¹Division of Dermatology, University of Alberta, Edmonton, AB, Canada
²Recordati Rare Diseases Canada Inc., Toronto, ON, Canada

Conflict of interest: Robert Gniadecki reports carrying out clinical trials for Bausch Health, Sanofi, AbbVie and Janssen and has received honoraria as a consultant and/or speaker from AbbVie, Bausch Health, Eli Lilly, Janssen, Mallinckrodt, Novartis, Kyowa Kirin, Recordati, Sun Pharma and Sanofi. Emilia Paron is an employee of Recordati Rare Diseases Canada Inc.

Funding sources: None.

Abstract:
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), representing almost 50% of all lymphomas arising in the skin. There is an unmet need in the treatment of MF in Canada, as current available therapies for early-stage MF are limited, without topical agents previously indicated. Chlormethine gel is a topical antineoplastic agent with phase II clinical trial and real-world data demonstrating safety and efficacy as a treatment option for adults with MF. Skin-related side effects such as dermatitis can be managed through appropriate strategies. The use of chlormethine gel can be considered for patients with stage IA and IB MF-CTCL as it provides an easily administered, skin-directed treatment option that fills an unmet need in Canada.

Keywords: mycosis fungoides (MF) cutaneous T-cell lymphoma, chlormethine gel, topical treatment, alkylating agent, Ledaga™

Introduction

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL), which primarily manifests in the skin.^1-5 The prognosis of MF depends on the type and extent of skin lesions and extracutaneous disease.⁶ In early stages (IA-IIA), the lesions comprise red, scaly patches or plaques and as disease progresses to late stages (≥IIB), the patients develop skin tumors, often with ulcerations.⁶ Diagnosis is often delayed as patients can experience several years of nonspecific skin changes that may resemble psoriasis or eczema.^5,7

MF typically affects adults with a median age at diagnosis of 55-60 years, and a male-to-female ratio of 1.6-2:1.⁸ In Canada, the annual national incidence of MF is estimated at 4 cases per million individuals per year, with a mortality rate of approximately 0.4 deaths per million annually observed from 1992 to 2010.⁹

Early-stage MF patients represent approximately 70% of cases and most achieve normal life expectancy, with treatment aiming to prevent evolution to more severe disease and relieve burden on quality of life. Approximately 30% of patients progress to advanced disease (stage IIB or higher), and the 5-year survival rate is unfavorable: only 47% (stage IIB) to 18% (stage IVB). Many patients with MF experience comorbidities impacting their functional, emotional, and social well-being, such as cardiovascular events and secondary cancers.^10-14 Currently, apart from allogeneic stem cell transplantation, there is no cure for MF, and treatment approaches focus on patients’ health-related quality of life (HRQOL).¹⁰ In Canada, there remains an unmet need for novel MF therapies to address treatment gaps.

Chlormethine gel is a Health Canada approved topical antineoplastic agent for the treatment of stage IA and IB MF-CTCL in adult patients who have received prior skin‐directed therapy.¹⁵ Regulatory approval for MF-CTCL has also been granted by the US FDA and European Medicines Agency. Evidence from a phase II clinical trial and real-world experience with chlormethine for over 30 years demonstrates chlormethine gel as a convenient topical agent with an efficacious and well-tolerated safety profile for adults.^16-22

Diagnosis, Pathogenesis and Treatments of MF

Diagnosis of MF is often performed by a multi-disciplinary team of specialists, including dermatologists, hematologists, dermatoand hematopathologists.^23,24 For histopathological confirmation, multiple skin biopsies are often required, and molecular studies (T-cell receptor clonality analysis) and immunostainings are needed. Full staging is usually not required in the early stage (IA) because the disease is confined to the skin, but imaging and peripheral blood flow cytometry should be considered in stages IB and higher. The diagnosis can be delayed for years due to the likeness of MF to benign conditions that lack specific diagnostic tests.^24,25 As such, guidelines have been prepared for recommendations of diagnosis, initial staging, and diagnostic algorithms for treatment (Table 1).^26,27

