View Public Comments for Extracorporeal Photopheresis (ECP)

Although survival after lung transplantation has improved (median survival 5.5 years), long-term survival remains poor and lags behind outocomes seen after other solid organ transplant procedures. Chronic rejection remains the primary obstacle to long-term survival after lung transplantation and to date no therapy has been shown to reliably improve outcome or prolong survival. Traditional approaches that augment immunosuppression are rarely effective and associated with significant adverse events (e.g. life threatening infections, malignancy and drug toxicity). Photopheresis is an important therapeutic option for patients with progressive chronic rejection. There have been numerous case reports and small series published over the last 20-years suggesting benefit in solid organ transplantation. However, the recent study (J Heart Lung Transplant 2010;29(4):424–31) reporting sustained benefit in lung transplant patients with chronic rejection provides compelling evidence that this treatment is beneficial. Most importantly, unlike other "off label" therapies, photopheresis is associated with relatively few side effects. I would strongly urge CMS to offer coverage for this therapy.

August 30, 2011

To: Centers for Medicare and Medicaid Services

Re: Extracorporeal Photopheresis in Lung Transplantation

While the following comments are lengthier than those that you have received from other clinicians and researchers, I thank you in advance for your time and patience in reading my rationale for a positive coverage determination for the use of extracorporeal photopheresis (ECP) in the field of lung transplantation. Although I am expressing my opinion as an individual involved in the fields of lung and cardiac transplantation for over twenty years, by way of my position as the Past President of the International Society for Heart and Lung Transplantation (ISHLT), past 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 lung transplant community. At a more personal level as a clinician and transplant program director, my direct patient care experience with the use of ECP for all types of organ transplants and specifically in lung transplantation is one of the longest and certainly the largest in the US involving well over 100 lung transplant recipients treated with this therapy over the past 18 years.

Our center strongly supports the use of photopheresis for the treatment of acute and chronic (bronchiolitis obliterans syndrome, BOS) rejection in lung transplantation, the later which is particularly devastating and for which no immunosuppressive agent has been shown to be effective. With the exception of the use of fundoplication in patients with demonstrated gastric reflux, there remain no therapeutic options for either the prevention or treatment of BOS / OB in lung transplant recipients – a disease process for which the magnitude of the gap in our current treatment strategies is so greatly under-appreciated. Our transplant center, as well as many others in the United States and Europe, have been using photopheresis “off label” routinely in lung transplant patients for almost two decades in conjunction with standard calcineurin-based immunosuppression.

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 lung transplantation is due to the “orphan status” of the field (total number of cases in the US being in the 1500 to 1600 range per year) and the very small market that this would or could yield for the pharmaceutical / biotechnology industry. In fact, the data collection forms that all transplant centers in the US 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.

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 lung transplantation community, find ourselves in 2011. 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 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 lung transplant recipients remains significant short and long-term causes of morbidity and mortality. Furthermore, re-transplantation remains an often impractical, high risk, and costly option if acute or chronic rejection cannot be treated.

The benefit of ECP in lung transplantation in patients with BOS in slowing progression of the decline in pulmonary function parameters has been shown in multiple single center publications (no need for me to repeat the references that others who have posted comments on the CMS public comment website have already listed) and the preponderance of the evidence suggests the effect is clinically significant although there have not been demonstrated effects on long term mortality. In my own experience of treating over 100 patients with ECP refractory to steroid and/or anti-lymphocytic antibody therapies, we have seen stabilization or a decline in the rate of deterioration of FEV1 in patients with BOS stage 0p or 1 approximately 50 to 60% of the time, and for BOS stage 2 in the 30 to 40% range. I personally have not seen any meaningful responses for patients with BOS stage 3. However, a large part of the reason that patients have been temporally delayed in referral for therapy until they are so advanced in their disease progression has been issues with reimbursement. I am greatly concerned that true proof with “harder” 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 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 and transplant pulmonologists who follow these transplant patients extremely closely. Thus, there will not be widespread or indiscriminate dissemination of this therapy should coverage approval be issued. 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 rejection in heart transplantation and for graft versus host disease in bone marrow transplant (and as such, CMS approved coverage for those indications back in 2007), 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 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 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 in vitro studies, in vivo animal studies, and some 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, and ingestion of apoptotic cells modulates dendritic cell function and generation of regulatory T cells, which then results in inhibition of T cell mediated diseases. Publications (Schwarz senior author and Maeda first author in J. Immunology, and Carsetti senior author and 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 reimbursement approval in the field of lung transplantation, although I do understand CMS’s concerns regarding the lack of randomized prospective trials with adequate non-historical control cohorts. However, 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 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 both 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 this therapy for a population of lung transplant recipients for which we have no other viable options.

