Coverage Policy Manual
Policy #: 2003008
Category: Medicine
Initiated: June 2003
Last Review: August 2018
  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment to Prevent Rejection Following Solid-Organ Transplant

Description:
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 cm2.
 
3. The light-sensitized lymphocytes are reinfused into the patient.
 
Reports of the successful use of ECP in human cardiac transplant recipients were published in 1992 (Costanzo-Nordin, 1992) (Rose, 1992) 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 (Hivelin, 2009). 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 (Szczepiorkowski, 2007).  
 
In the U.S., 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.
 
Related policies:
 
2003007:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Cutaneous T-Cell Lymphoma
2000026:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Autoimmune Disease
2002004:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Graft-versus-Host Disease
  

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Extracorporeal photochemotherapy for the treatment or prevention of rejection following cardiac transplantation meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Extracorporeal photochemotherapy for the treatment or prevention of rejection following any other solid organ transplant does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without Primary Coverage Criteria, Extracorporeal for the treatment or prevention of rejection following any other solid organ transplant is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates.
 
 

Rationale:
Photopheresis, or photochemotherapy, has been used as immunotherapy for cutaneous T-cell lymphoma, scleroderma, rheumatoid arthritis, and graft vs host disease. Leukocytes are separated from erythrocytes and exposed to 8-methoxypsoralen and ultraviolet light. The leukocytes that are rapidly proliferating (such as T-cells responding to alloantigens) are preferentially damaged. The damaged cells are reinfused and are believed to induce counterimmune responses such as T-cell vaccination. Photopheresis is usually performed twice per week for four weeks.
 
When used to treat cardiac transplant rejection, photopheresis appears to be as effective as high-dose methylprednisolone, but it avoids the side effects of corticosteroids (Costanzo-Nordin, 1993) . There are several reports of success with photopheresis in treating refractory rejection and in reducing the frequency of rejection in patients who have frequent recurrences of rejection; a few patients have been shown to have histologic reversal of rejection after photopheresis on two successive days (Lehrer, 2001; Dall’Amico, 1995).
 
Photopheresis may also be useful in preventing rejection when used in combination with other therapies. One study (Barr, 1998) randomized cardiac transplant recipients to standard triple therapy consisting of cyclosporine, azathioprine, and prednisone vs. triple therapy in conjunction with 24 photopheresis treatments (Barr, 1998). At six months, the number of episodes of acute rejection per patient was significantly reduced by photopheresis compared to conventional therapy alone (0.91 versus 1.44).  There was no significant difference in survival at six and 12 months.
 
2010 Update
This policy originally addressed extracorporeal photopheresis (ECP) only for the treatment of rejection following heart transplant. With this update the policy will be expanded to include the discussion of ECP for the prevention and treatment of rejection following solid-organ transplant.  A literature review was conducted using the MEDLINE database through December 2010. A summary of the identified studies evaluating ECP following heart, liver, lung and kidney transplantation are discussed below.
 
Cardiac
Acute Rejection
One randomized, controlled trial (RCT) was published in 1992 on the efficacy of extracorporeal photopheresis (ECP) versus corticosteroids in treating heart transplant rejection (Costanzo-Nordin, 1992). Costanzo-Nordin and colleagues enrolled 16 heart transplant patients and randomly assigned them to either 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 equal to or greater than 25% and an increase in mean pulmonary artery wedge pressure equal to or greater than 25%, and/or an allergy or intolerance to psoralen. Corticosteroids were dosed at 100 mg/day oral prednisone for 3 days or 1g/day IV 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 1 improved; all 7 of rejection episodes treated with corticosteroids resolved. Improvement was seen in a mean of 7 days (range: 5–20) for ECP and 8 days (range: 6–67 days) after corticosteroid treatment. Seven infections occurred during follow-up, 5 in the corticosteroid groups and 2 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 (Kirklin, 2006). Thirty-six of those patients were treated with ECP for rejection and formed the treatment group. Patients were at least 18 years or older, treated from 1990-93, and 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 to 6 weeks for 18 months; maintenance immunosuppression utilized 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 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 (risk reduction [RR]: 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; 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 (Dall”Amico, 2000). 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 1 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, 1 patient died from hepatitis C virus and 1 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 EMB with a grade of 0/1A increased during ECP from 46% to 72%, and those showing 3A/3B rejection decreased from 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, 2 during the tapering of oral corticosteroids. Four were reversed by ECP, 1 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) was reduced after 6 months of ECP therapy. One patient with anemia and low body weight experienced symptomatic hypotension episodes during treatment, and 1 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 (Maccherini, 2001). Inclusion criteria were recurrent rejection (n=5), recurrent infections associated with acute rejection (n=2), and 3A acute rejection 2 years after transplantation (n=5). Mean post-ECP follow-up was 23.3 months. ECP was performed as 2 treatments per week for 1 month, once a week for 2 months, then once a month for 1 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 was 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 (Lehrer, 2000). 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 at 9 weeks and 10 weeks after completion of ECP. The other 2 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 2 slightly larger studies.
 
