At the Penn Dermatology Cutaneous T-Cell Lymphoma Clinic (USA), ~ 200 patients with newly diagnosed MF are seen annually; of these, 70% have early-stage disease. This center uses chlormethine gel as a first-line SDT in patients with early-stage disease for whom topical corticosteroids have failed. It is applied as a localized spot treatment or, for patients with more-extensive BSA involvement, as full-body treatment (from the neck down). In advanced-stage disease, chlormethine gel is used as an adjunctive SDT to systemic therapy and other SDTs. For at-home administration, patients must take appropriate precautions to avoid inadvertent mucosal exposure to chlormethine gel in other household members/pets.

Patients are instructed to apply chlormethine gel thinly, initially only every other night or 2 nights/week, then slowly increase the application frequency as tolerance permits, to minimize irritant dermatitis. Patients may apply topical steroids every other day to the same area, but this treatment is eventually tapered if no AEs result from chlormethine gel treatment. Patients using full-body treatment are advised that they may notice new lesions during the first month; however, these are subclinical MF lesions unmasked by chlormethine gel, not necessarily a sign of true disease progression.

In our experience, a response to chlormethine gel treatment can be expected within 4–6 weeks. It takes 4–24 months to achieve a CR; the ORR is 70%, with 10% of these achieving a CR and 90% achieving a partial response (PR). ICD or allergic contact dermatitis (ACD) is observed in 20–25% of patients and occurs mostly within the first 6 months of therapy. When dermatitis or other skin AEs occur, we temporarily discontinue chlormethine gel treatment and apply potent topical steroids to the affected area twice daily (BID) for 2–3 weeks. A “patch test,” where chlormethine gel is applied daily to a small unaffected skin area, is then performed. If dermatitis reappears, this is suggestive of ACD, and chlormethine gel is discontinued permanently. If no dermatitis appears, the prior reactions are most likely ICD, and chlormethine gel may be reintroduced slowly with applications every other night or 2 nights/week. This practice of “starting low and going slow” with application frequency is analogous to how we use other SDTs with known irritant effects (e.g., topical retinoids). Patients who experience a moderate-to-severe dermatitis reaction to chlormethine gel may have complete clearance of the original MF lesion once the dermatitis is cleared with potent topical steroids, as has been observed in the literature [46].

At the Comprehensive Cutaneous Oncology Clinic at Columbia University (USA), a range of disease stages are seen, from early-stage IA and IB MF-CTCL to stage IV disease, including Sézary syndrome. The patients are managed according to published algorithms in a stage-based approach. For patients with early-stage skin-limited disease, topical steroids, narrowband ultraviolet B (NBUVB), and chlormethine gel are the first-line treatments. Based on their schedule, personal preferences, or medical history, and in consultation with their physician, patients choose a therapy that best fits their lifestyle and disease state. Light therapy is an effective way to treat cutaneous manifestations of MF, but it may necessitate frequent visits to the physician's office and may not be convenient for people with busy work and family schedules. Some of the benefits of chlormethine gel include the ability to apply the gel at home, reducing the need for office visits for light therapy in those patients unable to incorporate visits into their daily schedule. Chlormethine gel treatment can continue away from home, provided refrigeration is available, so travel need not interfere with the treatment schedule. Additionally, chlormethine gel is recommended over NBUVB for patients with high risk of melanoma or nonmelanoma skin cancers, including patients with significant personal history of these diseases as well as light skin, numerous atypical nevi, or immunosuppression [47]. Given that a link between chlormethine gel use and development of nonmelanoma skin cancers has been suggested, concurrent NBUVB and chlormethine gel treatment is not typically advised in our patient population [48].

While chlormethine gel is FDA approved for treating stage IA and IB MF in patients who received one prior treatment, we also use chlormethine gel therapy in combination with systemic therapies in more advanced disease, including Sézary syndrome.

At Columbia University, over 350 patients per year are treated with chlormethine gel, all with relatively low toxicity. The main AE is irritant dermatitis, seen in ~ 30% of treated patients. ACD may be observed, and chlormethine gel should be discontinued in these cases. However, ICD is generally well controlled with mid- to high-potency topical steroid use, and chlormethine gel treatment can be continued in most patients. Approximately 10% of patients develop severe ICD, with lymphomatoid papulosis observed in a few patients; this resolves upon discontinuation of chlormethine gel [49].

Patients generally start chlormethine gel with less frequent applications (one or two times/week, alternating with topical steroids). If the patient can tolerate the gel without ICD or other concerns, the frequency is increased to daily use. In some patients, the gel may be used BID depending on symptoms. In our experience, response rates of up to 80% have been seen in patients with early-stage disease. Initial response is typically observed 1–2 months after starting treatment, and therapy is continued for 12 months in responders. Frequency can subsequently be reduced during the “maintenance phase,” which may last from several months to several years, or chlormethine gel can be discontinued when cutaneous lesions disappear completely. A significant proportion of patients use skin-directed (mostly topical steroids) or systemic agents in combination with chlormethine gel.

