Extracorporeal Photopheresis

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The Centers for Medicare and Medicaid Services (CMS) has determined that extracorporeal photopheresis is reasonable and necessary for: Patients with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment; and Patients with chronic graft versus host disease whose disease is refractory to standard immunosuppressive drug treatment. CMS has determined that extracorporeal photopheresis is not reasonable and necessary for the treatment of bullous pemphigoid and pemphigus vulgaris. All other indications remain non-covered.

Decision Memo: To: Administrative File: CAG- 00324R Extracorporeal Photopheresis From: Steve Phurrough, MD, MPA Director, Coverage and Analysis Group Marcel Salive, MD, MPH Director, Division of Medical and Surgical Services Susan Harrison, MPP Lead Analyst, Division of Medical and Surgical Services Lori Paserchia, MD Lead Medical Officer, Division of Medical and Surgical Services Ross Brechner, MD, MS, MPH Medical Officer, Division of Medical and Surgical Services Subject: Decision Memorandum for Extracorporeal Photopheresis Date: December 19, 2006 I. Decision The Centers for Medicare and Medicaid Services (CMS) has determined that extracorporeal photopheresis is reasonable and necessary for: Patients with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment; and Patients with chronic graft versus host disease whose disease is refractory to standard immunosuppressive drug treatment. CMS has determined that extracorporeal photopheresis is not reasonable and necessary for the treatment of bullous pemphigoid and pemphigus vulgaris. All other indications remain non-covered. II. Background A. Background of the Procedure Extracorporeal photopheresis (also known as extracorporeal photochemotherapy) was first applied in the treatment of cutaneous T-cell lymphoma (CTCL) (Edelson, 1987). Over the years there has been an extension of extracorporeal photopheresis use in many diseases including rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, pemphigus vulgaris and more recently in solid organ allograft rejection and in graft versus host disease (Heshmati, 2003). Extracorporeal photopheresis is a medical procedure in which a patient’s white blood cells are exposed first to a drug called 8-methoxypsoralen (8-MOP) and then to ultraviolet A (UVA) light. The procedure starts with the removal of the patient’s blood, which is centrifuged to isolate the white blood cells. The drug is typically administered directly to the white blood cells after they have been removed from the patient (referred to as ex vivo administration) but the drug can alternatively be administered directly to the patient before the white blood cells are withdrawn. After UVA light exposure, the treated white blood cells are then re-infused into the patient. Extracorporeal photopheresis is usually performed on two consecutive days at four-week intervals with clinical evaluation at six months to determine response. The duration of treatment varies significantly depending on the medical condition being treated, and the patient’s response to the treatments. Today extracorporeal photopheresis is commonly administered via the UVAR® XTS™ system, which is an FDA-approved wholly-contained, automated processing system manufactured by Therakos, Inc. This system is a single unit that handles the collection of the patient’s blood, the isolation of the white blood cells, and the ex vivo administration of 8-MOP and UVA. The UVAR® XTS™ system evolved from the FDA-approved UVAR® system, which used the oral formulation of 8-MOP. Other systems and protocols have been used to administer extracorporeal photopheresis, however. In this decision memorandum, CMS is evaluating the extracorporeal photopheresis procedure, and not a specific system for administering extracorporeal photopheresis. The exact mechanism of action of extracorporeal photopheresis is still elusive (Edelson, 1987). The role of UVA is to activate the normally inert 8-MOP. The activated 8-MOP molecules bind with the DNA of the white blood cells, which kills the cells. The dead white blood cells, once reinfused into the patient, stimulate the multiple different cells and proteins of the patient’s immune system in a series of cascading reactions. This activation of the immune system then impacts the medical condition being treated; however, the precise manner in which the medical condition is affected is still largely unknown but is believed to vary by condition (Therakos, Inc. 2006). Hence, extracorporeal photopheresis is a procedure that attempts to negatively impact the ability of specific immune cells to function but without inducing a general state of immunosuppression (Dall’Amico, 1995). B. Disease Summary 1. Refractory Acute Cardiac Allograft Rejection Cardiac transplantation is a procedure that involves the replacement of a failing heart with another heart from a suitable donor. One potential complication of cardiac transplantation is rejection of the transplanted heart. During rejection, the cardiac transplant recipient’s immunological system produces cells and proteins that rightly recognize the transplanted heart as “foreign” and therefore attack it. Due to the serious nature of rejection, the patient is routinely started on immunosuppressive drug therapy immediately after the transplantation in an attempt to prevent the onset of rejection. Although acute rejection of the transplanted heart can occur within days, months or years of transplantation (www.heart-transplant.org 2006), rejection most frequently occurs during the first month after transplantation (Patel, 2004). Histological rejection refers to the microscopic detection of the immunological attack on the heart during an episode of rejection. This type of rejection is associated primarily with specific immunologic cells called T lymphocytes and is referred to as cell-mediated rejection. A patient may or may not have symptoms in the presence of histological rejection. In fact, most patients with histological