To address the question of what do we know from the literature about MF-CTCL topical treatment with CL-gel, literature searches were performed by a medical researcher using PubMed and Google Scholar (secondary source), first evaluating the title, the abstract, and then the full article. Search terms are detailed in Table 1. The searches included English language articles (randomized controlled trials, other clinical studies, guidelines, consensus articles, and review articles) published between January 2010 and July 20th, 2023. The searches yielded 62 articles comprising 27 clinical studies and 35 reviews. The clinical studies were graded using a grading method detailed in Begolka et al. (13)

A panel of 9 board-certified dermatologists with expertise in cutaneous lymphoma and 1 radiation oncologist from four different provinces (Quebec, British Columbia, Alberta, Ontario) used a modified Delphi process comprising a virtual meeting and an online follow-up. The process entailed preparing the project, selecting the panel, and using the systematic literature search results to inform 11 draft statements.

During a virtual meeting on September 14th, 2023, the panel discussed the systematic literature review results and evaluated the draft statements in a workshop. In a plenary discussion, drawing from clinical experience and opinions, the panel adopted five statements to provide clinical guidance on CL-gel as topical monotherapy in early stage disease or adjunctive to systemic treatment for Canadian healthcare providers treating patients suffering from MF-CTCL. The panel then voted, and all five statements (Table 2) met the criteria for consensus (>80%). After preparing the manuscript, the individual advisors reviewed it and agreed with its content and publication.

Four expert panelists volunteered to share real-world patient cases involving their use of CL gel to treat MF-CTCL. Two cases were offered by each expert. During the consensus meeting, the panel shared real-world patient cases to illustrate the use of CL-gel in a variety of patients across Canada. The presented cases discussed patient presentation, clinical challenges, and treatment outcomes. These cases served as a forum for dermatologists to exchange ideas and reflect on how to provide the best care for MF-CTCL patients.

The real-world cases (RWC) characterize dermatologists’ real-world experience (i.e., how are experienced specialists in practice using the product and how their patients are doing on the regimen) when using the treatment. The RWC did not require ethics committee approval as it reports real-world experience and does not make statements on the efficacy or safety of the treatment. The RWC was conducted complying with good clinical practice (GCP). All authors obtained written informed consent from the individuals who participated in the RWC. The participants in the RWC series allowed the recording of their photographs to be used for the manuscript and its publication.

For patients with low-risk stage IA MF-CTCL, an expectant or watch-and-wait policy may be sufficient to manage these patients (14). It is estimated that there is only a 10% risk of progression over 10 years in stage IA MF-CTCL (14). In PROCLIPI study, first-line treatments were analyzed in patients with newly diagnosed MF-CTCL (stages IA-IIA) (15). In this 395 patient cohort, expectant observation was only used in 7.3% of cases and 45% of patients treated initially with expectant policy received subsequent treatment after a median of 7.5 months (range 3–34 months), indicating an eventual need for treatment (15). Thus, while expectant policy may be used for short while, the general consensus is that most patients (81.5%) are started on SDT for first-line therapy (15).

Appropriate patient counseling and careful monitoring is required to determine a treatment plan for low-risk, early-stage MF-CTCL. While expectant policy may be considered upon initial diagnosis, SDT will prevent progression and ease patient discomfort.

SDTs are localized cutaneous treatments recommended as first-line agents for MF-CTCL Stages IA, IB, and IIA. TCS are the most commonly prescribed SDT (14). Despite little evidence for use of TCS in MF-CTCL, TCS are considered an economical and safe option to alleviate symptoms of itch/burning for early-stage MF-CTCL (14). However, TCS are palliative and not curative and can lead to long-term adverse effects (14). Originally derived from nitrogen mustard gas, topical CL is an alkylating agent that has long been used as a topical treatment for MF-CTCL with variable efficacy in various vehicles (14). Topical bexarotene is a retinoid that is available in a 1% gel formulation approved for MF-CTCL stages IA-IB (14). In two prospective trials evaluating bexarotene, response rates varied between 44 and 63% at the study end-point (14). Ultraviolet phototherapy such as PUVA, localized radiotherapy, and total skin electron beam therapy (TSEB) are also treatment options; albeit associated with significant long-term toxicity with prolonged use (14).

