Key points

Introduction

Cutaneous T-cell lymphoma (CTCL) is a broad term describing cancers of the T cell whereby the skin is the primary organ of involvement. Although the disease was first recognized in 1806 by Alibert, it was not until the 1970s when investigators discovered the T-cell origin of this malignancy. Extracorporeal photopheresis (ECP) or photopheresis is one of many treatment modalities to treat the cutaneous T-cell lymphomas. It is unique among those treatment modalities, however, in that it is the only treatment, aside from allogeneic stem cell transplantation, that specifically induces an immune reaction directed against the malignant T cell.

ECP is an apheresis procedure whereby a leukocyte-enriched fraction of blood spiked with 8-methoxypsoralen (8-MOP) is exposed to a UV-A light source and then returned to patients. ECP is similar to the psoralen followed by UV-A exposure (PUVA) form of phototherapy in that both take advantage of the photoactivated drug 8-MOP and are classified as photochemotherapies. In 1988, the US Food and Drug Administration (FDA) approved the use of a new medical device for the treatment of CTCL. The UVAR instrument (Therakos Inc, Exton, PA) combined, for the first time, leukapheresis with a modified phototherapy chamber.

Introduction

Cutaneous T-cell lymphoma (CTCL) is a broad term describing cancers of the T cell whereby the skin is the primary organ of involvement. Although the disease was first recognized in 1806 by Alibert, it was not until the 1970s when investigators discovered the T-cell origin of this malignancy. Extracorporeal photopheresis (ECP) or photopheresis is one of many treatment modalities to treat the cutaneous T-cell lymphomas. It is unique among those treatment modalities, however, in that it is the only treatment, aside from allogeneic stem cell transplantation, that specifically induces an immune reaction directed against the malignant T cell.

ECP is an apheresis procedure whereby a leukocyte-enriched fraction of blood spiked with 8-methoxypsoralen (8-MOP) is exposed to a UV-A light source and then returned to patients. ECP is similar to the psoralen followed by UV-A exposure (PUVA) form of phototherapy in that both take advantage of the photoactivated drug 8-MOP and are classified as photochemotherapies. In 1988, the US Food and Drug Administration (FDA) approved the use of a new medical device for the treatment of CTCL. The UVAR instrument (Therakos Inc, Exton, PA) combined, for the first time, leukapheresis with a modified phototherapy chamber.

Historical aspects

In 1921, J.F. Heymans first published the concept of treating blood by exposing it to physical agents, such as cold, heat, or radiation, as it flows through an extracorporeal shunt. A better understanding of lymphocyte function and life span emerged in the late 1950s leading to the development of procedures to deplete the body of lymphocytes to study lymphocyte kinetics and ultimately treat disease. In the early 1960s, Eugene Cronkite, MD, while at the Brookhaven National Laboratory in Upton, New York, developed an extracorporeal system using a venovenous shunt to expose whole blood to gamma rays generated by a ⁶⁰ cobalt irradiator. This modality, called extracorporeal irradiation of the blood (ECIB), was based on the difference between the radiosensitivity of lymphocytes and the radioresistance of erythrocytes. By 1970, at least 150 patients with acute and chronic leukemias were treated with ECIB; but remissions were short lived. Although most authorities thought only gamma radiation could kill activated lymphocytes and leukemic cells, a French team in the late 1960s led by J.L. Binet investigated the effects of using UV radiation (UVR) produced by mercury arc lamps. Their UVR ECIB system was tested on lymphocyte function and ultimately in several patients with chronic lymphocytic leukemia leading to transient clinical remission.

