Organ Rejection after Solid-Organ Transplant
A literature search using MEDLINE identified one randomized controlled trial (RCT) for the use of extracorporeal photopheresis (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.
One RCT was published in 1992 on the efficacy of ECP versus corticosteroids in treating heart transplant rejection. 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 three days or 1g/day IV (intravenous) methylprednisolone for three days at the discretion of the managing physician. The treatment was repeated if EMB at day seven showed no improvement in rejection grade. If the rejection grade persisted after retreatment, patients were given 10 mg oral methotrexate at weekly intervals for eight 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 nine rejection episodes treated with ECP, all but one improved; all seven of rejection episodes treated with corticosteroids resolved. Improvement was seen in a mean of seven days (range: 5–20) for ECP and eight days (range: 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. 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 two-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 one HC had already occurred. Hazard functions were used for analysis. Patients with at least three months of ECP were considered to have effective photopheresis treatment; if less than three 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 three 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 two 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. Participants were eligible if they had acute rejection and at least two rejection episodes in the three months prior to ECP, which recurred after standard immunosuppressive therapies. ECP was performed with the UVAR photopheresis instruments, with two consecutive treatments at weekly intervals for one month, two treatments twice weekly during the second and third months, then monthly for three 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 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, 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) was reduced after six 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. 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 as two treatments per week for one month, once a week for two months, then once a month for two months, totaling 20 ECP treatments during six months. Total number of rejection episodes decreased from a mean of three 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 four patients treated with ECP for severe refractory (grade IIIA to IV) cardiac allograft rejection. All four patients experienced reversal of their rejection. Three patients improved following two consecutive days of treatment, and the fourth patient responded following three 2-day treatments. Two of these patients subsequently died of acute rejection at nine weeks and 10 weeks after completion of ECP. The other two were without signs of rejection, one for six years and the other’s last report was four months after ECP ended. This small case series adds to the evidence provided by the prior two slightly larger studies.
Prevention of Rejection
An RCT by Barr and colleagues investigated ECP for the prevention of rejection after cardiac transplant. Sixty consecutive adult cardiac transplant recipients at 12 clinical sites (nine U.S., three 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 two 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 two consecutive days every two weeks in months 2 and 3; and two successive days every four weeks for months 4-6 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 six months; an additional six 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, five 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 six months between the two groups or number of infections. Time to a first rejection also did not differ between the groups. During the second six 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.
Villanueva and colleagues reported in 2000 on a retrospective review of data on 14 transplants (seven bilateral lung, six single lung, one heart-lung) recipients who received ECP for bronchiolitis obliterans syndrome (BOS). All patients were refractory to standard immunosuppressive therapy. ECP was administered every two weeks for two months followed by once a month for the next two months for a total of six 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. Three of these patients received ECP during a concurrent episode of acute rejection. All three 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 histologic reversal of concurrent acute rejection after treatment with ECP. These two studies reported on only five 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). Patients had biopsy-confirmed chronic acute rejection, defined as two 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. Patients were treated weekly with two sessions of pheresis for 3-4 weeks. Treatment then decreased in frequency to every 2-3 weeks, with the goal of getting treatment to every four 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. 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 two cycles on days 1, 2, 5, 6, 10, 11, 17, 18, 27, and 28 during the first month (10 treatments); biweekly for the next two months (eight treatments); and then monthly for the following three months (six treatments), 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 four 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 forced expiratory volume in the first second of expiration (FEV1) in the six 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 transplant patients (seven bilateral lung, six single lung, one heart-lung) recipients who received ECP for BOS. All patients were refractory to standard immunosuppressive therapy. ECP was administered every two weeks for two months followed by once monthly therapy for the next two months, for a total of six 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 six 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). 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 years), the median patient survival post-ECP was 4.9 years (range: 0.5–8.4 years). 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 six 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. ECP was performed on two consecutive days twice a month until stabilization of the FEV1. Treatment was then repeated every 4-6 weeks. Four of the six patients had temporary stabilization of their airflow obstruction with minimal adverse effects. Grade of BOS was not reported. Case report data suffer 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 RCTs are necessary to examine the comparative effects of ECP for patients with BOS stratified by BOS grade.
