Medicine Section - Extracorporeal Photopheresis as a Treatment of Graft-versus-Host Disease, Autoimmune Disease, and Cutaneous T-Cell Lymphoma

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

Description

Photopheresis, also called extracorporeal photochemotherapy (ECP), is a multistep procedure involving the following:

1. Patients ingest the drug psoralen (8-methoxypsoralen or 8-MOP), which functions to render cells (including lymphocytes) light sensitive.
2. Lymphocytes are collected by pheresis and exposed to UV-A light.  Alternatively, the photosensitizer agent 8-MOP is added directly to the lymphocyte fraction, which is then exposed to ultraviolet (UV)A light.
3. The light-sensitized lymphocytes are reinfused into the patient.

There is no standard schedule for photopheresis therapy. However, most reported schedules initiate therapy with 1-3 days of photopheresis at 1- to 3-week intervals, followed by a tapering of therapy.

ECP has been investigated for the treatment of patients with Graft-versus-Host Disease (GVHD), a variety of autoimmune diseases, and cutaneous T-Cell lymphoma (CTCL).

Graft-versus-Host Disease (GVHD)

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 disease, occurring within the first 100 days after infusion of allogeneic cells, or chronic disease, which develops some time after 100 days. Acute GVHD is commonly graded from 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 life-threatening. Chronic GVHD typically presents with more diverse symptomatology resembling autoimmune diseases such as 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 graft-versus-host disease. Other therapies may include antithymocyte globulin, corticosteroid monotherapy, and cytotoxic immunosuppressive drugs such as procarbazine, cyclophosphamide, or azathioprine. Refractory disease is defined as chronic graft-versus-host disease that fails to respond adequately to a trial of any of these therapies.

Autoimmune Disease

The use of photopheresis as a treatment of autoimmune disease is based on the premise that the pathogenic lymphocytes form an expanded clone of cells, which are then damaged when exposed to light. It is hypothesized that the resulting damage induces a population of circulating suppressor T-cells targeted against the light-damaged cells. It is further hypothesized that these suppressor T-cells are targeted at a component of the cell that is common to the entire clone of abnormal cells (not just the light-sensitized cells), thus inducing a systemic effect. However, although scleroderma and other autoimmune diseases are associated with the presence of circulating antibodies, it is not certain how these antibodies are related to the pathogenesis of the disease, and as discussed below, photopheresis is not associated with consistent changes in autoantibody levels.

Cutaneous T-Cell Lymphoma

According to the National Cancer Institute, cutaneous T-cell lymphomas (CTCL) are neoplasias of malignant T-lymphocytes that initially present as skin involvement. CTCL are extremely rare conditions, with an estimated incidence of about 0.4 per 100,000 annually but, because most are low-grade malignancies with long survival, the overall prevalence is much higher. Two CTCL variants, mycosis fungoides and the Sézary syndrome account for about 60% and 5% of new cases of CTCL, respectively.

CTCL is included in the Revised European-American Lymphoma (REAL) classification as a group of low-grade T-cell lymphomas, which should be distinguished from other T-cell lymphomas that involve the skin, such as anaplastic large cell lymphoma, peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma (usually with systemic involvement), or subcutaneous panniculitic T-cell lymphoma. In addition, a number of benign or very indolent conditions can be confused with mycosis fungoides, further complicating diagnosis.

According to the World Health Organization/European Organization for Research and Treatment of Cancer (WHO-EORTC), Sézary syndrome is defined by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T-cells (Sézary cells) in skin, lymph nodes, and peripheral blood. The International Society of Cutaneous Lymphomas recommends an absolute Sézary cell count of at least 1,000 cells per cubic mm, in the presence of immunophenotypical abnormalities (CD4/CD8 ratio greater than 10, loss of any or all of the T-cell antigens CD2, CD3, CD4, and CD5, or both), or the demonstration of a T-cell clone in the peripheral blood by molecular or cytogenetic methods.

