Extracorporeal photopheresis (ECP), an immunomodulating procedure involving treatment of pheresed blood with a photoactive agent, was given regulatory approval by the U.S. Food and Drug Administration (FDA) as a medical device for the treatment of cutaneous T-cell lymphoma in 1988 . It is one of many treatment options for cutaneous T-cell lymphoma (CTCL). In guidelines issued in the United Kingdom in 2003, ECP was recommended for advanced stages of CTCL, particularly after skin-directed therapies fail . Subsequent guidelines have made similar recommendations [3,4]. This modality is now also being actively investigated for primary treatment in earlier stages because the low risk of adverse events makes it attractive for slowing disease progression even in very indolent forms of CTCL .
Since the introduction of ECP the basic principles have remained unchanged, but the instrumentation has evolved. The most recent generation of the ECP device, the THERAKOS CELLEX Photopheresis System, requires a lower extracorporeal volume of blood than the THERAKOS UVAR XTS Photopheresis System, thereby increasing the proportion of patients with CTCL who may be candidates for this modality . There has been progress toward understanding the activities of ECP at the cellular level . This provides a basis for re-evaluating the role of this therapy in improving outcomes in a challenging disease.
CUTANEOUS T-CELL LYMPHOMA: PROFILE OF THE MALIGNANCY
CTCL describes a group of malignancies in which malignant T-lymphocytes localize at the skin . Of the CTCL types, mycosis fungoides and Sézary syndrome are by far the most common. Mycosis fungoides represents approximately 60% of CTCL cases, whereas Sézary syndrome, which is a more aggressive subtype, accounts for about 5% . Mycosis fungoides and Sézary syndrome were once considered the only CTCL subtypes, but the list of both indolent and aggressive CTCL subtypes with distinguishing characteristics has lengthened. The World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) recognize eight major subtypes, some of which have been further subclassified as the following :
- Cutaneous T-cell and natural killer (NK)-cell lymphomas
- Mycosis fungoides
- Mycosis fungoides variants and subtypes
- Folliculotropic mycosis fungoides
- Pagetoid reticulosis
- Granulomatous slack skin
- Sézary syndrome
- Adult T-cell leukemia/lymphoma
- Primary cutaneous CD30+ lymphoproliferative disorders
- Primary cutaneous anaplastic large cell lymphoma
- Lymphomatoid papulosis
- Subcutaneous panniculitis-like T-cell lymphoma
- Extranodal NK/T-cell lymphoma, nasal type
- Primary cutaneous peripheral T-cell lymphoma, unspecified
- Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional)
- Cutaneous γ/δ T-cell lymphoma (provisional)
- Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma (provisional)
- Cutaneous B-cell lymphomas
- Primary cutaneous marginal zone B-cell lymphoma
- Primary cutaneous follicle center lymphoma
- Primary cutaneous diffuse large B-cell lymphoma, leg type
- Primary cutaneous diffuse large B-cell lymphoma, other
- Intravascular large B-cell lymphoma
- Precursor hematologic neoplasm
- CD+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
CTCL is an uncommon malignancy, accounting for only about 4% of all non-Hodgkin's lymphomas, and less than 0.2% of all cancers . Data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program documented a more than three-fold increase in CTCL between 1973, when the incidence was 2.8 per 1 million patient years, to 2002, when it had climbed to 9.6 per 1 million patient years . The more recent rate predicts an incidence of about 2500–3000 new cases per year in the United States. According to the SEER data, the rise in the rates of CTCL has been observed across racial groups, although blacks continue to have about a 50% higher rate of CTCL than whites. There was a slightly faster increase among women over the time period, but the incidence of CTCL is about half as great in women as in men. The reason or reasons for the rise in the CTCL incidence are unknown. The same study identified modest geographic differences in incidence, but age was the dominant predictor of CTCL. Although this malignancy remains rare under the age of 40, the incidence climbs steeply by decade until the eighth decade of life, when it plateaus. The median age at diagnosis of CTCL is 55.
The prognosis of CTCL differs markedly by subtype, by risk factors, and by clinical stage. For patients with an indolent form of CTCL, including mycosis fungoides, who are node negative and have less than 10% of skin surface involved, there is no difference in expected lifespan relative to age and sex-matched controls . However, prognosis can be poor among aggressive subtypes. The 5-year survival rate for primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma is less than 20% . For other subtypes, including mycosis fungoides and Sézary syndrome, prognosis is highly dependent on disease stage. Such characteristics as lymph node involvement and clonal T cells in the peripheral blood predict a worse survival, which also correlates with increasing area of skin involvement . In Sézary syndrome, 5-year survival in patients with one or two adverse prognostic factors was 58% but fell to 5% in those with two or more adverse prognostic features . In a recently published cohort of 1502 patients with mycosis fungoides/Sézary syndrome using univariate and multivariate models, outcome was evaluated using the International Society for Cutaneous Lymphomas (ISCL)/EORTC revised-staging system . Over the course of follow-up, during which 34% of patients progressed and 26% of patients died due to mycosis fungoides/Sézary syndrome, multivariate analysis established that advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sézary cells (B0b), increased lactic dehydrogenase, and folliculotropic mycosis fungoides were independent predictors of poor survival and increased risk of disease progression. In addition, N, M, and B stages; age; male sex; and poikilodermatous mycosis fungoides were only significant predictors for poor survival.
