Coverage Policy Manual
Policy #: 2002004
Category: Medicine
Initiated: February 2002
Last Review: August 2018
  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Graft-versus-Host Disease

Description:
Photochemotherapy, extracorporeal (Photopheresis) is a multistep procedure involving the following:
    • Patients ingest the drug psoralen, which functions to render lymphocytes light sensitive;
    • Lymphocytes are collected by pheresis and exposed to UV-A light;
    • The light-sensitized lymphocytes are reinfused into the patient.
 
The use of photopheresis as a treatment of graft-versus-host disease (GVHD) after a prior allogeneic stem cell transplant is based on the fact that GVHD is an immunologically mediated disease.  GVHD can be categorized into acute, occurring within the first 100 days after infusion of allogeneic cells, or chronic disease, which develops sometime after 100 days.  Acute GVHD is commonly graded I-IV, ranging from mild disease characterized by a skin rash without involvement of the liver or gut, to grades III and IV, which are characterized by generalized erythroderma, elevated bilirubin levels, or diarrhea.  Grade III acute GVHD is considered severe, while Grade IV is considered threatening.  Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such a progressive systemic sclerosis, systemic lupus erythematosus, or rheumatoid arthritis.  It may affect the mouth, eyes, respiratory tract, musculoskeletal system, peripheral nerves, as well as the skin, liver, or gut - the usual sites of acute GVHD.
 
An alternating regimen of cyclosporine and prednisone are commonly used to treat chronic GVHD.  Other therapies include antithymocyte globulin, corticosteroid monotherapy, and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide, or azathioprine.  Therefore, refractory disease is defined as chronic GVHD that fails to respond adequately to a trial of any of the above therapies.  
 
There is no standard schedule for photopheresis therapy.  However, most reported schedules initiate therapy with 1-3 days of photopheresis at 1-3 week intervals, followed by a tapering of therapy.
 
The following observations were made by a 2001 Blue Cross Blue Shield Association Technology Evaluation Center assessment panel regarding the use of extracorporeal photopheresis for the treatment of acute and chronic GVHD:
    • For acute GVHD or chronic GVHD in previously untreated patients or in those responding to conventional therapy, there were no studies that met selection criteria and reported results of extracorporeal photopheresis, alone or in combination with other therapies;
    • Studies focusing on patients with chronic GVHD unresponsive to other therapies reported resolution or marked improvement of lesions in about 50% of patients;
    • Studies of patients with acute GVHD also reported a successful outcome in 67% to 84% of patients with Grade III disease, but patients with Grade IV disease rarely responded.
 
Related policies:
 
2003008:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment to Prevent Rejection Following Solid-Organ Transplant
2003007:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Cutaneous T-Cell Lymphoma
2000026:  Photochemotherapy, Extracorporeal (Photopheresis) as a Treatment of Autoimmune Disease
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Extracorporeal photopheresis as a technique to treat both acute and chronic graft-versus-host disease that is refractory to medical therapy 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 photopheresis as a technique to treat acute graft-versus-host disease or chronic graft-versus-host disease that is either previously untreated or is responding to established therapies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For contracts without primary coverage criteria, extracorporeal photopheresis as a technique to treat acute graft-versus-host disease or chronic graft-versus-host disease that is either previously untreated or is responding to established therapies is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates.

Rationale:
This policy was initiallly developed following the publication of the 2001 Blue Cross Blue Shield Technology Assessment.
 
Graft-versus-Host Disease:
    • For acute GVHD or chronic GVHD in previously untreated patients or in those responding to conventional therapy, there were no studies that met selection criteria and reported results of extracorporeal photopheresis, alone or in combination with other therapies. Therefore, photopheresis for these indications failed to meet the TEC Assessment criteria.
    • Studies focusing on patients with chronic GVHD unresponsive to other therapies reported resolution or marked improvement of lesions in about 50% of patients.
    • Studies of patients with acute GVHD also reported a successful outcome in 67% to 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 1 study, 8 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 (Halle et al, 2007).  Cutaneous status reportedly improved in 7 patients. Five patients stopped treatment and 3 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, 5 patients remained in remission without immunosuppressive therapy.  In 2001, Salvaneschi and colleagues reported on photopheresis results in refractory GVHD in 9 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 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 (Foss et al, 2005).  ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once weekly in 8 until best response or stable disease was achieved. With a 9-month median duration (range 3–24 months) of ECP, 20 patients had improvement in cutaneous GVHD and 6 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 policy 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 (Greinix et al, 2006).  ECP was initially administered on 2 consecutive days (one cycle) at 1- to 2-week intervals until improvement was noted and thereafter every 2 to 4 weeks until maximal response. At the start of ECP all patients had been receiving immunosuppressive therapy with prednisone and cyclosporine A. Complete resolution of GVHD was documented in 82% of 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 2-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 (Massimo et al, 2007).  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 7 days of methylprednisolone therapy. Patients received ECP on 2 consecutive days at weekly intervals for the first month, every 2 weeks during the second and third months, and then at monthly intervals for a further 3 months. ECP was progressively tapered and discontinued based on individual patient response. Response to ECP was assessed 3 months after ECP ended or after 6 months if the ECP protocol was prolonged. Among patients with 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 a 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 policy statement.
 
