Mycosis fungoides (MF) is a cutaneous T-cell lymphoma typically with an indolent course that is initially characterized by localized patches and plaques |
Chlormethine gel is a therapeutic option recommended by international guidelines for patients with MF skin lesions; a range of retrospective, prospective, and observational clinical data supports its use in all disease stages |
While chlormethine is an efficacious therapy, its usage may be complicated by the development of cutaneous reactions at the sites of application |
Real-world experience from clinical practice in the US, Israel, and France has shown that chlormethine gel is used as a skin-directed therapy in the first- and second-line setting in patients with early-stage MF and as an adjunctive therapy in patients with advanced-stage disease |
The emergent cutaneous adverse reactions can generally be managed through chlormethine gel dose adjustments or the use of topical steroids |
Digital Features
Introduction
Clinical Management Guidelines for MF
Chlormethine as Topical Chemotherapy for Managing MF
Chlormethine in MF Management: A Review of the Literature
First author (year) | Study description | Patients, n | Treatment(s) administered | Efficacy findings | Safety findings |
---|---|---|---|---|---|
Price et al. (1977) [29] | Retrospective case analysis | 51 | Topical chlormethine as adjuvant therapy after TSEB therapy vs. TSEB therapy alone | Disease-free interval: 25 months for chlormethine plus TSEB therapy vs. 17 months for TSEB therapy alone Relapse-free survival: 37% vs. 29% | Patients receiving adjuvant topical chlormethine had a low incidence of contact allergy |
Vonderheid et al. (1979) [30] | Retrospective case analysis | 243 | Topical chlormethine given as a dilute aqueous solution with or without systemic chemotherapy | Disease-free interval: > 3 years in 32 (13%) patients Equally effective as historical treatment with TSEB | NA |
Price et al. (1983) [31] | Retrospective case analysis | 43: stage IA, 17; stage IB, 22; stage II, 2; stage III, 2 | Topical chlormethine ointment | CR occurred in 26 patients over a 42-month evaluation period | Contact dermatitis occurred in 1 of 31 (3%) chlormethine-naive patients and 3 of 12 (25%) previously treated patients |
Ramsay et al. (1984) [32] | Retrospective case analysis | 76 | Topical chlormethine | Of 64 patients who continued therapy, 43 (67%) achieved CR and 12 (19%) achieved PR Median times to CR for stage I, II, and III disease were 6, 32, and 22 months, respectively | Allergic contact hypersensitivity reactions occurred in 51 (67%) patients No difference in response between patients with or without contact sensitivity |
Zachariae et al. (1985) [33] | Retrospective case analysis | 33 (with early MF in plaque stage) | Topical chlormethine | 14 patients in CR and 7 in PR, with a relapse-free survival of 50% after 6 and 12 years, respectively | 3 deaths due to disease 3 patients discontinued due to treatment-related contact dermatitis No hematologic AEs |
Hoppe et al. (1987) [34] | Retrospective case analysis | 123 (median age, 59 years [range 20–90]; 88% White, 6% Black, 5% Hispanic, 1% Asian): stage IA, 38; stage IB, 30; stage IIA, 33; stage IIB, 13; stage IIIA, 2; stage IIIB, 7 | Topical chlormethine 10–20 mg/dl given either as aqueous solution or ointment | Efficacy was similar for aqueous vs. ointment formulations ORR and CR rate: all, 72% and 32%; stage I, 88% and 51%; stage II, 69% and 26% Among those with CR, 40% of patients with stage I disease and 60% with stage II disease later relapsed Subsequent therapies including repeat treatments with chlormethine were successful in achieving later skin clearance Long-term remissions noted in 42% of patients with stage I and 31% with stage II disease No patients with stage III disease (n = 13) had CR, and all had progression 2 of 9 patients with stage IV disease had CR, but both later relapsed | When deaths occurred, they were typically unrelated to disease in stage I patients Half of deaths among stage II patients were attributable to disease Among 22 patients with stage III or IV disease, 80% were attributable to MF Cutaneous hypersensitivity was more common with aqueous than with ointment formulation 14 (11%) patients developed cutaneous malignancies |
