Blue Cross of Idaho Logo

Express Sign-on

Thank you for registering with Blue Cross of Idaho

If you are an Individual or Family Member, please register here.

If you are a Medicare Advantage or Medicare Supplement member, please register here.


MP 8.01.51 Extracorporeal Photophersis as Treatment for and Prevention of Organ Rejection after Solid Organ Transplant




Medical Policy    
Original Policy Date
Last Review Status/Date
Created with literature search/1:2011
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.






Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory procedure that involves the following steps: the patient’s blood is collected and the leukocyte-rich portion (buffy coat) is separated, the photosensitizer agent 8-methoxypsoralen (8-MOP) is added to the lymphocyte fraction, which is then exposed to ultraviolet A light, and the light-sensitized lymphocytes are re-infused into the patient.

This policy addresses (only) the use of ECP for the treatment and prevention of organ rejection after solid organ transplant. (See related policies for other applications.)

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 are also affected. This can in turn lead to serious infections, including opportunistic infections.

While first approved for the treatment of cutaneous T-cell lymphoma, ECP has more recently been used as a supplement to conventional therapies in the area of transplantation. [1] Extracorporeal photopheresis (ECP) is a leukapheresis-based immunomodulatory procedure that involves the following steps:

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

Reports of the successful use of ECP in human cardiac transplant recipients were published in 1992 [2, 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, while 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 immunosuppressant drugs. [5]

Regulatory Status

In the United States, the UVAR® XTS Photopheresis System was approved via premarket application (PMA) by the U.S. Food and Drug Administration (FDA) for use in the ultraviolet-A (UVA) irradiation (in the presence of the photoactive drug, methoxsalen) of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) in persons who have not been responsive to other therapy.

8-MOP (UVADEX®) is approved by the FDA for use in conjunction with UVAR XTS Photopheresis System for use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma in persons who have not been responsive to other therapy.

The use of the UVAR XTS photopheresis system or UVADEX for other conditions is an off-label use of a FDA-approved device/drug.





Extracorporeal photopheresis (ECP) may be considered medically necessary to treat cardiac allograft rejection, including acute rejection, that is either recurrent or that is refractory to standard immunosuppressive drug treatment.
Extracorporeal photopheresis (ECP) is considered investigational in all other situations related to treatment or prevention of rejection in solid organ transplantation.



Policy Guidelines




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 two 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 for one month, followed by bi-weekly therapy on 2 successive days for months 2 and 3, then monthly on 2 consecutive days for months 4-6.



Benefit Application

BlueCard/National Account Issues


State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.



Literature Review

A literature search using MEDLINE was performed for the period of 1992 through January 2010. The search identified one randomized controlled trial (RCT) for the use of ECP in cardiac transplant recipients and one nonrandomized comparative trial in liver transplant recipients. Other published data comes from small case series and/or case reports.

Acute Rejection

One randomized, controlled trial was published in 1992 on the efficacy of ECP versus corticosteroids in treating heart transplant rejection. [2] Costanzo-Nordin and colleagues enrolled 16 heart transplant patients and randomized them to wither ECP (n =9) or corticosteroids (n =7). Recipients of orthotopic transplanted hearts were eligible if endomyocardial biopsy (EMB) showed moderate rejection (grades 2, 3A and 3B). Participants were excluded for: leukopenia, hemodynamic compromise manifested clinically or by decrease in cardiac output >25% and an increase in mean pulmonary artery wedge pressure >25%, and/or an allergy or intolerance to psoralen. Corticosteroids were dosed at 100 mg/day oral prednisone for 3 days or 1g/day intravenous methylprednisolone for 3 days at the discretion of the managing physician. The treatment was repeated if EMB at day 7 showed no improvement in rejection grade. If the rejection grade persisted after retreatment, patients were given 10 mg oral methotrexate at weekly intervals for 8 weeks. Participants were followed for a mean of 6.2 months, and all participants completed the study. ECP participants were given one ECP treatment unless an inadequate number of cells were treated. In that case, an additional treatment was given 48 hours later. Of the 9 rejection episodes treated with ECP, all but one improved, all 7 of rejection episodes treated with corticosteroids resolved. Improvement was seen in a mean of 7 days (5-20) for ECP and 8 days (6-67 days) after corticosteroid treatment. Seven infections occurred during follow-up, five in the corticosteroid groups and two among those receiving ECP. No other adverse events were observed with ECP. The authors noted the major limitations of the study included the small sample size and the wide range of time from transplant to study entry. They concluded that ECP and corticosteroids in this small group with short-term follow-up appear to have similar efficacies for the treatment of moderate heart transplant rejection. They also noted the lower number of infections with no other observed harms associated with ECP.