Mycosis fungoides typically progresses from an eczematous patch/plaque stage covering less than 10% of the body surface (T1) to plaque stage covering 10% or more of the body surface (T2), and finally to tumors (T3) that frequently undergo necrotic ulceration. Sézary syndrome is an advanced form of mycosis fungoides with generalized erythroderma (T4) and peripheral blood involvement (B1) at presentation. Cytologic transformation from a low-grade lymphoma to a high-grade lymphoma sometimes occurs during the course of these diseases and is associated with a poor prognosis. A common cause of death during the tumor phase is sepsis from Pseudomonas aeruginosa or Staphylococcus aureus caused by chronic skin infection with staphylococcus species and subsequent systemic infections.

The natural history of mycosis fungoides is typically indolent. Symptoms may present for long periods, an average of 2 to 10 years, as waxing and waning cutaneous eruptions prior to biopsy confirmation. The prognosis of patients with mycosis fungoides/Sézary syndrome is based on the extent of disease at presentation and its stage. Lymphadenopathy and involvement of peripheral blood and viscera increase in likelihood with worsening cutaneous involvement and define poor prognostic groups. The median survival following diagnosis varies according to stage. Patients with stage IA disease have a median survival of 20 or more years, with the majority of deaths for this group typically unrelated to mycosis fungoides. In contrast, more than 50% of patients with stage III through stage IV disease die of their disease, with a median survival of less than 5 years.

Appropriate therapy of CTCL depends upon a variety of factors, including stage, the patient's overall health, and the presence of symptoms. In general, therapies can be categorized into topical and systemic treatments that include ECP. In contrast to the more conventional lymphomas, CTCL, possibly excepting the earliest stages, are not curable. Thus, systemic cytotoxic chemotherapy is avoided except for advanced-stage cases. Partial or complete remission is achievable, although the majority of patients require lifelong treatment and monitoring.

CTCL Staging (based on the TNM classification system)

Regulatory Status of Extracorporeal Photopheresis

In the U.S., the UVAR® XTS Photopheresis System was approved via premarket application (PMA) by the U.S. Food and Drug Administration (FDA) for use in the ultraviolet-A (UVA) irradiation (in the presence of the photoactive drug, methoxsalen) of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.

8-MOP (UVADEX®) is approved by the FDA for use in conjunction with UVAR XTS Photopheresis System for use in the ultraviolet-A (UVA) irradiation in the presence of the photoactive drug methoxsalen of extracorporeally circulating leukocyte-enriched blood in the palliative treatment of the skin manifestations of CTCL in persons who have not been responsive to other therapy.

The use of the UVAR XTS photopheresis system or UVADEX for other conditions is an off-label use of a FDA-approved device/drug.

Policy/Criteria

1. Extracorporeal photopheresis may be considered medically necessary as a technique to treat chronic GVHD that is refractory to an adequate trial of medical therapy.
2. Extracorporeal  photopheresis is considered investigational as a technique to treat acute GVHD or chronic GVHD that is either previously untreated or is responding to established therapies.
3. Extracorporeal photopheresis may be considered medically necessary as a technique to treat late-stage (III/IV) cutaneous T-cell lymphoma. (See CTCL Staging based on the TNM classification system above)
4. Extracorporeal photopheresis may be considered medically necessary as a technique to treat early stage (I/II) cutaneous T-cell lymphoma that is progressive and refractory to established nonsystemic therapies. (See CTCL Staging based on the TNM classification system above)
5. Extracorporeal photopheresis is considered investigational as a technique to treat early stage (I/II) cutaneous T-cell lymphoma that is either previously untreated or is responding to established nonsystemic therapies. (See CTCL Staging based on the TNM classification system above)
6. Extracorporeal photopheresis is considered investigational as a technique to treat either the cutaneous or visceral manifestations of autoimmune diseases, including but not limited to scleroderma, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, multiple sclerosis, or diabetes.

Scientific Background

Graft-versus Host Disease:

The policy on photopheresis as a treatment of GVHD is based on a 2001 BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment, which offered the following observations and conclusions. (2):

• For acute GVHD or chronic GVHD in previously untreated patients, or in those responding to conventional therapy,   no studies  met selection criteria and reported results of extracorporeal photopheresis, alone or in combination with other therapies. Therefore, it was not possible to draw conclusions concerning the effects of this therapy on health outcomes in previously untreated or responsive patients.
• 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 67-84% of patients with grade III disease, but patients with grade IV disease rarely responded.