Ramsay et al. (1988) [35] | Retrospective analysis of medical records | 117 (median age, 57 years; 56% male): stage IA, 28; stage IB, 35; stage IIA, 12; stage IIB, 32; stage IIIA, 1; stage IIIB, 9 | Chlormethine 10 mg dissolved in 60 ml of water applied QD until 6 months after CR, tapering over the following 18 months; concomitant therapy not allowed except for local RT for stage III disease | Median time to CR: stage I, 6.5 months; stage II, 41 months; stage III, 39 months Clinically apparent remission at 2 years: stage I, 76%; stage II, 45%; stage III, 49% | Delayed hypersensitivity reactions: 58% 1 patient discontinued due to hypersensitivity Death due to disease occurred in 9 cases, including 3 unrelated to treatment and 1 unknown |
Vonderheid et al. (1989) [26] | Retrospective analysis of medical records | 331 (mean age, 58 ± 0.7 years; 65% male): stage IA, 89; stage IB, 66; stage IIA, 46; stage IIB, 39; stage III, 37; stage IVA, 38; stage IVB, 9; lymphomatoid papulosis, 7 | Chlormethine 10–20 mg dissolved in 40–60 ml of water applied QD until CR, then continued QD or EOD depending on response; adjunctive therapy allowed for slowly responsive, extensive disease, or extracutaneous involvement (e.g., local RT, TSEB therapy, UV phototherapy, methotrexate, or other alkylating agents) | Initial CR defined as complete disappearance of clinically detectable disease ≥ 2 weeks and confirmed by skin biopsy: stage 1A, 80%; stage 1B, 68%; stage IIA, 61%; stage IIB, 49%; stage III, 60%; stage IVA, 13%; stage IVB, 11% Sustained remission for 4 and 8 years: 65 and 35 patients, respectively | Of patients with CR > 8 years, 12 (35%) experienced ACD |
Licata et al. (1995) [39] | Retrospective case analysis | 164 (who had received TSEB therapy between 1974 and 1990; median age, 59 years [range 20–88]; 62% males; 88% White, 10% Black) | Evaluated effects of therapy beyond TSEB, including topical chlormethine | NA | 6 patients developed malignant melanoma 12–95 months after TSEB therapy, including 2 treated with chlormethine During median follow-up of 6 years, no patient died of secondary cutaneous malignancy Additional use of chlormethine following TSEB therapy was associated with nonmelanoma skin cancer |
Estève et al. (1999) [40] | Multicenter, prospective study | 52 (mixed population of patients with CTCL including 35 with MF; age 18–87 years; 67% males) | Topical chlormethine 0.02% given as aqueous solution | NA | Follow-up data from 43 patients Intolerance to chlormethine developed in 23 patients (14 males, 9 females) 4 days to 9 months after initiation, including 15 of 35 (43%) patients with MF 12 patients overall were able to resume chlormethine after resolution of symptoms |
Foulc et al. (2002) [36] | Open-label, prospective study | 39 with CTCL (including 34 with MF: mean age, 63 years [range 31–82]; 59% males: stage IA, 8; stage IB, 14; stage IIA, 3; stage IIB, 8; stage IVA, 1) | Topical chlormethine 0.2% diluted in 10 ml solvent and 50 ml water and given either QD or intermittently | Response rate was 69%, with no difference between QD and intermittent application CR in 54%; PR in 15% CR in 59% with stage IA or IB CR in 45% with stage IIA or IIB However, response decreased with short-term application vs. comparison with literature | Cutaneous intolerance occurred in 19 of 39 (49%) patients, including 6 with ACD after a mean of 9 weeks; the other 13 patients developed contact dermatitis after a longer period (3 weeks to 17 months) |
Kim et al. (2003) [37] | Single-center, retrospective cohort analysis | 203 (with stage I–III disease; median age, 56 years [range 12–87]; 61% males; 86% White): stage IA, 103; stage IB, 74; stage IIA, 18; stage IIB, 4; stage III, 4 | Topical chlormethine 10–20 mg/100 ml aqueous solution or ointment | ORR and CR rate: all, 83% and 50%; stage I, 93% and 65%; stage II, 72% and 34% Median time to CR: all, 12 months; stage I, 10 months; stage II, 19 months Median time to relapse: 12 months When administered as salvage therapy, response rates were similar to initial therapy Efficacy similar for aqueous vs. ointment formulations | Contact hypersensitivity reactions occurred in < 10% when used as ointment 8 (4%) patients developed secondary cutaneous malignancies, with none attributed to chlormethine No significant toxic effects were observed |
