Extracorporeal Photopheresis

The physicians in the Division of Hematology and Hematopoietic Cell Transplantation (HCT) at City of Hope support Medicare coverage for extracorporeal photopheresis (ECP) for chronic graft versus host disease (cGVHD). As the largest provider of HCT in California and one of the largest centers nationally, we believe that ECP is the current standard of care for select patients with cGVHD.

We agree with the scientific studies reviewed for this proposal supporting the clinical efficacy of ECP for cGVHD. However, we believe that CMS should consider including Medicare coverage for ECP in select patients with acute GVHD. In Francine Foss’s 2003 article “Extracorporeal Photopheresis in the treatment of Graft-vs-Host Disease” she concludes, “ECP has proven to be an effective therapy for patients with acute and chronic GVHD” (Foss, 2003). For your reference, we attach two journal publications that include scientific studies to provide support for ECP treatment of patients with acute GVHD.

We thank you for the opportunity to comment on the proposed National Coverage Determination (NCD) reconsideration for ECP for cGVHD. Should you have any questions, please feel free to contact me at 626-256-4673 ext. 62405.
Sincerely,

Dr. Eileen Smith, M.D.
Associate Director
Clinical Research Division of Hematology
and Hematopoietic Cell Transplantation
City of Hope

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I have been a bone marrow transplant physician since 1997 practicing at MD Anderson Cancer Center in Houston until 2005 and presently practicing at Hackensack University Medical Center in NJ. I was the senior author for the paper published in the journal "Blood" in Dec 2005 and have extensive experience in this field.We have demonstrated the efficacy of photopheresis in patient with chronic graft versus host disease, with a response rate 61%. Photopheresis is a lifesaving procedure for many patient with steroid graft versus host disease. It is the best modality to treat scleroderma and bronchiolitis obliterans associated with GVHD and refractory chronic liver GVHD. It is imperative that we be able to treat our patients with this modality.

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As a Transfusion Medicine physician, I have been using photopheresis for more than 10 years in the management of patients with heart transplant rejection at the University of Alabama at Birmingham Hospital. By now, 104 patients with this diagnosis have been treated by our service. I am very excited with the new Medicare proposal because it is our combined experience at UAB that photopheresis is highly effective in these patients. Some of our observations have been published before and confirm my impression. Furthermore, our first-hand evaluation of patients that undergo these treatments (15 series of 2 consecutive daily treatments) demonstrates that photopheresis is a central tool in the long-term care of patients with rejection. Besides the histological evidence of benefit, patients stay well and away from the hospital much more consistently once they start photopheresis, sometimes even returning to work. I am convinced that photopheresis improves their quality of life and that of their families and friends. The cost of the treatments is clearly offset by the decreased expenses associated with less morbidity for extended periods of time during and after completion of the photopheresis protocol.

We started using photopheresis for chronic graft versus host disease in 2002 and have enrolled and treated more than 10 patients so far. The most common and debilitating manifestation of GvHD in our patients has been skin and mucosal involvement and I feel very strongly that the treatment has a dramatic effect. Many treated patients had very poor quality of life prior to starting photopheresis, with great difficulty swallowing, reading, or performing small tasks that require fine motor skills. Invariably, all patients have experienced significant improvement, some even considered dramatic. It appears that improvement starts early but continues throughout the months of procedures. In fact, some patients that had improved and were receiving treatment less often (monthly) showed exacerbation of their skin lesions and required to return to twice monthly series of two treatments. Thus, it is imperative that Medicare recognizes the need for photopheresis to maintain these patients comfortable and not requiring hospitalization.

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Thank you for allowing me the opportunity to make a public comment concerning the use of extracorporeal photopheresis for the treatment of refractory, chronic graft versus host disease (cGVHD).

I have been Director of the Bone Marrow Transplant Program at the Cleveland Clinic for the past 20 years. I have extensive experience with chronic GVHD and its therapy.

GVHD is arguably the most vexing problem associated with allogeneic bone marrow/stem cell transplantation. Part of the challenge in conducting clinical research to optimize treatment of this disorder is the fact that cGHVD can present in a myriad of ways, and classifying or grading cGVHD has been somewhat problematic. However, given that cGVHD can affect almost any organ and is frequently associated with immunosuppression and pancytopenia, cGVHD itself, as well as opportunistic infections associated with the required immunosuppressive therapy, lead to significant morbidity and mortality. Patients failing standard immunosuppressive therapy, such as corticosteroids, cyclosporine, and mycophenalate, generally have a poor outcome, especially if the cGVHD is associated with thrombocytopenia.