Recurrent, Multiple and/or Refractory Rejection

Kirklin and colleagues published a comparative study of 343 patients in 2006 who received heart transplants. [6] Thirty-six of those patients were treated with ECP for rejection and formed the treatment group. Patients were treated from 1990-93, and were at least 18 years or older, and were followed to May 2004. Indications for ECP were episodes of rejection with hemodynamic compromise (HC) (n =12), recurrent (n =9) or persistent (n =11) rejection, or as prophylaxis in the presence of anti-donor antibodies. ECP consisted of psoralen in a 2-day treatment protocol every 3-6 weeks for 18 months; maintenance immunosuppression utilized cyclosporine or tacrolimus-based therapy with prednisone for the first 4-6 months and azathioprine, which was replaced by mycophenolate mofetil during the later years of the study. The primary outcome was hazard rate of subsequent HC rejection after at least 1 HC had already occurred. Hazard functions were used for analysis. Patients with at least 3 months of ECP were considered to have effective photopheresis treatment, if less than 3 months they were considered to not have had treatment, but were analyzed as part of the photopheresis group. Risk factor analysis showed those who received photopheresis were at high-risk for HC rejection. The period after 3 months of ECP was associated with a reduction in risk of HC rejection or rejection death (RR 0.29). A sustained decrease in the risk of HC rejection or HC death was observed for the photopheresis group through two years of follow-up. This study is nonrandomized; there was imbalance in the pretreatment risk of rejection or rejection death between the two groups. Changes in maintenance immunotherapy over time may confound the results as patients in the comparison group did not receive a consistent regimen. However, these changes in maintenance immunotherapy would tend to make the identification of an effect of ECP created by the ever evolving immunotherapy regimen more difficult. This only strengthens the authors’ conclusion that ECP reduces the risk of subsequent HC rejection and/or death from rejection when initiated for patients with high risk of rejection.

Dall’Amico et al. reported in 2000 on a case series of 11 patients with recurrent rejection after heart transplant. [7] Participants were eligible if they had acute rejection and at least 2 rejection episodes in the 3 months prior to ECP, which recurred after standard immunosuppressive therapies. ECP was performed with the UVAR photopheresis instruments, with 2 consecutive treatments at weekly intervals for one month, 2 treatments twice weekly during the second and third months, then monthly for 3 additional months. One patient showing 3B rejection, received pulse IV corticosteroids during the first ECP cycle. Patients were followed for 60 months. During follow-up, one patient died from hepatitis C virus and one dropped out due to rejection unresponsive to ECP and high-dose corticosteroids, all others completed the study. All acute rejection was successfully reversed after a mean of 14.2 days (7–32 days). In terms of rejection relapse, the fraction of EMB with a grade of 0/1A increased during ECP from 46% to 72% and those showing 3A/3B rejection decreased fro 42% to 18%. One of 78 EMB during ECP showed 3B rejection compared to 13 of 110 during the pre-ECP period. Six rejection relapses were observed during follow-up, two during the tapering of oral corticosteroids. Four were reversed by ECP, one by IV corticosteroids, and the last by methotrexate after failure of both ECP and IV corticosteroids. Mean dose of immunosuppressive drugs (corticosteroids, cyclosporine and azathioprine) were reduced after 6 months of ECP therapy. One patient with anemia and low body weight experienced symptomatic hypotension episodes during treatment and one patient had interstitial pneumonia. The authors concluded ECP to be a well tolerated treatment, which allows for better recurrent rejection control and significant reductions in immunosuppressive therapy. The follow-up time and patient population are adequate; the study is limited by its small size and lack of a comparison group.

