Extracorporeal Photopheresis for the Inpatient Dermatologist

Evidence is lacking for a synergistic or additive effect ofcombination extracorporeal photopheresis with interferon alfa for cutaneousT-cell lymphoma

Evidence is lacking for a synergistic or additive effect of combination extracorporeal photopheresis with interferon alfa for cutaneous T-cell lymphoma

Extracorporeal photopheresis (ECP) is a technique that was developed > 20 years ago to treat erythrodermic cutaneous T-cell lymphoma (CTCL). The technique involves removal of peripheral blood, separation of the buffy coat, and photoactivation with a photosensitizer and ultraviolet A irradiation before re-infusion of cells. More than 1000 patients with CTCL have been treated with ECP, with response rates of 31-100%. ECP has been used in a number of other conditions, most widely in the treatment of chronic graft-versus-host disease (cGvHD) with response rates of 29-100%. ECP has also been used in several other autoimmune diseases including acute GVHD, solid organ transplant rejection and Crohn's disease, with some success. ECP is a relatively safe procedure, and side-effects are typically mild and transient. Severe reactions including vasovagal syncope or infections are uncommon. This is very valuable in conditions for which alternative treatments are highly toxic. The mechanism of action of ECP remains elusive. ECP produces a number of immunological changes and in some patients produces immune homeostasis with resultant clinical improvement. ECP is available in seven centres in the UK. Experts from all these centres formed an Expert Photopheresis Group and published the UK consensus statement for ECP in 2008. All centres consider patients with erythrodermic CTCL and steroid-refractory cGvHD for treatment. The National Institute for Health and Clinical Excellence endorsed the use of ECP for CTCL and suggested a need for expansion while recommending its use in specialist centres. ECP is safe, effective, and improves quality of life in erythrodermic CTCL and cGvHD, and should be more widely available for these patients.

Use of Extracorporeal Photopheresis (ECP) in the Treatment of Patients with Cutaneous T-Cell Lymphoma (CTCL), 2010-2015

Prec-P-01 - Preclinical investigation of new targeted combination therapies in cutaneous T-cell lymphoma

A Retrospective Study of Extracorporeal Photopheresis (ECP) in Treatment of Cutaneous T-Cell Lymphoma (CTCL) Evaluating Global, Skin and Blood Responses

Foxp3 Expression Is Induced in Peripheral Blood Mononuclear Cells from Patients with CTCL and GVHD after Extracorporeal Photopheresis

Induction of remission in a patient with end-stage cutaneous T-cell lymphoma by concurrent use of radiation therapy, gentian violet, and mogamulizumab

Aim:To present well-known and disputable mechanisms of the effects of extracorporeal photopheresis (ECP) in heterogeneous clinical conditions, as well as to demonstrate its advantages over conventional hormonal, immunosuppressive and cytostatic treatments, with a recommendation to widely implement it into practical management of autoimmune disease and cutaneous T-cell lymphomas (CTCLs).Key points:Despite convincing evidence of the ECP efficacy in the treatment of T-cell mediated disorders, a unifying concept of its mechanism has not been established so far. In this review, we attempted to determine the value of multiple, sometimes contradictory and equivocal points of view to immunobiochemical processes underlying the restoration of mechanism of immune tolerance in some autoimmune diseases and CTCLs. We focused our attention on our own clinical and immunological data obtained during a 20-years' experience with the use of ECP in clinical departments of MONIKI (Russia). Based on this, we have shown that ECP is more effective in autoimmune diseases than conventional treatment approaches with hormones, immunosuppressants and cytostatics. Unlike them, ECP is selectively targeted to auto-aggressive T-cells without induction of systemic immunosuppression. The leading role is played by the transformation of activated (immunogenic) myeloid dendrite cells (DC) into tolerogenic cell associated with their synthesis of inhibitor cytokines. The interplay of the cytokines with an antigen results in polarization of CD4+ Т lymphocytes via the Th2 pathway with restoration of the Th1/Th2 balance and their cytokine production. ECP triggers regulatory anti-clonotypic effector memory cells at the end stage of CD3+/CD8+/CD27-/CD28-/CD62L+ differentiation, that provide and maintain the peripheral immune tolerance, by deletion of the clone of auto-reactive cytotoxic lymphocytes and inducing their apoptosis. In autoimmune disorders, ECP results in reduction of the expression of integrin adhesion molecules on auto-reactive cell membranes with subsequent loss of their ability to migrate through the endothelium to their target cells. In its turn, it leads to decreasing immunoinflammatory response in the lesion. Both clinical and experimental data indicate that the mechanism of ECP action against CTCLs is characterized by activation of tumor cell apoptosis, unblocking of co-activation receptors on the antigen-presenting DC providing the functioning of the second signaling pathway for T lymphocyte activation. This results in proliferation of anti-tumor effector cells pool, production of DC activating cytokines that participate in the CD4+ polarization via Th1 pathway. In addition, this review considers the mechanism of the immunomodulating effect of ECP in the context of its influence at the levels of transcription and translation of proteins contributing to the pathophysiology of the disorders, based on molecular immunogenetic studies. Thus, ECP is able to induce antigen-specific immunological tolerance through the transformation of antigen-presenting cells, modulation of cytokine profile, adhesion and activation molecules, as well as through formatting of the regulatory T cells (Tregs).Conclusion:Undoubtedly, the immunobiological ECP technique has significant advantages over well-known conventional hormonal, immunosuppressive, and cytostatic therapies of autoimmune diseases and CTCLs.

