroid-resistant GVHD in pediatric patients (age, 6-18 years) who had undergone hematopoietic cell transplantation for a variety of cancers.37 Patients had acute GVHD (n=15, stages 2-4) or chronic GVHD (n=10, 7 deemed extensive) that had not responded to at least 7 days of methylprednisolone therapy. Patients received ECP on 2 consecutive days at weekly intervals for the first month, every 2 weeks for 2 months, and then monthly for 3 months. The use of ECP was progressively tapered and discontinued based on the individual patient response. Response to ECP was assessed 3 months after ECP ended or after 6 months if the ECP protocol was prolonged. Among patients with acute GVHD, CR occurred in all 7 (100%) patients with grade 2 and 2 (50%) of 4 patients with grade 3 disease; none of 4 patients with grade 4 disease responded to ECP. In the group with chronic GVHD, CR occurred in all 3 (100%) patients with limited disease and 1 (14%) of 7 patients with extensive disease. Five (71%) of 7 patients with extensive chronic GVHD had no response to ECP. Adverse events of ECP were generally mild in all cases. These results are similar to those summarized in the TEC Assessment (2001), previously discussed.

One of the 2 smaller studies reported on 8 children (age, 5-15 years) with refractory chronic GVHD who received ECP and either oral 8-methoxypsoralen or infusion of an 8-methoxypsoralen solution into the pheresed lymphocytes.35 Cutaneous status improved in 7 patients. Five patients stopped treatment; 3 patients decreased doses of immunosuppressive therapy. In addition, gut involvement resolved in all patients, and liver involvement resolved in 4 of 6 patients. Two years after discontinuation of ECP, 5 patients remained in remission without immunosuppressive therapy. Salvaneschi et al (2001) reported on the use of ECP for refractory GVHD in 23 pediatric patients (age, 5.4-11.2 years).36 Seven (78%) of 9 patients with acute GVHD experienced either PR or CR. Nine (64%) of 14 patients with chronic GVHD experienced PR or CR. 

Treatment in Adults
Acute GVHD
Systematic Reviews
Zhang et al (2015) in China reported on a systematic review of prospective studies of ECP for acute GVHD.38 Literature was searched through September 2014, and 7 cohort studies were included (total N=121 patients). In meta-analyses, pooled overall and CR rates were both 71%. Statistical heterogeneity was considered not high for either result (I2<50%). The response rate was highest for cutaneous disease (86%), although a funnel plot indicated the presence of publication bias.

Nonrandomized Studies
Greinix et al (2006) reported on findings from a phase 2 (nonrandomized) study of intensified ECP as second-line therapy in 59 patients with post stem cell transplant, steroid-refractory, acute GVHD (grade 2-4).39 ECP was initially administered on 2 consecutive days (1 cycle) at 1- to 2-week intervals, until improvement was noted and thereafter every 2 to 4 weeks until maximal response. At the start of ECP, all patients had been receiving immunosuppressive therapy with prednisone and cyclosporine A. Complete resolution of GVHD was documented in 82% of patients with cutaneous manifestations, 61% with hepatic involvement, and 61% with gut involvement. Further, CR occurred in 87% and 62% of patients with exclusively skin or skin and liver involvement, respectively; only 25% with GVHD of skin, liver, and gut involvement and 40% with skin and gut involvement obtained a CR of GVHD with ECP therapy. The probability of survival was 59% among patients with CR to ECP, compared with 11% of those who did not achieve CR. Although these results would suggest ECP may be beneficial in the treatment of acute GVHD, the small sample size, few study details in the report, and lack of a standard treatment comparator group limit inferences about the clinical efficacy of ECP for acute GVHD.

Retrospective Studies
Jagasia et al (2013) reported on an international, retrospective comparative analysis of nonconcurrent cohorts who received ECP (n=57) or anticytokine therapy (inolimomab or etanercept; n=41) for steroid-refractory acute GVHD (grade 2 or higher).40 ECP was initiated at 2 to 3 treatments weekly or biweekly until maximal response and then discontinued (European sites) or tapered (U.S. sites). More patients in the ECP group than in the anticytokine group experienced overall response (CR plus PR; 66% vs 32%, p=0.001) and CR (54% vs 20%, p=0.001). The 2-year overall survival rate was 59% in the ECP group and 12% in the anticytokine group (p not reported). 

A single-center cohort of 9 patients with grade 2 or 3 steroid-refractory acute GVHD was reported by Rubegni et al (2013).41 ECP was administered on 2 consecutive days weekly until improvement and then every 2 weeks; treatment was then tapered as tolerated. At 3 months, the mean dose of methylprednisolone decreased from 2.22 mg/kg to 0.27 mg/kg, and mean dose of cyclosporine decreased from 2.46 mg/kg to 0.77 mg/kg. Six (67%) patients showed a complete skin response. Five (83%) of 6 patients with liver and gastrointestinal tract involvement had CRs. All patients developed chronic GVHD, 7 (78%) while still receiving ECP.  