Due to nonspecific skin lesions, the delay from the onset of symptoms to the diagnosis is often measured in years . In many patients, mycosis fungoides passes through three stages . At the early stage, the papulosquamous eruption often resembles eczema characterized by erythematous patches, which may or may not be pruritic. The second stage resembles psoriasis with sharply demarcated plaques. In the advanced stage, plaques thicken and ulcerate and mushroom-shaped tumors emerge. Skin infections in the advanced stages of mycosis fungoides and Sézary syndrome are a source of significant morbidity and mortality. The pace of progression through these stages varies among CTCL subtypes, and patients with indolent forms may never advance to the thick plaque and tumor stages . However, the clinical variation in advanced stages of disease may involve thickening of the palms and soles as well as alopecia, nail dystrophy, and ocular changes . Erythema over more than 80% of the skin surface (erythrodermic mycosis fungoides) is predictive of visceral or systemic disease and/or leukemic involvement in the peripheral blood . Patients with less extensive skin disease may also have leukemic involvement.
The newly published international guidelines for the diagnosis of mycosis fungoides/Sézary syndrome mycosis suggest that definitive diagnosis requires a combination of clinical and pathologic findings . According to these guidelines, a collaboration of the ISCL, the U.S. Cutaneous Lymphoma Consortium, and the EORTC, the hallmark appearance of mycosis fungoides on skin histopathology is a Pautrier microabscess, characterized by malignant CD4+ lymphocytes clustering around Langerhans cells in the epidermis. However, these are not uniformly present, and histopathology alone cannot be used to distinguish indolent from aggressive CTCL, particularly in the early stages . Evidence of significant blood involvement includes a lymphocytosis, a ratio of CD4/CD8 cells of 10 or greater, an increase in circulating T cells with aberrant marker expression, and evidence of a T cell clone in the peripheral blood .
Several staging systems have been proposed on the basis of clinical appearance, lymph node involvement, and atypical cells in the blood. In the most recent staging and classification systems, elements from several previous classification systems have been synthesized, creating stages from involvement of the skin (T), lymph nodes (N), viscera (M), and blood (B) .
The causal factors, like the precipitating molecular events, in CTCL are unknown, but there has been progress in identifying specific genetic abnormalities that appear to be involved in the emergence of aberrant T cells and impairments in apoptosis that permits these cells to proliferate . Recent data suggest that the malignant T cells that characterize several forms of CTCL, including both mycosis fungoides and Sézary syndrome, are clonal in origin and unlike other homing T cells present in skin lesions of inflammatory diseases . The group that isolated these clonal cells from benign-activated T cells in mycosis fungoides skin lesions also found the same cells in the blood of patients with leukemic CTCL. These malignant cells underwent apoptosis in both the skin and the blood in patients who had successful treatment with ECP but persisted in those who did not respond . Isolation of specific genetic abnormalities may prove useful in the future for distinguishing CTCL subtypes in regard to prognosis and possible therapies .
Five therapies have been approved by the U.S. FDA for the treatment of mycosis fungoides and Sézary syndrome. These, in the chronological order of approval, are ECP, denileukin diftitox, the retinoid bexarotene, and the histone deacetylase (HDAC) inhibitors vorinostat and romidepsin. However, treatment guidelines, such as those from the National Comprehensive Cancer Network (NCCN) and the WHO-EORTC, include a much longer list of therapies with the potential for benefit despite the absence of regulatory approval [3,24].
In the NCCN guidelines, skin-directed therapies are used to initiate therapy in stage IA or IB mycosis fungoides or Sézary syndrome . The skin-directed therapies for limited or localized skin involvement are topical corticosteroids, topical chemotherapy (such as nitrogen mustard or carmustine), local radiation, topical retinoids (such as bexarotene or tazarotene), phototherapy (including plus long-wave UV-A for thicker plaques), and topical imiquimod . These recommendations are primarily based on retrospective case studies rather than randomized trials and so there is little or no information regarding relative rates of response and failure. The guidelines suggest that maintenance regimens should be considered for the therapies to which patients respond. The NCCN guidelines also advise that the same treatment employed initially can often be successfully reintroduced after a relapse.
