Extracorporeal Photopheresis and Its Use in Clinical Dermatology in Canada

François Lagacé, MD; Elena Netchiporouk, MD, MSc, FRCPC; Irina Turchin, MD, FRCPC; Wayne Gulliver, MD, FRCPC; Jan Dutz, MD, PhD, FRCPC; Mark G. Kirchhof, MD, PhD, FRCPC; Gizelle Popradi, MD, FRCPC; Robert Gniadecki, MD, PhD, FRCPC; Charles Lynde, MD, FRCPC; Ivan V. Litvinov, MD, PhD, FRCPC

Disclosures

Skin Therapy Letter. 2022;27(5):1-6.

Abstract and Introduction

Abstract

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions. ECP was initially approved by the US FDA in 1988 for the treatment of Sézary syndrome, a leukemic form of cutaneous T-cell lymphoma (CTCL). Although CTCL remains the only FDA-approved indication, ECP has since been used off-label for numerous other conditions, including graft-versus-host disease (GvHD), systemic sclerosis, autoimmune bullous dermatoses, Crohn's disease, and prevention of solid organ transplant rejection. In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis. Herein, we review the current concepts regarding ECP mechanism of action, treatment considerations and protocols, and efficacy.

Introduction

Extracorporeal photopheresis (ECP) is an immunomodulatory therapy that has been used for over 35 years to treat numerous conditions (Figure 1).^[1,2] ECP was initially approved by the Food and Drug Administration (FDA) in the United States in 1988 for the treatment of S.zary syndrome (SS), a leukemic form of cutaneous T-cell lymphoma (CTCL) with an aggressive clinical course, characterized by a triad of circulating neoplastic T-cells, erythroderma, and lymphadenopathy.^[1] Although CTCL remains the only FDA-approved indication, ECP has since been used as an off-label treatment for numerous other conditions, including graft-versus-host (GvHD) disease, systemic sclerosis (SSc), autoimmune bullous dermatoses, Crohn's disease, and to prevent solid organ transplant rejection.^[1,2] In Canada, ECP is mainly used to treat CTCL, acute and chronic GvHD, and in some instances systemic sclerosis (Table 1 and Table 2). The goal of this article is to review the current concepts regarding ECP mechanism of action, treatment considerations as well as suggested treatment protocols and efficacy in CTCL, GvHD, systemic sclerosis and other skin diseases.

(Enlarge Image)

Figure 1.

Mechanism of action of ECP. Figure adapted from Comprehensive Dermatologic Drug Therapy by Wolverton SE.¹

ECP involves placing a catheter to gain access to the venous circulation and collecting blood via continuous or discontinuous cycles, which is then centrifuged to create a leukocyte-rich buffy coat. The isolated leukocytes are then placed in a sterile treatment cassette, injected with liquid 8-methoxypsoralen (8-MOP) and exposed to ultraviolet A (UVA) radiation. Afterwards, the photochemically-altered white blood cells are returned to the patient's venous circulation (Figure 1).^[1,2] The Therakos® ECP machine (the only available unit for this treatment) represents an automated closed system. Each treatment lasts approximately 1.5–3 hours, and the scheduling and frequency of treatments depend on the disease being treated.

The exact mechanism of action of ECP remains unknown, however, in CTCL, it is believed that the procedure leads to DNA-crosslinking and apoptosis of pathogenic T cells induced by 8-MOP with UVA exposure, the differentiation of monocytes to dendritic cell that present tumor antigens from apoptotic lymphocytes, stimulation of anti-tumor immune responses, and shifting of immunoregulatory cytokines to Th1 cytokine profile, such as interferon-gamma and tumor necrosis factor (TNF) alpha, thus restoring the Th1/Th2 balance.^[1–4] In particular, ECP targets mostly tumor cells since the absolute number of normal T cells remains relatively stable after the procedure.^[1] Given its therapeutic benefit in transplant rejection and autoimmune diseases, ECP is also believed to have unique immunomodulatory properties generating needed responses in an autoimmune setting, which are thought to be similarly mediated by DNA-crosslinking and apoptosis of autoreactive leucocytes (natural killer (NK) and T cells) and induction of T-regulatory cells after treatment, although this phenomenon was not observed in patients with SS.^[2] However, unlike immunosuppressive therapies, ECP is not associated with an increased risk of opportunistic infections.^[2] In fact, ECP is overall well-tolerated, with no reports of post-treatment Grade III or IV side effects, as per the World Health Organization classification.^[2] In particular, ECP is not associated with side-effects that are observed with skin systemic psoralen with UVA (PUVA) therapy, since the psoralen is not ingested orally nor applied to the skin.^[2] The side-effects are primarily related to fluid shifts and the need for a central catheter. Rare side-effects of ECP include nausea, photosensitivity, transient hypotension, flushing, tachycardia, congestive heart failure and thrombocytopenia.^[1,2] Contraindications to the use of ECP are summarized in Table 3. Currently, ECP is available in over 200 treatment centers across the world treating numerous diseases.^[2] The use of ECP by hospital, region and indication in Canada is summarized in Table 1 and Table 2. Unfortunately, treatment access is limited in Canada and significant knowledge gaps are recognized (i.e., paucity of randomized clinical trials and real-world evidence) amongst physicians and patients. As a result, this treatment may be significantly underused in Canada.