Maccherini and colleagues 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 3A acute rejection two years after transplantation (n =5). Mean post-ECP follow-up was 23.3 months. ECP was performed 2 treatments per week for 1 month, once a week for 2 months, then once a month for one month, totaling 20 ECP treatments during 6 months. Total number of rejection episodes decreased from a mean of 3 per patient per-ECP to 0.4 per patient post-ECP. Reduction in immunosuppressive therapy was achieved by all patients. There were no adverse effects or infections reported during follow-up. The authors concluded that ECP is safe and effective for heart transplant patients with recurrent rejection, allowing for both a reduction in rejection episodes and immunosuppressive therapy.

Similar results were presented by Lehrer and colleagues describing the experience of 4 patients treated with ECP for severe refractory (grade IIIA to IV) cardiac allograft rejection. [9] All 4 patients experienced reversal of their rejection. Three patients improved following 2 consecutive days of treatment, and the fourth patient responded following three 2-day treatments. Two of these patients subsequently died of acute rejection 9 weeks and 10 weeks after completion of ECP. The other two were without signs of rejection, one for 6 years and the other’s last report was 4 months after ECP ended. This small case series adds to the evidence provided by the prior two slightly larger studies.

Prevention of Rejection

A randomized, controlled trial by Barr and colleagues investigated ECP for the prevention of rejection after cardiac transplant. [10] Sixty consecutive adult cardiac transplant recipients at 12 clinical sites (9 U.S., 3 in Europe) were randomized to both immunosuppressive therapy and ECP (n =33) or immunosuppressive therapy alone (n =27). Standard immunosuppressive therapy consisted of cyclosporine, azathioprine and prednisone. To be eligible, participants needed adequate peripheral venous access and had to reside 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 2 consecutive days every 2 weeks in months 2 and 3; and 2 successive days every 4 weeks for months 4 to 6 for a total of 24 ECP procedures per patient. Primary endpoint of the study was the number and frequency of histological acute rejection episodes. Pathologists were blinded to treatment assignment. Follow-up for the primary endpoint was 6 months; an additional 6 months of follow-up was completed to assess safety and survival.

Average number of acute rejection episodes per patient was statistically different with 1.44 in the standard therapy group and 0.91 in the ECP group. In the standard therapy group, 5 patients had no rejection episodes, 9 had one, 9 had two, and 4 had three or more. In the ECP group, 13 had none, 14 had one, 3 had two and 3 had three or more. These differences were statistically significant. There were no differences in survival at 6 months between the two groups or number of infections. Time to a first rejection also did not differ between the groups. During the second 6 months of follow-up, there were no differences between the numbers of acute rejection episodes between the two groups; however, due to time management issues, institutions reverted to nonstandardized protocols during this time. The authors concluded that using ECP in addition to standard immunosuppressive therapy significantly reduced the risk of cardiac rejection without increasing the rate of infections. More long-term follow-up will be necessary to see the effects of a reduction of acute rejection on long-term graft function, the survival over time of the transplant recipient, and the development of graft vasculopathy.

Acute rejection

Villanueva and colleagues reported in 2000 on a retrospective review of data on 14 lung transplant (6 bilateral lung, 4 single lung, 1 heart-lung) recipients who received ECP for bronchiolitis obliterans syndrome (BOS). [11] All patients were refractory to standard immunosuppressive therapy. ECP was administered every 2 weeks for 2 months followed by once a month for the next two months for a total of 6 treatments. Four of 8 patients with initial BOS grade of 0 or 1 had improvement in BOS or stabilization of BOS after treatment. Mean survival after ECP was 14 +/- 12 months. Three of these patients received ECP during a concurrent episode of acute rejection. All 3 of these patients had complete resolution of the acute rejection following therapy. Another study published in 1999 completed by Salerno et al. reported on two patients with histological reversal of concurrent acute rejection after treatment with ECP. [12] These 2 studies reported on only 5 cases of ECP used to treat acute rejection. Additional prospective trials are needed to determine the efficacy of ECP to treat acute rejection after lung transplantation.