In refractory patients or those with stage IIB or higher disease, the NCCN guidelines group systemic therapies into two categories. The first includes retinoids, such as bexarotene or isotretinoin, interferons-α or γ, HDAC inhibitors such as vorinostat or romidepsin, ECP, denileukin diftitox, and methotrexate. The second, generally reserved for mycosis fungoides or Sézary syndrome patients with solid organ involvement or who have been refractory to therapies in the first category, are cytotoxic agents further subdivided into first and second-line choices. The first-line agents are liposomal doxorubicin and gemcitabine. The list of second-line agents is longer and includes chlorambucil, temozolomide, and high-dose methotrexate. Again, prospective, controlled studies validating the utility of any single approach over another are limited.
Large, prospective trials in rare forms of CTCL are challenging. In a controlled trial, outcomes such as disease-free or overall survival may be particularly difficult to measure in indolent CTCL subtypes because of the prolonged survival in a relatively uncommon malignancy. Remissions are an important outcome independent of a survival benefit, particularly for therapies that are well tolerated, due to the potential for extended periods without overt disease. However, quality of life is a meaningful variable for comparing treatment strategies. In the absence of objective comparisons of available strategies in the context of specific outcomes that include quality of life, current guideline recommendations are largely based on expert opinion informed by small uncontrolled studies. Although progress toward understanding of molecular targets may yield more rational ordering of first and second-line treatments, there is an urgent need for more data that reflect an impact of treatment on meaningful outcomes, such as progression-free or overall survival. In addition, more studies are needed to determine whether an intensification of treatment over that currently used will improve overall survival in those types of CTCL in which adverse prognostic signs have been established.
EXTRACORPOREAL PHOTOPHERESIS: DESCRIPTION OF A THERAPEUTIC OPTION IN CUTANEOUS T-CELL LYMPHOMA
ECP is a systemic therapy in which leukocytes separated from pheresed whole blood are exposed to 8-methoxypsoralen (8-MOP) that is then activated by ultraviolet A light before being returned to the patient  (Fig. 1) . Several case series have demonstrated encouraging response rates in treatment-refractory stage IA–IIB disease [26,27]. However, most clinical studies with ECP have been conducted in patients with advanced mycosis fungoides and Sézary syndrome, and current guidelines, including those from the EORTC and the NCCN, do not include ECP among first-line therapies in early stages of these diseases [3,24].
The EORTC guidelines list ECP among options for stage III mycosis fungoides and Sézary syndrome [3,10]. The NCCN guidelines list ECP among options for stage IIB, III, or IV mycosis fungoides and Sézary syndrome in the absence of lymph node or visceral involvement . Both guidelines suggest that it may be possible to combine ECP with other therapies, such as radiotherapy or other skin-directed or systemic therapies either as primary treatment or in refractory patients. In the treatment of stage III Sézary syndrome, for example, the EORTC guidelines include data suggesting an increase in survival duration when ECP is combined with interferon-α .
At the time of initial approval of ECP for use in CTCL, 8-MOP was taken orally in order to achieve adequate plasma levels before pheresis and light activation . Today, a liquid formulation of 8-MOP, methoxsalen, is added directly to the leukopheresed blood circumventing the risk of gastrointestinal side-effects and standardizing the concentration . Because extracorporeal 8-MOP treatment was introduced, the basic principles of this treatment have remained unchanged but there have been incremental improvements in the process and instrumentation . The manufacturer of the only ECP device approved by the FDA available has estimated that more than 100 centers in the United States offer this therapy . The features of the updated commercial ECP system, the THERAKOSCELLEX Photopheresis System (Therakos Inc., Raritan, New Jersey, USA) include the option of using two needles to accelerate blood collection, a smaller extracorporeal blood volume requirement, and a reduction in the approximate procedure time from 3 to 1.5 h. Of these improvements, the reduction in the volume extraction requirement may have been most important . The reduction eliminates a relative contraindication for patients with small body size who were at risk for tachycardia and hypotension from the previous volume requirements.
ECP is typically performed on two consecutive days and then repeated at 1-month intervals for a minimum of 6 months. Methoxsalen, 8-MOP is administered in a dose of 0.017 ml per 1 ml of pheresed leukocyte volume. For example, 240 ml of pheresed leukocyte volume would receive 4.1 ml of methoxsalen, 8-MOP (240 × 0.017 = 4.1). If there is a worsening of disease (increased skin score) from baseline after 3 months (four treatments), the consecutive treatment days can be accelerated to once every two weeks. If there is a partial improvement in skin scores, it is reasonable to resume monthly treatment, on the basis of the protocol employed a hallmark 1987 study with ECP . Although that study was designed primarily to test the safety of ECP, there are no large trials testing alternative protocols, and this approach has been employed widely in most subsequent studies . In patients with rapidly progressive disease, the addition of adjunctive therapies may be appropriate based on evidence that immunostimulatory agents, such as interferon-α, may be beneficial .