Shaughnessy et al (2010) studied ECP to prevent acute GVHD in 62 patients undergoing standard myeloablative conditioning and allogeneic transplant.42 ECP was administered before a standard conditioning regimen. Results were compared with historical controls from the Center for International Blood and Marrow Transplant Research database. Multivariate analysis indicated a lower incidence of grade 2, 3, or 4 acute GVHD among patients who received ECP. Adjusted overall survival at 1 year was 83% in the ECP group and 67% among historical controls (relative risk, 0.44; 95% confidence interval, 0.24 to 0.80). 

Perfetti et al (2008) reported on a retrospective review of 23 patients with corticosteroid-refractory acute GVHD (n=10 grade 2; n=7 grade 3; and n=6 grade 4).43 The median duration of ECP was 7 months (range, 1-33 months) and the median number of cycles per patient was 10. CRs were seen in 70%, 42%, and 0% of patients with GVHD grades 2, 3, and 4, respectively. Eleven (48%) patients survived, and 12 (52%) died (10 of GVHD, 2 of relapse of leukemia); 83% of patients treated within 35 days from onset of GVHD responded compared with 47% of patients treated after 35 days (p=0.1). Although these findings would suggest that ECP may provide benefit for patients with refractory acute GVHD, there is a lack of certainty in the findings due to the small sample size and noncomparative study design.

Chronic GVHD
Systematic Reviews
Malik et al (2014) published a systematic review evaluating ECP for steroid-refractory chronic GVHD.44 Literature was searched through July 2012 and 18 studies were selected (4 prospective, including 1 RCT [2008],28 and 14 retrospective; total N=595 patients). In meta-analyses, overall response and CR rates were 64% and 29%, respectively. The pooled response rate was highest for cutaneous disease (74%) and lowest for lung disease (48%). Statistical heterogeneity was high for all results (I2>60%). 

The Ontario Health Technology Advisory Committee (OHTAC; 2006) published the results of a systematic review of ECP for the treatment of refractory chronic GVHD.45 OHTAC reported that there was low-quality evidence that ECP improves response rates and survival in patients with chronic GVHD unresponsive to other forms of therapy. Limitations in the literature on ECP for treating refractory GVHD mostly pertained to study quality and size and heterogeneity in both treatment regimens and diagnostic criteria. OHTAC did, however, recommend a 2-year field evaluation of ECP for chronic GVHD, using standardized inclusion criteria and definitions to measure disease outcomes including response rates, quality of life, and morbidity. There is no current evidence on the OHTAC website of an update.

Prospective Studies
Foss et al (2005) reported on results of a prospective (nonrandomized) study of ECP in 25 patients who had extensive corticosteroid-refractory or -resistant chronic GVHD after allogeneic cell transplantation.46 ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once weekly in 8 patients until best response or stable disease was achieved. With a 9-month median ECP duration (range, 3-24 months), 20 patients had improvement in cutaneous GVHD, 6 had oral ulcer healing, and 80% of patients reduced or discontinued immunosuppressive therapies. Overall, improvement was reported in 71% of cases with skin and/or visceral GVHD and 61% of those cases deemed to be high-risk patients. 

Dignan et al (2014) reported on a series of 38 consecutive adults who received ECP for chronic GVHD.47 Median patient age was 47 years (range, 18-73 years). Patients had a steroid-refractoryor steroid-dependent disease or were intolerant of corticosteroids. Thirty-six (95%) patients were receiving immunosuppressive therapy. ECP was administered on 2 consecutive days every 2 weeks until PR was achieved and was then reduced to monthly treatments. Of note, PR was defined as a minimum 50% improvement from baseline in 1 organ and no evidence of GVHD progression in other organs). Median time from transplant to first ECP was 1.7 years (range, 0.25-7.25 years). Response was assessed after 6 months. Nineteen (50%) patients had a CR (n=2; defined as complete resolution of all signs and symptoms of GVHD) or PR (n=17); all 19 had completed 6 months of ECP. Of 25 patients receiving immunosuppressive therapy who completed 6 months of ECP, 20 (80%) reduced immunosuppressive dose; 5 patients discontinued steroids, and 8 patients had a 50% or greater reduction in steroid dose. Mean improvements in validated quality-of-life measures (Lee Chronic Graft-Versus-Host Disease Symptom Scale and Dermatology Life Quality Index) were clinically and statistically significant in 17 (94%) of 18 patients who completed the questionnaires at 6 months. Five patients developed indwelling catheter-related infections, one had a catheter-related thrombosis, and another had an increase in red cell transfusion requirements which was attributed to ECP treatments. 

Section Summary: Graft-Versus-Host Disease
Evidence for the use of ECP for the treatment of GVHD assesses acute GVHD and chronic GVHD in pediatric and adult populations. The published literature, which includes systematic reviews, prospective and retrospective studies, and case series, lacks randomized trials. These data have consistently shown improvements in GVHD unresponsive to standard therapy and are consistent with conclusions from a 2001 TEC Assessment. Additionally, there is a lack of other treatment options for these patients; adverse events of ECP are minimal; and, if there is a response to ECP, some patients are able to reduce or discontinue treatment with corticosteroids and other immunosuppressive agents.23,48,49

Autoimmune Diseases
Clinical Context and Therapy Purpose
The purpose of administering ECP in patients who have autoimmune diseases is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does the use of ECP in patients improve the net health outcome in those with autoimmune diseases?