Background.Extracorporeal photopheresis (ECP) is a therapy indicated for various T cell–mediated conditions, including cutaneous T-cell lymphoma (CTCL), graft-versus-host disease (GVHD), and solid organ transplant rejection. ECP comprises the treatment of patients’ leukocytes with 8-methoxypsoralen and ultraviolet-A light followed by autologous reinfusion. ECP exerts therapeutic immune-stimulatory effects in CTCL and immune regulatory effects in GVHD and solid organ transplant rejection. Besides cellular mediators, secreted molecules can contribute to ECP’s therapeutic effect.Methods.We conducted a comprehensive review of the literature on ECP-induced secreted factors and their immunomodulatory roles.Results.8-Methoxypsoralen/ultraviolet-A treatment drives leukocyte apoptosis, resulting in the release of damage-associated molecular patterns that promote apoptotic cell phagocytosis by dendritic cells (DCs) and promote or impair DC maturation. In CTCL, the increased production of proinflammatory cytokines in photopheresates, including interferon-γ, interleukin (IL)-2, tumor necrosis factor-α, IL-1β, and IL-8, is linked to antitumor responses. Conversely, ECP upregulates anti-inflammatory cytokine production in photopheresates from GVHD patients’ cells. Upon reinfusion of photopheresates containing anti-inflammatory factors, untreated immature DCs are converted to tolerogenic DCs with increased IL-10 and transforming growth factor-β secretion and regulatory T cell–inducing functions. In allograft models, ECP increases IL-4, IL-10, and IL-13, which reduce allograft rejection. Moreover, ECP influences the level of immunomodulatory metabolites and the composition of exosomes. However, further research, for example, using multi-omics approaches, are needed to provide a more comprehensive picture of the ECP-induced secretome and to identify relevant factors that could contribute to ECP’s therapeutic effects.Conclusions.ECP induces the release of different pro/anti-inflammatory factors in different preexisting conditions that determine different DC maturation status and immunomodulatory effects.

Cutaneous T-cell lymphoma (CTCL) is the general term used to describe extracutaneous non-Hodgkin’s lymphomas characterized by monoclonal expansion of skin-homing malignant T cells that can further be defined by the use of immunophenotypic markers and the presence of specific rearrangements of the T-cell receptor. The most frequently diagnosed form of CTCL is mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SS). MF most often presents as chronic eczematous or psoriasiform patches or plaques and can remain stable for many years. In some patients, MF progresses to involve lymph nodes, peripheral blood, bone marrow, and visceral organs. SS may present de novo with persistent exfoliative erythroderma accompanied by staphylococcal colonization, perivascular atypical lymphocytes in the dermis, and ‡1000 atypical T lymphocytes/mm in the blood, a criterion recently defined as a B2 blood rating by the International Society for Cutaneous Lymphomas. Extracorporeal photopheresis (ECP) combines blood apheresis with ultraviolet-A irradiation of psoralen-photosensitized peripheral blood mononuclear cells. ECP was first introduced in 1987 for the treatment of erythrodermic MF and SS. ECP was the first therapy to receive FDA approval for the treatment of CTCL based on a multicenter trial. Twenty-seven of 37 patients (76%) achieved a 25%–100% reduction in their erythroderma skin score. The Yale–New Haven Hospital experience has been reviewed by Heald et al. who treated 32 patients with ECP. Of 19 erythrodermic patients who were treated with ECP as their first therapy at Yale, five had greater than 75% improvement of their skin score, ten had 25%– 50% improvement, and four had less than 25% improvement. The majority of patients had improved quality of life. Heald et al. also evaluated long-term followup in 29 original CTCL patients in the original multicenter study. Their mean survival from the time of diagnosis was 60.3 months and from beginning of therapy it was 47.9 months, which exceeds their expected mean overall survival of 24–30 months reported in the literature. Four of six patients in the original study had prolonged responses. Favorable prognostic factors in both analyses were normal CD4-to-CD8 ratios at baseline suggesting that the presence of CD8+ cytotoxic T cells is required for response. Other studies conducted by investigators around the world have verified the initial study, reporting response rates between 50% and 75%, with complete response rates of 10%–5% (Table I). In patients with stable disease, investigators have claimed that photopheresis improves overall patient survival, improves quality of life, and extends response to total body skin electron beam radiation. This is in contrast to chemotherapy that does not increase overall survival if used as front-line therapy for CTCL patients. Although approved for treatment of erythrodermic patients (T4 skin rating), ECP has also produced remissions in patients with clinically early MF and with tumor phase disease. The addition of biological response modifiers, such as interferon a, granulocyte macrophage colony stimulating factor (GM-CSF), and retinoids, to ECP has been shown to result in higher response rates as reviewed by Rook et al. Gottlieb et al. reported a ten-year experience at the University of Pennsylvania using ECP alone and in combination with rIFN-a. Thirty-one of the 41 patients with CTCL who received more than six months of photopheresis therapy had evaluable disease. Twentyeight of the 31 patients had ECP monotherapy, with the following results: 7 of 28 patients had complete remission (25%), 13 of 28 patients had partial remissions (46%), and 8 out of 28 were nonresponders (29%). Seventy-one percent of the patients had greater than 50% clearing. This study found an overall intent-to-treat response rate of 48%, with 17% complete responses and 31% partial responses. A favorable response predictor was the presence of Sezary cells in the peripheral blood at onset of therapy. The median time to treatment failure was 18 months. The median survival from initiation of therapy was 77 months. The median survival from diagnosis was greater than 100 months and 77 months from initiation of ECP, suggesting that photopheresis increased overall survival in advanced patients.