2009 Update
Extracorporeal Photopheresis as a treatment for acute Graft-Versus-Host disease is currently being studied in active phase II and III clinical trials.  A search of the MEDLINE database did not reveal any published literature that would prompt a change in the coverage statement at this time.  The policy remains unchanged.
 
2012 Update
A search of the MEDLINE database through July 2012 did not reveal any new publications that would prompt a change in the coverage statement. The following is a summary of the relevant identified information.
 
Treatment of GVHD in Pediatrics
The most recent and largest series was a retrospective review of 50 pediatric patients (age <18 years) with acute or chronic GVHD after an allogeneic stem-cell transplant unresponsive to 1-week steroid treatment. These patients were given ECP for a minimum of 10 treatments. ECP was administered 2-3 procedures per week on alternating days until clinical improvement. Treatment was then reduced to 2 procedures per week for 2 weeks, then 2 procedures every other week for 3 weeks, ending with 2 procedures per month until maximum response as clinically indicated. ECP was discontinued if no improvement was seen after 4 weeks. Eighty-three percent (39/47) of patients had improvement in cutaneous acute GVHD, and 87.5% (7/8) saw improvement in the oral mucosa. Among patients with chronic GVHD, the greatest improvement was seen in the liver, with 100% (4/4) seeing improvement, followed by 95.6% (22/23) showing improvement of skin lesions (Perotti, 2010).
 
These findings are also consistent with the current policy statements.
 
Treatment of GVHD in Adults
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. (36) 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 1 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.
 
Ongoing Clinical Trials
A search of online site ClinicalTrials.gov  found three ongoing randomized trials and one prospective case-only observational study:
 
  • A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy With UVADEX for the Treatment of Patients With Moderate to Severe Chronic Graft-versus-Host Disease (cGvHD) trial (NCT01380535) is a Phase II randomized trial evaluating the safety and effectiveness of ECP when added to standard drug therapies and given to adult patients with moderate-to-severe cGVHD. Primary outcome is overall response. They aim to enroll 60 participants and follow them for 28 weeks.
  • A Randomized Phase II Study for the Evaluation of Extracorporeal Photopheresis (ECP) in Combination With Corticosteroids for the Initial Treatment of Acute Graft-Versus-Host Disease (GVHD) trial (NCT00609609) is a Phase II randomized trial evaluating whether the addition of ECP to standard drug therapies for acute GVHD improves response to treatment, length of treatment, and survival. Primary outcome is overall response. They aim to enroll 80 participants and follow them for 6 months after treatment completion.
  • Randomized trial NCT00402714 is registered, but its status was unknown and has not been updated since April 2009.
  • The Outcomes ofCutaneous T-Cell Lymphoma and Chronic Graft-Versus-Host Disease in Patients Treated with Extracorporeal Photopheresis trial (NCT01460914). This is a prospective observational case-only study looking to measure response rates. In addition, a prospective database will be maintained so that new patient data can be collected.
 
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.
 
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.
 
In 2014, the Cochrane Collaboration childhood cancer group published 2 systematic reviews on aGVHD (Weitz, 2014a) and cGVHD (Weitz, 2014b) in pediatric patients. Literature searches were performed in September 2012, and no RCTs were found. The authors cited the need for RCTs but stated that “performing RCTs in this patient population will be challenging because of the limited number of patients, the variable disease presentation, and the lack of well-defined response criteria.” (36) International collaboration and establishment of patient registries was encouraged.
 