In the mid-1970s, Barbara Gilchrest and colleagues at Massachusetts General Hospital discovered that PUVA phototherapy was effective in treating the early skin lesions of mycosis fungoides (MF), the most common subtype of CTCL. At about the same time, Richard L. Edelson, MD, while at the National Cancer Institute, worked with colleagues to treat several patients with Sézary syndrome (SS) using leukapheresis to debulk the circulating tumor load of malignant T cells. The question arose whether the malignant circulating lymphocytes in SS would respond to PUVA phototherapy if the energy could be directed at blood cells. Initial experiments performed in Edelson’s laboratory found evidence that an anti-idiotypic response to disease-specific T-cell receptors could be found after exposing autoreactive T cells from rats to 8-MOP and UV-A in an ex vivo system inspired by Cohen and colleagues at the Weizmann Institute. With the help of engineers at Therakos, Inc, a subsidiary of Johnson and Johnson, Edelson designed a device that could expose a fraction of leukocyte-enriched blood, removed from patients after they had taken psoralen, to UV-A light in an extracorporeal system before returning the treated blood products back to the patients. After a promising phase I clinical trial, a multicenter clinical trial was performed from 1982 to 1986 testing the efficacy of ECP after ingestion of 8-MOP in the management of refractory erythrodermic patients with MF/SS. In 1987, the landmark report was published that found a significant response in 27 of 37 patients treated with ECP.

In 2000, the FDA approved a sterile liquid formulation of 8-MOP to replace the oral formulation. The liquid formulation (UVADEX) is added directly to the collection bag in the extracorporeal circuit, thus avoiding the gastrointestinal intolerance and unreliable blood levels of the oral formulation. The latest fourth-generation photopheresis instrument, the CELLEX System (Therakos, Inc, Raritan, NJ), was approved in 2009 by the FDA and combines state-of-the-art cell collection, photoactivation, and reinfusion technologies in a single, integrated, closed system.

Mechanism of action

Despite the safe and effective use of ECP for more than 25 years, the precise mechanism of action continues to be explored. There is good evidence that ECP induces an immune-mediated response to the malignant T-cell clone. This is supported, in part, by the clinical observation that, although less than 10% of the total population of white blood cells is treated during one ECP treatment, there is often a larger reduction of malignant T cells in the peripheral circulation. The proposed mechanism of action involves the following processes: (1) the induction of apoptosis of malignant T cells, (2) the conversion of circulating monocytes to immature dendritic cells (DCs), (3) the presentation of tumor-loaded DCs to cytotoxic T cells, and (4) expansion of a population of cytotoxic T cells against the malignant T-cell clone.

Because they lack nuclei, the radioresistance of erythrocytes and platelets may be expected. However, the differences in the radiosensitivity of peripheral blood mononuclear cells (PBMCs) are more difficult to explain. Why are lymphocytes more radiosensitive than other peripheral blood mononuclear cells? Also intriguing are the results of Spary and colleagues demonstrating enhancement of the Th1 T-cell responses as a result of synergy between lower doses of ionizing radiation (0.6–2.4 Gy) and T-cell stimulation. Further studies are needed that focus on the impact of ECP (UV energy) on enhancement of Th1 T-cell responses of normal T cells. ECP and PUVA induce apoptosis in CD4+ and CD8+ lymphocytes but not monocytes, and the apoptosis is likely attributed to dysregulation in the expression of the apoptotic genes Bcl-2 and Bax. But what about the surviving malignant T cells exposed to UV-A energy and psoralen? Studies using ionizing radiation demonstrate alteration in the biology of surviving tumor cells from patients with solid organ carcinomas, rendering them more susceptible to T cell–mediated killing possibly via increased cell-surface expression of calreticulin.

It has been established that monocytes differentiate to immature DCs in the presence of interleukin (IL)-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). In 2001, Berger and colleagues published their observation of the conversion of monocytes to immature DCs during overnight incubation in gas-permeable bags of ECP-treated leukocytes from 5 patients with refractory CTCL. Further observations confirmed that both the initial leukapheresis step and subsequent passage through the narrow plastic photoactivation plate initiated and contributed to the monocyte to immature dendritic cell differentiation. Edelson proposed that the frequent encounters of monocytes with the plastic surface of the photoactivation plate activated the cells to begin differentiation to immature DCs. The adsorption of fibronectin on the photoactivation plate may be a convincing candidate for influencing monocyte biology during ECP and participating in the early events of monocyte-to-DC conversion. Recently, Berger and colleagues demonstrated that ECP-derived DCs are maturationally synchronized and show a reproducible distinctive molecular signature, common to ECP-processed monocytes from normal subjects and those from patients.