In 2008, Bended and colleges published a single-center experience with ECP, which included 24 patients treated with ECP, 12 for recurrent acute rejection and 12 for BOS (see review in the next section). [13] Patients had biopsy-confirmed chronic acute rejection, defined as 2 or more biopsy-proven episodes of acute rejection prior to the start of ECP. The primary outcome measure was clinical stabilization of rejection after ECP. All but one patient had follow-up biopsies during treatment, two patients had an episode of biopsy proven acute rejection. All patients with recurrent acute rejection experienced clinical stabilization after 12 cycles of ECP, none experienced BOS. Treatment was well tolerated with no adverse events related to ECP reported. Median patient survival was 7.0 (range: 3.0–13.6) years, the median patient survival post-ECP was 4.9 (range: 0.5–8.4) years. However, these are for the 24 patients as a whole, not broken down by indication for ECP.

Chronic rejection refractory to corticosteroid/Refractory Bronchiolitis Obliterans Syndrome (BOS)
Lucid and colleagues published a review of nine patients treated with ECP between July 2008 and August 2009. Median follow-up was 23 months post-transplant (range: 9-93 months) and the median age was 38 years (range: 21-54 years). The primary indication for ECP was symptomatic progressive BOS, which failed prior therapy. (14) Patients were treated weekly with two sessions of pheresis for 3-4 weeks. Treatment then decreased in frequency to every 2 to 3 weeks, with the goal of getting treatment to every 4 weeks. Clinical response was defined as symptomatic improvement, decreased dependency on supplemental oxygen, and improvement in pulmonary function tests (PFTs). Sixty-seven percent (6 of 9) patients responded to ECP after a median of 25 days. No ECP-related complications occurred in this series. As with prior studies, this report has no control group for comparison.

Morrell et al. published a retrospective case series of all lung transplant recipients treated with ECP for progressive BOS at Barnes-Jewish Hospital-Washington University. (15) Ninety-five percent of the patients had received a bilateral lung transplant and were BOS grade 3. The indication for ECP was progressive decline in lung function that was refractory to standard immunosuppressive therapy. Primary endpoint of the study 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; biweekly for the next 2 months; and then monthly for the following 3 months, for a total of 24 treatments. Patients were followed from the time of lung transplantation to death or the end of the study (July 1, 2008). Median follow-up time was 5.4 years (range: 1.0–16.6 years). Sixty patients were followed; at the end of the study, 33 patients were still alive, with 4 deaths occurring early in the study. The majority of deaths were due to progression of respiratory failure, except for one death due to sepsis and one to graft failure. The mean rate of decline in FEV1 in the 6 months prior to ECP was -116.0 mL per month; after ECP the mean rate of decline decreased to -28.9 mL per month. The mean difference in the rate of decline was 87.1 mL (95% confidence interval [CI]: 57.3–116.9 mL per month). The rate of decline in lung function was reduced in 44 patients (78.6%), and lung function improved for 14 (25%) of these patients, with an increase in the FEV1 above pretreatment values. Through 12 months of follow-up, the mean improvement in FEV1 was 145.2 mL. Ten of 60 patients experienced adverse events. Eight were hospitalized for catheter-related bacteremia; one 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 limitation of this study is its retrospective nature and the lack of a control group for comparison. A majority of these patients had BOS grade 3, and therefore, may be different than patients with other grades. The statistical analysis was well done, with robust methods to analyze the available data.

As noted above, Villanueva and colleagues retrospectively reviewed data on 14 lung transplant (6 bilateral lung, 4 single lung, 1 heart-lung) recipients who received ECP for BOS. [11] All patients were refractory to standard immunosuppressive therapy. ECP was administered every 2 weeks for 2 months followed by once monthly therapy for the next two months, for a total of 6 treatments. Four of eight patients with initial BOS grade of 0 or 1 had improvement in BOS or stabilization of BOS after treatment. Mean survival after ECP was 14 ± 12 months. The 6 patients with initial BOS grade 2 or higher suffered progression of their BOS after ECP. Mean survival after ECP was 14 ± 10 months. Four of these patients died of chronic rejection, one of lung cancer. The remaining patient survived to re-transplantation. Two of the 14 patients developed line related sepsis which was cleared with antibiotics and the removal of the vascular catheter.