Prevention of Bronchiolitis Obliterans Syndrome (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. The first paper is a retrospective review of five patients who received liver transplants and ECP for biopsy-proven allograft rejection, in which the indications for ECP were recalcitrant ductopenic rejection with Hepatitis C virus recurrence, corticosteroid-resistant acute rejection in two patients, severe acute rejection in a major ABO-incompatible liver graft, and severe acute rejection in a patient with a proven corticosteroid allergy. ECP was performed twice a week for four weeks, then every two weeks for two 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, three 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. Patients were included if they were at risk of post-liver transplant renal impairment and neurologic complications, defined as having at least one of the following risk factors: a calculated glomerular filtration rate equal to or less than 50 mL/min at transplantation; severe ascites; history of more than one hospitalization for encephalopathy within one year of transplant and/or one hospitalization within one 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 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 eight days for 17 patients, while one patient remained CNI free for 22 months. Acute rejection was higher but not significantly higher in the ECP group (5/18) versus in controls (3/18). One-, 6-, and 12-month survival rates were 94.4, 88.1, and 88.1%, respectively, for ECP recipients versus 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. The three fields include use of ECP:
- To delay CNI among high-risk liver transplant recipients to avoid toxicity (discussed above),
- 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,
- 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. ECP was delivered weekly for four weeks, then every two weeks. Total treatment range was 2-12 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 nine 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, three patients were stable, and four 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, five had improved function at one year, one was stable at 25 months, five were stable at one year, seven were rejection-free at 2-5 years, and one graft was lost. Three patients did not have long-term outcome reports.
The evidence for the use of ECP in cardiac transplant patients relates to three 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 in which 33 patients were randomly assigned 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 six 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 experimental, investigational and unproven 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 are from nonrandomized studies, a comparative study of 343 cardiac transplant patients in which 36 received ECP has been completed. The authors present data showing that at three months, ECP was related to a risk reduction of hemodynamic compromise (HC) rejection or rejection death (risk ratio [RR]: 0.29). A reduction in HC rejection or rejection death was observed through two 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 one nonrandomized comparative study, two case series and a case report of four 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 (nearly 60% of these patients were BOS grade 3). Prospective, RCTs 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 numbers of subjects and longer follow-up are needed. Therefore, ECP is considered experimental, investigational and unproven 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 involves only 18 cases and 18 controls. There is a need for RCTs. The effort in liver transplant patients has been on prevention of rejection with ECP. This question lends itself well to an RCT 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 experimental, investigational and unproven 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 histologic 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 of 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 experimental, investigational and unproven in renal transplant patients for any indication
A search of www.ClinicalTrials.gov 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) does not have any policies related to ECP in the treatment or prevention of any form of rejection following solid-organ transplant.
Graft-versus-Host Disease (GVHD)
Extracorporeal photopheresis (ECP) for the treatment of acute and chronic GVHD was initially addressed by a 2001 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment that offered the following observations and conclusions: 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, photopheresis for these indications failed to meet TEC criteria. 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 a successful outcome in 67–84% of patients with grade III disease, but patients with grade IV disease rarely responded.
Following the TEC Assessment in 2001, two small studies that focused on photopheresis for treatment of GVHD in children were published. In one study, eight children (aged 5–15 years) with refractory extensive chronic GVHD were treated with ECP and either oral 8-methoxypsoralen (8-MOP) or infusion of an 8-MOP solution into the pheresed lymphocytes. Cutaneous status reportedly improved in seven patients. Five patients stopped treatment and three others decreased doses of immunosuppressive therapy. In addition, gut involvement resolved in all patients, and liver involvement resolved in 4 of 6 patients. Two years following discontinuation of photopheresis, five patients remained in remission without immunosuppressive therapy. Salvaneschi and colleagues reported on photopheresis results in refractory GVHD in nine acute pediatric cases and in 14 chronic pediatric cases (aged 5.4–11.2 years). In the acute GVHD cases, 7 of 9 experienced either partial response (PR) or complete response (CR), while in the chronic GVHD patients, 9 of 14 experienced either partial or complete remission. These findings are consistent with the current policy statements.
Several additional publications subsequently reported on the use of ECP for the treatment of GVHD. Foss and colleagues reported results of a prospective (non-randomized) study of ECP in 25 patients who had extensive corticosteroid-refractory or corticosteroid-resistant chronic GVHD secondary to allogeneic stem-cell transplantation. ECP was administered for two consecutive days every two weeks in 17 patients and once weekly in eight until best response or stable disease was achieved. With a nine-month median duration (range 3–24 months) of ECP, 20 patients had improvement in cutaneous GVHD, and six had healing of oral ulcerations. ECP allowed cessation or reduction of immunosuppressive medication treatment in 80% of patients. Overall, improvement was reported in 71% of cases with skin and/or visceral GVHD and 61% of those deemed to be high-risk patients. These results are consistent with the current coverage statements.
Greinix and coworkers reported findings from a Phase II (nonrandomized) study to evaluate the efficacy of intensified ECP as second-line therapy in 59 patients with post-stem cell transplant acute (grades II-IV), steroid-refractory GVHD. ECP was initially administered on two consecutive days (one cycle) at 1- to 2-week intervals until improvement was noted and thereafter every 2-4 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 cases with cutaneous manifestations, 61% with hepatic involvement, and 61% with gut involvement. A CR was noted 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 to 11% of those who did not respond completely. While these results suggest ECP may be beneficial in the treatment of acute GVHD, the small size, few study details in the report, and lack of a standard treatment comparator group limit inferences as to the clinical efficacy of ECP for acute GVHD.