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Table 1. The use of ECP by hospital and by city in Canada in 2020.
Center (City, Province)	# of Procedures (# of Patients)
Atlantic Health Sciences (Saint John, NB)	416 (18)
Foothills Centre (Calgary, AB)	407 (15)
L'Enfant-Jesus (Quebec City, QC)	426 (19)
Hospital for Sick Children (Toronto, ON)	40 (1)
University Health Network (Toronto, ON)	N/A
Maisonneuve-Rosemont (Montreal, QC)	546 (25)
Royal Victoria (Montreal, QC)	294 (11)
Vancouver General Hospital (Vancouver, BC)	336 (20)
Total	2,465 (109)

Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society.

Table 2. The use of ECP by city and by indication in Canada in 2020.
# of Procedures (# of Patients)
Indication	Calgary	Montreal	Quebec City	Saint John	Vancouver	Total
CTCL (MF/SS)	131 (8)	145 (5)	195 (7)	40 (2)	84 (5)	595 (27)
aGvHD	137 (3)	33 (3)	28 (2)	8 (1)	55 (3)	261 (12)
cGvHD	137 (3)	631 (27)	89 (5)	310 (13)	197 (12)	1,364 (60)
SSc	0 (0)	0 (0)	92 (3)	30 (1)	0 (0)	122 (4)
Other	2 (1)	31 (1)	22 (2)	28 (1)	0 (0)	83 (5)
Total	407 (15)	840 (36)	426 (19)	416 (18)	336 (20)	2,425 (108)

Data from the University Health Network, Toronto, ON, where service is available, was not provided for this analysis. Data source: 2020 Canadian Apheresis Society.
CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD- acute graft vs host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

Table 3. Summary of contraindications to the use of ECP
Contraindications
Absolute	• Known sensitivity to psoralen compounds; • Pregnancy/lactation; • Aphakia; • Severe cardiac disease.
Relative	• Poor venous access; • Thrombocytopenia; • Hypotension; • Congestive heart failure; • Photosensitivity; • Personal history of heparin-induced thrombocytopenia; • Low hematocrit; • Rapidly progressing disease.

Table 4. Treatment options for CTCL (MF) ^5,6
Topical therapies	• Corticosteroids • Bexarotene gel (United States) • Chlormethine gel/nitrogen mustard Tazaroten • Imiquimod
Ultravioletlight therapies	• Narrow band UVB (if patches only) • PUVA (alone or in combination)
Systemic therapies	• Interferon alpha • Oral bexarotene • Oral alitretinoin Mogamulizumab (anti-CCR4) • Brentuximab vedotin (anti-CD30 with monomethyl auristatin E) • Histone deacetylase inhibitors Methotrexate (low dose) • Alemtuzumab (low dose)
Chemotherapy	• Pralatrexate (United States) • Gemcitabine (low dose) • Pegylated liposomal doxorubicin • CHOP (chemotherapy combination)
Additional treatments	• Local radiotherapy (solitary or few tumors) • Total skin electron beam (generalized thick plaques and tumors) • Extracorporeal photopheresis (erythrodermic MF) • Allogenic hematopoietic stem cell transplantation