In early stages of MF, malignant T-cells accumulate in the papillary dermis and epidermis and are accompanied by an abundant inflammatory infiltrate. With disease progression, malignant T-cells become polarized into the T helper 2 (Th2) pattern and secrete cytokines impairing local and systemic immunity and promoting inflammation.²⁸ Recent evidence suggests that hematogenous spread of malignant cells between different areas of the skin is responsible for disease progression.²⁹ Secondary infections with Staphylococcus aureus are common and may further exacerbate the disease.^30,31 Extracutaneous involvement comprises most commonly in the peripheral blood and the lymph nodes, with occasional metastases to parenchymatous organs such as the spleen, brain, lung, kidney or liver.^30,31

At all stages, the aim of treatment is to decrease malignant cell burden and identify and control comorbidities.^23,32 As MF is a rare disease, randomized clinical studies are lacking and treatment nationally is based mainly on international guidelines and clinical experience. Given the limited evidence base for many treatments, there have been no topical pharmacotherapies specifically approved for MF in Canada until chlormethine gel was approved in 2021.¹⁵ In all stages, skin directed therapies (SDT) remain the mainstay of treatment and are combined with systemic therapies when needed.^8,24,26,27 SDT for early-stage MF may consist of one or more of the following: topical corticosteroids, topical retinoids (including tazarotene indicated for the topical treatment of acne vulgaris),³³ topical imiquimod, topical carmustine, psoralen plus ultraviolet A (PUVA), narrowband ultraviolet B (UVB), radiation therapy and total skin electron beam therapy (TSEBT).²⁷

Topical steroids are typically used for patients as background treatment to manage the symptoms of MF, such as pruritus, rather than to treat the disease.²³ Data supporting the use of imiquimod and carmustine are limited to case series.^34-36 Phototherapies (PUVA, narrowband UVB) are the most frequently used treatments for early-stage disease,^8,23,27 however many patients in Canada have limited access.

Thus, the scarcity of robust, comparative data informing treatment guidelines underscores the unmet need for accessible SDT in MF.³⁷

Chlormethine Gel: Mechanism of Action, Completed and Ongoing Studies

Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells. Chlormethine binds to N7 positions in guanines via reactive chloroethyl moieties and potentially also binding to N3 positions in adenines in DNA. The bifunctional nature of chlormethine along with its small molecular size allows it to form interstrand cross-links within DNA, making it a more effective tumor chemotherapeutic agent than monofunctional analogues. Unrepaired cross-links prevent transcription, replication, and segregation of DNA, ultimately causing cell death.¹⁵ Indeed, a recent in vitro study by Chang YT et al. demonstrated that chlormethine, as an alkylating agent, is able to inhibit predominantly rapidly proliferating malignant skin T-cells, through the induction of DNA breaks, the impairment of the DNA repair machinery and by increasing the expression of apoptotic gene (CASP3).³⁸ The formulation of chlormethine gel was designed to maximize efficacy and tolerability. The non-aqueous nature of chlormethine gel imparts high stability, and the solvent, diethylene glycol monoethyl ether (DEGEE), promotes delivery of the drug to the epidermis,³⁹ with no evidence of systemic absorption of chlormethine following gel application.⁴⁰ DEGEE has shown to be non-skin irritating even after prolonged and repeated contact.⁴¹ No risk to patients with suppressed bone marrow or COVID-19 has currently been identified in the literature with chlormethine gel.

The pivotal phase II study (201) evaluated 0.02% chlormethine gel (n=130) vs. 0.02% chlormethine ointment (n=130) for the treatment of patients with persistent or recurrent stage I or IIA disease. Diagnosis was confirmed with a skin biopsy of a representative lesion, obtained in the 90 days prior to study initiation and after a 4-week treatment washout period of treatments directed at the disease.⁴² Patients were not taking concomitant corticosteroids during the study. Chlormethine gel was applied once-daily to specific lesions (stage IA) or to the total skin surface (stage IB/IIA) for up to 12 months. Study 201 comprised a pre-study visit (screening), a baseline (Day 1) visit, and monthly visits for 6 months and then visits every 2 months up to month 12.⁴³