The following PICOTS were used to select literature to inform this review. 

Patients
The relevant populations of interest are autoimmune diseases (eg, cutaneous or visceral manifestations of autoimmune diseases including but not limited to scleroderma, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, multiple sclerosis, diabetes, autoimmune bullous disorders, severe atopic dermatitis, and Crohn disease).

Interventions
The therapy being considered is ECP.

Comparators
The following practices are currently being used to treat autoimmune diseases: medical management and immunosuppression. 

Outcomes
The general outcomes of interest are overall survival, recurrence of graft failure, reduction in immunosuppressive agents, and treatment-related adverse events (eg, infections). 

Timing
Follow-up varies by treatment response and medical condition. Clinical follow-up to assess treatment response may take up to 6 months. 

Setting
ECP would be administered in an outpatient setting. The number of treatments varies by medical condition and treatment response. Each procedure can take between 2 and 4 hours. 

Systematic Reviews
The use of ECP for the treatment of autoimmune diseases was addressed by a TEC Assessment (2001) that considered a variety of autoimmune diseases: systemic sclerosis, 1 diabetes, multiple sclerosis, type 1 diabetes, pemphigoid, severe atopic dermatitis, and Crohn disease.50 The Assessment concluded that, for all indications, available evidence was insufficient to permit conclusions on outcomes. At the time, photopheresis had been most thoroughly studied as a treatment for scleroderma, in a single-blind RCT by Rook et al (1992)51 and 3 small, uncontrolled series. Although the RCT reported positive outcomes in terms of skin manifestations, a number of methodologic flaws have been discussed in the literature,52,53,54 including inadequate treatment duration and follow-up, excessive dropouts, a mid-study change of primary outcome, and inadequate washout of prior penicillamine therapy. Results reported on other small case series regarding systemic sclerosis conflict with each other and do not resolve the difficulties in interpreting the randomized trial.

Scleroderma (Systemic Sclerosis
In addition to the RCT by Rook previously discussed,51 a cohort study by Papp et al (2012) enrolled 16 patients from a single institution in Hungary who had diffuse cutaneous systemic sclerosis.55 ECP was administered on 2 consecutive days every 6 weeks for 6 cycles. At the end of the treatment period, statistically significant reductions from baseline dermal thickness (by echography) were observed at 4 extensor surfaces (upper arm, forearm, hand, finger). Lung diffusing capacity did not decrease more than 5% in any of 9 patients with pulmonary fibrosis at baseline. 

Multiple Sclerosis
Cavaletti et al (2006) published a small case series of 5 patients with immunorefractory relapsing-remitting multiple sclerosis who received ECP.56 ECP appeared safe and tolerable in these patients, with some evidence for a reduction in the relapse rate and symptom stabilization. However, this case series is insufficient to support conclusions on the use of ECP for multiple sclerosis. 

Type 1 Diabetes
An RCT on the use of ECP to treat diabetes was published by Ludvigsson et al (2001).57 This double-blind RCT assessed 49 children with newly diagnosed type 1 diabetes. Forty children (age, 10-18 years) completed the trial and were followed for 3 years. All received standard treatment with insulin therapy and diet, exercise, and self-management education. Of these patients, 19 received active photopheresis treatment with oral 8-methoxypsorslen, and 21 received placebo tablets and sham pheresis. Hemoglobin A1c level did not differ statistically between groups. 

Bullous Disorders
Sanli et al (2010) retrospectively assessed 11 patients with drug-resistant autoimmune bullous diseases.58 ECP was performed between 2005 and 2010. Patients were treated on 2 consecutive days at 4-week intervals. Of 8 patients with pemphigus vulgaris, 7 (87.5%) experienced CR after 2 to 6 cycles. Of 3 patients with epidermolysis bullosa acquisita, 2 (67%) had CR and 1 (33%) had PR. All patients with pemphigus vulgaris reduced corticosteroid dose. Decrease in the frequency of ECP resulted in progression of lesions for 3 patients with pemphigus vulgaris and 2 patients with epidermolysis bullosa acquisita. No adverse events were observed. RCTs are necessary to adequately assess the efficacy of ECP for patients with drug-resistant autoimmune bullous diseases.

Severe Atopic Dermatitis
Some patients with atopic dermatitis do not respond to standard treatments and require immunosuppression with traditional (eg, systemic corticosteroids, azathioprine, cyclosporine, mycophenolate mofetil, methotrexate) or biologic (eg, alefacept, rituximab, intravenous immunoglobulin, infliximab, omalizumab) agents for chronic disease. Rubegni et al (2013) reported on 7 patients and summarized previous case series and case reports of patients with varying disease severity who were treated with ECP.59 Of 81 total patients, 69 (85%) were considered responders to ECP. Wolf et al (2013) subsequently published a case series of 10 adults with severe, refractory atopic dermatitis of at least 1-year duration.60 ECP was administered for 2 consecutive days biweekly for 12 weeks and then monthly for 2 months. Only concomitant topical treatments and antihistamine were allowed. Mean (SD) baseline SCORAD (Scoring of Atopic Dermatitis) was 64.8 (18.9) on a 0- to 103-point scale, indicating moderate-to-severe disease. At week 20, mean (SD) SCORAD was 54.5 (22.8), a statistically significant improvement (p=0.015) of uncertain clinical significance. Improvements in quality-of-life measures were not statistically significant.