Prevention of Rejection
The RCT by Barr and colleagues (mentioned in initial rationale) investigated ECP for the prevention of rejection after cardiac transplant (Barr, 1008). Sixty consecutive adult cardiac transplant recipients at 12 clinical sites (9 U.S., 3 in Europe) were randomly assigned 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 histologic 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.
 
Lung
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) (Villanueva, 2000). 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 2 patients with histologic reversal of concurrent acute rejection after treatment with ECP (Salerno, 1999). 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, Benden and colleagues 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) (Benden, 2008). 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 years (range: 3.0–13.6 years), the median patient survival post-ECP was 4.9 years (range: 0.5–8.4 years). However, these rates 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 (Lucid, 2010). 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 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 (Morrell, 2010) 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 (Villanueva, 2000). 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 retransplantation. 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 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) (Benden, 2008). 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 of 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 years (range: 3.0–13.6), the median patient survival post-ECP was 4.9 years (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 (O’Hagan, 1999). 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, 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.
 
Liver
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 (Urbani, 2008) (Urbani, 2007) (Urbani, 2004). 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 (Urbani, 2004). 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 ( Urbani, 2007). 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 (Urbani, 2008). 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.
 
Renal
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, (Kumlien, 2005) 1 was stable at 25 months, (Dall”Amico) 5 were stable at 1 year, (Dall’Amico, 2002) (Dall’Amico, 1998) 7 were rejection free at 2 to 5 years, (Dall’Amico, 1998) and 1 graft was lost (Dall’Amico, 1998). Three patients did not have long-term outcome reports (Sunder-Plassman, 1995) (Baron, 2001).
 
Summary
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. 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 the treatment or prevention of rejection following cardiac transplantation.
 
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.
 
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 a 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.
 
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.
 
ClinicalTrials.gov
A search of ClinicalTrials.gov 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.
 
2012 Update
This policy was reviewed with a literature search of the MEDLINE database through July 2012.  There was no new information identified that would prompt a change in the coverage statement.
  
2013 Update
A literature search conducted using the MEDLINE database through the period of July 2013 did not reveal any new literature that would prompt a change in the coverage statement. One study was identified assessing ECP for the treatment of Corticosteroid refractory Bronchiolitis Obliterans Syndrome (BOS).
 
Jaksch and colleagues reported on a series of 194 patients who developed BOS and received standard treatment and 51 of those received additional ECP. Patients who did not respond to standard immunosuppressive therapy and showed further decline of lung function received EPC when reaching BOS stage greater or equal to 1 (Jaksch, 2012). ECP was performed on two successive days every two weeks during the first 3 months and every four weeks after until the end of therapy. ECP was stopped after a minimum of 3 months of therapy when lung function decreased significantly. If improvement or stabilization of FEV1 occurred, ECP was continued for a minimum of 6 months. FEV1 values at 3, 6, and 12 months after EPC initiation were used as a surrogate for treatment response. The primary endpoint was change in lung function before and after ECP. Changes in lung function was compared to patients with BOS who did not receive add on EPC. Eighteen percent of patients receiving ECP experienced an improvement in FEV1 for more than one year after initiation of ECP treatment and 12% showed improvement for only 3 to 6 months. FEV1 stabilized in 31% of patients and declined in 39%. Kaplan-Meier analysis showed a significant difference in responders and non-responders in survival and the need for a transplant. When compared to patients with BOS who did not receive EPC but with similar demographics and prior treatment, the ECP treated groups had longer survival (p=0.046) and underwent fewer transplantations: 18 versus 21 (p=0.04). Time to transplant was also twice as long in the ECP group 1,839 ± 1,090 days versus 947 ± 861 days. No adverse events were reported as a result of EPC. While this was not a randomized study, a group was available for comparison with similar demographics, and treatment history.
  