In 2006, the Ontario Health Technology Advisory Committee (OHTAC) published results of a systematic review of ECP for the treatment of refractory chronic GVHD. In summary, OHTAC reported that there is low quality evidence that ECP improves response rates and survival in patients with chronic GVHD who are unresponsive to other forms of therapy. Limitations in the literature related to ECP for the treatment of refractory GVHD mostly pertained to the quality, size, and heterogeneity in treatment regimens and diagnostic criteria of available clinical studies. The committee did, however, recommend a two-year duration 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.
A retrospective case series published in 2007 reported results of ECP for steroid-resistant GVHD in pediatric (aged 6–18 years) patients who had undergone hematopoietic stem-cell transplantation to treat a variety of cancers. Patients had acute GVHD (aGVHD, n=15, stages II-IV) or chronic GVHD (cGVHD, n=10, 7 deemed extensive) that did not respond to at least seven days of methylprednisolone therapy. Patients received ECP on two consecutive days at weekly intervals for the first month, every two weeks during the second and third months, and then at monthly intervals for a further three months. ECP was progressively tapered and discontinued based on individual patient response. Response to ECP was assessed three months after ECP ended or after six months if the ECP protocol was prolonged. Among patients with aGVHD, a CR was observed in 7 of 7 (100%) with grade II and 2 of 4 (50%) with grade III illness, whereas none with grade IV responded to ECP. In the group with cGVHD, 3 of 3 (100%) with limited disease had CR, compared to 1 of 7 (14%) with extensive disease who had CR; 5 of 7 (71%) of patients with extensive cGVHD had no response to ECP. Adverse effects of ECP were generally mild in all cases. These results are similar to those summarized in the 2001 TEC Assessment cited previously and thus do not alter the current coverage statements.
In 2008, Perfetti and colleagues reported on a retrospective review of 23 patients with corticosteroid-refractory acute GVHD, 10 grade II, seven grade III, and six grade IV. Median duration of ECP was seven months (1–33 months) and median number of cycles per patient was 10. Complete responses were seen in 70%, 42%, and 0% of patients with GVHD grades II, III, and IV, respectively. Eleven patients (48%) survived and 12 died: 10 of GVHD and two of relapse of their leukemia. Patients treated within 35 days from onset of GVHD had a higher but not statistically significant different response (83 vs. 47%, respectively; p=0.1). While these findings suggest that ECP may provide benefit for patients with refractory acute GVHD, they are limited by the small sample size and non-comparative nature of the study.
One study was published in 2010 by Shaughnessy and colleagues using ECP to prevent acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic transplant. ECP was administered prior to a standard conditioning regimen. Results were compared to historical controls from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Multivariate analysis indicated a lower rate of grade II-IV acute GVHD in patients receiving ECP. Adjusted overall survival at one year was 83% in the ECP group and 67% among historical controls (relative risk [RR]: 0.44; 95% confidence interval [CI]: 0.24-0.80). Additional prospective randomized trials are necessary to confirm these findings.
Cutaneous T-Cell Lymphoma
Stage III/IV MF and Sezary Syndrome
The initial report on the use of ECP as therapy for cutaneous T-cell lymphoma (CTCL) was published by Edelson and colleagues. Twenty-seven of 37 (73%) patients with otherwise resistant CTCL responded to the treatment, with an average 64% decrease in cutaneous involvement after 22 + 10 weeks (mean + SD). The responding group included 8 of 10 (80%) patients with lymph-node involvement, 24 of 29 (83%) with exfoliative erythroderma, and 20 of 28 (71%) whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. These results showed that ECP is safe and effective in advanced, resistant CTCL. Subsequent results from numerous small, nonrandomized studies have been generally 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.
Together, these data provide the basis for several evidence-based guideline or consensus statements on the use of ECP in CTCL, as well as the position of the National Cancer Institute (NCI) available online at <http://www.cancer.gov>. They consistently recommend ECP as first-line treatment for patients with stage III/IV CTCL. Therefore, in this policy, ECP may be considered medically necessary as a technique for the treatment of patients with stages III/IV CTCL.
In 2006, OHTAC published results of a systematic review of ECP for the treatment of erythrodermic CTCL. In summary, OHTAC reported that there is low-quality evidence that ECP improves response rates and survival in patients with CTCL who are unresponsive to other forms of therapy. Limitations in the literature related to ECP for the treatment of refractory erythrodermic CTCL mostly pertained to the quality, size, and heterogeneity in treatment regimens and diagnostic criteria of available clinical studies. The committee did, however, recommend a two-year duration 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.