Systemic therapies are generally recommended as first-line agents for MF-CTCL stage IIB and second-line agents for MF-CTCL stages IA, IB, and IIA (14). Common systemic therapies include methotrexate, retinoids, interferon-α (IFNα), targeting immunotherapy, extracorporeal photochemotherapy, select forms of chemotherapy, hematopoietic stem cell transplantation, and histone deacetylase inhibitors (14). These agents may be used in monotherapy or in combination with other agents and SDTs.

There are no gold standard treatments for MF-CTCL and limited SDT options. Even for the widely prescribed TCS, only one uncontrolled study by Zackheim et al. demonstrates that high-potency TCS, clobetasol propionate, was effective in 79 stage IA/B MF-CTCL patients (16). Further, topical bexarotene has two clinical trials, which showed variable efficacy (14). In addition, bexarotene is highly teratogenic, which restricts its use in certain populations (14).

Topical CL is an alkylating agent with many large, uncontrolled studies demonstrating its efficacy in various compounded formulations. Early CL preparations were aqueous or compounded ointment-based formulations, which were difficult to apply and less efficacious than the newer gel formulation (14). Compounded ointments were also available in some pharmacies and found to have limited stability (14). Alternatively, in addition to being easy to apply and fast-drying, the CL gel demonstrated non-inferiority (58.5%) to the chlormethine ointment (47.7%) in a pivotal phase II study (Study 201) (8). Study 201 demonstrated higher response rates for CL 0.02% gel compared to CL ointment at primary endpoint of CAILS in a 260-patient randomized, clinical trial (8). The response rate also increased with time, with 76% of patients achieving a complete response by week 52 compared to 46% in week 24 (8).

Adverse events were experienced by 61.7 and 50.4% of patients who received the gel and ointment, respectively (8). The most common adverse event was dermatitis, experienced by more than half of the patients (8). Dermatitis was managed by suspension of reduction of CL treatment and use of emollients or oral antihistamines (8). Treatment was resumed upon improvement at a reduced frequency (once every 3 days) (8).

Following the results of Study 201, CL (0.02%) gel was approved by Health Canada for treatment of stage IA and IB MF-CTCL in adult patients who have received prior SDT. Since its approval, the CL gel has been evaluated in a multitude of small and large observational and case series studies (17–19). Notably, the PROVe Study demonstrated that in 298 patients, under real-world conditions without any specific visit schedules or clinical assessments, CL gel was an efficacious and important therapeutic option for MF-CTCL patients (20).

The 2018 World Health Organisation- EORTC classifies CTCL as primary cutaneous lymphomas that exist as MF-CTCL, MF-CTCL variants, or Sezary syndrome (SS) (21). SS is closely related to MF-CTCL and shares clinical and histopathological similarities (21). However, while MF-CTCL is largely indolent, SS is characterized by aggressive clinical behavior presenting as a triad of generalized erythroderma, lymphadenopathy, and other systemic manifestations (21). In rare cases, MF-CTCL may evolve to SS for which there is only a 36% 5-year disease-specific survival rate (22). MF-CTCL and SS are classified using a modified TNMB-classification system in which disease stage is based on skin, nodal, and visceral organ or blood involvement (Table 3) (14, 21, 22). From these stages (IA-IVB), a 5-year survival prognosis is predicted (22). Early stages IA and IIA have high 5-year survival rates, 98 and 89%, respectively (22). Thus, treatment at early stages is aimed at preventing evolution and progression of disease to SS and improving symptoms and quality of life.