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,

September 1, 2011

US Department of Health and Human Services
Centers for Medicare and Medicaid Services (CMS)

Re: National Coverage Determination for Extracorporeal Photopheresis (ECP) (CAG-00324R2) – Comments from American Society for Apheresis (ASFA)

The American Society for Apheresis (ASFA), the leading organization of apheresis medicine experts in the United States, is composed of physicians, nurses, medical technologists and quality assurance professionals. Every three years, we perform a systematic review of the published literature to evaluate the evidence in support of the best apheresis practices. The principle outcome of this process is the formulation of clinical guidance regarding the merit of an apheresis solution to a particular clinical condition. The transparency of our approach provides end users an opportunity to guide their practice with published evidence. It must be clearly understood, the ASFA Indication Category (I, II, III, or IV) and the ASFA recommendation (1 (recommend) vs. 2 (suggest)) synthesize our position on any reviewed disease entity.

Definitions of the indication category and recommendation are available in Table I (page 84) and Table III (page 85) of the following publication:

Szczepiorkowski ZM, Winters JL, Bandarenko N, Kim HC, Linenberger ML, Marques MB, Sarode R, Schwartz J, Weinstein R, Shaz B. Guidelines on the use of therapeutic apheresis in clinical practice – evidence-based approach from the apheresis applications committee of the American Society for Apheresis. Journal of Clinical Apheresis 2010; 25: 83-177.

In regard to the use of ECP for the specific indication of lung allograft rejection, ASFA considers this therapeutic option a category II indication (apheresis is accepted as second-line therapy), with a recommendation grade 1C (Strong recommendation, evidence largely limited to observational studies). To put that in perspective, this is the same category and grade as the use of plasma exchange to treat Familial Hypercholesterolemia (Subcategory - homozygote with small blood volume) and the use of red cell exchange to treat acute chest syndrome in sickle cell anemia. Both of these entities are widely covered.

To conclude, the American Society of Apheresis believes that Extracorporeal Photopheresis is a reasonable and clinically appropriate second line therapy to addressing lung allograft rejection. Further, though the published evidence is limited to observational studies, it is still strongly recommended as it is implicitly acknowledged that gathering randomized clinical trial evidence on specific treatments of rare disorders is extremely difficult and that should not deter their use. The available evidence suggests efficacy of ECP for this indication.

Thank you kindly,

Christopher Chun, MT(ASCP)HP
ASFA President

Few (if any) effective treatment options exist for patients who are s/p lung transplantation and who develop BOS. Photopheresis appears to be a well tolerated and effective treatment option, based on published data and discussion with large lung transplant center directors. Provision of photopheresis as a covered benefit for lung transplant recipients with BOS is necessary.

Ted. Gronski M.D.

Lung Transplant Medical Director

Aurora St. Luke's Medical Center

I am writing in favor of reimbursement for ECP for bronchiolitis obliterans syndrome after lung transplant. Our group was among the first to report the benefit of ECP for this indication (Salerno CT, Park SJ, Kreykes NS, Kulick DM, Savik K, Hertz MI, Bolman RM. Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis. Journal of Thoracic & Cardiovascular Surgery. 1999;117(6):1063-9.). In the 15 years since our manuscript was published, we have treated at least 20 additional BOS patient with ECP, and continue to note its benefit, i.e. stablilization of lung function, with minimal side-effects. All of the published reports of ECP after organ transplantation report similar findings. One might wonder why a larger, randomized trial has not been conducted to answer the question of efficacy once and for all. This is primarily the result of unavailability of industry funding, and not due to lack of interest among clinicians in the field. Bottom line: we owe it to our CMS-covered patients to provide the most effective treatments for BOS.

At the University of California San Diego Medical Center, in the period May 2003 until now, we have used photopheresis to treat 22 lung transplant recipients for lung transplant rejection (which includes bronchiolitis obliterans syndrome). Our results have been excellent, commensurate with those published from other centers, or slightly better. All patients had deteriorating lung function when referred for photopheresis, and with treatment 18 achieved lasting stabilization or improvement of their condition, as demonstrated objectively by reversal of the downward trend in lung function testing. In several cases the effect has been dramatic, with greatly improved overall functionality and quality of life.

Medical evidence, and our experience, is that almost all of these patients would have progressed to a fatal outcome without this treatment, except for the few who would be re-transplanted. We agree with the now-prevailing medical opinion that the quality and quantity of clinical evidence is now more than sufficient to remove any doubt that photopheresis is a highly effective treatment for lung transplant rejection. Also it has very few side-effects and is well-tolerated, much better than anti-rejection drugs. The benefit to individuals whose lives are saved and health improved is obvious. The benefit to society by avoiding re-transplantation is also substantial, because re-transplantation increases costs and diverts donor lungs away from other patients on the waiting list.

Photopheresis therapy for lung transplant rejection is available in many advanced countries, and in the USA to those with good medical insurance. The arguments in favor of making it available also to Medicare beneficiaries include medical, economic and ethical considerations. I strongly urge CMS to offer this therapy.