Early Stage (I/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 (n=45) including retinoids and interferon-alfa. Many of these patients were refractory to numerous other therapies, including topical corticosteroids, interferon alfa, or whole-skin irradiation. Response rates (partial plus complete) in these studies ranged from 33% to 88% with monotherapy and 50–60% with ECP and adjuvant therapies. While these findings suggest ECP may provide benefit in early-stage CTCL, none of the studies was randomized or comparative. Furthermore, many of the studies preceded universal acceptance of standardized elements of classification and diagnosis of CTCL, such as those proposed by the World Health Organization and European Organization for Research and Treatment of Cancer (WHO-EORTC). 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 CTLC that progresses while receiving nonsystemic therapies, the relative lack of adverse events with ECP compared to other systemic treatments, and the good response rates often associated with ECP, ECP may be considered medically necessary as a technique for the treatment of patients with refractory or progressive early-stage CTCL. By contrast, because early-stage CTCL typically responds to less-invasive, topical therapies, patients whose disease remains quiescent under such treatments usually experience a near-normal life expectancy. As a consequence ECP is considered experimental, investigational and unproven as a technique for the treatment of patients with stage I/II CTCL that is either previously untreated or is responding to established therapies.
National Cancer Institute (NCI) Physician Data Query (PDQ®) Database
The NCI PDQ database indicates no RCTs on the use of ECP in CTCL are recruiting or are otherwise in development.
ClinicalTrials.gov indicates there are at least nine active Phase II/III clinical trials seeking to assess the efficacy of ECP as a treatment of acute or chronic GHVD or for the prevention of GVHD. No trials of ECP for any autoimmune disease were identified (available online at >http://www.clinicaltrials.gov>).
National Comprehensive Cancer Network (NCCN)
The NCCN 2010 guidelines for the treatment of CTCL recommend the use of ECP alone or in combination with other agents (retinoids, interferon alfa, denileukin diftitox) as first-line systemic therapy for advanced (stages III/IV) disease as well as for patients either with earlier stage mycosis fungoides with Sezary syndrome involvement or with disease that has failed multiple courses of topical skin-directed treatments
ECP for the treatment of autoimmune diseases was initially addressed by a 2001 TEC Assessment, which offered the following observations and conclusions. A variety of autoimmune diseases were considered, including systemic sclerosis, pemphigoid, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, and type I diabetes. For all of these indications, the available evidence was insufficient to permit conclusions on outcomes. At the time, photopheresis had been most thoroughly studied as a treatment of scleroderma. However, the data on this indication include one single-blind RCT and three small, uncontrolled series. While the randomized study reported positive outcomes in terms of skin manifestations, a number of methodologic flaws have been discussed in the literature, 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 from other small case series regarding systemic sclerosis conflict with each other and do not resolve the difficulties in interpreting the randomized trial.
One clinical trial on diabetes was found for a subsequent update of the original policy through 2003. No clinical trials were found on photopheresis for other autoimmune diseases. For diabetes, Ludvigsson and colleagues reported a double-blind, RCT on photopheresis in 49 children with newly diagnosed type 1 diabetes. A total of 40 children aged 10–18 years completed the study and were followed up for three years. All patients received standard treatment with insulin therapy and diet, exercise, and self-management education. Of these patients, 19 received active photopheresis treatment with oral 8-MOP, and 21 received placebo tablets and sham pheresis in the control group. Hemoglobin A1C results, a key clinical outcome in diabetes control, were not statistically different in the two groups.
In 2007, one small series was identified in which ECP was administered to treat immunorefractory relapsing-remitting multiple sclerosis in five patients. ECP appeared safe and tolerable in these patients, with some evidence for a reduction in the relapse rate and symptom stabilization. However, the data are insufficient to alter the coverage statement for this use of ECP.
In 2010, Sanli and colleagues published a retrospective report on 11 patients with drug-resistant autoimmune bullous diseases. ECP was performed between January 2005 and January 2010. Eight of these patients had pemphigus vulgaris (PV), while the others had epidermolysis bullosa acquisita (EBA). Patients were treated on two consecutive days at four-week intervals. Among the patients with PV, all experienced complete remission after 2-6 cycles, except one. Two patients with EBA had complete remission, while one patient had partial remission. Corticosteroids were reduced in all patients with PV. Decrease in the frequency of ECP resulted in progression of lesions for three patients with PV and in two of the patients with EBA. No adverse effects were observed. RCTs are necessary to adequately assess the efficacy of ECP for patients with drug-resistant autoimmune bullous diseases.
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