changes consistent with rejection have no change in heart function that could lead to symptoms (Hosenpud, 2005). The chance that a patient may not have symptoms due to acute rejection mandates that routine testing be performed to detect the presence of rejection and to measure the effect of immunosuppressive drug treatment (Patel, 2004). An endomyocardial biopsy (EMB) is the gold standard for monitoring for the presence or absence as well as the severity of histological rejection. The degree of rejection present in the heart muscle has traditionally been graded as noted in the following table from the International Society of Heart and Lung Transplantation (ISHLT) (Billingham, 1990). Billingham Classification for Grading Endomyocardial Biopsy 1 Grade Degree of Rejection 0 None 1 A: focal (perivascular or interstitial) infiltrate without necrosis B: diffuse but sparse infiltrate without necrosis 2 One focus only with aggressive infiltration and/or focal myocyte damage 3 A: multifocal aggressive infiltrates and/or myocyte damage B: diffuse inflammatory process with necrosis 4 Diffuse aggressive polymorphous +/- infiltrate +/- edema +/- hemorrhage +/- vasculitis, with necrosis Once diagnosed, the management of acute rejection is dependent on the severity of the signs, symptoms, and changes in the histology (Patel, 2004). The majority of episodes of histological rejection are effectively treated with modification of the immunosuppressive drug therapy (Hosenpud, 2005). Using the Billingham classification, Grade 1A/B or 2 rejection without clinical signs or symptoms generally does not lead to a change in immunosuppression management. Steroids are typically administered for an asymptomatic Grade 3A/B rejection. Asymptomatic Grade 4 or symptomatic Grade 3A/B rejection is treated with anti-rejection drugs such as OKT3, daclizumab, basaliximab or high doses of methylprednisolone. For a patient who has persistent cell-mediated rejection that is unresponsive (i.e., refractory) to all attempts at treatment with the typical types and doses of drugs, extracorporeal photopheresis has been proposed and used as therapy (Patel, 2004). Cardiac transplant rejection can result in significant morbidity and mortality. The increased doses of immunosuppressive drugs required to treat an episode of severe rejection substantially increase the risk of severe infections and malignancies (Dall’Amico, 1997). Recurrent episodes of rejection impact the patient’s quality of life as well as graft survival (Guinti, 1999), which can ultimately lead to death if the patient is not retransplanted (Costanzo-Nordin, 1992). 2. Refractory Chronic Graft versus Host Disease (cGvHD) Allogeneic hematopoietic cell transplantation (aHCT) is performed to treat and potentially cure a variety of malignant or non-malignant diseases. In an aHCT, cells are taken from the bone marrow or blood of a human donor and administered to a human host. Prior to transplantation, the host’s bone marrow is destroyed with chemotherapy or radiation in order to eradicate the cancer cells and to prepare the host to accept the transplanted cells. After transplantation, immunosuppressive drugs are administered to the host to permit the new cells to implant without being destroyed by the host’s immune system. Unless the donor and host are identical twins, the genetic profile of the donor and of the host is similar but not identical. The degree of similarity between the two genetic profiles is an important factor in determining the risk of triggering immunologically-mediated complications after the transplantation. For any transplantation, it is critical to match the donor’s genetic profile as much as possible to the host’s genetic profile in order to minimize this risk. Graft versus host disease (GvHD) is a complication of transplantation that can develop in the host. The complication occurs when the transplanted immune cells from the donor recognize the host’s cells as foreign and therefore attack them. In other words, GvHD occurs due to the presence of immunologic mismatch between the donor’s stem cells and the host’s cells. Graft versus host disease may have an acute or chronic onset. The clinical profile of each is distinct. The signs and symptoms of acute GvHD (aGvHD) typically start within a month of transplantation and include skin rash, diarrhea, and abnormal liver function tests. In addition to skin rash and abnormal liver function tests, the signs and symptoms of chronic GvHD (cGvHD) are more systemic and include dry eyes and mouth, hair loss, lung and gastrointestinal disorders. The severity of the clinical manifestations is denoted as mild, moderate, or severe. Severe or treatment-refractory cases can be life-threatening. Chronic GvHD can arise in a progressive, quiescent, or de novo manner. In progressive cGvHD, the disease initially manifests as aGvHD, which doesn’t resolve prior to the onset of the systemic signs and symptoms typically associated with cGvHD. With quiescent cGvHD, the patient’s aGvHD is successfully treated prior to the onset of cGvHD. Patients with the de novo form of cGvHD do not have aGvHD at all. Treatment of cGvHD consists of suppressing the immune response, but doing so without damaging the new marrow. High doses of corticosteroids or antibodies to T lymphocytes are administered to accomplish this goal. An alternative therapy does not currently exist if the disease does not respond to either of these treatments. 