Crohn Disease
Patients with steroid-dependent Crohn disease may respond to double immunosuppression with azathioprine and infliximab, but these treatments are associated with significant adverse events, particularly with long-term use. Reinisch et al (2013) assessed the steroid-sparing effect of ECP in 31 patients with steroid-dependent Crohn disease in clinical remission (Crohn Disease Activity Index, <150).61 Other immunosuppressive treatments were tapered and discontinued before ECP initiation and steroid tapering. ECP was administered on 2 consecutive days every 2 weeks for 24 weeks. Steroids were tapered as tolerated during this 24-week period. Nineteen (61%) patients completed 24 weeks of treatment; 7 (23%) patients achieved steroid-free remission at week 24 (the primary end point), and 20 (65%) patients, maintained remission with a 50% or greater reduction in steroid dose from baseline. Three (10%) patients maintained steroid-free remission after 48 weeks of ECP (frequency decreased to monthly after week 24), and 3 others who discontinued steroids experienced mild disease (Crohn Disease Activity Index <220) at 48 weeks of ECP. One catheter-related complication was reported.

Section Summary: Autoimmune Disorders
Evidence for the use of ECP for the treatment of autoimmune diseases, including scleroderma, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, multiple sclerosis, diabetes, autoimmune bullous disorders, severe atopic dermatitis, and Crohn disease, is sparse and insufficient to permit conclusions. There are randomized trials for 2 indications: scleroderma and type 1 diabetes. Methodologic flaws in the scleroderma trial limit applicability of the data. In the type 1 diabetes trial, no difference in hemoglobin A1c levels was observed between those treated with and without ECP.

T-Cell Lymphoma
Clinical Context and Therapy Purpose
The purpose of administering ECP in patients who have cutaneous or noncutaneous T-cell lymphomas is to provide a treatment option that is an alternative to or an improvement on existing therapies. 

The question addressed in this evidence review is: Does the use of ECP in patients improve the net health outcome in those who have cutaneous or noncutaneous T-cell lymphomas?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with cutaneous or noncutaneous T-cell lymphomas.

Interventions
The therapy being considered is ECP. 

Comparators
The following practices are currently being used to treat those with cutaneous or noncutaneous T-cell lymphomas: medical management and immunosuppression.

Outcomes
The general outcomes of interest are overall survival, reduction in immunosuppressive agents, and treatment-related adverse events (eg, infections).

Timing
Follow-up varies by treatment response and medical condition. Clinical follow-up to assess treatment response may take up to 6 months. For advance-stage disease, long-term follow-up is out to 5 years based on survival rates. For early-stage disease, follow-up extends beyond 20 years.

Setting
ECP would be administered in an outpatient setting. The number of treatments varies by medical condition and treatment response. Each procedure can take between 2 and 4 hours.

Cutaneous T-Cell Lymphoma
Advanced-Stage (III or IV) Cutaneous T-Cell Lymphoma
Systematic Reviews
OHTAC (2006) published the results of a systematic review of ECP for the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL).45 OHTAC reported that there was low-quality evidence that ECP improves response rates and survival in patients with CTCL unresponsive to other forms of therapy. Limitations in the literature related to ECP for the treatment of refractory erythrodermic CTCL mostly pertained to study quality and size and heterogeneity in both treatment regimens and diagnostic criteria. The committee did, however, recommend a 2-year field evaluation of ECP for refractory erythrodermic CTCL, using standardized inclusion criteria and definitions to measure disease outcomes including response rates, quality of life, and morbidity. There is no current evidence on the OHTAC website of an update.

Nonrandomized Studies
The initial report on the use of ECP as therapy for CTCL was published by Edelson et al (1987).62 Twenty-seven (73%) of 37 patients with otherwise resistant CTCL responded, with a mean 64% decrease in cutaneous involvement after a mean of 22 weeks. Responders included 8 (80%) of 10 patients with lymph node involvement, 24 (83%) of 29 with exfoliative erythroderma, and 20 (71%) of 28 whose disease was resistant to standard chemotherapy. Adverse events of standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. 

Knobler et al (2012) reanalyzed these data using current response criteria and reported no change in overall response rate.63 Response was defined as 90% or greater (near CR) or 50% or greater (PR) improvement in skin score for 4 weeks; in the original study, response was defined as 25% or greater improvement for 4 weeks. With 7 years of follow-up, median overall survival was 9 years from diagnosis and 7 years from the start of ECP. (The mean age at study entry was 57 years [range, 24-80 years]). These results showed that ECP is safe and effective in advanced, resistant CTCL. 