In the hallmark 1987 study with ECP, 27 (73%) of 37 treated patients with otherwise treatment-resistant CTCL responded, which was defined as greater than 25% clearing of skin . The average decrease in skin involvement was 64% after an average of 22 weeks of follow-up. When the 27 patients with a response were further subdivided by degree of response, nine (33%) had more than a 75% response (average 86%), 13 patients (48%) had a 50–75% response (average 60%), and five (18%) had a 25–49% response (average 34%). Responses were seen in eight of 10 patients with lymph node involvement at baseline and in 24 of 29 patients with exfoliative erythroderma. This encouraging degree of activity in a difficult patient population was not accompanied by significant side-effects.
Numerous studies have been published subsequently. All have been small, and few were controlled. Most studies have been conducted in the mycosis fungoides and Sézary syndrome subtypes of CTCL. In one summary of 19 ECP studies, the overall response rate was 55.5%, and the complete response rate was 14.8% . Only five studies evaluated ECP as a monotherapy. The others included one or more adjunctive agents, often an interferon or bexarotene. Stage-specific response rates were higher in early-stage disease: IB (64%) and IIA (56%). In the five studies that evaluated patients with stage III mycosis fungoides, an indication that is consistent with current guideline recommendations, the overall response was 35.7%. When ECP was used as a monotherapy in Sézary syndrome, the overall response rate, defined as greater than 50% skin clearing, approached 25% [33–39]. The rate of complete response in this group was near 10%. The efficacy of ECP in subtypes of CTCL other than mycosis fungoides and Sézary syndrome has not been evaluated. ECP is not generally considered appropriate in these subtypes due to their more rapidly progressive course.
Due to the lack of randomized studies, a survival benefit from ECP has not been prospectively established in any stage or subtype of CTCL. However, in long-term follow-up of an early series of patients, the median survival was 60 months, which was double that of the historical controls used for comparison . In a patient series with a median of 70 months of follow-up in individuals with stage III or IV mycosis fungoides, a prolonged survival after ECP was documented . Another single-institution study showed a 39-month median survival after ECP compared with a 26.5-month median survival in a similar group of patients who did not receive ECP . In this nonrandomized study of 29 patients, the difference did not reach statistical significance, but the numerical disparity in outcome underlines the need for larger, randomized trials to quantify an effect size for hard endpoints, particularly survival.
Several efforts have been made to identify characteristics that predict response to ECP. Such characteristics as the presence of elevated Sézary cell count or erythrodermic skin stage have been identified as potential useful predictors of benefit with this modality [27,43], but these findings have not been convincingly corroborated. Clinically, the most useful predictor of a long-term response is an early response, defined as a meaningful reduction (>50%) in skin lesions by 6 months. In one small study, this criterion had 100% sensitivity and 90% specificity for predicting a response that persisted for more than 4 years .
ECP is among several therapies associated with activity in relatively advanced mycosis fungoides and Sézary syndrome. The chief advantage may be the relative tolerability and safety of this modality, but treatments are difficult to stratify by efficacy because of the absence of controlled comparisons. Gains in objective outcomes, including progression-free survival, for one therapy over another, including ECP relative to its alternatives in stage III mycosis fungoides and Sézary syndrome, remain poorly documented. The indications for ECP are outlined in current guidelines [20,24], but it is hoped that the ongoing studies of ECP will contribute to the efforts to unravel the basic pathophysiology of CTCL and the basis for its therapeutic effect.
EXTRACORPOREAL PHOTOPHERESIS FOR THE TREATMENT OF CUTANEOUS T-CELL LYMPHOMA: CURRENT PRACTICE
For stage III or higher mycosis fungoides or Sézary syndrome, ECP is included on a lengthy list of systemic treatment options for stage III mycosis fungoides and Sézary syndrome in the EORTC guidelines (Table 1) . A lack of comparative data has prevented guidelines from prioritizing these options.
However, efforts to provide more specific guidance have been attempted within expert consensus panels, experts consolidating published data in review articles, and authors reviewing strategies based on experience at single centers [2,3,32,44]. A consensus statement published in the United Kingdom in 2008 was specifically developed to standardize patient selection criteria, treatment schedules, monitoring protocols and patient assessment criteria . Based on efficacy, the UK consensus group expressed the opinion that the application of ECP should be expanded in the treatment of mycosis fungoides and Sézary syndrome, and criticized the inconsistent standards currently employed for applying this modality.