Extracorporeal photopheresis for paediatric patients experiencing graft-versus-host disease (GVHD).

Tre-P-20 - Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T cell lymphoma at a tertiary care centre

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy characterized by the exposure of leukocytes to 8-methoxypsoralen and UV light irradiation, followed by reinfusion of the treated cells into the patient. ECP is considered a safe and well-tolerated procedure that preserves the beneficial aspects of immunity, such as antitumor and antiviral activities, with a low rate of side effects. Currently, ECP is used for the treatment of immune-mediated conditions, such as cutaneous T-cell lymphoma, graft-versus-host disease, solid organ transplant rejection, and autoimmune disorders. ECP is an immunomodulatory therapy characterized by multiple complex events that lead to the modulation of the immune response. Modifying the activity of myeloid antigen-presenting cells with apoptotic cell remnants is key to the therapeutic action of ECP; however, because the pathological roles of macrophages and dendritic cells are context specific, the precise effects of ECP vary between different diseases. Consequently, we need a much better understanding of the immunology and pharmacology of ECP to extend its use in solid organ transplantation and beyond. During the past decades, important advances were made using animal models of ECP, leading to a better mechanistic understanding and its more rational use in many T cell-mediated conditions. This review summarizes the available information on animal models of ECP, providing insights into the mechanisms of action, therapeutic applications, limitations, and translational potential from preclinical animal models to human clinical practice.

Introduction: Extracorporeal photopheresis (ECP) has been extensively used for the treatment of immune-mediated diseases for over 20 years and has a consistent and predictable safety profile with long-term use. Documenting the efficacy of ECP as therapeutic treatment has long been a matter of importance for physicians. Areas covered: The authors reviewed publications in this field with the goal of providing an overview of this therapeutic approach. Expert opinion: ECP is efficacious in a high percentage of those cutaneous T-cell lymphoma patients who have circulating malignant T cells in the context of a still-near-normal immune competence. From the side of graft-versus-host disease (GVHD), the use of ECP showed a clinical benefit in patients with steroid-refractory acute GVHD (aGVHD) and it is believed that ECP deserves to be evaluated as part of a combination strategy in first-line therapy of aGVHD. In chronic GHVD, the published data show that ECP can be effective in extensive and long-standing disease even when treatment is initiated at an advanced stage after conventional immunosuppressive and corticosteroid therapy has failed. ECP should be considered most beneficial for patients with predominantly mucocutaneous chronic GVHD. The fields of application of the procedure could be vast, and could also include autoimmune and metabolic diseases. The most important methodological issues which affect ECP evaluation is that the large majority of data about ECP result from single-arm observational series and the significant efficacy is mainly based on small and retrospective studies. ECP has never been proved to offer any survival advantage in a context of a randomized trial and the above-mentioned limitation also affects the accuracy of many biological modifications observed during ECP. Starting from these considerations, the need of a prospective randomized study becomes increasingly urgent.