In 2014, Dignan et al reported on a series of 38 consecutive adults who received ECP for cGVHD (Dignan, 2014). Median patient age was 47 years (range, 18-73). Patients had steroid-refractory or steroid-dependent disease or were intolerant of corticosteroids. Thirty-six patients (95%) were receiving immunosuppressive therapy. ECP was administered on 2 consecutive days every 2 weeks until PR (defined as minimum 50% improvement from baseline in 1 organ and no evidence of GVHD progression in other organs) was achieved and was then reduced to monthly treatments. Median time from transplant to first ECP was 1.7 years (range, 0.25-7.25). Response was assessed after 6 months. Nineteen patients (50%) had a CR (n=2; defined as complete resolution of all signs and symptoms of GVHD) or PR (n=17); all 19 had completed 6 months of ECP. Of 25 patients receiving immunosuppressive therapy who completed 6 months of ECP, 20 (80%) reduced immunosuppressive dose; 5 patients discontinued steroids, and 8 patients had a 50% or greater reduction in steroid dose. Mean improvements in validated quality-of-life (QOL) measures (Lee chronic GVHD symptom scale and dermatology QOL index) were clinically and statistically significant in 17 (94%) of 18 patients who completed the questionnaires at 6 months. Five patients developed indwelling catheter-related infections, 1 patient had a catheter-related thrombosis, and 1 patient had an increase in red cell transfusion requirements, which was considered due to ECP alone.
 
Jagasia et al (2013) reported an international, retrospective comparative analysis of nonconcurrent cohorts who received ECP (n=57) or anticytokine therapy (inolimomab or etanercept; n=41) for grade 2 or higher steroid-refractory aGVHD (Jagasia, 2013). ECP was initiated at 2 to 3 treatments weekly or biweekly until maximal response and then discontinued (European sites) or tapered (U.S. sites). More patients in the ECP group than in the anticytokine group experienced overall response (CR plus PR; 66% vs 32%, p=0.001) and CR (54% vs 20%, p=0.001). Two-year OS was 59% in the ECP group and 12% in the anticytokine group (p value not reported).
 
Rubegni et al (2013) reported on a cohort of 9 patients with grade 2 to 3 steroid-refractory aGVHD at a single institution in Italy (Rubegni, 2013). ECP was administered on 2 consecutive days weekly until improvement and then every 2 weeks; treatment was then tapered as tolerated. At 3 months, mean dose of methylprednisolone decreased from 2.22 mg/kg to 0.27 mg/kg, and mean dose of cyclosporine decreased from 2.46 mg/kg to 0.77 mg/kg. Six patients (67%) showed a complete skin response. Five (83%) of 6 patients with liver and gastrointestinal tract involvement had CRs. All patients developed cGVHD, 7 (78%) while still receiving ECP.
 
 aGVHD and cGVHD
Hautmann et al (2013) reported on a cohort of 62 patients with aGVHD (n=30) or cGVHD (n=32) at a single institution in Germany (Hautmann, 2013). For aGVHD, ECP was administered 2 or 3 times weekly on consecutive days until clinical improvement, then 2 treatments on consecutive days biweekly, reducing to monthly, if tolerated. At 3 months, 15 patients (50%) achieved CR or PR (9 [30%] complete). Ten (83%) of 12 patients who continued ECP beyond 3 months and had data available decreased steroid dose by 50% or more. For cGVHD, ECP was administered on 2 consecutive days weekly until improvement, then biweekly for 3 to 4 weeks, and then monthly. At 3 months, 14 patients (44%) achieved CR or PR (2 [6%] complete). Five (29%) of 17 patients who continued ECP beyond 3 months had data available and were taking steroids at baseline, decreased steroid dose by 50% or more.
 
Ussowicz et al (2013) reported on 21 patients with steroid-refractory or steroid-dependent, grade 3 or 4 acute (n=8) or extensive chronic (n=13) GVHD in Poland (Ussowicz, 2013). For aGVHD, ECP was administered on 2 consecutive days weekly for up to 4 weeks. Although clinical response was noted in 3 patients (37.5%), there were no long-term (more than 18 months after ECP) survivors. For cGVHD, ECP was administered on 2 consecutive days every 2 weeks for 14 weeks and then monthly for up to 8 weeks. Four-year OS was 67.7%.
 
Practice Guidelines and Position Statements
aGVHD and cGVHD
Evidence-based guidelines from the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation (2012) recommend ECP in aGVHD as second-line treatment for steroid-refractory disease (Dignan, 2012a) and in cGVHD as second-line treatment for skin, oral, or liver involvement (Dignan, 2012b)
 
Treatment schedule
  • For aGVHD, no recommendation is provided.
  • For cGVHD, 1 cycle (ie, ECP on 2 consecutive days) every 2 weeks; no benefit has been associated with more regular treatments (Dignan, 2012b). Responders may taper to monthly treatments (Scarisbrick, 2008).
 