This analysis and other expert options are useful for considering the role of ECP for various stages of CTCL subtypes, particularly mycosis fungoides and Sézary syndrome, in the absence of data-derived guidelines, which are likely to remain suboptimal because of the difficulties posed by conducting adequately powered randomized trials in an uncommon disease. Indeed, although some CTCL subtypes are sufficiently uncommon that well controlled trials may never be performed, such trials are possible and needed in mycosis fungoides and Sézary syndrome. Regulatory approval of ECP in 1988 was largely made on the basis of a multicenter study that showed activity in a challenging disease, but the study was uncontrolled and only included 37 patients . Of the multiple subsequent studies, none have been adequate to draw evidence-based conclusions about relative safety and efficacy.
Ultimately, therapy selection in CTCL, including mycosis fungoides and Sézary syndrome, requires consideration of the preponderance of data within an effort to make practical choices. ECP is most strongly supported for the treatment of Sézary syndrome and for stage III mycosis fungoides. In stage III erythrodermic mycosis fungoides, it has been suggested that specific features, such as the absence of bulky lymph node involvement and relatively low blood tumor burden may be useful for selecting those individuals most likely to respond to ECP . In responders, ECP has the relative advantage of being well tolerated. The contraindications for the methoxsalen, 8-MOP include previous idiosyncratic reactions to psoralen compounds, diseases associated with photosensitivity, such as lupus erythematosus, porphyria cutanea tarda, erythropoietic protoporphyria, variegate porphyria, xeroderma pigmentosum, and albinism . It is also contraindicated in patients with aphakia because of the potential for retinal damage. Although caution has been advocated for the use of ECP in those highly sensitive to volume shifts, the reduced volume requirement in newer systems has modified this risk. Hematomas at the injection site occur but are typically of a mild grade. Catheter-related infections and hypotension associated with changes in volume are potential but uncommon adverse events particularly when treatments are conducted by trained and experienced operators.
If one focuses on a subset of patients with Sézary syndrome in whom response was defined as greater than 50% clearing of skin and who received ECP in combination with other biologic therapies, the following approximate response rates can be extracted from the literature: ECP–interferon approximately 45% (n = 22), [1,33,34,46–50] ECP–bexarotene approximately 50% (n = 6), [51–53] ECP–interferon and bexarotene approximately 88% (n = 34) [49,54,55]. These estimates of response rates in patients with Sézary syndrome favor ECP in combination with biologic therapies over ECP monotherapy.
Current NCCN guidelines do not recommend ECP as primary treatment in stage IB or IIA disease, but it is an option in those patients even with this early stage who are refractory to skin-directed treatments . It is listed as an option for stage IIB, III, and IV disease except in cases of solid organ tumors or lymph node-positive mycosis fungoides (it can be considered in lymph node-positive Sezary syndrome). Skin-directed therapies and alternative systemic agents, such as HDAC agents, interferons, and denileukin can be considered in combination with ECP, in difficult cases, but conventional cytotoxic agents, such as gemcitabine and liposomal doxorubicin may be reasonable when there is significant visceral involvement . Again, the support of these recommendations by level-one evidence (randomized trials) is limited. Rather, evidence of both benefit and safety is largely derived from published experiences in noncontrolled studies.
Although this summary has employed the term CTCL to refer to the broad array of diseases that fall under this classification, most clinical data have been generated by experience in the treatment of mycosis fungoides and Sézary syndrome. Relative benefit in other subtypes of CTCL is essentially unknown as most of the currently published data are observational. Although the same therapies that have demonstrated efficacy in mycosis fungoides and Sézary syndrome may also be active in other CTCL subtypes, randomized or otherwise-controlled evaluations are needed .
The goals in CTCL vary according to stage, but treatment appears to delay progression more often than it cures disease even if introduced in very early stages . As a result, it is important to consider relative tolerability of any therapeutic choice and its impact on quality of life. This is the reason that ECP is being pursued as a potential second-line option even in early stages of disease refractory to first-line therapies. Results from an uncontrolled study indicating benefit from ECP in refractory stage IB disease underline the potential advantage of skin-directed treatment options in indolent CTCL .
A multicenter, prospective study has extended this evidence . In this study, 19 patients with stages IA-IIA (T1 or T2) mycosis fungoides were treated with ECP. Oral bexarotene and/or interferon-α could be added after 6 months in patients without partial response or with stable or progressive disease in skin. For entry, patients had to be refractory to one or more standard therapies, such as oral or high potency topical steroids, nitrogen mustard ointment, bexarotene, or phototherapy. The overall response rate was 42% with overall duration of response of 6.5 months. The authors of this article note that ECP appears to be effective for patients with early-stage disease with or without blood involvement, which suggests that blood involvement may not be required for response. There were low rates of adverse events, most of which were associated with the biological adjunctive therapies, whereas significant improvements in quality of life were observed. Although ECP has an indication only for monotherapy, the data from this study extend evidence of a benefit from ECP, with or without biological response modifiers, in early stage mycosis fungoides.