3. Bullous Pemphigoid and Pemphigus Vulgaris Pemphigoid/Pemphigus is a group of autoimmune blistering diseases of the skin and/or mucous membranes. In an autoimmune disease, the body's immune system attacks its own organs or tissues by producing autoantibodies (antibodies against the self). Our immune system produces antibodies that normally attack hostile viruses and bacteria in an effort to keep us healthy. In a person with pemphigus, however, the immune system mistakenly perceives the cells in skin and/or mucous membrane as foreign, and attacks them. Antibodies that attack one's own cells are called autoantibodies. The parts of the cells that are attacked in pemphigus are proteins called desmogleins. Desmogleins form the glue that attaches adjacent skin cells, keeping the skin intact. When autoantibodies attack desmogleins, the cells become separated from each other. The skin virtually becomes unglued. This causes burn-like lesions or blisters that do not heal. In some cases, these blisters can cover a significant area of the skin Treatment requires prescription drugs, many of which have side effects that often must be managed with other drugs. Additionally, these diseases can cause problems such as infection due to open wounds which may also require medication. The major modality of treatment is with immunosuppressive drugs, usually in combination with a corticosteroid. When an immunosuppressant is used with corticosteroids (steroid sparing), the dose of corticosteroid can often be reduced. Use of a steroid-sparing immunosuppressant, therefore, can help lower the undesirable side effects of prednisone. Ultimately deaths in pemphigus and pemphigoid patients result more commonly from either complications of steroid therapy or unassociated diseases than the primary disease itself. In fact the severity and natural history of PV are variable, but before the advent of steroids, most patients with PV died as a result of this disease. Treatment with systemic steroids has reduced the mortality rate from the disease to 5-15%. III. History of Medicare Coverage In April 1998, CMS issued a national coverage determination for extracorporeal photopheresis providing coverage by Medicare only when used in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that has not responded to other therapy. CMS is not considering any change to this policy with respect to treatment of CTCL at this time. On March 21, 2006, CMS received a formal request for reconsideration from the University of Pennsylvania Health System. The University requests that CMS update its NCD by allowing for the additional indications for extracorporeal photopheresis in treating the following specific disorders: refractory acute cardiac transplant rejection, refractory chronic graft versus host disease, pemphigus vulgaris, and bullous pemphigoid refractory to conventional immunosuppressive therapy. In addition they request allowing Medicare contractor discretion for other conditions. Benefit Category Determination For an item or service to be covered by the Medicare program, it must meet one of the statutorily defined benefit categories outlined in the Social Security Act. Extracorporeal photopheresis, at a minimum, falls under the benefit category set forth in section 1861(s)(1) (physician services), a part B benefit. IV. Timeline of Recent Activities On March 21, 2006, CMS received a formal request for reconsideration from the University of Pennsylvania Health System. On April 6, 2006 CMS opened a national coverage determination request to review the coverage of extracorporeal photopheresis. CMS requested public comment on whether there is adequate evidence, including clinical trials, for evaluating health outcomes of extracorporeal photopheresis for the requested indications in the Medicare population? On October 4, 2006 CMS posted the proposed decision memorandum. V. FDA Status In 1999, The FDA approved UVADEX® (methoxsalen) Sterile Solution, which is indicated for extracorporeal administration with the UVAR Photopheresis System in the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL) that is unresponsive to other forms of treatment. (http://www.fda.gov/cder/foi/label/1999/20969lbl.pdf) VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that are used to evaluate the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix B. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results. Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum (see Appendix A). VII. Evidence A. Introduction This section provides a summary of the evidence that CMS considered during the review. No randomized controlled clinical trials were found that investigated the use of extracorporeal photopheresis in patients with acute cardiac allograft rejection and cGvHD that is refractory to conventional immunosuppressive therapy. Additionally, there were no randomized controlled clinical trials found that investigated the use of extracorporeal photopheresis in pemphigus vulgaris or bullous pemphigoid. The evidence reviewed for this decision memorandum, therefore, consists of results from uncontrolled clinical trials and case studies that were published in a full length literature article. B. Discussion of evidence 1. Questions Is the evidence sufficient to conclude that extracorporeal photopheresis will have health benefits for the treatment of Medicare patients with acute cardiac allograft rejection that is refractory to standard immunosuppressive drugs? Is the evidence sufficient to conclude that extracorporeal photopheresis will have health benefits for the treatment of Medicare patients with cGvHD that is refractory to standard immunosuppressive drugs? Is the evidence sufficient to conclude that extracorporeal photopheresis will have health benefits for the treatment of Medicare patients with Bullous Pemphigoid and Pemphigus Vulgaris? Outcomes: 1) Refractory Acute Cardiac Allograft Rejection The goal of therapy is to eliminate the immunological attack on the heart. The primary outcome measured in the clinical studies and case studies that were reviewed for this decision memorandum was the change in the histology of serial endomyocardial biopsies. One clinical study also measured the change in the dose of the various drugs administered for immunosuppression. The EMB-focused outcome measures the impact of extracorporeal photopheresis on the severity of the immunological attack, which is a treatment effect. An outcome such as the change in immunosuppressive drug dose also measures a treatment effect. None of the studies reviewed for this decision memorandum included health outcomes actually experienced by the patient, such as mortality or change in quality of life. However, an improvement in the rejection status with a concomitant reduction of immunosuppression drug doses can result in an improved clinical outcome if it leads to less risk of graft failure and infection (and cancer in the long term). 