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.
Skin
• Erythroderma • Plaques <10–15% total skin surface
Blood and immune system
• Low percentage of elevated circulating Sézary cells • Presence of a discrete number of Sézary cells (10–20% mononuclear cells) • CD4/CD8 ratio <10–15 • Percentage of CD4+CD7- <30% • Percentage of CD4+CD26- <30% • Normal LDH levels • Blood stage B0 or B1 • Lymphocyte count <20,000/μL • Percentage of monocytes >9% • Eosinophil count >300/mm³ • No previous intense chemotherapy • Increased NK cell count at 6 months into ECP therapy • Near-normal NK cell activity • CD3+CD8+ cell count >200/mm³ • High levels of CD4+Foxp3+CD25- cells at baseline
Lymph nodes
• Lack of bulky adenopathy
Visceral organs
• Lack of visceral organ involvement
Other
• Short disease duration before ECP (<2 years from diagnosis) • Increased peripheral blood mononuclear cell microRNA levels at 3 months into ECP monotherapy • Decreased soluble IL-2 receptor at 6 months into ECP • Decreased neopterin at 6 months into ECP • Decreased beta2-microglobulin at 6 months into ECP • Response at 5–6 months of ECP

LDH - lactate dehydrogenase; NK - natural killer; CD - cluster of differentiation; ECP - extracorporeal photopheresis

Table 6. TNMB classification of MF and SS. ⁶
T (skin)	• T1: limited patch/plaque (involving <10% of total skin surface) • T2: generalized patch/plaque (involving ≥10% of total skin surface) • T3: tumor(s) • T4: erythroderma
N (lymph node)	• N0: no enlarged lymph odes • N1: enlarged lymph nodes, histologically uninvolved • N2: enlarged lymph nodes, histologically involved (nodal architecture uneffaced) • N3: enlarged lymph nodes, histologically involved (nodal architecture (partially) effaced)
M (viscera)	• M0: no visceral involvement • M1: visceral involvement
B (blood)	• B0: no circulating atypical (Sézary) cells (or <5% of lymphocytes) • B1: low blood tumor burden (≥5% of lymphocytes are Sézary cells, but not B2) • B2: high blood tumor burden (≥1000/mcl Sézary cells + positive clone)

TNMB - tumor-node-metastasis-blood; MF - mycosis fungoides; SS - Sézary syndrome

Table 7. Clinical staging for MF and SS. ⁶
Clinical Stage	T (skin)	N (lymph node)	M (viscera)	B (blood)
IA	T1	N0	M0	B0–1
IB	T2	N0	M0	B0–1
IIA	T1–2	N1–2	M0	B0–1
IIB	T3	N0–1	M0	B0–1
III	T4	N0–2	M0	B0–1
IVA1	T1–4	N0–2	M0	B2*
IVA2	T1–4	N3*	M0	B0–2
IVB	T1–4	N0–3	M1*	B0–2

MF - mycosis fungoides; SS - Sézary syndrome
*The required features for the three subdivisions of stage IV disease

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020. ^2,11
Cutaneous Disease	Patient Selection	Treatment Schedule	Maintenance Treatment	Response Assessment
CTCL (MF/SS)	First-line treatment in erythrodermic stage IIIA or IIIB, or stage IVA1-IVA2	One cycle every 2 weeks at first, then every 3–4 weeks. Continue treatment for at least 6–12 months	Treatment should not be stopped, but prolonged for >2 years, with treatment intervals up to 8 weeks	To be conducted every 3 months. Treatment failure with ECP cannot be established before 6 months
aGvHD	Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day	2–3 treatments per week for 4 weeks	There is no evidence that maintenance therapy is beneficial. Discontinue ECP in patients with complete response	Every 7 days with staging
cGvHD	Second-line therapy in patients that are refractory to corticosteroids at a dose of 2 mg/kg/day or steroid intolerant or steroid dependant	One cycle every 1–2 weeks for 12 weeks followed by interval prolongation depending on response	Treatment intervals can be increased by 1 week every 3 months depending on response, and only after 12 weeks of treatment	Disease monitoring as per the National Institutes of Health guidelines
SSc	Second-line or adjuvant therapy as monotherapy or in combination with other therapy. Can be used to treat skin (but not internal organ involvement)	One cycle every 4 weeks for 12 months	Based on clinical response, increase intervals by 1 week every 3 months	Clinically, and with validated scoring systems and photography
Atopic dermatitis	Second-line therapy if: • >18 months duration • SCORAD >45 • refractory to all first-line therapies and one second line therapy	One cycle every 2 weeks for 12 weeks	Intervals depend on the individual response; at maximal treatment response, ECP should be tapered by one treatment cycle every 6–12 weeks	SCORAD assessment every 2 weeks for the first 12 weeks, then every ≥4 weeks
Pemphigus, epidermolysis bullosa acquisita, erosive oral lichen planus	Recalcitrant to conventional systemic therapies	One cycle every 2–4 weeks for 12 weeks, then one cycle every 4 weeks	Taper by increasing intervals by 1 week every 3 months	Clinically, and with validated scoring systems and photography (and with antibody titers in the case of pemphigus)
Lupus erythematosus, psoriasis, morphea, nephrogenic fibrosing dermopathy and scleromyxedema			No current recommendations, more studies needed