Treatment recommendations are stratified by disease stage in the EORTC MF-CTCL classification system (Table 3) (14, 21). EORTC first-line recommendations for MF-CTCL Stages IA, IB, and IIA are expectant policy, TCS, UVB, PUVA, localized radiotherapy, and topical CL (14, 21). The highest level of evidence exists for CL, UVB, and PUVA. Similarly, ESMO also recommends expectant policy, TCS, UVB, PUVA, local radiotherapy, and topical CL for first-line treatment of stage IA, IB, and IIA MF-CTCL (Table 3) (23). Unlike EORTC, ESMO consensus indicates that topical CL has the highest level of evidence for use (23). It must also be noted that TCS provide an effective and cost-effective first-line approach. However, few randomized clinical trials have been conducted on TCS in MF-CTCL, TCS have long been used in clinical practice with effective results (16). However, TCS is not appropriate for long-term use as it may lead to straie, skin atrophy, hypopigmentation, skin irirration, and skin infections. ESMO also indicates that SDT should be combined with systemic therapies such as retinoids or IFNα in stage IIB MF-CTCL (23).

Topical application of CL undergoes rapid metabolization via hydrolysis and demethylation within minutes of contact with the body’s hydrophilic surface (24). In vitro release testing reveals that rate of CL release from the gel formulation is significantly greater than the ointment-based formulation (24). Both the rate and cumulative amount of CL released were significantly greater from the CL gel than from the ointment (24). CL gel was also shown to exert its primary activity at the epidermal layer (24). It has a mean flux of 10.8 ng/cm²/h in the epidermal membrane with its peak occurring at 2 h post-application (24). Penetration testing showed that mean residual CL on the surface of skin after 24 h was 21 ng (1.3% of applied dose) in epidermis and undetectable in the dermis (24). This indicates that the CL-gel action is restricted to the epidermis, which explains its effectiveness in early-stage MF-CTCL solely localized to the epidermis (24).

To ensure safety of CL gel, bioanalytic assays were performed from patient samples from study 201 to determine CL concentrations in the plasma. The assays found that there was no measurable evidence of CL in plasma samples after topical once-daily application of 0.02% CL gel or ointment, or 0.04% CL gel. Laboratory monitoring of hematologic parameters also showed no abnormalities or changes over time. In summary, CL uniquely targets the epidermis and dermis following topical administration, with no evidence of systemic absorption.

The lack of systemic absorption with CL gel positions it as a valuable adjunctive treatment for systemic therapies due to minimal risk of drug–drug interactions and systemic toxicity. Both ESMO and EORTC recommend combining SDTs such as topical CL-gel with systemic therapies in stage IIB-III MF-CTCL (14, 21–23). The literature also confirms that CL-gel is frequently and successfully used in combination with other SDT and systemic therapies (25). In the real-world PROVe study, combination treatment regimens were common, with 78% of patients using CL-gel combined with other SDT and 30% of patients using systemic therapies combined with CL gel (20). TCS, phototherapy, and oral bexarotene were the most commonly combined therapies with topical CL gel. Another real-world clinical experience examined 23 patients’ responses to CL-gel (26). In this study, 11 of the 12 patients received CL gel in combination with either methotrexate (MTX) or pegylated IFNα-2A (26). In 5 patients with stage IIB MF-CTCL, CL gel was added to treat localized tumor lesions and saw a significant clinical response (26). Case studies have also shown the successful use of CL-gel combined with phototherapy, retinoids, IFNα, acitretin, and mogamulizumab (27). Lastly, CL-gel can be an adjunctive maintenance therapy for TSEB and has been shown to prolong the time needed for upstaging by approximately 22 months (28).

Although there is a potential risk for dermatitis, CL gel remains a safe and efficient treatment that may be used long-term as maintenance (1–4 times weekly) or active treatment (once daily). In Study 201, the duration of response was maintained through month 12 in 86% of patients in the gel arm and 82% in the ointment arm (8). It was estimated that at least 90% of the responses would be maintained for at least 10 months after the study endpoint (8). Durable responses with active use of chlormethine gel (once daily) make the gel a reliable treatment option (8). However, few studies have documented the continued efficacy after gel discontinuation.

A Stanford group reported an average 12-month time period until relapse in 203 MF-CTCL patient-responders who discontinued topical CL treatment (aqueous solution) (29). The group also noted that patients who used a maintenance regimen had longer-lasting responses during maintenance therapy than those who did not continue a CL maintenance therapy regimen (29).