2) Refractory Chronic GvHD The goal of therapy is to eliminate the immunological attack on the body. This attack can manifest in a variety of ways. For example, the main manifestation may be only cutaneous, or only pulmonary. Alternatively, a patient may experience the cutaneous, pulmonary, and hepatic manifestations of cGvHD. Accordingly, the assessment of the effects of treatment with extracorporeal photopheresis in patients with refractory cGvHD is dependent on the manifestations of the disease. The primary outcome measured in the clinical studies and case studies that were reviewed for this decision memorandum was the response rate. A positive response meant that there was a decrease in the activity of disease. The appearance (e.g., skin) or the function (e.g., blood liver function tests) of each part of the body involved by cGvHD was noted before and after treatment with extracorporeal photopheresis and then a response rate was calculated. The change in the dose of each immunosuppressive drug was also typically determined. A few of the studies also examined survival. Survival is a health outcome actually experienced by the patient, which is the type of outcome that CMS prefers. Another health outcome is quality of life. It is possible that a positive response rate, especially regarding the cutaneous effects of cGvHD, which can significantly decrease a patient’s quality of life, can result in an improved clinical outcome for the patient. Additionally, an improvement in disease activity due to extracorporeal photopheresis, even if it is less than a total resolution of disease activity, with a concomitant reduction of immunosuppression drug doses may result in an improved clinical outcome if it leads to less risk of infection. However, it is also possible that improved response rates, while improving quality of life, could also have negative effects on survival. 3) Bullous Pemphigoid and Pemphigus Vulgaris The effects of treatment with photopheresis in patients with pemphigoid/pemphigus are assessed clinically for complete remission (absence of skin or mucous membrane lesions) or disease-free remission, a positive clinical response and decreased serum antibody levels. This is measured in relation to the type of drug/treatment and dosage. 2. External technology assessment a. Refractory Acute Cardiac Allograft Rejection For refractory acute cardiac allograft rejection, CMS did not commission an external technology assessment. b. Refractory Chronic GvHD CMS did not commission an external technology assessment for refractory cGvHD. The BlueCross/BlueShield Association’s TEC group performed a technology assessment (TA) titled “Extracorporeal Photophoresis for Graft-Versus-Host Disease” that was published in November, 2001. The objectives of the TA were to review the evidence for the use of extracorporeal photopheresis for patients with GvHD who were previously untreated, who were responding to established therapies, or who were refractory to established therapies. Only studies that reported outcomes on symptoms or disease activity were included. The TA reviewed six studies of patients (cumulative sample size: 112) with refractory cGvHD, which the TEC group felt provided sufficient evidence to permit conclusions. All of the studies were uncontrolled. CMS reviewed only three of these six studies for this decision memorandum (Child, 1999; Smith, 1998; Besnier, 1997) because, of the remaining three studies, two were in abstract form only and one was a review. In its review of the evidence, the TEC group found that the amount of benefit varied from study to study as well as by type of cGvHD. Two of six studies reported complete resolution of all disease activity plus discontinuation of immunosuppressive drug treatment for thirteen of 25 patients. Three studies reported significant symptomatic improvement in the majority of patients but no complete resolution of disease activity. The remaining study showed improvement of disease activity for half of the patients with de novo cGvHD but for only 25% of patients with progressive or quiescent cGvHD. The TEC group concluded that the evidence demonstrates that extracorporeal photopheresis improves the net health outcome for patients with refractory cGvHD, and therefore extracorporeal photopheresis met their criteria when used to treat patients with cGvHD that is refractory to established therapy (Blue Cross/Blue Shield Association TEC, 2001). c. Bullous Pemphigoid and Pemphigus Vulgaris For bullous pemphigoid and pemphigus vulgaris, CMS did not commission an external technology assessment. 3. Internal technology assessment a. Evidence Collection 1) Refractory Acute Cardiac Allograft Rejection For refractory acute cardiac allograft rejection, CMS performed a literature search using PubMed to find clinical trials or meta-analyses evaluating the use of extracorporeal photopheresis in the treatment of patients with acute cardiac transplantation rejection refractory to standard immunosuppressive drugs. The search terms used were “graft rejection,” “heart transplantation,” and “photopheresis.” The search was limited to the English language and specific for the human population. CMS also reviewed the information submitted by the NCD requestor. This evidence consisted of eleven published articles of which only one, a case study, reported health-related outcomes around the use of extracorporeal photopheresis to treat patients with acute cardiac transplantation rejection (Lehrer, 2001). Of the remaining ten articles, seven provided background information about cardiac transplantation, heart failure or immunosuppression. The other three articles, which provided either expert opinion about extracorporeal photopheresis or a clinical trial regarding the use of extracorporeal photopheresis to prevent acute cardiac allograft rejection, are presented in the Expert Opinion section of this decision memorandum. 