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Chronic Rejection Refractory to Corticosteroid/Refractory BOS
In 2013, Greer et al reported a retrospective analysis of 65 patients treated at a single institution with ECP for chronic lung allograft dysfunction, defined as deteriorating FEV1 due to BOS, as well as reduced total lung capacity and broncho-alveolar lavage neutrophilia (Greer, 2013). Fifty-one patients (78%) had undergone double lung transplant, 9 patients (14%) had undergone single-lung transplant, and 5 patients (8%) had undergone heart-lung transplant. Median time to CLAD diagnosis was 3 years (interquartile range [IQR] =2-5). Patients had progressed (10% or greater decline in FEV1) on first-line azithromycin. At ECP initiation, 35 patients (54%) were graded BOS stage 3; 21 patients (32%) were BOS stage 2; and 9 patients (14%) 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. Median follow-up was 17 months; 44 patients who continued treatment beyond 3 months received a median of 15 ECP treatments. Eight patients (12%) achieved a 10% or greater improvement in FEV1, considered treatment response; 27 patients (42%) experienced no change in FEV1; and 30 patients (46%) experienced a 10% or greater decline in FEV1, considered progressive disease. Median progression-free survival was 13 months (IQR=10-19) among responders and 4 months (IQR=3-6) among those who did not respond. These data are retrospective and lack a control group.
 
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov in July 2014 found 1 registered clinical study seeking to assess ECP for acute rejection of liver transplantation (NCT01824368). This is a single-arm, Phase 2 study of 10 patients. The study is conducted in Spain, status shows active and not recruiting.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Carlo and colleagues reported their experience with ECP in 20 pediatric heart transplant recipients between 1990 and 2012 at the University of Birmingham in Alabama (Carlo, 2014). Patients were transplanted at a median age of 12.7 years (range, 0.3–18.5) and received first ECP at a median age of 15.3 years (range, 7.3–31). Indications for ECP included rejection with hemodynamic compromise, rejection without HC, and prophylaxis. One- and 3-year survival after ECP was 84% and 53%, respectively. Survival outcomes were worse in noncompliant patients compared with compliant patients.
  
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through July 2018. No new literature was identified that would prompt a change in the coverage statement.   
 
 
 

CPT/HCPCS:
36522Photopheresis, extracorporeal

References: Baron ED, Heeger PS, Hricik DE et al.(2001) Immunomodulatory effect of extracorporeal photopheresis after successful treatment of resistant renal allograft rejection. Photodermatol Photoimmunol Photomed 2001; 17(2):79-82.

Barr ML, Baker CJ, Schenkel FA, et al.(2000) Prophylactic photopheresis and chronic rejection: effects on graft intimal hyperplasia in cardiac transplantation. Clin Transplant Apr 2000;14(2):162-6.

Barr ML, Meiser BM, Eisen HJ et al.(1998) Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998; 339(24):1744-51.

Barr ML, Meiser BM, Eisen HJ, et al.(1998) Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. NEJM Dec 10 1998; 339(24):1744-51.

Benden C, Speich R, Hofbauer GF et al.(2008) Extracorporeal photopheresis after lung transplantation: a 10-year single-center experience. Transplantation 2008; 86(11):1625-7.

Carlo WF, Pearce FB, George JF, et al.(2014) Single-center experience with extracorporeal photopheresis in pediatric heart transplantation. J Heart Lung Transplant. Jun 2014;33(6):624-628. PMID 24661684

Costanzo-Nordin MR, Hubbell EA, O'Sullivan EJ et al.(1992) Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report. Circulation 1992; 86(5 Suppl):II242-50.

Costanzo-Nordin MR, McManus BM, et al.(1993) Efficacy of photopheresis in the rescue therapy of acute cellular rejection in human heart allografts: a preliminary clinical and immunopathologic report. Transplant Proc. 1993; 25(1 Pt 2):881-3.