There are practical considerations that may make ECP more or less attractive for the individual patient, particularly access to a facility in which ECP is available. Although the demands of the 2-day per month schedule of ECP are relatively modest, a substantial travel distance may impose time or cost burdens that may not be acceptable. The relative costs of different treatment options for palliative care are also relevant, but this is an area difficult to explore without comparisons providing relative efficacy for reaching specific endpoints. In the absence of geographic constraints, ECP is a generally tolerable experience for most patients, requiring a relatively short period of blood collection and reinfusion. The most common side-effect is mild hypotension due to extracorporeal volume changes. Patients should be compliant with sun protection measures to avoid skin and eye complications. With current ECP integrated systems, each session can now be completed in 1.5 h. For the operator, the automated closed design of both the earlier and newer generation machines offer additional benefits of the treatment. Although the newest ECP device is equipped with some technical advances, including a new separation technology, the most significant change from the practical standpoint is the lower extracorporeal blood volume requirement.
More definitive data are needed to establish the relative effect of different therapeutic choices on survival. However, clinical studies designed to evaluate combinations for additive or synergistic antitumor effects are needed with similar urgency. Although the exact immunomodulatory mechanisms of ECP are unknown, the ability of this therapy to alleviate symptoms is presumably a direct consequence of its influence on T cell behavior.
Although the instrumentation of ECP has passed through several generations, the basic principles of this therapy remain unchanged. Efforts to isolate the mechanism of benefit of ECP are relevant to efforts to better understand the pathogenesis of mycosis fungoides, Sézary syndrome, and other CTCL subtypes. The nature of the influence of ECP on T cell activity appears to be important to restoring regulatory functions, including antitumor effects. Even though ECP has been in clinical use for more than 20 years, efforts to build on the activity of ECP with additional immunomodulatory treatments remain a promising if unproven area of CTCL control.
The relatively low incidence of CTCL has been an important barrier to the randomized trials most useful for comparing therapeutic strategies and to the development of standards upon which to innovate and propel clinical advances. ECP is recognized as one of several options in both Sézary syndrome and stage III mycosis fungoides, but more data are needed to better understand the merits of this therapy relative to alternatives, especially in reference to meaningful clinical stratifications by disease stage and CTCL subtype.
The heterogeneity of the presentation and course of CTCL encourage the individualization of therapy. In indolent disease and in advanced progressive disease, a careful evaluation of the relative benefit-to-risk ratio of current therapy must be undertaken in regard to both response and quality of life. One of the most important assets of ECP is that its activity is accompanied by a low risk of adverse events. In the palliative setting, tolerability is a particularly compelling asset.
Important safety information for the THERAKOS photopheresis procedure are as follows:
- The THERAKOSUVAR XTS or THERAKOS CELLEX photopheresis systems are not designated, sold or intended for use except as indicated. Certain underlying medical conditions contraindicate THERAKOS Photopheresis, including patients who cannot tolerate extracorporeal volume loss during the leukocyte-enrichment phase, patients exhibiting idiosyncratic or hypersensitivity reactions to 8-MOP/psoralen compounds, and patients with coagulation disorders.
- Warnings and precautions
- THERAKOS photopheresis treatments should always be performed in locations where standard medical emergency equipment is available. Volume replacement fluids and/or volume expanders should be readily available throughout the procedure.
- Adverse reactions
- Hypotension may occur during any treatment involving extracorporeal circulation. Closely monitor the patient during the entire treatment for hypotension.
- Transient pyretic reactions, 37.7–38.9°C (100–102°F), have been observed in some patients within six to eight hours of reinfusion of the photoactivated leukocyte-enriched blood. A temporary increase in erythroderma may accompany the pyretic reaction.
- Treatment frequency exceeding labeling recommendations may result in anemia.
- Venous access carries a small risk of infection and pain.
Conflicts of interest
The development of this publication was fully funded by THERAKOS. THERAKOS provided input on editor selection and reviewed the manuscript for content accuracy and fair balance.
The staff of Wolters Kluwer Health/Lippincott Williams & Wilkins and J.Z. developed the manuscript for this clinical supplement. J.Z. was paid by Wolters Kluwer Health/Lippincott Williams & Wilkins for his contribution to the development of the manuscript.
1. Rook AH, Prystowsky MB, Cassin M, et al. Combined therapy for Sezary syndrome with extracorporeal photochemotherapy and low-dose interferon alfa therapy. Clinical, molecular, and immunologic observations. Arch Dermatol 1991; 127:1535–1540.