Also as mentioned earlier, Benden and colleagues published (2008) a single-center experience with ECP, which accounted for 24 patients treated with ECP (12 for BOS and 12 for recurrent acute rejection, see previous section). [13] ECP was delivered once the BOS grade worsened, despite standard therapy. At the start of therapy, the distribution of BOS was as follows; BOS grade 1 (n =5), BOS grade 2 (n =2), BOS grade 3 (n =5). Before ECP, the decline in FEV1 was 112 mL per month, compared to 12 mL per month post-ECP, mean change in rate of decline of FEV1 100 (range: 28–171); however, ECP did not seem to have an effect on absolute FEV1 among this subgroup. Treatment was well tolerated with no adverse events related to ECP reported. Median patient survival was 7.0 (range: 3.0–13.6) years, the median patient survival post-ECP was 4.9 (range: 0.5–8.4). However, these are for the 24 patients as a whole, not broken down by indication for ECP.

O’Hagan and colleagues published in 1999, case reports of 6 patients at the Cleveland Clinic who received ECP for BOS refractory to standard immunosuppressive therapy and various other strategies including antithymocyte globulin, methotrexate, monomurine anti-C3 antibody, and tacrolimus. [15] ECP was performed on 2 consecutive days twice a month until stabilization of the FEV1. Treatment was then repeated every 4 to 6 weeks. Four of the 6 patients had temporary stabilization of their airflow obstruction with minimal adverse effects. Grade of BOS was not reported. Case report data suffers from the lack of a control group, which allows for a measurement of the difference in outcomes between two treatments. In this case that would be the difference in FEV1 between those receiving immunosuppressive therapies alone versus those being treated with immunosuppressive therapy combined with ECP.

Larger trials prospective randomized trials are necessary to examine the comparative effects of ECP for patients with BOS stratified by BOS grade.

Prevention of BOS and/or Rejection

There are no studies addressing the prophylactic effects of ECP for lung transplant recipients.


The published evidence on the use of ECP in liver recipients is from one group in Italy. Urbani and colleagues have published a series of papers on various potential applications of ECP for liver transplant patients. (17-19) The first paper is a retrospective review of 5 patients who received liver transplants and ECP for biopsy-proven allograft rejection, where the indications for ECP were recalcitrant ductopenic rejection with Hepatitis C virus recurrence, corticosteroid-resistant acute rejection in 2 patients, severe acute rejection in a major ABO-incompatible liver graft, and severe acute rejection in a patient with a proven corticosteroid allergy. (19) ECP was performed twice a week for 4 weeks, then every 2 weeks for 2 months and once a month, thereafter. ECP was stopped when indicated by biopsy-proven rejection reversal or the absence of clinically evident rejection relapse. Liver function tests improved to baseline in all but one patient, and no procedure-related complications were reported. At a median follow-up of 7.9 months, 3 patients were off ECP with normal liver tests and low level immunosuppressive therapy. Two were receiving continued ECP treatments with full dose immunosuppressive therapy.

The second paper from 2007 was a nonrandomized comparative study of 36 patients (18 treatment and 18 historic matched controls) who were treated with ECP to delay the introduction of calcineurin inhibitors (CNI) with the goal of preventing toxicity. (18) Patients were included if they were at risk of post-liver transplant renal impairment and neurological complications, defined as having at least one of the following risk factors: a calculated glomerular filtration rate ≤ 50 mL/min at transplantation; severe ascites; history of more than one hospitalization for encephalopathy within 1 year of transplant and/or one hospitalization within 1 month of transplantation; or age 65 years or greater. Outcome measures were treatment success rate, defined as the ratio of patients with full CNI-sparing or delayed immunosuppression, interval from liver transplant to CNI introduction, safety of ECP, and need for biopsy. ECP was initiated in the first week post-transplant; two different systems (Therakos and PIT) for photopheresis were used and treatment was given according to a common schedule for the system used. All 18 patients completed the scheduled course and tolerated the ECP. CNI was introduced at a mean number of 8 days for 17 patients, while one patient remained CNI free for 22 months. Acute rejection was higher but not significantly higher in ECP group (5/18) vs. controls (3/18). 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, among controls. The authors concluded that the addition of ECP offers better management of liver transplant patients in the early transplant phase, delayed CNI introduction and lower CNI-related mortality. This study was not randomized and had a small number of patients.