There are 2 major subsets of DCs in human peripheral blood: myeloid (mDC) and plasmacytoid (pDC). It is known that mDCs primarily polarize naïve T cells toward a Th1 phenotype, whereas pDCs primarily result in a Th2/Treg phenotype. Recently, Shiue and colleagues found increased mDC populations, increased mDC/pDC ratios, and upregulation of HLA-DR expression on DCs following ECP in two-thirds of patients with MF and B1/B2 blood stage or SS. Their results suggest that ECP treatment is associated with favorable mDC modulation.

Inducing a Th1 phenotype produces a cell-mediated T-cell response capable of launching a cytotoxic T-cell response against a malignant clone. Clinical improvements after ECP in patients with MF/SS are associated with a shift from Th2 to IL-12/Th1 phenotype.

Using an animal model of ECP, investigators identified the induction of a CD8+ T-cell response against expanded clones of pathogenic T cells. Moor and Schmitt demonstrated increased synthesis of class I major histocompatibility complex molecules on the surface of a murine T-cell lymphoma line after exposure to UV-A and 8-MOP. In addition, Berger and colleagues used monoclonal antibodies and magnetic bead technology to demonstrate a tumor-specific cytolytic CD8+ T-cell response to distinctive class I–associated peptides on the surface of CTCL tumor cells in blood samples from 4 ECP patients with advanced CTCL. These data support the assertion that ECP exerts its immunologic effects by stimulating a tumor-specific CD8 T-cell response triggered by a population of tumor-loaded DCs after the ECP procedure.

To summarize: In patients with MF/SS and significant blood involvement, ECP treatment not only induces apoptosis of malignant Th2/Treg cells but also induces more mDCs, creates a proinflammatory environment for DCs to activate, and further stimulates Th1/cytotoxic T cells and immune responses.

Pharmacokinetics

8-MOP or methoxsalen is a furocoumarin with photoactivating properties. Methoxsalen, on photoactivation, conjugates and forms covalent bonds with DNA, which lead to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional (crosslinking of psoralen to both strands of DNA) adducts. Reactions with proteins have also been described. The formation of photoadducts results in inhibition of DNA synthesis, cell division, and epidermal turnover. Liquid methoxsalen (UVADEX 20 mcg/mL) is administered in a dose of 0.017 mL per 1 mL of pheresed leukocyte volume. The total dose of methoxsalen delivered in UVADEX is substantially less than (approximately 200 times) that used with oral administration. More than 80% of blood samples collected 30 minutes after reinfusion of the photoactivated cells had methoxsalen levels less than the detection limits of the assay (<10 ng/mL).

Just and colleagues explored the trafficking of the treated leukocytes following ECP using radioactively labeled leucocytes and monitoring with whole-body scintigraphy. Comparison of distribution patterns showed that PBMCs and neutrophils have different kinetic patterns after intravenous reinjection. The most prominent difference was immediate retention of PBMCs but not of neutrophils in the lungs corresponding to a signal 3 times more intense. After 24 hours, more than 80% of both cell populations could be detected in the liver and spleen.

Typical regimen

For patients with MF/SS, the typical ECP regimen is one treatment on 2 consecutive days every 4 weeks. Since FDA approval of ECP in 1988, there has been minor variability in the 2-day cycle every 4 weeks in the treatment of MF/SS. Duvic and colleagues found no increased response rate using an accelerated regimen of one 2-day cycle every 2 weeks to treat a small cohort of patients with MF/SS. More recently, Siakantaris and colleagues from Greece published their retrospective experience (N = 18) using an accelerated treatment schedule of one cycle of ECP every week for 1 month, followed by 1 cycle of ECP every 2 weeks for 2 months, and then one cycle of ECP every month. The overall response rate of 61% compares quite favorably with previously published response rates of patients with MF/SS treated with ECP combined with other systemic therapies.