Dall'Amico R, Montini G, Murer L et al.(2000) Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection. Int J Artif Organs 2000; 23(1):49-54.

Dall'Amico R, Murer L(1998) Montini G et al. Successful treatment of recurrent rejection in renal transplant patients with photopheresis. J Am Soc Nephrol 1998; 9(1):121-7.

Dall'Amico R, Murer L.(2002) Extracorporeal photochemotherapy: a new therapeutic approach for allograft rejection. Transfus Apher Sci 2002; 26(3):197-204.

Dall'Amico R; Livi U, et al.(1995) Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation/ 1995; 60(1):45-9.

Greer M, Dierich M, De Wall C et al.(2013) Phenotyping established chronic lung allograft dysfunction predicts extracorporeal photopheresis response in lung transplant patients. Am J Transplant 2013; 13(4):911-8.

Hivelin M, Siemionow M, Grimbert P et al.(2009) Extracorporeal photopheresis: from solid organs to face transplantation. Transpl Immunol 2009; 21(3):117-28.

Jaksch P, Scheed A, Keplinger M et al.(2012) A prospective interventional study on the use of extracorporeal photopheresis in patients with bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2012; 31(9):950-7.

Jardine MJ, Bhandari S, Wyburn KR et al.(2009) Photopheresis therapy for problematic renal allograft rejection. J Clin Apher 2009; 24(4):161-9.

Kirklin JK, Brown RN, Huang ST et al.(2006) Rejection with hemodynamic compromise: objective evidence for efficacy of photopheresis. J Heart Lung Transplant 2006; 25(3):283-8.

Kumlien G, Genberg H, Shanwell A et al.(2005) Photopheresis for the treatment of refractory renal graft rejection. Transplantation 2005; 79(1):123-5.

Leher MS, Rook AH, et al.(2001) Successful reversal of severe refractory cardiac allograft rejection by photophoresis. Heart Lung Transplant. 2991;20(11):1233-6.

Lehrer MS, Ruchelli E, Olthoff KM et al.(2000) Successful reversal of recalcitrant hepatic allograft rejection by photopheresis. Liver Transpl 2000; 6(5):644-7.

Lucid CE, Savani BN, Engelhardt BG et al.(2010) Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transplant 2010 [Epub ahead of print].

Maccherini M, Diciolla F, Laghi Pasini F et al.(2001) Photopheresis immunomodulation after heart transplantation. Transplant Proc 2001; 33(1-2):1591-4.

Marques MB, Tuncer HH.(2006) Photopheresis in solid organ transplant rejection. J Clin Apher 2006; 21(1):72-7.

Morrell MR, Despotis GJ, Lublin DM et al.(2010) The efficacy of photopheresis for bronchiolitis obliterans syndrome after lung transplantation. J Heart Lung Transplant 2010; 29(4):424-31.

O'Hagan AR, Stillwell PC, Arroliga A et al.(1999) Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation. Chest 1999; 115(5):1459-62.

Rose EA, Barr ML, Xu H et al.(1992) Photochemotherapy in human heart transplant recipients at high risk for fatal rejection. J Heart Lung Transplant 1992; 11(4 Pt 1):746-50.

Salerno CT, Park SJ, Kreykes NS et al.(1999) Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. J Thorac Cardiovasc Surg 1999; 117(6):1063-9.

Sunder-Plassman G, Druml W, Steininger R et al.(1995) Renal allograft rejection controlled by photopheresis. Lancet 1995; 346(8973):506.

Szczepiorkowski ZM, Bandarenko N, Kim HC et al.(2007) 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.

Urbani L, Mazzoni A, Catalano G et al.(2004) The use of extracorporeal photopheresis for allograft rejection in liver transplant recipients. Transplant Proc 2004; 36(10):3068-70.

Urbani L, Mazzoni A, Colombatto P et al.(2008) Potential applications of extracorporeal photopheresis in liver transplantation. Transplant Proc 2008; 40(4):1175-8.

Urbani L, Mazzoni A, De Simone P et al.(2007) 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.

Villanueva J, Bhorade SM, Robinson JA et al.(2000) Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 2000; 5(3):44-7.


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