Following the TEC Assessment in 2001, two small studies focusing on photopheresis for the treatment of GVHD in children. (3,4) In the study by Halle and colleagues, 8 children (ages 5-15 years) with refractory extensive chronic GVHD were treated with photopheresis and either oral 8-MOP or infusion of an 8-MOP solution into the pheresed lymphocytes. (3) Cutaneous status reportedly improved in 7 patients. Five patients stopped 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. Salvaneschi and colleagues reported on photopheresis results in refractory GVHD in 9 acute pediatric cases and 14 chronic pediatric cases (ages 5.4-11.2 years). (4) In the acute GVHD cases, 7 of 9 experienced either partial or complete response, while in the chronic GVHD patients, 9 of 14 experienced either partial or complete remission.

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 (5). 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 months 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.

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 (6). 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. Complete response (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 (7). 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 (age 6-18 years) patients who had undergone hematopoietic stem cell transplantation to treat a variety of cancers.(8) 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 month, 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 complete response (CR) was observed in 7/7 (100%) with Grade II and 2/4 (50%) with Grade III illness, whereas none with Grade IV responded to ECP. In the group with cGVHD, 3/3 (100%) with limited disease had CR, compared to 1/7 (14%) with extensive disease who had a CR; 5/7 (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.

Data in these reports confirm the conclusions of the TEC Assessment regarding outcomes of photopheresis for chronic GVHD. However, the evidence they report is insufficient to alter conclusions concerning photopheresis for acute GVHD.

Autoimmune Disease:

The policy on photopheresis as a treatment of autoimmune diseases is based on a 2001 BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment, which offered the following observations and conclusions (9):

• A variety of autoimmune diseases were considered in the TEC Assessment, including systemic sclerosis, pemphigoid, systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, rheumatoid arthritis, and Type I diabetes.
• For all of these indications, the available evidence was insufficient to permit scientific conclusions concerning health outcomes. Of all the above diseases, photopheresis has been most thoroughly studied as a treatment of scleroderma. However, the data on this indication only included one single-blind randomized controlled trial (10) and three small uncontrolled series. While the randomized study reported positive outcomes in terms of skin manifestations, a number of methodological flaws have been discussed in the literature (11-13), including inadequate treatment duration and follow-up, excessive drop outs, a mid-study change of primary outcome, and inadequate wash out of prior penicillamine therapy.
• Results reported from other small case series regarding systemic sclerosis conflict with each other and do not resolve the difficulties in interpreting the randomized trial.

An updated search of the MEDLINE database with regard to autoimmune diseases and photopheresis identified one randomized double-blind, placebo-controlled trial of photopheresis in systemic sclerosis patients.  Knobler and colleagues randomized 64 patients to receive either active or sham photopheresis. (14) At six and twelve months follow-up, between-group differences did not reach statistical significance.  Larger studies are needed to confirm the positive trend noted in this trial.

A randomized, double-blind, controlled clinical trial on diabetes by Ludvigsson and colleagues reported results of photopheresis in 49 children with newly diagnosed type 1 diabetes.  (15) Forty children, aged 10-18 years, completed the study and were followed for 3 years. All patients received standard treatment with insulin therapy and diet, exercise, and self-management education. Of these patients, 19 received active photopheresis treatment with oral 8-MOP and 21 received placebo tablets and sham pheresis in the control group. Hemoglobin A1C results, a key clinical outcome in diabetes control, were not statistically different between the two groups. Therefore, the available evidence does not alter the conclusions reached in the TEC Assessment for diabetes.

In 2007, one small series was identified in which ECP was administered to treat immuno refractory relapsing-remitting multiple sclerosis in five patients. (16) ECP appeared safe and tolerable in these patients, with some evidence for a reduction in the relapse rate and symptom stabilization. However, the data are insufficient to alter the policy conclusions for this use of ECP.

In summary, an updated search of the MEDLINE database through  January 2009 identified no new trials that would alter the conclusions reached in the 2001 TEC assessments with regard to photopheresis for graft versus host disease or autoimmune diseases.