Subsequent results from numerous small, nonrandomized studies generally have been consistent with the initial conclusion that ECP treatment can produce clinical improvement and may prolong survival in a substantial proportion of patients with advanced-stage CTCL.64-68 These data have informed several evidence-based guidelines and consensus statements on the use of ECP in CTCL.69-71 The National Cancer Institute has consistently recommended ECP as first-line treatment for patients with stage III or IV CTCL.72 

Early-Stage (I or II) CTCL
Between 1987 and 2007, data were reported from at least 16 studies including 124 patients with CTCL in early stages IA, IB, or II who were treated with ECP alone (n=79) or in combination with other agents (eg, retinoids and interferon-a [n=45]).73 Many of these patients were refractory to numerous other therapies, including topical corticosteroids, interferon-a, or whole skin irradiation. Response rates (PR plus CR) in these studies ranged from 33% to 88% with monotherapy and 50% to 60% with ECP plus adjuvant therapies. 

Although these findings suggested that ECP may provide benefit in early-stage CTCL, none of the studies was randomized or comparative. Furthermore, many preceded universal acceptance of standardized elements of classification and diagnosis of CTCL, such as those proposed by the World Health Organization and the World Health Organization-European Organization for Research and Treatment of Cancer.74 Thus, the actual disease spectrum and burden represented in the available database likely vary between studies, and this complicates conclusions about the efficacy of ECP in this setting. Nonetheless, given the unfavorable prognosis for patients with early-stage CTCL that progresses on nonsystemic therapies, the relative lack of adverse events with ECP compared with other systemic treatments, and the good response rates often observed with ECP, ECP may provide benefit as a treatment for patients with refractory or progressive early-stage CTCL. In contrast, because early-stage CTCL typically responds to less-invasive, topical therapies, patients whose disease remains quiescent under such treatments usually experience near-normal life expectancy. 

Section Summary: Cutaneous T-Cell Lymphoma
Advance-Stage (III or IV) CTCL
A systematic review of small case series has shown that some patients with stages III or IV CTCL who have failed therapy may benefit from ECP and have improved survival rates. 

Early-Stage (I or II) CTCL
Given the unfavorable prognosis for patients with early-stage CTCL that progresses on nonsystemic therapies, the relative lack of adverse events with ECP compared with other systemic treatments, and the good response rates often observed with ECP, ECP may be considered as a treatment for patients with refractory or progressive early-stage CTCL. 

Summary of Evidence
Graft Rejection After Solid Organ Transplant
Heart Transplant
For individuals who are heart transplant recipients who experience acute graft rejection refractory to immunosuppression who receive ECP, the evidence includes a small RCT. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. The small RCT, while suggesting similar outcomes for ECP and corticosteroids, is insufficient to permit conclusions on the utility of ECP. Studies with more patients and longer follow-up are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

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

For individuals who are heart transplant recipients who require prophylaxis to prevent graft rejection who receive ECP, the evidence includes a small RCT. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. The small randomized trial is insufficient to permit conclusions on the utility of ECP. Studies with more patients and longer follow-up are needed. The evidence is insufficient to determine the effects of the technology on health outcomes. 

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

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

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

Kidney Transplant
For individuals who are kidney transplant recipients who experience recurrent graft rejection who receive ECP, the evidence includes a small prospective study and numerous case reports. Relevant outcomes are overall survival, change in disease status, and treatment-related mortality and morbidity. Current evidence does not permit conclusions on the effect of ECP on net health outcome. RCTs, comparing immunosuppressive therapy with immunosuppressive therapy using ECP and examining histologic confirmation of treatment response, are needed.The evidence is insufficient to determine the effects of the technology on health outcomes.

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

Clinical input obtained in 2014 supported the use of ECP in patients with refractory acute GVHD.

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

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

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

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received through 2 academic medical centers and 5 Blue Distinction Centers for Transplant when this policy was under review in 2014. Respondents agreed unanimously that extracorporeal photopheresis should not be medically necessary for previously untreated acute graft-versus-host disease but should be medically necessary foracute graft-versus-host disease that is refractory to medical therapy.

PRACTICE GUIDELINES AND POSITION STATEMENTS
Graft-Versus-Host Disease
Acute GVHD
UK Photopheresis Society
An evidence-based consensus statement from the UK Photopheresis Society (2014) recommended ECP as second-line therapy in combination with other agents for patients with steroid-refractory, steroid-dependent, or steroid-intolerant grade II, III, or IV acute graft-versus-host disease (GVHD).75

American Society of Blood and Marrow Transplantation
Evidence-based recommendations from the American Society of Blood and Marrow Transplantation (2012) advised that ECP cannot be considered superior to horse antithymocyte globulin for treatment of acute GVHD.76 This conclusion was based on older studies.43,77

Acute and Chronic GVHD
British Committee for Standards in Haematology et al
Evidence-based guidelines from the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation (2012) recommended ECP in acute GVHD as a second-line treatment for steroid-refractory disease78 and in chronic GVHD as a second-line treatment for skin, oral, or liver involvement.79

Italian Society of Hemapheresis and Cell Manipulation et al
A nine-member panel representing the Italian Society of Hemapheresis and Cell Manipulation and the Italian Group for Bone Marrow Transplantation (2013) published consensus recommendations for ECP in adults and children with acute or chronic GVHD.81 The panel recommended ECP: for treatment of acute GVHD in adults and children who are nonresponsive to steroids or calcineurin inhibitors or have contraindications to immunosuppressive therapy because of viral reactivation or other infectious complication (“better results are expected in patients with isolated skin involvement”); and for treatment of chronic GVHD in adults and children who are steroid-resistant or steroid-dependent. 