Response rates (RR) for chlormethine gel were consistently higher than those for chlormethine ointment for the primary endpoint of Composite Assessment of Index Lesion Severity (CAILS). In the intention-to-treat (ITT) population, the confirmed RR was higher for the gel than ointment (59% vs. 48%) and the criterion for non-inferiority was met.⁴² Similar efficacy results were seen between stratum 1 (stage IA) and stratum 2 (stages IB/IIA) patients. In the efficacy evaluable (EE) population, 77% of patients receiving gel vs. 59% of patients receiving ointment achieved a confirmed CAILS response (Figure 1). In study 201, time to CAILS response was defined as the time from baseline to the first confirmed CAILS response [complete response (CR), defined as 100% improvement, with a score of 0, or partial response (PR), defined as a 50% to 100% reduction from baseline score]⁴³ and was achieved in the gel arm at 26 weeks and 42 weeks in the ointment arm. Therefore, patients in the gel arm attained a 50% RR approximately 16 weeks sooner than patients in the ointment arm.

In addition, the RR improved the longer patients were treated with chlormethine gel. Approximately 46% of patients treated with gel achieved a confirmed response at 24 weeks and 76% achieved a confirmed response at 52 weeks. Continued treatment and monitoring is recommended to ensure optimal patient response as the maximum response to chlormethine gel treatment was observed between 8 and 10 months in the pivotal study,^42,43 and a by-time reanalysis of study 201 demonstrated early, late and intermittent response patterns.⁴⁴

Duration of response (DOR) based on CAILS score in the ITT population was analyzed and 86% patients in the gel arm and 82% patients in the ointment arm maintained their response through the end of the trial (12 months). It is estimated that at least 90% of responses will be maintained for ≥10 months, the maximum follow-up in the trial.^42,43

In study 201, 61.7% of patients who received gel and 50.4% of patients who received ointment reported at least one adverse event (AE) that was considered related to the study drug.⁴² Dermatitis (54.7%) was most common,¹⁵ although this was managed with treatment adjustments, such as suspension or reduction of chlormethine treatment and the use of emollients or oral antihistamines.⁴² In study 201, the following guidance was implemented in the protocol to manage dermatitis: treatment should be stopped for any grade of skin ulceration or blistering, or moderately severe or severe dermatitis. Upon improvement, treatment can be restarted at a reduced frequency (once every 3 days), and if treatment is tolerated for at least 1 week, the frequency of application can be increased to every other day for at least 1 week and then to once-daily application if further tolerated.¹⁵ No treatment-related serious AEs were reported, and no statistically significant differences were observed in the overall incidence of AEs or any other subcategory between the gel and the ointment arms.⁴² The safety data from study 201 was consistent with the lack of systemic exposure to chlormethine or its degradation product.⁴² In real-world practice, irritant contact dermatitis has been observed most frequently.⁴⁵ Results from the Mechlorethamine Induced Contact Dermatitis Avoidance Study (MIDAS) study suggest that patients who develop allergic contact dermatitis in response to chlormethine gel treatment may have an allergic-type phenotype that predisposes to cutaneous reactions to common allergens, unrelated to chlormethine treatment.⁴⁶ Chlormethine gel is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.¹⁵

Real-world evidence has shown further efficacy and safety of chlormethine gel in the treatment of MF as demonstrated in the prospective, observational, non-interventional US-based PROVe trial over a 2-year period.⁴⁷ Patients were enrolled if they were diagnosed with any stage of MF and were being treated with chlormethine gel in combination with other MF therapies. The proportion of stage IA and IB responders [defined as ≥50% reduction from baseline in body surface area (BSA) involvement] was 44% in patients who received chlormethine gel plus topical corticosteroids plus other treatment and 45% in patients who receive chlormethine and other treatment at 12-month evaluation. Peak response occurred at 18 months for stage IA and IB patients in the chlormethine gel plus other treatment group (67%). In this study, HRQOL was assessed with the Skindex-29 questionnaire. Post-baseline weighted mean subscale scores for responders showed a better HRQOL than for non-responders. The differences between responders and non-responders were statistically significant (p<0.001 for each subscale) indicating that chlormethine gel improved HRQOL in patients responding to treatment. Treatment-related AEs were experienced in 28% of patients; most commonly dermatitis (12%), pruritus (7%), skin irritation (7%) and erythema (4%).⁴⁷