The third paper (2008) was a report on three fields of interest for ECP as prophylaxis of allograft rejection in liver transplant patients. (17) The three fields include:

  • use of ECP to delay CNI among high-risk liver transplant recipients to avoid toxicity (discussed above),
  • use of ECP for prophylaxis of acute cellular rejection among ABO-incompatible liver transplant recipients where 11 consecutive patients underwent ECP with immunosuppression with no evidence of acute rejection through 568 days of follow-up,
  • use of ECP in hepatitis C virus-positive patients (the use of ECP for the prevention of Hepatitis C virus recurrence is beyond the scope of this policy).

Except for the first area, these studies were small and had no comparison group. Randomized, clinical trials are needed for the proper assessment of outcomes.

Recurrent, Multiple and/or Refractory Rejection
The largest reported group of renal patients to receive ECP was at the Royal Prince Alfred Hospital, Sydney, Australia. In 2009, Jardine et al. published a prospective case series of 10 patients treated with ECP for recurrent and/or refractory rejection after renal transplant at this center. (20) ECP was delivered weekly for 4 weeks, then every 2 weeks. Total treatment range was 2 to 12 treatments for more than 5-20 weeks. Median follow-up time was 66.7 months following transplant and 65.0 months from commencement of ECP. Indication for ECP was acute resistant/recurrent rejection in 9 patients and the need to avoid high dose corticosteroids in another. Refractory rejection was resolved in all patients through the stabilization of renal function. The authors concluded that ECP may have a role as an adjunct to current therapies in patients with refractory rejection. While this is the largest series of renal patients, it is small and there is no comparison group. It also suffers from the fact that renal biopsies were not used to document therapeutic response.

The remainder of the evidence in renal transplant recipients comes from case reports on 32 patients. Twenty-six of these patients had refractory rejection. After ECP, renal function improved in 19 of 26 patients, 3 patients were stable and 4 patients returned to dialysis due to deteriorating function. Reports of long-term outcomes varied. Among the 22 patients who showed initial improvement and or stabilization of renal function, 5 had improved function at 1 year, (21)1 was stable at 25 months, (22) 5 were stable at 1 year, (21,23) 7 were rejection free at 2 to 5 years, (22) and 1 graft was lost. (23) Three patients did not have long-term outcome reports. (24,25)

The evidence for the use of ECP in cardiac transplant patients relates to 3 indications: acute rejection, recurrent, multiple and/or refractory rejection, and prevention of rejection. For acute rejection, a randomized trial was published in 1992 which enrolled 16 heart transplant patients. ECP in combination with immunosuppressive therapy had similar efficacy compared to immunosuppressive therapy alone, with fewer infections in the ECP group. This study was of a small size and there was heterogeneity in the time from transplant to study entry. For prevention of rejection, there is a randomized trial from 12 clinical sites where 33 patients were randomized to immunosuppressive therapy and ECP and compared to 27 on immunosuppressive therapy alone. Differences between numbers of acute rejection episodes were statistically significant; however, there were no differences in survival at 6 months. Thus, the evidence to date is insufficient to permit conclusions concerning the effect of ECP on net health outcome for the treatment and prevention of acute cardiac rejection. Therefore, ECP is considered investigational for the treatment and prevention of acute rejection in cardiac transplant recipients. Studies with more patients and longer follow-up are needed.

ECP for recurrent, multiple and/or refractory cardiac allograft rejection has been the focus of most of the research on ECP. While the data is from nonrandomized studies, a comparative study of 343 cardiac transplant patients where 36 received ECP has been completed. The authors present data showing at 3 months, ECP was related to a risk reduction of hemodynamic compromise (HC) rejection or rejection death (RR 0.29). A reduction in HC rejection or rejection death was observed through 2 years of follow-up. While the results of this trial may be confounded by altercations in the immunosuppressive therapy regimen over time, they are consistent with the remainder of the literature for this indication showing a benefit of ECP in patients with recurrent or refractory cardiac rejection. Thus, the evidence to date, which consists of 1 nonrandomized comparative study, 2 case series and a case report of 4 patients, provides consistent evidence for a beneficial effect of ECP for cardiac transplant patients with rejection refractory to standard therapy. Therefore, ECP is considered medically necessary for the treatment of recurrent, multiple and/or refractory cardiac rejection.