National Cancer Institute
In its guidelines on childhood hematopoietic cell transplantation, the National Cancer Institute listed ECP as a second-line treatment for patients with acute GVHD resistant to first-linemethylprednisolone.82 For chronic GVHD therapy, the guidelines recommended that steroids are first-line therapy, but steroid-sparing approaches, including ECP, are being developed. In this setting, ECP has shown “some efficacy in a percentage of patients.”

Cancer Care Ontario
Cancer Care Ontario (2014) published evidence-based consensus guidelines on ECP for GVHD.83 ECP was recommended as “an acceptable therapy for the treatment of steroid-dependent or refractory acute GVHD in adult and pediatric patients” and for “steroid-dependent or refractory chronic GVHD in adult and pediatric patients.” The strength of the recommendations was not graded. 

T-Cell Lymphoma 
National Comprehensive Cancer Network guidelines on T-cell lymphomas (v.5.2018) lists the use of ECP as a category A treatment alone or in combination with other agents as first-line systemic therapy for advanced (stages III-IV) disease, as well as for patients with either earlier stage mycosis fungoides with Sézary syndrome involvement.84 

U.S. Preventive Services Task Force Recommendations 
Not applicable.

Graft-Versus-Host Disease
Effective 2006, CMS provided coverage of ECP for patients with chronic GVHD “whose disease is refractory to standard immunosuppressive drug treatment.”85

Autoimmune Disorders
There are no national coverage decisions on the use of ECP for the treatment of autoimmune disease. 

T-Cell Lymphoma
Effective 1988, CMS provided coverage for ECP as “palliative treatment of skin manifestations of cutaneous T-cell lymphoma that has not responded to other therapy.”85 

Ongoing and Unpublished Clinical Trials 
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

 

 

 

Graft-versus-host disease

 

 

NCT00637689

Improving Outcomes Assessment in Chronic GVHD

601

Feb 2020

NCT01460914

Outcomes of Cutaneous T-Cell Lymphoma and Chronic Graft-Versus-Host Disease in Patients Treated with Extracorporeal Photopheresis

100

Oct 2050

Autoimmune disorders

 

 

NCT02296346a

Open-Label Study to Evaluate the Efficacy of ECP in Secondary Progressive Multiple Sclerosis

66

Oct 2017
(suspended)

T-cell lymphoma

 

 

NCT01460914

Outcomes of Cutaneous T-Cell Lymphoma and Chronic Graft-Versus-Host Disease in Patients Treated with Extracorporeal Photopheresis

100

Oct 2050

Unpublished

 

 

 

Solid organ transplants

 

 

NCT01824368

Extracorporeal Photopheresis in Liver Transplantation. Phase 2 Clinical Trial in Safety and Efficacy in Patients With Gradual Decrease of Immunosuppression (FEC-TH)

10

Apr 2016

(completed)

Graft-versus-host disease

 

 

NCT01380535a

A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy With UVADEX for the Treatment of Patients With Moderate to Severe Chronic Graft-versus-Host Disease (cGvHD)

60

Mar 2017
(completed)

NCT00609609

A Randomized Phase 2 Study for the Evaluation of Extracorporeal Photopheresis (ECP) in Combination With Corticosteroids for the Initial Treatment of Acute Graft-Versus-Host Disease (GVHD)

81

Jan 2016
(completed)

 

NCT: national clinical trial. 
a Denotes industry-sponsored or cosponsored trial.