Treatment duration
  • For aGVHD, guideline authors observed that optimal treatment duration “has yet to be established” and cited a case series of 19 patients (published as an abstract (Das-Gupta, 2011) who received at least 8 weekly cycles, continued until maximal response (undefined) or CR (defined as “resolution of features of acute GVHD with reduction of prednisolone dose to 20 mg/day or less”).
  •  For cGVHD, no specific treatment duration was recommended, but an earlier evidence-based consensus statement was cited (Scarisbrick, 2008). This statement included recommendations for baseline, monthly, and every 3-monthly assessments and criteria for discontinuation based on response and ability to taper concomitant immunosuppressive therapy. Typical treatment duration of 3 or 4 months was noted.
 
In 2013, a 9-member panel representing the Italian Society of Hemapheresis and Cell Manipulation and the Italian Group for Bone Marrow Transplantation published consensus recommendations for ECP in adults and children with aGVHD or cGVHD (Pierelli, 2013). The panel recommended ECP: for treatment of aGVHD in adults and children who are nonresponsive to steroids or calcineurin inhibitors or have contraindications to immunosuppressive therapy because of viral reactivation or other infectious complication (“better results are expected in patients with isolated skin involvement”); and for treatment of cGVHD in adults and children who are steroid-resistant or steroid-dependent.
 
Treatment schedule
  • “For either acute or chronic GVHD, in the absence of controlled trials, the most frequently applied schedule is 2 ECP sessions weekly.”
Treatment duration
  • For aGVHD or cGVHD, treatments continue until maximum response. Clinical response should be assessed weekly in aGVHD and every 8 to 12 weeks in cGVHD.
  • ECP should be discontinued in the case of no response or minimal response.
 
In its guideline on childhood hematopoietic cell transplantation, the National Cancer Institute lists ECP as a second-line treatment for patients with aGVHD who are resistant to first-line methylprednisolone (National Cancer Institute, 2014). For cGVHD therapy, the guideline states that steroids are first-line therapy, but steroid-sparing approaches, including ECP, are being developed. In this setting, ECP shows “some efficacy in a percentage of patients.
 
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.
 
Malik and colleagues published a systematic review of ECP for steroid-refractory cGVHD (Malik, 2014).  Literature was searched through July 2012 and 18 studies were included (4 prospective, including 1 RCT (Flowers, 2008) and 14 retrospective; N=595). In meta-analyses, overall and CR rates were 64% and 29%, respectively. Pooled response rate was highest for cutaneous disease (74%) and lowest for lung disease (48%). Statistical heterogeneity was high for all of these results (I2>60%).
 
In 2014, Abu-Dalle and colleagues published a systematic review of prospective studies in patients with steroid refractory acute or chronic GVHD (Abu-Dalle, 2014).  Literature was searched through February 2013, and 1 RCT in patients with cGVHD (Zhang, 2015) and 8 cohort studies in patients with aGVHD and/or cGVHD were identified (N=323). In meta-analyses, overall response rates (ORR) for aGVHD and cGVHD were 69% and 64%, respectively. In both aGVHD and cGVHD, ORR was highest in cutaneous disease (84% and 71%, respectively) followed by gastrointestinal disease (65% and 62%, respectively. Rates of immunosuppression discontinuation were 55% and 23% for aGVHD and cGVHD, respectively. Statistica heterogeneity for most meta-analyses was high (I2>60%).
 
Ongoing Clinical Trials
Ongoing
 
NCT00637689 Improving Outcome Assessment in Chronic GVHD; planned enrollment 601; projected completion date May 2015.
 
NCT00609609 A Randomized Phase 2 Study for the Evaluation of Extracorporeal Photopheresis (ECP) in Combination with Corticosteroids for the Initial Treatment of Acute Graft-Versus-Host Disease (GVHD); planned enrollment 95; projected completion date January 2016.
 
NCT01380535 A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX for the Treatment of Patients with Moderate to Severe Chronic Graft-Versus-Host Disease (cGVHD); planned enrollment 60; projected completion date March 2017.
 
NCT01460914 Outcomes of Cutaneous T-Cell Lymphoma and Chronic Graft-Versus-Host /Disease I Patients Treated with Extracorporeal Photopheresis; planned enrollment 100; projected completion date October 2050
 
In 2014, the Program in Evidence-Based Care and the Stem Cell Transplantation Steering Committee of Cancer Care Ontario published an evidence-based consensus guideline on ECP for GVHD (Bredeson, 2014).  ECP is recommended as “an acceptable therapy for the treatment of steroid-dependent or refractory aGVHD in adult and pediatric patients” and for “steroid-dependent or refractory cGVHD in adult and pediatric patients.” Strength of recommendations was not graded.
 
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

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