The evidence on the use of ECP in lung transplant recipients falls under two indications: acute rejection and chronic rejection refractory to corticosteroids/refractory BOS. The data for acute rejection are very limited and do not permit any conclusions. These are subsets of patients who have been pulled from a larger group because they were treated with ECP during a period of acute rejection. This area needs a prospective, randomized, clinical trial focused specifically on the treatment of patients in acute rejection.

The bulk of the ECP in lung transplant literature focuses on treatment of refractory BOS. The primary limitations in these data are that they are nonrandomized with no control group. Further, the evidence is not entirely consistent, with some studies reporting ECP to be beneficial in those with early refractory BOS but not those with grade 2 or higher which is in contrast to the largest series of 60 patients who responded well to ECP (almost 60% of these patients were BOS grade 3). Prospective, randomized, controlled studies are necessary and analyses should be stratified by BOS grade, as there is some preliminary evidence that ECP may work differently based on BOS grade at the start of therapy.

The evidence to date, which consists of small case series, is insufficient to permit conclusions concerning the effect of this procedure on health outcomes in lung transplant. Studies with larger number of subjects and longer follow-up are needed. Therefore, ECP is considered investigational when used in lung transplantation.

In liver transplantation, the evidence for the use of ECP is limited and the research to date has been generated by one group in Italy. While there is one comparative (nonrandomized) study, this trial is of only 18 cases and 18 controls. There is a need for randomized, controlled trials. The effort in liver transplant patients has been on prevention of rejection with ECP. This question lends itself well to an randomized, controlled trial comparing immunosuppressive therapy alone to immunosuppressive therapy with ECP. The evidence to date, which consists of small case series and one comparative study, is insufficient to permit conclusions concerning the effect of ECP on net health outcome for liver transplant patients. Therefore, ECP is considered investigational in liver transplant patients for any indication.

For renal transplant recipients, the evidence for the use of ECP is sparse. There are a total of 42 patients whose treatment has been reported in the literature. The available evidence appears to consistently report evidence of benefit from ECP for those with refractory rejection. However, there are no comparative studies and current numbers are too small to permit conclusions. A prospective, randomized trial, with histological confirmation of treatment response is needed. This trial would randomize patients to immunosuppressive therapy or immunosuppressive therapy with ECP with the primary aim of addressing the question whether there is an additional benefit from ECP for patients with refractory rejection after renal transplant. The evidence to date, which consists of small case series, is insufficient to permit conclusions concerning the effect of ECP on net health outcome for renal transplant patients. Therefore, ECP is considered investigational in renal transplant patients for any indication.
A search of in December 2010 found no registered clinical trials seeking to assess ECP as a treatment of solid-organ transplant rejection in any organ.

Technology Assessments, Guidelines, and Position Statements
United Network of Organ Sharing (UNOS)
UNOS does not have any policies related to ECP in the treatment or prevention of any form of rejection following solid-organ transplant.

Medicare National Coverage
Based upon a 2006 evidence review, the Centers for Medicare and Medicaid Services concluded that extracorporeal photopheresis is reasonable and necessary for persons with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment. (26)