Chlormethine gel has demonstrated efficacy and safety in the treatment of patients with MF globally, and experience from clinical practice has shown chlormethine gel used both as monotherapy in early-stage MF and in combination with other therapies in advanced-stage disease. Emergent cutaneous reactions can be managed if appropriate protocols are followed. Application frequency modifications such as gradual initiation of chlormethine gel 1-4 times a week and increasing to once daily application upon toleration, with most centers using topical steroids to manage skin-related AEs.^45,48,49

The incidence and severity of contact dermatitis following treatment with chlormethine gel alone or in combination with triamcinolone ointment in patients with MF has been evaluated in the MIDAS study⁵⁰ and the ongoing REACH trial (Study to Determine the Aetiology of Chlormethine Gel Induced-skin Drug Reaction in Early-Stage Mycosis Fungoides Cutaneous T cell Lymphoma) (NCT04218825), may provide further information on how to manage dermatitis for patients treated with chlormethine gel.

Conclusion

Major international guidelines recommend the use of chlormethine gel as a first-line treatment in adult patients with early-stage MF^{8,23,26,27,51} and chlormethine gel is approved for the treatment of stage IA and IB MF-CTCL in adults who have received prior skin‐directed therapy in Canada.¹⁵ Chlormethine gel demonstrates improvements in CAILS, mSWAT and BSA during a phase II clinical trial with patients treated with chlormethine gel achieving response faster and maintaining response for a longer period of time.⁴² Real-world evidence demonstrates improvements in HRQOL for patients on treatment.⁴⁷ AEs related to chlormethine gel use are overall consistent with the lack of systemic exposure to chlormethine and its degradation product, and the occurrence of skin-related events such as dermatitis can be managed through frequency of application reduction and appropriate strategies.^45,48,49 Overall, chlormethine gel provides a valuable role in the management of MF.

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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.

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.

Key Words:
extracorporeal photopheresis, cutaneous T-cell lymphoma, S.zary syndrome, systemic sclerosis, graft-versus-host disease, safety.

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 (Tables 1-2). 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.

Table 1. The use of ECP by hospital and by city in Canada in 2020.

Table 2. The use of ECP by city and by indication in Canada in 2020.

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 Tables 1-2. 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.

Table 3. Summary of contraindications to the use of ECP

CTCL

CTCL represents a group of lymphoproliferative disorders where there is an accumulation of malignant T-cell clones in the skin.² The most commonly recognized forms of CTCL are mycosis fungoides (MF) and SS. There are currently no curative treatments for CTCL, except for allo-transplantation which has been successful in select patients.² ECP is often used as a first-line treatment for SS, as well as for patients with erythrodermic MF or advanced CTCL.¹ Its use in early stages of CTCL remains controversial and impractical in Canada as many other effective treatment modalities are available (Table 4).^5,6 ECP can be used as monotherapy or it can be safely given in combination with phototherapy (narrow band or broadband UVB), radiotherapy, total skin electron beam (TSEB), systemic retinoids, interferons, anti-CCR4 monoclonal antibodies, histone deacetylase inhibitors, methotrexate, and/or other treatments.^1,2 One meta-analysis of 400 patients with all stages of CTCL showed a combined overall response rate (ORR) of 56% both when ECP was used as monotherapy and in combination with other therapies.² The complete response (CR) rates were 15% and 18% for monotherapy and combination therapy, respectively.² However, the ORR and CR were 58% and 15%, respectively, in erythrodermic patients, and 43% and 10% in patients with SS.² The CR was defined as a complete resolution of clinical evidence of disease and for normalization of CD4/CD8 ratio for at least 1 month. The partial response (PR) was defined as greater than 25% but less than 100% decrease in lesions and no development of new lesions for at least 1 month. ORR was defined as a sum of PR and CR. Furthermore, the United Kingdom consensus statement analyzed 30 studies between 1987 to 2007 and determined that the mean ORR and CR rates were 63% (range 33-100%) and 20% (range 0-62%), respectively, with higher response rates observed in erythrodermic patients. Many factors can explain the variability in the results of these studies, such as patient selection bias, stage of the disease, ECP treatment schedule, prior treatments, and end-point definitions.² In addition, there is a significant amount of inter-subject variability in response rates to ECP and factors that predict treatment response, as summarized in Table 5.²

Table 4. Treatment options for CTCL (MF)

Table 5. Baseline parameters and predictors of response to ECP in the treatment of cutaneous T-cell lymphoma, as per the European Dermatology Forum.