Case reports and expert experience demonstrate that reducing the frequency of CL gel application as maintenance treatment can delay the progression of disease and reduce the frequence of side effects such as skin irritation (28, 29). CL gel is an optimal maintenance therapy as it is safe to use long-term, accessible, and easy to apply. In one study, reducing CL gel application to 1–4 times weekly maintained approximately half of patients in a stable disease state (30). In a case series, two patients had maintained response 1–5 months after stopping CL gel application (31). While no large-scale studies exist to investigate the efficacy of CL gel after discontinuation, clinical experience suggests that CL gel is a feasible and reliable maintenance treatment for patients who may titrate up or down the dosage to maintain initial response (32).

Despite high efficacy rates, CL use is accompanied by a high discontinuation rate due to adverse effects such as skin irritation. With both the gel and ointment preparations, CL application leads to contact dermatitis characterized by skin irritation, erythema, and pruritus in 50–60% of patients (8). Mild-to-moderate dermatitis may not require suspension of treatment and can be palliated with TCS or decreased dosing frequency (3 times per week) (9, 11). Severe dermatitis requires discontinuation until improvement is seen (11). Dermatitis reactions vary from delayed hypersensitivity reactions to non-delayed hypersensitivity reactions such as irritant contact dermatitis, bullous reactions, and burning. Improving differentiating and understanding the various reactions will aid in patient compliance and outcomes. Hypersensitivity to CL or any ingredient in the gel is a contraindication for treatment (11).

To address the high discontinuation rates, some experts have recommended decreasing the application frequencies or titrating up the frequency of use. However, decreased CL use will inevitably lead to slower treatment responses and decreased efficacies. In addition, the efficacy of CL gel increases over time with continual use with some peak responses occurring between 8 and 10 months; thus, tolerance and adherence to treatment is crucial for positive outcomes (8, 33). Other appropriate treatment strategies for CL gel include choice of application site, proper patient selection, and adjunctive therapies to mitigate adverse events. Dermatitis can occur at any skin site; however, the risk for dermatitis is increased if applied to the face, genital area, anus, or skin folds (11). Any site may be affected by dermatitis. In general, application to mucous membranes should be avoided. Thus, choosing skin sites at lower risk of dermatitis may improve patient outcomes.

The prospective, randomized, controlled MIDAS study investigated the ability of topical triamcinolone ointment to prevent dermatitis associated with CL gel (12). Twenty-five patients with early-stage MF-CTCL were followed for 12 months (12). Two similar MF-CTCL lesions were chosen on each patient (11). One lesion was treated with once-daily CL gel for 4 months while the second lesion was treated with both CL gel and triamcinolone 0.1% ointment, daily (12). The study identified that the peak of adverse reactions occurred at months 2 and 3 and those lesions treated with the TCS had decreased contact dermatitis and greater improvement in quality of life (12). Importantly, the coadministration of triamcinolone 0.1% and CL gel did not affect the efficacy of the therapy (12). Further analysis of the MIDAS study also revealed that patients who developed allergic contact dermatitis to CL-gel may have an allergic-type phenotype that triggers reactions to common allergens unrelated to the CL-gel (34). Improving patch testing sensitivity, patient education, and understanding of the dermatitis reaction is necessary to improve the tolerability and clinical utility of CL-gel.

CL gel is a first-line, effective SDT for early-stage MF-CTCL in Europe and the United States. Recently, the SDT was also approved in Canada. The real-world cases presented here demonstrate how the gel was used for various patients with MF-CTCL across Canada. The consensus advisors reported on real-world patient cases that illustrate the clinical experiences that have informed their expert consensus statements. The cases covered diverse patient presentations, clinical challenges, and treatment outcomes, which were discussed during the virtual meeting.

The expert opinions and real-world cases presented highlight the expert panel’s experience with CL gel in various patients under real-world conditions. All outcome measures were reported from providers in the clinic and reflect real-life data rather than data from controlled, clinical trial environment. Actual experience with CL gel may differ with each patient, provider, and treatment regimen. All expert opinions have been drawn from their own experiences with CL gel and do not encompass all possible reactions and outcomes of the gel’s use.