Cutaneous T-Cell Lymphoma

Stage III/IV MF and Sézary Syndrome

The initial report on the use of ECP as therapy for CTCL was published by Edelson and colleagues. (17) Twenty-seven of 37 (73%) patients with otherwise resistant CTCL responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 + 10 weeks (mean + SD). The responding group included 8 of 10 (80%) patients with lymph-node involvement, 24 of 29 (83%) with exfoliative erythroderma, and 20 of 28 (71%) whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. These results showed ECP is safe and effective in advanced, resistant CTCL. Subsequent results from numerous small, nonrandomized studies have been generally consistent with the initial conclusion that ECP treatment can produce clinical improvement and may prolong survival in a substantial proportion of patients with advanced stage CTCL (18-22).

Together, these data provide the basis for several evidence-based guideline or consensus statements on the use of ECP in CTCL (23-25), as well as the position of the National Cancer Institute (NCI Mycosis Fungoides and the Sézary Syndrome Treatment ).

These guidelines consistently recommend ECP as first-line treatment for patients with stage III/IV CTCL. Therefore, in this policy, ECP may be considered medically necessary as a technique for the treatment of patients with stages III/IV CTCL.

In 2006, the Ontario Health Technology Advisory Committee (OHTAC) published results of a systematic review of ECP for the treatment of erythrodermic CTCL. (7) In summary, OHTAC reported that there is low quality evidence that ECP improves response rates and survival in patients with CTCL who are unresponsive to other forms of therapy. Limitations in the literature related to ECP for the treatment of refractory erythrodermic CTCL mostly pertained to the quality, size, and heterogeneity in treatment regimens and diagnostic criteria of available clinical studies. The Committee did, however, recommend a 2-year duration field evaluation of ECP for refractory erythrodermic CTCL, using standardized inclusion criteria and definitions to measure disease outcomes including response rates, quality of life and morbidity.

Early-Stage (I/II) CTCL

Between 1987 and 2007, data were reported from at least 16 studies including 124 patients with CTCL in early stages IA, IB, or II who were treated with ECP alone (n=79) or in combination with other agents (n=45) including retinoids and interferon-alfa (26). Many of these patients were refractory to numerous other therapies, including topical corticosteroids, interferon alfa, or whole-skin irradiation. Response rates (partial plus complete) in these studies ranged from 33% to 88% with monotherapy and 50–60% with ECP and adjuvant therapies. While these findings suggest ECP may provide benefit in early stage CTCL, none of the studies was randomized or comparative. Furthermore, many of the studies preceded universal acceptance of standardized elements of classification and diagnosis of CTCL, such as those proposed by the World Health Organization and European Organization for Research and Treatment of Cancer. (27) Thus, the actual disease spectrum and burden represented in the available database likely vary between studies and this complicates conclusions about the efficacy of ECP in this setting. Nonetheless, given the unfavorable prognosis for patients with early stage CTLC that progresses while receiving nonsystemic therapies; the relative lack of adverse events with ECP compared to other systemic treatments; and, the good response rates often associated with ECP, ECP may be considered medically necessary as a technique for the treatment of patients with refractory or progressive early stage CTCL. By contrast, because early stage CTCL typically responds to less-invasive, topical therapies, patients whose disease remains quiescent under such treatments usually experience a near-normal life expectancy. As a consequence ECP is considered investigational as a technique for the treatment of patients with stage I/II CTCL that is either previously untreated or is responding to established therapies.

The NCCN 2008 guidelines for the treatment of CTCL recommend the use of ECP alone or in combination with other agents (retinoids, interferon alfa. denlieukin diftitox) as first-line systemic therapy for advanced (stages III/IV) disease as well as for patients with earlier stage mycosis fungoides with Sézary syndrome involvement or that has failed multiple courses of topical skin-directed treatments (28)

The National Cancer Institute Physician’s Data Query (PDQ®) Database indicates no randomized clinical trials on the use of ECP in CTCL are recruiting or otherwise in development. (29)