Different countries have varying guidelines with respect to the use of ECP in CTCL. Most recently, the European Dermatology Forum (EDF) published new recommendations in 2020. They recommend considering ECP as first-line therapy in patients with MF clinical stages IIIA or IIIB (erythroderma), or MF/SS stages IVA1 or IVA2 (Tables 6-7). Treatments are recommended every 2 weeks for the first 3 months, then every 3-4 weeks, with a treatment period of at least 6 months or until remission is achieved, followed by a maintenance period (Table 8).² ECP can take 3-6 months before a clinical response is appreciated, and therefore, no conclusions regarding its success should be drawn before that timeframe in erythrodermic patients.^1,2

Table 6. TNMB classification of MF and SS

Table 7. Clinical staging for MF and SS.

Table 8. ECP recommendations by cutaneous disease, as per the revised guidelines by the European Dermatology Forum in 2020.

GvHD

GvHD can be either acute or chronic based on clinical presentation and time to disease development.¹ Classic acute GvHD (aGvHD) occurs within 100 days of the transplantation with typical features, whereas chronic GvHD (cGvHD) presents after 100 days. However, persistent, recurrent or lateonset aGvHD can occur after 100 days with typical features of aGvHD. If features of both aGvHD and cGvHD are present, it is considered an overlap syndrome.⁷ cGvHD occurs in 30- 50% of patients receiving an allogenic transplant, involves multiple systems and most commonly presents with mucosal, skin, gastrointestinal and liver involvement.² First-line therapy consists of systemic glucocorticosteroids with or without a calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, calcineurin inhibitor. Second-line therapies include ruxolitinib, ECP, mycophenolate mofetil, mTOR inhibitors, methotrexate, imatinib, ibrutinib and rituximab.² Notably, phase III randomized clinical trials evaluating ruxolitinib versus best available therapy for steroid refractory or dependent cGvHD demonstrated superiority of this drug when compared to ECP and other agents (ORR 50% vs. 26%, p<0.001).⁸ The average response rate to ECP is approximately 60% and studies have shown ORR rates ranging from 36-83%. In addition, CR in the skin, oral disease, and liver ranged from 31-93%, 21-100% and 0-84%, respectively.² Best responses using ECP are seen in skin followed by gastrointestinal and then hepatic GvHD. The EDF recommends considering ECP as an additional secondline therapy in patients with cGvHD that is steroid-dependent, steroid-intolerant, or steroid-resistant, as well as for those with recurrent infections or with a high-risk of relapse (Table 8). Also, steroid-dependent patients (i.e., inability to reduce corticosteroid dose to <0.5 mg/kg/day without recurrence of Grade II or worse cGvHD) could benefit from ECP.

Similarly, systemic glucocorticoids are currently used as firstline therapy for aGvHD.² However, response rates are <50%.² In 2019, the US FDA approved ruxolitinib for steroid-refractory aGVHD in adult and pediatric patients ≥12 years of age. This approval was based on an open-label, single-arm, multicenter study of ruxolitinib that enrolled 49 patients with steroidrefractory aGVHD Grades II-IV occurring after allogeneic hematopoietic stem cell transplantation.⁹ Clinical trials have shown the superiority of ruxolitinib therapy when compared to ECP and other treatments (ORR 62% vs. 39%, p<0.001).¹⁰ In these patients, ECP may serve as an additional second-line treatment with ORR of 65-100% in the skin, 0-100% in the liver, and 40-100% in the gastrointestinal tract.² As such, the EDF recommends adjunct ECP, as second-line therapy, in patients not responding to appropriate doses of systemic corticosteroids (Table 8). Interestingly, it is also showing promising results as a prophylaxis therapy to prevent cGvHD.¹ This treatment option may be considered by dermatologists consulting on these patients in acute setting in the hospital especially at times when the diagnosis is uncertain, as ECP is recognized as not being an immunosuppressive therapy.