2) Refractory Chronic GvHD CMS performed a literature search using PubMed to find clinical trials or meta-analyses evaluating the use of extracorporeal photopheresis in the treatment of Medicare patients with cGvHD refractory to standard immunosuppressive drugs. The use of extracorporeal photopheresis for the treatment of aGvHD or for the prevention of cGvHD was not reviewed for this NCD. The search terms used were “graft vs. host disease,” or “graft vs. host reaction,” and “photopheresis.” The search was limited to the English language and specific for the human population. CMS reviewed the information submitted by the NCD requestor. This evidence consisted of eight published articles of which four reported the health-related outcomes of a clinical trial about the use of extracorporeal photopheresis to treat patients with steroid-resistant or refractory cGvHD (Foss, 2005; Ilhan, 2004; Child, 1999; Greinix, 1998), of the remaining four articles; one presented a study that examined the immunologic mechanism of action of extracorporeal photopheresis. The other three articles are presented in the Expert Opinion section of this decision memorandum. CMS also reviewed the information submitted in a public comment by Therakos, Inc. Of the nineteen published full length articles contained in the public comment that reported the health-related outcomes of a clinical trial or meta-analysis or case study in adult patients treated with extracorporeal photopheresis for cGvHD but were not already submitted by the requestor, seven were clinical trials (Garban, 2005; Couriel, 2005; Rubegni, 2005; Apisarnthanarax, 2003; Seaton, 2003; French, 2002; Smith, 1998) and one was a case study in patients with refractory cGvHD (Besnier, 1997). Of the remaining eleven articles, eight provided background about cGvHD or the mechanism of action of extracorporeal photopheresis or information about the use of extracorporeal photopheresis in patients who did not have cGvHD. The other three articles are presented in the Expert Opinion section of this decision memorandum. A Blue Cross/Blue Shield TEC technology assessment from 2001 was also submitted in the public comment. This technology assessment is presented in the External Technology Assessment section of this decision memorandum. 3) Bullous Pemphigoid and Pemphigus Vulgaris CMS performed a literature search using PubMed to find any peer reviewed journal literature evaluating the use of extracorporeal photopheresis in the treatment of patients with PV or PB. The search terms used were ("Pemphigus"[MeSH Major Topic] OR "Pemphigoid, Bullous"[MeSH Major Topic] OR "Pemphigoid, Benign Mucous Membrane"[MeSH Major Topic]) AND ("Immunotherapy"[MeSH Major Topic] OR "Photopheresis"[MeSH Major Topic]). CMS also reviewed the information submitted by the NCD requestor, and examined a TA by Blue Cross/Blue Shield. The resulting literature we reviewed including the submissions by the requesters is as follows: Published full length articles that were not submitted by the requesters included one review article by Shih WY, Sami N and Razzaque AA (2005) and a TA (BC/BS 2006 update). Articles submitted by the requesters included two single-case reports (Gollnick HPM et al. 1993, Liang G, Nahass G, Kerdel FA. 1992), one 4-case report (Rook AH et al. 1990), and a non-controlled trial of 7 patients (Wollina U, Lange D, Looks A. 1999). b. Evidence Summary 1) Refractory Acute Cardiac Allograft Rejection Clinical Trials Five clinical trials evaluating the use of extracorporeal photopheresis in the treatment of patients with acute cardiac allograft rejection refractory to standard immunosuppressive drugs were identified. Dall’Amico R, Montini G, Murer L, et al. Extracorporeal photochemotherapy after cardiac transplantation: a new therapeutic approach to allograft rejection. International Journal of Artificial Organs 2000;23:49-54 This was a prospective, uncontrolled study conducted in eleven patients with a history of two or more grade 3A-3B acute rejection episodes during the three months prior to extracorporeal photopheresis despite standard immunosuppression therapy regimen extracorporeal photopheresis was performed as 2 consecutive daily treatments each week for one month, then two treatments biweekly for two months, then two treatments monthly for three months using the UVAR system and 200 micrograms of 8-MOP administered ex vivo. The change in EMB histology was the measured health outcome. A grade of 0 or 1A was considered to represent complete resolution of rejection. Five men and six women were in the study. The age range was 35 to 65 years. One patient died during the six-month treatment period due to hepatitis C infection (details not provided) and one patient dropped out due to a relapse of rejection that was unresponsive to extracorporeal photopheresis and high doses of steroids. For the nine patients who completed six months of extracorporeal photopheresis treatment, all episodes of rejections were reversed after a mean time of 14.2 days (range 7-32 days). The changes in the EMB results are shown in the following table. Change in EMB Results (n= 11 patients) Histological Grade Pre-extracorporeal photopheresis (% of biopsies; n= 110 biopsies) During extracorporeal photopheresis (% of biopsies; n= 78 biopsies) Negative (Grade 0) 25 27 1A 21 45 1B 6 2 2 6 8 3A 29 17 3B 13 1 Six of nine patients experienced a rejection relapse during the sixty-month follow-up period after extracorporeal photopheresis. Of these, four episodes were reversed with the resumption of extracorporeal photopheresis (details not provided by the authors), one episode was reversed using high-dose steroids, and one episode was reversed with methotrexate after failure of extracorporeal photopheresis and high-dose steroids. During extracorporeal photopheresis there was one case of interstitial pneumonia and one case of symptomatic hypotension in a patient with pre-existing anemia and low body weight. The authors