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  26. Sunder-Plassman G, Druml W, Steininger R, et al. Renal allograft rejection controlled by photopheresis. Lancet. Aug 19 1995;346(8973):506. PMID 7637500
  27. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies. Biol Blood Marrow Transplant. Nov 2014;20(11):1677-1686. PMID 24867779
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  35. Halle P, Paillard C, D'Incan M, et al. Successful extracorporeal photochemotherapy for chronic graft-versus-host disease in pediatric patients. J Hematother Stem Cell Res. Jun 2002;11(3):501-512. PMID 12183835
  36. Salvaneschi L, Perotti C, Zecca M, et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion. Oct 2001;41(10):1299-1305. PMID 11606832
  37. Berger M, Pessolano R, Albiani R, et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol. Oct 2007;29(10):678-687. PMID 17921848
  38. Zhang H, Chen R, Cheng J, et al. Systematic review and meta-analysis of prospective studies for ECP treatment in patients with steroid-refractory acute GVHD. Patient Prefer Adherence. Feb 2015;9:105-111. PMID 25653504
  39. Greinix HT, Knobler RM, Worel N, et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica. Mar 2006;91(3):405-408. PMID 16531267
  40. Jagasia M, Greinix H, Robin M, et al. Extracorporeal photopheresis versus anticytokine therapy as a second-line treatment for steroid-refractory acute GVHD: a multicenter comparative analysis. Biol Blood Marrow Transplant. Jul 2013;19(7):1129-1133. PMID 23623892
  41. Rubegni P, Feci L, Poggiali S, et al. Extracorporeal photopheresis: a useful therapy for patients with steroid-refractory acute graft-versus-host disease but not for the prevention of the chronic form. Br J Dermatol. Aug 2013;169(2):450-457. PMID 23534380
  42. Shaughnessy PJ, Bolwell BJ, van Besien K, et al. Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. Jun 2010;45(6):1068-1076. PMID 19915634
  43. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photopheresis for the treatment of steroid refractory acute GVHD. Bone Marrow Transplant. Nov 2008;42(9):609-617. PMID 18660840
  44. Malik MI, Litzow M, Hogan W, et al. Extracorporeal photopheresis for chronic graft-versus-host disease: a systematic review and meta-analysis. Blood Res. Jun 2014;49(2):100-106. PMID 25025011
  45. Ontario Health Technology Advisory Committee. OHTAC Recommendation: Extracorporeal Photopheresis. 2006; http://www.hqontario.ca/english/providers/program/ohtac/tech/recommend/rec_ecp_032806.pdf. Accessed September 24, 2018.
  46. Foss FM, DiVenuti GM, Chin K, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant. Jun 2005;35(12):1187-1193. PMID 15852025
  47. Dignan FL, Aguilar S, Scarisbrick JJ, et al. Impact of extracorporeal photopheresis on skin scores and quality of life in patients with steroid-refractory chronic GVHD. Bone Marrow Transplant. May 2014;49(5):704-708. PMID 24566709
  48. Greinix HT, Volc-Platzer B, Knobler R. Criteria for assessing chronic GVHD. Bone Marrow Transplant. Mar 2000;25(5):575. PMID 10713639
  49. Rubegni P, Cuccia A, Sbano P, et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. Br J Haematol. Jul 2005;130(2):271-275. PMID 16029456
  50. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Extracorporeal photopheresis for autoimmune disease. TEC Assessments. 2001;Volume 16:Tab 10.
  51. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol. Mar 1992;128(3):337-346. PMID 1550365
  52. Fries JF, Seibold JR, Medsger TA, Jr. Photopheresis for scleroderma? No! J Rheumatol. Jul 1992;19(7):1011-1013. PMID 1512753
  53. Melski JW. Price of technology. A blind spot. JAMA. Mar 18 1992;267(11):1516-1518. PMID 1538542
  54. Trentham DE. Photochemotherapy in systemic sclerosis. The stage is set. Arch Dermatol. Mar 1992;128(3):389-390. PMID 1550373
  55. Papp G, Horvath IF, Barath S, et al. Immunomodulatory effects of extracorporeal photochemotherapy in systemic sclerosis. Clin Immunol. Feb 2012;142(2):150-159. PMID 22036269
  56. Cavaletti G, Perseghin P, Dassi M, et al. Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol Sci. Apr 2006;27(1):24-32. PMID 16688596
  57. Ludvigsson J, Samuelsson U, Ernerudh J, et al. Photopheresis at onset of type 1 diabetes: a randomised, double blind, placebo controlled trial. Arch Dis Child. Aug 2001;85(2):149-154. PMID 11466190
  58. Sanli H, Akay BN, Ayyildiz E, et al. Remission of severe autoimmune bullous disorders induced by long-term extracorporeal photochemotherapy. Transfus Apher Sci. Dec 2010;43(3):353-359. PMID 21035398
  59. Rubegni P, Poggiali S, Cevenini G, et al. Long term follow-up results on severe recalcitrant atopic dermatitis treated with extracorporeal photochemotherapy. J Eur Acad Dermatol Venereol. Apr 2013;27(4):523-526. PMID 22540319
  60. Wolf P, Georgas D, Tomi NS, et al. Extracorporeal photochemotherapy as systemic monotherapy of severe, refractory atopic dermatitis: results from a prospective trial. Photochem Photobiol Sci. Jan 2013;12(1):174-181. PMID 22948099
  61. Reinisch W, Knobler R, Rutgeerts PJ, et al. Extracorporeal photopheresis (ECP) in patients with steroid-dependent Crohn's disease: an open-label, multicenter, prospective trial. Inflamm Bowel Dis. Feb 2013;19(2):293-300. PMID 22573600
  62. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N Engl J Med. Feb 5 1987;316(6):297-303. PMID 3543674
  63. Knobler R, Duvic M, Querfeld C, et al. Long-term follow-up and survival of cutaneous T-cell lymphoma patients treated with extracorporeal photopheresis. Photodermatol Photoimmunol Photomed. Oct 2012;28(5):250-257. PMID 22971190
  64. Freiman A, Sasseville D. Treatment of mycosis fungoides: overview. J Cutan Med Surg. Sep-Oct 2006;10(5):228-233. PMID 17234106
  65. Keehn CA, Belongie IP, Shistik G, et al. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control. Apr 2007;14(2):102-111. PMID 17387295
  66. Knobler E. Current management strategies for cutaneous T-cell lymphoma. Clin Dermatol. May-Jun 2004;22(3):197-208. PMID 15262305
  67. Scarisbrick JJ. Staging and management of cutaneous T-cell lymphoma. Clin Exp Dermatol. Mar 2006;31(2):181-186. PMID 16487086
  68. Whittaker SJ, Foss FM. Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sezary syndrome variants of cutaneous T-cell lymphoma. Cancer Treat Rev. Apr 2007;33(2):146-160. PMID 17275192
  69. Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol. Apr 2008;158(4):659-678. PMID 18241274
  70. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer. May 2006;42(8):1014-1030. PMID 16574401
  71. 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. Dec 2003;149(6):1095-1107. PMID 14696593
  72. National Cancer Institute. Mycosis Fungoides (Including Sézary Syndrome) Treatment (PDQ®)-Health Professional Version. 2018; https://www.cancer.gov/types/lymphoma/hp/mycosis-fungoides-treatment-pdq?redirect=true. Accessed September 24, 2018.
  73. Miller JD, Kirkland EB, Domingo DS, et al. Review of extracorporeal photopheresis in early-stage (IA, IB, and IIA) cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed. Oct 2007;23(5):163-171. PMID 17803594
  74. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. May 15 2005;105(10):3768-3785. PMID 15692063
  75. Das-Gupta E, Dignan F, Shaw B, et al. Extracorporeal photopheresis for treatment of adults and children with acute GVHD: UK consensus statement and review of published literature. Bone Marrow Transplant. Oct 2014;49(10):1251-1258. PMID 24887389
  76. Martin PJ, Rizzo JD, Wingard JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Aug 2012;18(8):1150-1163. PMID 22510384
  77. Messina C, Locatelli F, Lanino E, et al. Extracorporeal photochemotherapy for paediatric patients with graft-versus-host disease after haematopoietic stem cell transplantation. Br J Haematol. Jul 2003;122(1):118-127. PMID 12823353
  78. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol. Jul 2012;158(1):30-45. PMID 22533831
  79. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-host disease. Br J Haematol. Jul 2012;158(1):46-61. PMID 22533811
  80. Das-Gupta E, Watson LB, J., Russell N. Physicians Poster Sessions. P503: a single-centre experience of the efficacy of extracorporeal photopheresis in the treatment of steroid-refractory acute graft-versus-host disease. Bone Marrow Transplant. 2011;46(S1):S114.
  81. Pierelli L, Perseghin P, Marchetti M, et al. Extracorporeal photopheresis for the treatment of acute and chronic graft-versus-host disease in adults and children: best practice recommendations from an Italian Society of Hemapheresis and Cell Manipulation (SIdEM) and Italian Group for Bone Marrow Transplantation (GITMO) consensus process. Transfusion. Oct 2013;53(10):2340-2352. PMID 23305044
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  83. Bredeson C, Rumble RB, Varela NP, et al. Extracorporeal photopheresis in the management of graft-versus-host disease. Curr Oncol. Apr 2014;21(2):e310-325. PMID 24764713
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  85. Center for Medicare & Medicaid Services (CMS). National Coverage Determination (NCD) for Extracorporeal Photopheresis (110.4). 2012; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=113&ncdver=3&bc=AAAAgAAAAAAAAA%3d%3d&. Accessed September 24, 2018.