2. Whittaker SJ, Marsden JR, Spittle M, Russell Jones R. Joint British Association of Dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous T-cell lymphomas. Br J Dermatol 2003; 149:1095–1107.
3. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer 2006; 42:1014–1030.
4. 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; 158:659–678.
5. Talpur R, Demierre MF, Geskin L, et al. Multicenter photopheresis intervention trial in early-stage mycosis fungoides. Clin Lymphoma Myeloma Leuk 2011; 11:219–227.
6. Bisaccia E, Vonderheid EC, Geskin L. Safety of a new, single, integrated, closed photopheresis system in patients with cutaneous T-cell lymphoma. Br J Dermatol 2009; 161:167–169.
7. Voss CY, Fry TJ, Coppes MJ, Blajchman MA. Extending the horizon for cell-based immunotherapy by understanding the mechanisms of action of photopheresis. Transfus Med Rev 2010; 24:22–32.
8. Kim EJ, Hess S, Richardson SK, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest 2005; 115:798–812.
9. Siegel RS, Pandolfino T, Guitart J, et al. Primary cutaneous T-cell lymphoma: review and current concepts. J Clin Oncol 2000; 18:2908–2925.
10. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768–3785.
11. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol 2007; 143:854–859.
12. Zackheim HS, Amin S, Kashani-Sabet M, McMillan A. Prognosis in cutaneous T-cell lymphoma by skin stage: long-term survival in 489 patients. J Am Acad Dermatol 1999; 40:418–425.
13. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression. Arch Dermatol 2003; 139:857–866.
14. Bernengo MG, Quaglino P, Novelli M, et al. Prognostic factors in Sezary syndrome: a multivariate analysis of clinical, haematological and immunological features. Ann Oncol 1998; 9:857–863.
15. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28:4730–4739.
16. Diamandidou E, Cohen PR, Kurzrock R. Mycosis fungoides and Sezary syndrome. Blood 1996; 88:2385–2409.
17. Glass LF, Keller KL, Messina JL, et al. Cutaneous T-cell Lymphoma. Cancer Control 1998; 5:11–18.
18. Hwang ST, Janik JE, Jaffe ES, Wilson WH. Mycosis fungoides and Sezary syndrome. Lancet 2008; 371:945–957.
19. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004; 350:1978–1988.
20. Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and sezary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol 2011; 29:2598–2607.
21. Vonderheid EC, Bernengo MG, Burg G, et al. Update on erythrodermic cutaneous T-cell lymphoma: report of the International Society for Cutaneous Lymphomas. J Am Acad Dermatol 2002; 46:95–106.
22. Mao X, Lillington D, Scarisbrick JJ, et al. Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sezary syndrome and mycosis fungoides. Br J Dermatol 2002; 147:464–475.
23. Clark RA, Shackelton JB, Watanabe R, et al. High-scatter T cells: a reliable biomarker for malignant T cells in cutaneous T-cell lymphoma. Blood 2011; 117:1966–1976.
25. Zic JA. The treatment of cutaneous T-cell lymphoma with photopheresis. Dermatol Ther 2003; 16:337–346.
26. Zic JA, Stricklin GP, Greer JP, et al. Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy. J Am Acad Dermatol 1996; 35:935–945.
27. Gottlieb SL, Wolfe JT, Fox FE, et al. Treatment of cutaneous T-cell lymphoma with extracorporeal photopheresis monotherapy and in combination with recombinant interferon alfa: a 10-year experience at a single institution. J Am Acad Dermatol 1996; 35:946–957.
28. Pothiawala SZ, Baldwin BT, Cherpelis BS, et al. The role of phototherapy in cutaneous T-cell lymphoma. J Drugs Dermatol 2010; 9:764–772.
29. Knobler R, Barr ML, Couriel DR, et al. Extracorporeal photopheresis: past, present, and future. J Am Acad Dermatol 2009; 61:652–665.
31. Edelson R, Berger C, Gasparro F, et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 1987; 316:297–303.
32. Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002; 138:1054–1060.
33. Dippel E, Schrag H, Goerdt S, Orfanos CE. Extracorporeal photopheresis and interferon-alpha in advanced cutaneous T-cell lymphoma. Lancet 1997; 350:32–33.
34. Vonderheid EC, Zhang Q, Lessin SR, et al. Use of serum soluble interleukin-2 receptor levels to monitor the progression of cutaneous T-cell lymphoma. J Am Acad Dermatol 1998; 38 (2 Pt 1):207–220.
35. Bouwhuis SA, el-Azhary RA, Gibson LE, et al. Effect of insulin-dependent diabetes mellitus on response to extracorporeal photopheresis in patients with Sezary syndrome. J Am Acad Dermatol 2002; 47:63–67.