stated that “despite the efficacy and safety reported…extracorporeal photopheresis cannot be recommended for the treatment of all rejection episodes. Most allograft rejections are easily reversed by an inexpensive course of IV steroids and rejection relapses are observed only in a limited number of cases.” Furthermore, the authors suggest extracorporeal photopheresis may be indicated “for the treatment of allograft rejection in patients needing a reduction in standard immunosuppression because of complications such as severe infections, nephrotoxicity, obesity, osteopenia…and in recipients with refractory and recurrent rejections.” Giunti G, Schurfeld K, Maccherini M, et al. Photopheresis for recurrent acute rejection in cardiac transplantation. Transplantation Proceedings 1999;31:128-129 In Giunti, 1999 a prospective, uncontrolled trial with six patients with a history of recurrent acute rejection despite daily triple immunosuppressive therapy was conducted. Extracorporeal photopheresis using the UVAR system and 200 micrograms of 8-MOP administered ex vivo was performed on 2 consecutive days weekly for 1 month, then once weekly for 1 month, then biweekly for 2 months, and then monthly for 2 months. The change in EMB histology was the measured outcome. All of the patients were men. The age range was 50 to 66 years. Moderate acute rejection episodes decreased from 0.4 to 0.07 rejections per month per patient (p<0.02). Further details regarding how this outcome was determined were not provided. The number of patients who experienced a response to extracorporeal photopheresis, and to what degree, was also not provided. Immunosuppressive drug doses were reduced in all patients during the extracorporeal photopheresis treatment period. Four of six patients remained on reduced doses of immunosuppressive drugs after discontinuation of extracorporeal photopheresis treatment while two of the six patients had a single episode of grade IIIA rejection over the three months after extracorporeal photopheresis was discontinued that necessitated an increase in immunosuppressive dose levels. The authors observed that extracorporeal photopheresis for acute recurrent cardiac transplant rejection is “safe, efficient and free of major side effects” but also stated that the use of extracorporeal photopheresis in this patient population “is still largely unexplored.” Dall’Amico R, Montini G, Murer L, et al. Benefits of Photopheresis in the treatment of heart transplant patients with multiple/refractory rejection. Transplantation Proceedings 1997;29:609-611 This was a prospective, uncontrolled study in 22 cardiac transplant patients with a history of 2 or more acute episodes of rejection refractory to standard therapy during the 3 months prior to study entry. The UVAR system was used. One hundred micrograms of 8-MOP were administered ex vivo. There were two extracorporeal photopheresis groups: Group 1: 2 consecutive daily extracorporeal photopheresis treatments every 4 weeks for 6 months (twelve treatments total) Group 2: 2 consecutive daily extracorporeal photopheresis treatments weekly for 1 month then every 2 weeks for 2 months, then monthly for 3 months (22 treatments total) There were twelve patients in Group 1 and ten patients in Group 2. The outcome of interest was the change in EMB histology. A Grade of 0 or 1A was considered to represent complete resolution of rejection. Fifteen men and seven women were in the study. The mean age was 49.8 years in Group 1 and 50.4 years in Group 2. Each group had 1 patient drop out of the study. In Group 1, the patient dropped out due to a lack of vascular access. In Group 2, a patient died due to hepatitis C infection; further details were not provided. Nine of eleven patients in Group 1 had resolution of rejection while all nine patients in Group 2 had resolution. The mean time to resolution was 29.5 days in Group 1 and 13.8 days in Group 2. The mean number of relapses of rejection per patient during 6 months of extracorporeal photopheresis was 1.36 in Group 1 and 0.8 in Group 2. The number of courses of steroid-based rejection therapy used to treat the relapse was seven in Group 1 and one in Group 2. The number of courses of methotrexate-based rejection therapy used to treat the relapse was one in Group 1 and one in Group 2. One patient in Group 1 experienced a herpes zoster infection. One patient in Group 2 developed interstitial pneumonia, and one patient with pre-existing anemia and low body weight had symptomatic hypotension during an extracorporeal photopheresis procedure. The authors highlighted that a higher frequency of treatment (as given in Group 2) was associated with a lower number of rejection relapses and hence a corresponding decrease in immunosuppressive drug therapy. They concluded that extracorporeal photopheresis “could be considered safe and efficacious treatment for patients with repeated rejection episodes,” that a more aggressive treatment protocol is advisable, and that “increased clinical experience is necessary to evaluate and individualize frequency of treatment.” Dall’Amico R, Livi U, Milano A, et al. Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation 1995;60:45-49 The authors performed a prospective, uncontrolled study in eight cardiac transplant patients with a history of multiple acute rejection episodes despite a routine immunosuppression regimen. The UVAR system was used. Two hundred micrograms of 8-MOP was administered ex-vivo. Extracorporeal photopheresis was performed on 2 consecutive days every 4 weeks for 6 months. The outcomes measured were change in EMB histology, and the change in the dose of each immunosuppressive drug. Six men and two women were studied. The age range was 36-58 years. The fraction of EMB biopsies that did not show evidence of rejection increased from 13% to 41% after extracorporeal photopheresis. A steroid dose reduction of 44% was seen in 7 patients, a cyclosporine dose reduction of 21% occurred in 5 patients, and an azathioprine dose reduction of 29% was demonstrated in 3 patients. The authors