Coding Section 

Codes Number Description
CPT 36522

Photopheresis, extracorporeal

ICD-9 Procedure 99.88

Therapeutic photopheresis (includes extracorporeal photopheresis)

ICD-9 Diagnosis 202.10-202.18

Mycosis fungoides (type of cutaneous T-cell lymphoma)

  202.20-202.28

Sézary’s disease (type of cutaneous T-cell lymphoma)

  279.50-279.53

Graft-versus-host disease, code range

  996.83

Complications of transplanted organ, heart (includes rejection)

  996.85

Complications of transplanted organ; bone marrow (i.e., graft vs. host disease)

HCPCS    
ICD-10-CM (effective 10/01/15) C84.00-C84.09

Mycosis fungoides; code range

  C84.10-C84.19

Sézary’s disease; code range

  D89.810-D89.813

Graft-versus-host disease; code range

  T86.00-T86.09

Complications of bone marrow transplant; code range

  T86.20-T86.298

Complication of heart transplant code range

ICD-10-PCS (effective 10/01/15)  

ICD-10-PCS codes are only used for inpatient services.

  6A650ZZ, 6A651ZZ

Phototherapy, Circulatory, codes for single or multiple

Type of Service Therapy  
Place of Service Outpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/01/2019 

Annual review, no change to policy intent. Updating description, regulatory status, rationale and references. 

08/01/2018 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

07/03/2017 

Annual review, no change to policy intent. 

09/28/2016 

Updated the word guideline to policy. when applicable. No change to policy intent. 

07/01/2016 

Annual review, no change to policy intent.

08/05/2015

Annual review, no change to policy intent. Updated background, descriptionl, rationale and references. Added regulatory status and coding. 

07/21/2014 

Updated policy: "New policy statement added that ECP is medically necessary in refractory acute graft-versus-host disease. For autoimmune diseases, Investigational policy statement updated to include severe atopic dermatitis and Crohn disease; no other changes to policy statements.." Updated rationale and references, regulatory/FDA status, and guidelines. 

03/17/2014

Annual review.  Updated description, background, rationale and references. No change to policy intent.


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