We have significant experience at the Cleveland Clinic utilizing photopheresis to treat refractory cGVHD. While extracorporeal photopheresis is not a panacea, the fact is that a significant percentage of patients do have a positive clinical response that can be sustained. This allows reduction in other immunosuppressive therapy and reduces the risk of opportunistic infection and generally enhances quality of life.

I am therefore in favor of this CMS Proposal that ECP is a reasonable and necessary therapy for patients with chronic GVHD. It is a key part of our treatment strategy for this disorder, and I support its use for patients with significant cGHVD.

Respectfully submitted,

Brian J. Bolwell, MD
Director, BMT Program
Chairman, Department of Hematologic Oncology and Blood Disorders
Cleveland Clinic

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November 1, 2006

To: Centers for Medicare and Medicaid Services

Re: Extracorporeal Photopheresis

I am thanking you in advance for permitting me to share my thoughts regarding the use of extracorporeal photopheresis in the fields of both heart and lung transplantation. Although I am expressing my personal opinions as an individual involved in the cardiothoracic transplant field for almost twenty years, by way of my position as the Immediate Past President of the International Society for Heart and Lung Transplantation (ISHLT), current Chair of the Thoracic Committee of the American Society of Transplant Surgeons (ASTS), and former member of the Board of Directors of both the ASTS and the AST (American Society of Transplantation), as well as through extensive public discussions at the major transplant society meetings and with many colleagues at leading transplant centers domestically and abroad, I feel that my thoughts are representative of a large segment of the medical and surgical heart and lung transplant community.

As your announcement for public comment has clearly identified, there remains an unmet medical need in cardiac transplantation in terms of refractory acute rejection. I also feel that your committee should strongly consider the current deficiencies in therapeutic options for the treatment of both acute and chronic rejection in lung transplant recipients for which the magnitude of the gap in our current treatment strategies is greatly under- appreciated.

I am in strong support of your proposed coverage of extracorporeal photopheresis (ECP) for the treatment (as well as prophylaxis, which is not specifically itemized in your announcement) of acute rejection in cardiac transplant recipients. Our transplant center, as well as many others in the United States (as well as in Europe), have been using photopheresis “off label” routinely in heart transplant patients for steroid refractory rejection (or in cases where high-dose steroids and / or antibodies are contraindicated) for over a decade in conjunction with standard calcineurin-based immunosuppression. In fact, the data collection forms that all transplant centers are required to complete on an annual basis for their patients (this being mandatory by governmental oversight bodies through the OPTN and UNOS) have extracorporeal photopheresis listed in the non - experimental list of immunosuppressive agents. UNOS is directly contracted by HRSA, so the fact that this is their view of the use of photopheresis, as well as the transplant community’s opinion, should be considered as additional support in your decision to approve reimbursement for this technology.

While not listed in your call for public comment, our center also strongly supports the use of photopheresis for the treatment of acute and chronic (bronchiolitis obliterans syndrome) rejection in lung transplantation, the later which is particularly devastating and for which no immunosuppressive agent has been shown to be effective. As you are well aware, there are no immunosuppressive drugs (including even cyclosporine), or immunomodulatory techniques, that actually have FDA approval for use in lung transplantation - yet they are all routinely reimbursed. From my perspective, the only reason that photopheresis has not undergone large scale clinical trials for formal FDA approval in heart or lung transplantation is due to the “orphan status” of heart and lung transplantation in the US (total number of cases for both organs being approximately 4000 per year) and the very small market that this would or could yield for the pharmaceutical / biotechnology industry.

To be able to assess the safety and efficacy of a drug or technology requires an understanding of the clinical context in question. This assessment shouldn’t be made in absolute terms, as no transplant drug is fully safe or fully efficacious. It is necessary to determine if the therapy is sufficiently safe and effective given the medical condition being treated, and with an adequate understanding of the medical issues and patient needs.

Let me review where we, in the heart and lung transplantation community, find ourselves as 2006 draws to an end. While the FDA approval of the various small molecule drugs and monoclonal / polyclonal antibody preparations in kidney transplantation have had a “spill-over effect” for heart and lung transplantation and have lead to a widespread change in our practice of immunosuppression over the past three decades, treatment is far from satisfactory. Both acute and chronic rejection in heart and lung transplant recipients remain significant short and long-term causes of morbidity and mortality. Furthermore, re-transplantation remains an often impractical, high risk, and costly option if acute and chronic rejection cannot be treated.