In Israel, in daily practice the first-line treatment for early-stage MF (after topical steroids) is usually phototherapy, while chlormethine gel is used as a second-line treatment in patients for whom phototherapy has failed or who have developed intolerability. Chlormethine gel as a first-line therapy (after topical steroids) is reserved for patients with early-stage MF who have contraindications to phototherapy (e.g., history of melanoma or multiple nonmelanoma skin cancers) or those who foresee adherence problems to phototherapy. Regional or whole-body application depends on the distribution of lesions and extent of cutaneous involvement. Since chlormethine gel has the potential to cause irritation, treatment initiation involves gradually increasing the application frequency up to the maximal tolerable frequency, but no more than QD, to minimize the occurrence and degree of irritation. The process is similar to that adopted with other topical treatments with irritant potential (e.g., retinoids) [50]. The skin folds and face are generally more susceptible to irritant reactions; hence, the maximal recommended application frequency is usually alternate days.

ICD is the most common AE and is usually mild. In the case of mild irritation, patients may benefit from temporary addition of topical steroids without a change in chlormethine gel application frequency, although in some patients, emollients are sufficient to alleviate symptoms. If irritation is moderate to severe, topical steroid application is advocated alongside temporary reduction (moderate irritation) or temporary discontinuation (severe irritation) of chlormethine gel application. Once irritation is under control or resolved, the application frequency is gradually increased or chlormethine gel is reintroduced at the highest tolerable frequency. In many patients, topical steroids may be withdrawn or minimized to once-weekly application. In the case of severe irritation, reintroduction of chlormethine gel may be attempted but is initially limited to a small area to assess tolerability.

The main differential diagnosis of ICD is ACD. Patch tests are not done routinely, and the diagnosis is based solely on clinical judgment. Key diagnostic features are: (1) timing of appearance, with delayed-type hypersensitivity occurring at least 2–4 weeks following treatment initiation versus primary irritation, which may develop as early as a few days after application; (2) distribution, where extension of dermatitis beyond treated areas indicates delayed-type hypersensitivity versus primary irritation, which is localized to treated areas only. ACD is suspected in few patients. If the allergic reaction is mild to moderate, the protocol is the same as for severe irritation. For patients with severe ACD, permanent discontinuation is required. It is important that any type of dermatitis is distinguished clearly from the unmasking effect of chlormethine gel, where new lesions are observed in the treated areas; this is seen in a small fraction of patients and usually occurs during the first month of treatment. Patients should be encouraged to continue with treatment, and whole-body application should be considered.

Hôpital Saint-Louis (France) sees ~ 320 patients per year with cutaneous lymphomas of any MF stage; ~ 80% have early-stage and 20% have advanced-stage disease. In patients with early-stage IA MF, chlormethine gel is prescribed after failure of high-potency corticosteroids, whereas for patients with stage IB, chlormethine gel may be prescribed as a first-line therapy, particularly in patients for whom phototherapy is not possible or contraindicated. In patients with late-stage disease, chlormethine gel is used in combination with systemic treatments when insufficient effect is observed on patch or plaque lesions. Response to chlormethine gel may occur 9 months after treatment initiation, but in some patients a period of 12 or 15 months may be required to achieve remission. In our experience, 19% of patients achieve a CR, and 66% have a PR.

The most common AE is skin reactions, mostly contact irritation versus real allergic dermatitis. When severe skin reactions are observed (e.g., moderately severe to severe dermatitis), chlormethine gel is discontinued and topical steroids are prescribed. Once the reactions have disappeared, chlormethine gel may be applied to a limited zone with persisting lesions on the trunk or the limb, with a reduced schedule (one or two times/week). If the patient presents with real sensitization, contact allergy will develop on the limited area, thereby indicating the patient has a true allergy, and chlormethine gel is contraindicated. In most patients, however, this limited application is well tolerated, and it is possible to apply chlormethine gel to the whole skin, up to three times/week, and often every day. Real patch testing to determine whether the response is ICD or ACD may be very informative in such situations.

A 58-year-old male with a history of melanoma on his back presented with stage IB MF. The patient had disseminated pruriginous erythematosquamous patches and plaques, although there were no adenopathies or blood involvement. A cutaneous biopsy demonstrated a band-like infiltrate with epidermotropism and atypical lymphocytes, and the patient was diagnosed with stage IB MF. Treatment with topical clobetasol yielded no response, while treatment with phototherapy was not possible due to the history of melanoma. Consequently, this patient was treated with chlormethine gel QD. Due to the dissemination of lesions, chlormethine gel was applied to the whole body, except for the face and scalp, where no lesions were present. After 9 months of chlormethine gel treatment, the patient was in full remission and treatment was stopped (Fig. 1).

Patient case images. a Epidermotropism and atypical lymphocytes, diagnostic of mycosis fungoides. b Skin lesions on the patient’s legs before and after 3 and 6 months of once-daily chlormethine gel application