  1. Marques MB, Tuncer HH. Photopheresis in solid organ transplant rejection. J Clin Apher 2006; 21(1):72-7.
  2. Costanzo-Nordin MR, Hubbell EA, O'Sullivan EJ et al. Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report. Circulation 1992; 86(5 Suppl):II242-50.
  3. Rose EA, Barr ML, Xu H et al. Photochemotherapy in human heart transplant recipients at high risk for fatal rejection. J Heart Lung Transplant 1992; 11(4 Pt 1):746-50.
  4. Hivelin M, Siemionow M, Grimbert P et al. Extracorporeal photopheresis: from solid organs to face transplantation. Transpl Immunol 2009; 21(3):117-28.
  5. Szczepiorkowski ZM, Bandarenko N, Kim HC et al. Guidelines on the use of therapeutic apheresis in clinical practice: evidence-based approach from the Apheresis Applications Committee of the American Society for Apheresis. J Clin Apher 2007; 22(3):106-75.
  6. Kirklin JK, Brown RN, Huang ST et al. Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant 2006; 25(3):283-8.
  7. Dall'Amico R, Montini G, Murer L et al. Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection. Int J Artif Organs 2000; 23(1):49-54.
  8. Maccherini M, Diciolla F, Laghi Pasini F et al. Photopheresis immunomodulation after heart transplantation. Transplant Proc 2001; 33(1-2):1591-4.
  9. Lehrer MS, Ruchelli E, Olthoff KM et al. Successful reversal of recalcitrant hepatic allograft rejection by photopheresis. Liver Transpl 2000; 6(5):644-7.
  10. Barr ML, Meiser BM, Eisen HJ et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998; 339(24):1744-51.
  11. Villanueva J, Bhorade SM, Robinson JA et al. Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 2000; 5(3):44-7.
  12. Salerno CT, Park SJ, Kreykes NS et al. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 1999; 117(6):1063-9.
  13. Benden C, Speich R, Hofbauer GF et al. Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation 2008; 86(11):1625-7.
  14. Lucid CE, Savani BN, Engelhardt BG et al. Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transplant 2010 [Epub ahead of print].
  15. Morrell MR, Despotis GJ, Lublin DM et al. The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2009 [Epub ahead of print].
  16. O'Hagan AR, Stillwell PC, Arroliga A et al. Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999; 115(5):1459-62.
  17. Urbani L, Mazzoni A, Colombatto P et al. Potential applications of extracorporeal photopheresis in liver transplantation. Transplant Proc 2008; 40(4):1175-8.
  18. Urbani L, Mazzoni A, De Simone P et al. Avoiding calcineurin inhibitors in the early post-operative course in high-risk liver transplant recipients: the role of extracorporeal photopheresis. J Clin Apher 2007; 22(4):187-94.
  19. Urbani L, Mazzoni A, Catalano G et al. The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients. Transplant Proc 2004; 36(10):3068-70.
  20. Jardine MJ, Bhandari S, Wyburn KR et al. Photopheresis therapy for problematic renal allograft rejection. J Clin Apher 2009; 24(4):161-9.
  21. Kumlien G, Genberg H, Shanwell A et al. Photopheresis for the treatment of refractory renal graft rejection. Transplantation 2005; 79(1):123-5.
  22. Dall'Amico R, Murer L. Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection. Transfus Apher Sci 2002; 26(3):197-204.
  23. Dall'Amico R, Murer L, Montini G et al. Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol 1998; 9(1):121-7.
  24. Sunder-Plassman G, Druml W, Steininger R et al. Renal allograft rejection controlled by photopheresis. Lancet 1995; 346(8973):506.
  25. Baron ED, Heeger PS, Hricik DE et al. Immunomodulatory effect of extracorporeal photopheresis after successful treatment of resistant renal allograft rejection. Photodermatol Photoimmunol Photomed 2001; 17(2):79-82.
  26. Services CfMaM. Decision memo for extracorporeal photopheresis (CAG-00324R). December 19, 2006; Available online at: Last accessed Feburary 2010.






CPT 36522 Photopheresis, extracorporeal
ICD-9-CM Procedure 99.88 Therapeutic photopheresis (includes extracorporeal photopheresis)
ICD-9-CM 996.83 Complications of transplanted organ, heart
ICD-10-CM (effective 10/1/13) T86.20 T86.298 Complication of heart transplant code range
ICD-10-PCS (effective 10/1/13) 6A650ZZ Extracorporeal therapies physiological systems phototherapy circulatory single




Photopheresis, Solid Organ Transplant Rejection



Policy History

Date Action Reason
03/11/10 Add to Therapy section New policy
01/13/11 Replace policy Policy updated with literature search, reference 14 added, policy statements unchanged



Resource Center

Find a Provider Find a Pharmacy Medicare Medicare Formulary