noted the small sample size of this study but concluded that extracorporeal photopheresis was a safe procedure that allowed for improved control of recurrent rejection, particularly by permitting for the reduction in doses of steroids. Costanzo-Nordin MR, Hubbell EA, O’Sullivan EJ, et al. Successful treatment of heart transplant rejection with photopheresis. Transplantation 1992;53:808-815. A prospective, uncontrolled study was conducted on seven patients with histological evidence of moderate cardiac transplantation rejection despite routine immunosuppressive regimen. The UVAR system was used. The oral formulation of 8-MOP was administered. The frequency and total duration of extracorporeal photopheresis treatments were not provided. The outcome measured was change in EMB histology. Efficacy based on EMB results was classified as ongoing rejection, resolving rejection, or absent rejection. Three men and four women were studied. The age range was 19-64 years. The average duration of post-extracorporeal photopheresis follow-up was five months. The seven patients had a total of nine episodes of rejection; five episodes were treated with one extracorporeal photopheresis procedure and the remaining four episodes were treated with two procedures. Eight of the nine rejection episodes were successfully treated with extracorporeal photopheresis. Resolution of histological evidence of rejection was seen an average of 33 days after the administration of extracorporeal photopheresis. No adverse events occurred during extracorporeal photopheresis. There were no deaths during the study. Two infections occurred after extracorporeal photopheresis but the details were not provided. The authors concluded that the results of their study demonstrate that extracorporeal photopheresis may “be effective” for the treatment of hemodynamically-stable patients with moderate acute cardiac transplant rejection. They noted the preliminary nature of this study and called for further studies to determine the full extent of usefulness of extracorporeal photopheresis and to determine the optimal number of treatments needed to sustain a response. The authors state that they have initiated a prospective, randomized open-label trial to study patients with moderate rejection. Meta-analyses No meta-analyses were identified. Case Study One case study was reviewed. Lehrer MS, Rook AH, Tomaszewski JE, DeNofrio D. Successful reversal of severe refractory cardiac allograft rejection by Photopheresis. Journal of Heart and Lung Transplantation 2001;20:1233-1236 This case study presented the results of four patients treated with extracorporeal photopheresis. Each patient had acute heart transplant rejection (Grade III or IV) refractory to standard immunosuppression therapy and anti-rejection therapy. All but one of the four patients began to experience rejection within weeks of transplantation. The details of extracorporeal photopheresis administration were not provided. The age range was 20 to 54 years. All patients tolerated the extracorporeal photopheresis well. The delivery of extracorporeal photopheresis resulted in a change of the rejection status to Grade 0 or I. Two of four patients experienced a sustained response to extracorporeal photopheresis (four months and six years after completion of extracorporeal photopheresis). The remaining two patients had rejection-related complications within one year of completing extracorporeal photopheresis that resulted in death. The authors “strongly recommend” the addition of extracorporeal photopheresis as a possible treatment for refractory acute rejection. They also noted that larger clinical trials are needed to determine the best way to insert extracorporeal photopheresis into the treatment protocol for acute rejection. 2) Refractory Chronic GvHD Clinical Trials Eleven clinical trials evaluating the use of extracorporeal photopheresis in patients with refractory cGvHD were reviewed. All of the clinical trials were uncontrolled. Foss FM, DiVenuti GM, Chin K, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplantation 2005;35:1187-1193. A prospective, uncontrolled, single center clinical trial was conducted on adult patients with steroid-resistant or refractory cGvHD. The UVAR system was used; 8-MOP was administered ex vivo. Sixteen patients received extracorporeal photopheresis on two consecutive days every two weeks (Group 1) and the remaining seven patients received extracorporeal photopheresis on two consecutive days every week (Group 2). Extracorporeal photopheresis was performed until either a response plateau of two or more months or progression was seen. Overall response rate, survival, and the change in the dose of immunosuppression drugs were the outcomes assessed. Twenty five patients were studied; 23 of these patients were adults (sixteen men and seven women). The age range was eighteen to 59 years. Extracorporeal photopheresis was performed for a median of nine months (range: three-24 months). The overall response rate was 64%. Twenty of 25 patients had improvement of cutaneous manifestations of cGvHD. Six of thirteen patients with oral mucosal involvement had healing of the ulcerations. Three of six patients with joint involvement had increased flexibility. One patient with lung disease had 50% improvement. One patient with gastro-intestinal involvement had resolution of diarrhea. The median survival was 51 months (measured from day of transplantation). Median survival for responders was 55 months and for non-responders was 39 months (p= 0.3). A dose reduction or the complete discontinuation of immunosuppressive drug therapy was seen in 11 patients on steroids, in twelve patients on mycophenolate mofetil, and in five patients on tacrolimus. Fifteen patients had serious adverse events that were determined not to be related to the extracorporeal photopheresis procedure. One patient discontinued extracorporeal photopheresis due to recurrence of the primary disease. Ten deaths were reported but the details were not provided except to note that those who died