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.36
2. BlueCross and BlueShield Association Technology Evaluation Center (TEC) Assessment  : Extracorporeal photopheresis for graft versus host disease, 2001; BlueCross and BlueShield Association Technology Evaluation Center, Vol. 16, No. 9
3. Halle P, Paillard C, D'Incan M et al. Successful extracorporeal photochemotherapy for chronic graft-versus-host disease in pediatric patients. J Hematother Stem Cell Res 2002;11(3):501-12
4. Salvaneschi L, Perotti C, Zecca M et al. Extracorporeal photochemotherapy for treatment of acute and chronic GVHD in childhood. Transfusion 2001;41(10):1299-305
5. 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 Transplant 2005; 35(12):1187-93
6. Greinix HT, Knobler RM, Worel N et al. The effect of intensified extracorporeal photochemotherapy on long-term survival in patients with severe acute graft-versus-host disease. Haematologica 2006; 91(3):405-8
7. OHTAC Recommendation: Extracorporeal Photopheresis. March 28, 2006. Accessible at: Ontario Health Technology Advisory Committee. (Verified 01/19/09)
8. Massimo B, Rosanna P, Roberto A et al. Extracorporeal photopheresis for steroid resistant graft versus host disease in pediatric patients: a pilot single institution report. J Pediatr Hematol Oncol 2007; 29(10):678-87
9. BlueCross and BlueShield Association Technology Evaluation Center (TEC) Assessment  : Extracorporeal photopheresis for the treatment of autoimmune disease; 2001; BlueCross and BlueShield Association Technology Evaluation Center, Vol. 16, No. 10
10. Rook AH, Freundlich B, Jegasothy BV et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy. Results of a multicenter trial. Arch Dermatol 1992;128:337-46
11. Trentham DE. Photochemotherapy in systemic sclerosis. Arch Dermatol 1992;128:389-90
12. Melski JW. Price of technology: A blind spot. JAMA 1992;267:1516-17
13. Fries JF, Seibold JR, Medsger TA. Photophoresis for scleroderma? No! J Rheumatol 1992;19:1011-13
14. Knobler R, French L, Kim Y et al. A randomized, double-blind, placebo-controlled trial of photopheresis in systemic sclerosis : J Am Acad Dermatol 2006;54(5):793-9
15. Ludvigsson J, Samuelsson U, Ernerudh J et al. Photopheresis at onset of type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Arch Dis Child 2001;85(2):149-54
16. Cavaletti G, Perseghin P, Dassi M et al. Extracorporeal photochemotherapy: a safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis. Neurol Sci 2006; 27(1):24-32
17. Edelson R, Berger C, Gasparro F et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 1987; 316(6):297-303
18. Knobler E. Current management strategies for cutaneous T-cell lymphoma. Clin Dermatol 2004; 22(3):197-208
19. Freiman A, Sasseville D. Treatment of mycosis fungoides: overview. J Cutan Med Surg 2006; 10(5):228-33
20. Keehn CA, Belongie IP, Shistik G et al. The diagnosis, staging, and treatment options for mycosis fungoides. Cancer Control 2007; 14(2):102-11
21. Scarisbrick JJ. Staging and management of cutaneous T-cell lymphoma. Clin Exp Dermatol 2006; 31(2):181-6
22. Whittaker SJ, Foss FM. Efficacy and tolerability of currently available therapies for the mycosis fungoides and Sézary syndrome variants of cutaneous T-cell lymphoma. Cancer Treat Rev 2007; 33(2):146-60
23. Whittaker SJ, Marsden JR, Spittle M et al. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of cutaneous T-cell lymphomas. Br J Dermatol 2003; 149(6):1095-107
24. Scarisbrick JJ, Taylor P, Holtick U et al. U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease. Br J Dermatol 2008; 158(4):659-78
25. Trautinger F, Knobler R, Willemze R et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. Eur J Cancer 2006; 42(8):1014-30
26. Miller JD, Kirkland EB, Domingo DS et al. Review of extracorporeal photopheresis in early stage (IA, IB, and IIA) cutaneous T-cell lymphoma. Photodermatol Photoimmunol Photomed 2007; 23(5):163-71
27. Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105(10):3768-85
28. National Comprehensive Cancer Network Practice Guidelines for Non-Hodgkin’s Lymphomas http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf (Verified 01/19/09)
29. National Cancer Institute Physician’s Data Query (PDQ®) Database http://www.cancer.gov/ (Verified 01/19/09)
30. Clinicaltrial.gov:  Clinical trials on Graft-versus-Host Disease (Verified  01/19/09)

Cross References

Photopheresis for the Treatment of Solid Organ Transplant Rejection, Regence Medical Policy Manual, Medicine, Policy No. 70

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