36. Crovetti G, Carabelli A, Berti E, et al. Photopheresis in cutaneous T-cell lymphoma: five-year experience. Int J Artif Organs 2000; 23:55–62.
37. Stevens SR, Baron ED, Masten S, Cooper KD. Circulating CD4+CD7- lymphocyte burden and rapidity of response: predictors of outcome in the treatment of Sezary syndrome and erythrodermic mycosis fungoides with extracorporeal photopheresis. Arch Dermatol 2002; 138:1347–1350.
38. Russell-Jones R, Fraser-Andrews E, Spittle M, Whittaker S. Extracorporeal photopheresis in Sezary syndrome. Lancet 1997; 350:886.
39. de Misa RF, Harto A, Azana JM, et al. Photopheresis does not improve survival in Sezary syndrome patients with bone marrow involvement. J Am Acad Dermatol 2005; 53:171–172.
40. Heald P, Rook A, Perez M, et al. Treatment of erythrodermic cutaneous T-cell lymphoma with extracorporeal photochemotherapy. J Am Acad Dermatol 1992; 27:427–433.
41. Jiang SB, Dietz SB, Kim M, Lim HW. Extracorporeal photochemotherapy for cutaneous T-cell lymphoma: a 9.7-year experience. Photodermatol Photoimmunol Photomed 1999; 15:161–165.
42. Fraser-Andrews E, Seed P, Whittaker S, Russell-Jones R. Extracorporeal photopheresis in Sezary syndrome: no significant effect in the survival of 44 patients with a peripheral blood T-cell clone. Arch Dermatol 1998; 134:1001–1005.
43. Demierre MF, Foss FM, Koh HK. Proceedings of the International Consensus Conference on Cutaneous T-cell Lymphoma (CTCL) Treatment Recommendations. Boston, Massachusetts, Oct. 1 and 2, 1994. J Am Acad Dermatol 1997; 36 (3 Pt 1):460–466.
44. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fungoides and Sezary syndrome. Blood 2009; 114:4337–4353.
46. Cohen JH, Lessin SR, Vowels BR, et al. The sign of Leser-Trelat in association with Sezary syndrome: simultaneous disappearance of seborrheic keratoses and malignant T-cell clone during combined therapy with photopheresis and interferon alfa. Arch Dermatol 1993; 129:1213–1215.
47. Bouwhuis SA, McEvoy MT, Davis MD. Sustained remission of Sezary syndrome. Eur J Dermatol 2002; 12:287–290.
48. Ferenczi K, Yawalkar N, Jones D, Kupper TS. Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy. Arch Dermatol 2003; 139:909–913.
49. McGinnis KS, Shapiro M, Vittorio CC, et al. Psoralen plus long-wave UV-A (PUVA) and bexarotene therapy: an effective and synergistic combined adjunct to therapy for patients with advanced cutaneous T-cell lymphoma. Arch Dermatol 2003; 139:771–775.
50. Bouwhuis SA, Davis MD, el-Azhary RA, et al. Bexarotene treatment of late-stage mycosis fungoides and Sezary syndrome: development of extracutaneous lymphoma in 6 patients. J Am Acad Dermatol 2005; 52:991–996.
51. Haley HR, Davis DA, Sams WM. Durable loss of a malignant T-cell clone in a stage IV cutaneous T-cell lymphoma patient treated with high-dose interferon and photopheresis. J Am Acad Dermatol 1999; 41 (5 Pt 2):880–883.
52. Richardson SK, Lin JH, Vittorio CC, et al. High clinical response rate with multimodality immunomodulatory therapy for Sezary syndrome. Clin Lymphoma Myeloma 2006; 7:226–232.
53. Bagazgoitia L, Perez-Carmona L, Rios L, et al. Acute hyperkeratotic and desquamative reaction in a patient with Sezary syndrome treated with bexarotene. J Eur Acad Dermatol Venereol 2008; 22:389–390.
54. Vonderheid EC, Bigler RD, Greenberg AS, et al. Extracorporeal photopheresis and recombinant interferon alfa 2b in Sezary syndrome: use of dual marker labeling to monitor therapeutic response. Am J Clin Oncol 1994; 17:255–263.
55. Shapiro M, Rook AH, Lehrer MS, et al. Novel multimodality biologic response modifier therapy, including bexarotene and long-wave ultraviolet A for a patient with refractory stage IVa cutaneous T-cell lymphoma. J Am Acad Dermatol 2002; 47:956–961.
56. Babic AM. Extracorporeal photopheresis: lighting the way to immunomodulation. Am J Hematol 2008; 83:589–591.
57. Rubegni P, De Aloe G, Fimiani M. Extracorporeal photochemotherapy in long-term treatment of early stage cutaneous T-cell lymphoma. Br J Dermatol 2000; 143:894–896.