Has ECP been proven to reduce acute cardiac rejection? Yes. Has it been proven to reduce acute and chronic lung rejection? No, the benefit of ECP in lung transplantation isn’t proven, but the preponderance of the evidence suggests it to be real. I am greatly concerned that true proof with hard endpoints will never be fully achievable within the context of randomized clinical trials in this small field –we must be realistic.

I would hope that the decision to approve or not approve reimbursement and therefore the ability to offer a specific treatment as an option, would consider not only the medical condition, but also the available treatment options for the potential prescribers. The treating community in this case is a small, highly-specialized subgroup of thoracic surgeons, pulmonologists, and cardiologists who follow these transplant patients extremely closely. Moreover, the potential risks of ECP are known, are minimal in nature, and are predominately related to the need for central venous access in those patients with insufficient peripheral venous access. Experience in both the US and Europe supports that ECP is efficacious for refractory rejection in heart transplantation and experience from my center and several other centers in the US and Europe suggest that this is the case for acute and chronic rejection in lung transplantation as well. Additionally, we have had a very high rate (greater than 80%) of third party reimbursement from the private-sector insurance industry for treating both heart and lung transplant patients, so it would certainly be concerning if the population of patients who are solely covered by Medicare or Medicaid were not able to receive the same form of treatments.

The medical needs of the heart and lung transplant patient population are driving an increasing demand for alternative treatments that are not based on the use of escalating doses of drugs with significant acute and chronic toxicities. The use of photopheresis in solid organ transplantation has been increasing, and now that a potential mechanism for this therapy appears to be understood, the use of this therapy will continue to increase. Based on fairly recent in vitro studies, in vivo animal studies, and some very preliminary human data, the current hypothesis for the mechanism of photopheresis involves the following sequence: photopheresis induces cells to undergo apoptosis, dendritic cells ingest apoptotic cells, ingestion of apoptotic cells modulates dendritic cell function and generation of regulatory T cells, which then results in inhibition of T cell mediated diseases. Recent publications (Schwarz senior author and A. Maeda first author in J. Immunology, and Carsetti senior author and A. Lamioni first author in Transplantation) have very interesting data supporting the above theory of regulatory T cell generation in photopheresis.

I feel strongly that the data already present in the literature supports the approval in the field of heart transplantation and I completely understand CMS’s concerns regarding reimbursement approval for this therapy in the field of lung transplantation in which published data is clearly lacking, but I hope you understand my concerns. I think that allowing reimbursement of ECP, recognizing that more data will come from ongoing and future studies to refine the treatment regimen, will bring an important treatment option to both our heart and lung transplant patients.

If you objectively look at the data that has been extrapolated from the field of kidney transplantation and subsequently used to justify reimbursement of many drugs in the orphan fields of heart and lung transplantation where “the bar has been lowered” in terms of organ specific proof of efficacy, given the high unmet medical needs in our field, at the very least, let’s not “raise the bar” when evaluating ECP. If it is possible to add the lung transplant population to your approval process at this stage, this would be greatly appreciated.

If you need any further information or have any questions, please feel free to contact my office and I would be happy to speak with you. Thank you for your time and consideration of my thoughts.

With respect,

Mark L. Barr, M.D.
Associate Professor of Cardiothoracic Surgery
Co-Director, Cardiothoracic Transplantation
Associate Director, Cardiothoracic Surgical Research
Director, Photopheresis Service
University of Southern California and Childrens Hospital Los Angeles
Department of Cardiothoracic Surgery
1520 San Pablo Street
Los Angeles, CA 90033
Phone: 323-442-5849
Email: mbarr@surgery.usc.edu

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I am a physician treating patients with graft-versus-host disease (GVHD). Patients developing GVHD particularly the chronic form have few options after they have failed conventional first line treatment with corticosteroids. The data with extra corporeal photopheresis (ECP) is very promising and it is my personal opinion that this should be available for patients who have failed standard treatment options. This is a very debilitating condition and difficult to treat with poor quality of life once it progresses. Therefore, the availability of ECP is very important for such patients failing or intolerant to standard therapy.