received a median of five extracorporeal photopheresis cycles and the survivors received a median of twelve (a “cycle” refers to the collection of the white blood cells by the UVAR system). The authors concluded that the results suggest a trend toward a higher response rate for patients with the progressive form of cGvHD compared to the de novo form, and that there does not appear to be an association between extracorporeal photopheresis dose and clinical response. Garban F, Drillat P, Makowski C, et al. Extracorporeal chemophototherapy for the treatment of graft-versus-host disease: hematologic consequences of short-term, intensive courses. Haematologica 2005;90:1096-1101. Garban, et al. conducted a prospective, uncontrolled, single center clinical trial in patients with steroid-resistant cGvHD. A Spectra cell separator was used rather than the UVAR system; 8-MOP was administered ex vivo. Six courses of extracorporeal photopheresis were given during the first three weeks (induction regimen). If a complete response or no response was seen, then treatment was discontinued. If a partial response was seen, then one course was administered per week until a complete response was achieved (consolidation regimen). Clinical response was the outcome assessed. A complete response was defined as a total resolution of all manifestations of cGvHD and a discontinuation of all immunosuppression drugs. A complete response for cutaneous involvement occurred when there was 100% resolution of all skin lesions or the presence of fixed and pigmented lesions. A partial response for cutaneous involvement was defined as a fifty percent or greater improvement of the skin manifestations, or complete resolution but continuation of immunosuppression. A fifty percent or greater improvement in one involved organ was also declared to be a partial response (further details not provided). Fifteen patients with cGvHD were studied. The age range was fourteen to 62 years. Twelve of fifteen patients experienced at least a partial response. Twelve patients had cutaneous involvement; all completely responded with most responses occurring in the first weeks of treatment. Skin and GI involvement resolved in parallel fashion. Improvement in liver function was transient. The three patients with bronchiolitis obliterans experienced stabilization of disease without the need for steroids. Four patients became totally free of immunosuppression for more than one year. The range of the duration of response was zero to 72 months. Six patients died from relapse of their malignant disease. Four of fifteen patients developed thrombocytopenia but most of these patients did not receive a blood transfusion. The authors concluded that extracorporeal photopheresis is effective treatment for patients with steroid-resistant cGvHD, especially the lung forms of cGvHD, and that the use of extracorporeal photopheresis can reduce the duration of immunosuppression therapy. The authors also stated that more study is needed to determine the most effective manner to administer extracorporeal photopheresis (i.e., frequency, intensity and duration of dose administration). Couriel DR, Hosing C, Saliba R, et al. Extracorporeal photochemotherapy for the treatment of steroid resistant chronic GVHD. Blood Prepublished online on December 20, 2005. The authors performed a single-center retrospective chart review for all patients regardless of age with steroid-refractory cGvHD who were treated with extracorporeal photopheresis between January, 1998 and October, 2002. The UVAR system was used; 8-MOP was administered ex vivo. Extracorporeal photopheresis was performed two to four times per week until a partial response was observed; then the number of treatments was decreased by one per week. A maintenance schedule then consisted of two treatments every two weeks. The need for treatment discontinuation, the amount of titration, and the duration of treatment was determined by each patient’s treating physician. Response to therapy (complete, partial, mixed or no response), the non-relapse mortality rate, and overall survival were assessed. Seventy-one patients were included in the study (33 men and 38 women). The age range was five to 70 years (median age of 39 years). Neither the number of children nor the number of patients 65 years old or greater was reported. The overall response rate was 61%. There were 43 patients who initially responded to treatment (fourteen complete responses and 29 partial responses). The median time from the onset of extracorporeal photopheresis to achieving a complete response was 27 days (range of thirteen to 238 days). Thirty of 43 patients maintained the initial response for a median duration of 18 months (range of 0.4-65 months); the remaining thirteen progressed after a median of 23 days (range of sixteen to 188 days). Overall survival at 5 years was nineteen percent. The non-relapse mortality rate at five years was 46%. Causes of death included GvHD plus infection in 67% of deaths, relapse of primary disease in 29%, infection outside the setting of cGvHD or its treatment in two percent, and hemorrhage in two percent. Four patients experienced mild, reversible toxicity that did not require discontinuing extracorporeal photopheresis (abdominal pain in one patient, hypertension in one patient, hypotension in one patient, and fever in one patient). The authors concluded that their results demonstrated the “objective activity” of extracorporeal photopheresis in patients with steroid-resistant cGvHD and that the patients who responded had significantly lower non-relapse mortality. They also noted that extracorporeal photopheresis was “overall well tolerated, with no fatal toxicities.” Rubegni P, Cuccia A, Sbano P, et al. Role of extracorporeal photochemotherapy in patients with refractory chronic graft-versus-host disease. British Journal of Haematology 2005;130:271-275. Rubegni, 2005 presented the results of a prospective, uncontrolled, single center clinical trial in patients with steroid-refractory cGvHD. The UVAR system was used