SSc

SSc is a multisystemic connective tissue disease characterized by collagen deposits in the skin and other visceral organs.^1,11 Although there are currently no FDA-approved treatments for cutaneous involvement in SSc, limited studies have investigated the use of ECP and have shown promising results.¹¹ For example, one multicenter trial showed that ECP was well-tolerated and improved disease severity, the mean percentage of skin involvement (-7.7% from baseline after 10 months, p=0.01) and the mean oral aperture measurements (+2.1 mm from baseline after 10 months, p=0.02).^11,12 Other studies have shown that ECP leads to improvement in dermal edema and skin elasticity, normalization of collagen synthesis, and improvement of extracutaneous symptoms, and that ECP-treated patients with SSc have a favorable long-term survival.^1,13 Further, one study found that, in most patients, ECP leads to a reduced usage of corticosteroids and other immunosuppressive agents, which have numerous adverse effects.¹⁴ The EDF currently recommends ECP as second-line or adjuvant therapy for SSc, either as monotherapy or in combination with other treatments (Table 8).¹¹

Other Cutaneous Conditions

ECP has been studied in numerous other cutaneous diseases, including atopic dermatitis (AD), immunobullous diseases, eosinophilic fasciitis and others. Although there are many other treatment options for AD, including emollients, topical therapies, phototherapy/photochemotherapy, immunosuppressive medications, targeted therapies¹⁵ and monoclonal antibodies, several small open-label trials have shown that ECP is beneficial in patients with severe AD, including erythrodermic AD, that are not responding to standard therapy. Although previous guidelines have not recommended routinely treating AD with ECP given the lack of consistent findings and the multiple other treatment options available, the EDF’s revised guidelines recommend its use as second-line therapy in patients that meet specific criteria (Table 8).¹¹ However, as new effective treatments are emerging for the treatment of AD, ECP should only be reserved for exceptional patients. Studies have also shown promising results for the use of ECP in pemphigus. One study of 11 patients with severe treatment-resistant pemphigus vulgaris or foliaceus showed an OR rate of 91% and CR rate of 73%.¹¹ As such, the EDF recommends ECP in patients with pemphigus vulgaris or foliaceus that is recalcitrant to conventional first- and second-line therapies.¹¹ Further, the EDF recommends considering ECP for severe epidermolysis bullosa acquisita (EBA) and erosive oral lichen planus that is refractory to conventional topical and/or systemic therapies.¹¹ Low level evidence suggests a possible role for ECP in the treatment of lupus erythematosus, however, further controlled clinical trials are needed to assess its efficacy. For this reason, no official recommendations for the use of ECP in lupus erythematosus have been published to date.¹¹ Studies have also investigated the use of ECP in other cutaneous diseases, including psoriasis, nephrogenic fibrosing dermopathy, morphea and scleromyxedema, however, the results have been inconclusive.¹¹

Pediatric Population

Many studies support the use of ECP in a pediatric population. It has been used as an off-label treatment for various conditions, including aGvHD and cGvHD.¹¹ In this patient population, the ECP protocol is adapted and can vary depending on the patient’s weight. Importantly, very few side effects are reported in this population, which further supports the favorable safety profile of ECP.¹¹

Conclusion

In conclusion, ECP has been used on- and off-label for decades to treat numerous diseases, including SS, CTCL, GvHD, and SSc, among others. Results from multiple studies have shown promising response rates, and ECP has an overall excellent safety profile with very few adverse events reported.^2,11 Unlike many other immunomodulatory therapies, an increased risk of infection has not been observed with ECP, which can be a significant cause of morbidity and mortality for patients on other immunosuppressive therapies.¹¹ Although ECP is still being studied for multiple diseases, in Canada clinicians should restrict its use to the diseases that have been extensively studied, as per the EDF guidelines.

Funding: The genesis of the paper was initiated at a meeting organized by a pharmaceutical company (Mallinckrodt Inc.) and EN, IT, WG, JD, MK, RG, CL and IVL were provided honoraria to attend that meeting. No funding bodies or other organizations had any role in data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgment: We thank RBC Consultants for editorial support, facilitating the preparation of tables, and coordinating the review of the manuscript.

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