SCORAD - SCORing atopic dermatitis; ECP - extracorporeal photopheresis; CTCL - cutaneous T-cell lymphoma; MF - mycosis fungoides; SS - Sézary syndrome; aGvHD - acute graft vs. host disease; cGvHD - chronic graft vs. host disease; SSc - systemic sclerosis

Authors and Disclosures

François Lagacé, MD¹, Elena Netchiporouk, MD, MSc, FRCPC¹, Irina Turchin, MD, FRCPC^2–4, Wayne Gulliver, MD, FRCPC⁵, Jan Dutz, MD, PhD, FRCPC⁶, Mark G. Kirchhof, MD, PhD, FRCPC⁷, Gizelle Popradi, MD, FRCPC⁸, Robert Gniadecki, MD, PhD, FRCPC⁹, Charles Lynde, MD, FRCPC¹⁰ and Ivan V. Litvinov, MD, PhD, FRCPC¹

¹Division of Dermatology, McGill University, Montreal, QC, Canada
²Brunswick Dermatology Center, Fredericton, NB, Canada
³Division of Clinical Dermatology & Cutaneous Science, Dalhousie University, Halifax, NS Canada
⁴Probity Medical Research, Waterloo, ON, Canada
⁵Department of Dermatology, Discipline of Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
⁶Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
⁷Division of Dermatology, University of Ottawa, Ottawa, ON, Canada
⁸Division of Hematology, Department of Medicine, McGill University, Montreal, QC, Canada
⁹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
¹⁰Division of Dermatology, University of Toronto, Toronto, ON, Canada

Conflict of interest
Elena Netchiporouk has received grants, research support from Novartis, Sanofi, Sun Pharma, AbbVie, Biersdorf, Leo Pharma, Eli Lilly; speaker fees/honoraria from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma and consulting fees from Bausch Health, Novartis, Sun Pharma, Eli Lilly, Sanofi Genzyme, AbbVie, Galderma, Novartis, Sanofi Genzyme, Sun Pharma, Bausch Health and Leo Pharma. Irina Turchin served as advisory board member, consultant, speaker and/or investigator for AbbVie, Amgen, Arcutis, Aristea, Bausch Health, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Incyte, Janssen, Kiniksa, Leo Pharma, Mallinckrodt, Novartis, Pfizer, Sanofi, UCB. Wayne Gulliver received grants/research support from AbbVie, Amgen, Eli Lilly, Novartis and Pfizer; honoraria for advisory boards/invited talks from AbbVie, Actelion, Amgen, Arylide, Bausch Health, Boehringer, Celgene, Cipher, Eli Lilly, Galderma, Janssen, Leo Pharma, Merck, Novartis, PeerVoice, Pfizer, Sanofi-Genzyme, Tribute, UCB, Valeant and clinical trial (study fees) from AbbVie, Asana Biosciences, Astellas, Boehringer-Ingelheim, Celgene, Corrona/National Psoriasis Foundation, Devonian, Eli Lilly, Galapagos, Galderma, Janssen, Leo Pharma, Novartis, Pfizer, Regeneron, UCB. Gizelle Popradi has received honoraria or speaker fees from Jazz Pharma, Seattle Genetics, Abbvie, Kite Gilead, Pfizer, Taiho, Servier, Novartis, Merck, Kyowa Kirin, Abbvie, Avir Pharma, Mallinckrodt. Robert Gniadecki reports carrying out clinical trials for Bausch Health, AbbVie and Janssen and has received honoraria as consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallincrodt, Novartis, Kyowa Kirin, Sun Pharma and Sanofi. Charles Lynde was a consultant, speaker, and advisory board member for Amgen, Pfizer, AbbVie, Janssen, Novartis, Mallincrodt, and Celgene, and was an investigator for Amgen, Pfizer, AbbVie, Janssen, Lilly, Novartis, and Celgene. Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Topics included in this article were based on, but not limited to, broad discussions at an advisory board meeting, which was sponsored and funded by Mallinckrodt, Inc. Consultancy fees were paid to meeting participants (EN, IT, WG, JD, MK, RG, CL and IVL). All other authors declare no existing competing interests.