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Extracorporeal photopheresis (ECP) is a important and scientifically established was to treat GVHD, both acute (steroid dependent or steroid refarctory) and chronic GVHD. Recent data suggests earlier intervention with ECP may be beneficial. It has an importand advantage that it does not increase risk of systemic infections. The development of this modality has been hampered by lack of thrid party coverage and thus has been used as a last resort where the data still looks convincing. Earlier use of ECP probably has increased benefit and would strongly encourage approval by Medicare of this important modlaity in the arsenal against GVHD

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We have utilized photopheresis to treat heart transplant rejection since 1993. It continues to produce an extraordinarily high response rate among previously treatment refractory patients. Among over 25 patients treated, only one has failed to respond to photopheresis and that patient had antibody mediated rejection. Similarly, for patients with refractory graft versus host disease, photopheresis has produced significant benefit for the majority of treated patients. Photopheresis is extremely well tolerated. Unlike most immunosuppressants, photopheresis does not produce measureable immunosuppression and is associated with minor adverse effects in the vast majority of patients. At our center we have also had success with a small number of patients with treatment refractory pemphigus vulgaris which can be a life threatening disease. Our observations are supported by publications in the medical literature.

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I support the use of extrcorporeal photopheresis in the management of chronic graft versus host disease. I am of the opinion that it is most effective if used early in the course of the disease rather than exhausting other immunosuppressive drugs that are ineffective. If the patient is steroid refractory, this option should be available. The frequency of the treatments should be at the physician's discretion based on patient tolerance. Initially it would be ideal to offer 3 treatments per week and then perhaps scale back to 1 -2 treatments per week until maximal benefit is acheived. Then there should be a maintenance program. I have treated several patients with graft versus host disease with this therapy and it does provide a partial response though the response varies in its durability.

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Extracorporeal photopheresis for chronic graft vs. host disease following allogeneic stem cell transplantation is a widely accepted form of treatment for this disease. I have found that the majority of adult patients that we treat with this therapy have benefited and particularly when other forms of therapy are no longer effective. In particular, we have found that patients on ECP can be tapered off of steroids and have better quality of life as a result.
Kaaron Benson, M.D.
Associate Professor of Interdisciplinary Oncology and Pathology
H. Lee Moffitt Cancer Center
University of South Florida College of Medicine
Tampa, Florida

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The use of extracorporeal photopheresis for chronic graft vs. host disease s/p allogeneic stem cell transplantation is a widely accepted form of treatment for this disease. I have seen great improvement in the disease in pediatric patients from this treatment when other treatment modalities have failed. This is a very cost effective procedure and successful use outweighs the cost of the procedure especially when the high morbidity and mortality and the associated costs are taken into account

Edward Wong, M.D.
Children's National Medical Center
Director of Hematology/Associate Director of Transfusion Medicine
111 Michigan Ave., N.W.

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The Robert Wood Johnson Univesity Hospital has been working towards acquiring a Photopheresis machine for the past 5 years. Finally thanks to a persist patient and family and the generous contributions from a Pharmaceutical Company we have the machine which was delivered within a week of the PO being placed. Thanks to the donating corporation and Therakos we look forward to making many a NJ patient well and happy and cut down on distances the need to travel to get this very vital treatment.

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I am the Medical Director of the Photopheresis Center at Morristown Memorial Hospital. We are one of the largest Photopheresis treatment centers in the United States. We have been involved in several published research studies that involve treating patients with Photopheresis, who have Cutaneous T Cell Lymphoma, cardiac and lung transplant rejection, and chronic Graph verses Host Disease. Our experience has been published in several peer review journal articles. The most recent appeared in the Journal of Apheresis, June 2006, titled "Treatment of Extensive Chronic Graph verses Host Disease with Extracorporeal Photopheresis". This recent publication further supports the positive impact this therapy has on patients with cGVHD.

My years of extensive experience treating patients with the aforementioned diseases are inline with the published literature used by CMS to reach their proposed decision. Besides being effective, I have found the Photopheresis therapy to be well tolerated by patients. I strongly support the proposed decision to provide coverage for patients treated with cGVHD and cardiac transplant rejection who are refractory to standard therapy.

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Chronic graft-versus-host disease (ChGVHD) is a major problem after allogeneic bone marrow transplantation. In my experience, in patients who failed multiple other immunosuppressive modalities, extracorporal photopheresis (ECP) was able to offer significant improvement. The cure rate for steroid-resistant ChGVHD treated with ECP approached 35%. If not for its heavy demand on resources, on the individual patient and his/her family as well as the medical institution, it would be used at a much higher frequency, and quite possibly with improved outcome for patients with ChGVHD.

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