The European Dermatology Forum’s guidelines on the use of ECP published in January 2014 recommends the following ECP schedule for the treatment of MF/SS: 1 cycle every 2 weeks for the first 3 months then once monthly or every 3 weeks. The investigators note, however, that there is no clear optimal therapy; other published guidelines, including the UK consensus statement on the use of ECP, have recommended 1 cycle every 2 to 4 weeks followed by tapering after maximum response.

Each ECP procedure varies between 2 and 3 hours in length based on several factors, including venous access, blood flow, hemoglobin concentrations, and technical issues. Most centers achieve peripheral access using one 16-gauge or 18-gauge needle inserted into the antecubital vein though central venous catheters, or specialized subcutaneous ports (eg, Vortex AngioDynamics, Latham, NY) that allow for rapid reverse flow during the blood collection phase of the procedure may also be used.

Response to therapy

The efficacy of ECP has been reported in more than 500 patients worldwide. Most of these reports have been small to medium size case series. There are no randomized controlled clinical trials demonstrating the efficacy of photopheresis as monotherapy in the treatment of MF/SS. Despite this, several national and international organizations have listed photopheresis as first-, second-, or third-line therapy for various stages of MF/SS.

The clinical data support the use of ECP to treat patients with erythrodermic MF (T ₄ N _0-3 M0B ₁ ) with at least some atypical circulating lymphocytes or SS (T ₄ N _0-3 M0B ₂ ), which requires significant blood involvement for diagnosis. The clinical data do not support the use of ECP to treat patients with tumor stage MF. There is some clinical data to support the use of photopheresis to treat early stage patients with MF, especially those that have at least some atypical circulating lymphocytes.

Early stage mycosis fungoides

After ECP was FDA approved in 1988, several reports emerged of patients with early stage MF responding to ECP often combined with other treatment modalities. Zic and colleagues at Vanderbilt reported preliminary and long-term follow-up data on a cohort of 20 refractory patients with MF/SS treated with ECP and adjunctive therapies. This cohort included 14 treatment-refractory patients with early stage disease (T2). Nine of 14 (64%) achieved an objective response (OR) in the skin (greater than 50% clearing of skin lesions) with 4 complete responses (CRs). For the 7 patients who at some point in their treatment achieved a CR, the median time to clearing was 11 months. For the 7 patients weaned from ECP, the mean relapse-free interval was approximately 45 months (range, 20–64 months, 2 relapses). Another important observation was that patients who responded within 6 to 8 months after starting ECP maintained their response over time.

In 2004, Child and colleagues published the results of a randomized crossover study comparing PUVA and ECP in the treatment of 20 patients with plaque stage (T2) MF who had a detectable peripheral blood T-cell clone. Eight patients completed the study. Although PUVA was more effective than ECP in improving skin scores, neither treatment modality cleared malignant T cells from the peripheral blood.

In a retrospective analysis of patients treated with ECP combined with adjuvant therapies, Siakantaris and colleagues from Greece reported a response rate of 40% (2 of 5) in patients with early stage MF as compared with a response rate of 62% (9 of 13) in patients with advanced MF/SS.

Recently, a prospective, open-label, single-arm, multicenter, investigator-initiated pilot study was completed to assess the response to ECP in patients with early stage MF (stages IA–IIA). The UVAR XTS Photopheresis System (Therakos, Inc Raritan, NJ) was used to administer ECP for 2 consecutive days once monthly for 12 months. Patients who did not respond after 6 months of ECP were treated adjunctively with oral bexarotene (150 mg/m ² ) alone or combined with interferon (IFN) alfa (1–3 million units 3 times per week). Patients with stage IA disease were only enrolled if they showed evidence of minor blood abnormality by flow cytometry assessment (B1). The primary end point was a skin involvement response assessed monthly by using the modified severity weighted assessment tool (mSWAT) assessment tool (partial response [PR] >50% improvement in mSWAT). A total of 19 patients with early stage MF (IA = 3, IB = 14, IIA = 2) were enrolled. Eight of the 12 patients who were treated with ECP monotherapy responded (67%, 2 CR), and 4 of the 7 patients who received combination therapy responded (57%, 0 CR). The overall response rate for the entire cohort (12 of 19) was 63.1%. However, if the 7 patients requiring combination therapy are considered ECP treatment failures, then the overall response rate for ECP alone was 42% (8 of 19). The median time to response was 4 months (3–8 months), and the median duration of response was 6.5 months (1–48 months). Also, quality-of-life measurements indicated an improvement in emotional scores over time.

Current National Comprehensive Cancer Network (NCCN) guidelines for non-Hodgkin lymphoma (NHL) (Version 5.2014) do not recommend ECP as primary treatment in early stage MF (IA, IB, IIA). However, in patients with stage IA, IB, and IIA disease and B1 blood involvement or those with treatment refractory disease, ECP is listed as a systemic treatment option along with retinoids, IFNs, histone deacetylase inhibitors, and methotrexate. The European Dermatology Forum published guidelines on the use of ECP in January 2014. The consensus decision was that ECP should only be considered in patients with early stage MF for clinical trial purposes as a variety of other safe, effective, and easily accessible treatment options are available for use at these stages.

Tumor stage mycosis fungoides

ECP should not be considered a primary treatment option in patients with tumor stage MF (stage IIB). In 15 patients extracted from the literature with skin stage T3 (tumor stage), no patient responded to photopheresis. One retrospective study examined the use of ECP or chemotherapy as a maintenance adjuvant treatment regimen in patients with tumor stage MF (N = 41) or erythrodermic MF/SS (N = 21) who had achieved a CR from total skin electron beam radiotherapy (TSEB). The difference between overall survival for those who received ECP (100% at 3 years) versus those who received no adjuvant therapy (50% at 3 years) approached statistical significance ( P <.06), whereas significant survival benefit from the addition of chemotherapy (75% at 3 years) for TSEB CRs was not observed. Neither adjuvant therapy provided benefit with respect to relapse-free survival after TSEB.

Erythrodermic mycosis fungoides and Sézary syndrome

Erythrodermic CTCL may be divided into erythrodermic MF (stage III, T ₄ N _0-2 M ₀ B _0-1 ) and SS (stage IVA _{1 or 2} , T ₄ N _0-3 M ₀ B ₂ ). Although there is considerable variability in the presentation and prognosis of patients with erythrodermic MF/SS, photopheresis is considered the first-line treatment by most experts. The publication of the landmark article in 1987 by Edelson and colleagues established the safety and efficacy of ECP in 22 of 29 erythrodermic patients with MF/SS. Since then, the responses of more than 518 ECP-treated patients with erythrodermic MF/SS have been published and summarized with a wide range of response rates from 33% to 74%. Many of these patients were treated with photopheresis in combination with other therapies. In addition, none of the patients were part of prospective randomized controlled clinical trials.

The United States Cutaneous Lymphoma Consortium (USCLC) recently published guidelines for the treatment of SS. In this review 118 patients with SS treated with ECP as monotherapy were extracted from the literature based on clearly defined criteria and an overall response rate defined as at least 50% clearing. Of these 118 patients, 28 (24%) responded to ECP monotherapy and 11 patients achieved a CR (9%). Higher response rates were seen in patients who received ECP in combination with other therapies ( Fig. 1 ). ECP was recommended by the USCLC as one of the primary (category A) systemic monotherapies for the treatment of SS (II-2 evidence: ≥1 prospective, well-designed cohort or case-controlled study, preferably >1 center or research group). Others in this category included IFN alfa, bexarotene, low-dose methotrexate, and denileukin diftitox plus corticosteroids.

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