de Quatrebarbes et al. (2005) [38] | Multicenter, prospective, nonrandomized study | 64 (newly diagnosed, early-stage disease; mean age, 63 years [range 7–82]; 67% males): stage IA, 33; stage IB, 26; stage IIA, 5 | Topical chlormethine 0.02% aqueous given twice weekly followed by betamethasone cream over 6 months | CR in 58% after a mean of 4 months, including 61% with stage IA disease, 58% with stage IB, 40% with stage IIA disease Relapse in 17 (46%) patients after a mean of 7.7 months | 58% of patients did not experience any adverse cutaneous reactions Severe cutaneous reactions requiring discontinuation developed in 18 (28%) patients, including erythema, severe pruritus, or burning sensation in 11 cases, and eczematous reaction in 7 cases |
Lindahl et al. (2013) [27] | Retrospective analysis of medical records (116) | 116: stage IA, 11; stage IB, 68; stage IIA, 10; stage IIB, 13; stage III, 9; stage IVA, 4; stage IVB, 1 | Chlormethine ointment (concentration not mentioned) | ORR, 92%; CR rate, 53% | |
Lessin et al. (2013) [15] | Phase II multicenter, randomized, observer-blinded, noninferiority trial in patients with persistent/recurrent stage I–II disease | 260 (median age, 58 years [range 11–88]; 59% male; 74% Caucasian): stage IA, 141; stage IB, 115; stage IIA, 4 | Chlormethine 0.02% gel or ointment applied QD for 12 months; no concomitant corticosteroids were permitted | CAILS (severity score for ≤ 5 lesions; CR, 100% improvement from BL; PR, ≥ 50 to < 100% improvement from BL: gel, 14% CR and 45% PR; ointment, 12% CR and 36% PR Chlormethine gel was noninferior to ointment by prespecified criteria | No drug-related severe AEs were reported Drug-related skin AEs in the gel and ointment arms were reported by 62% and 50% of patients, respectively These included: skin irritation (n = 32 vs. 18); pruritus (n = 25 vs. 20); erythema (n = 22 vs. 18); contact dermatitis (n = 19 vs. 19); skin hyperpigmentation (n = 7 vs. 9); folliculitis (n = 7 vs. 5) 11 patients overall including 3 in gel arm and 8 in ointment arm were diagnosed with 20 secondary nonmelanoma skin cancers |
Kim et al. (2014) [17] | Phase II extension study with patients who completed the Lessin 2013 [15] study (12 months of treatment) but did not achieve CR (N = 98) | 98 (mean age, 53 ± 14 years; 55% male; 68% Caucasian) | Chlormethine 0.04% gel applied QD for 7 months (application frequency could be reduced for toxicity) | CAILS (severity score for ≤ 5 lesions, confirmed ≥ 4 weeks later): CR in 6 patients and PR in 20 patients | Mild-to-moderate drug-related skin AEs were reported by 31 (32%) patients Most common drug-related skin AEs were skin irritation (11%), erythema (10%), and pruritus (6%) |
Lindahl et al. (2014) [41] | Population-based cohort study | 303; including 110 using chlormethine (mean age, 69 years [range 30–98]; 69% males: stage IA, 14; stage IB, 39; stage IIA, 8; stage IIB, 25; stage IIIA, 15; stage IV, 9) | Topical chlormethine | NA | Secondary cancers were not significantly increased (HR 0.8; 95% CI 0.5–1.6) in patients receiving chlormethine Subanalyses showed no significantly increased risk of nonmelanoma skin cancers, malignant melanomas, or cancers of the respiratory organs Mortality and cause-specific mortality were not influenced by treatment |
Kim et al. (2020) [42] | Prospective, observational, noninterventional study | 301 (298 monitored) stage IA–IIA: 62%; stage IIB–IV: 8% | Topical chlormethine gel in combination with other therapies | ORR of 44% in patients who received chlormethine gel plus corticosteroids and/or NBUVB phototherapy, oral bexarotene, PUVA, local electron-beam therapy, topical bexarotene, and imiquimod ORR of 45% in patients who received chlormethine gel plus any other treatment | 42% experienced ≥ 1 AE Most common skin-related AEs were: dermatitis (13%); pruritus (10%); skin irritation (7%); and erythema (5%) |
Phase II, nonrandomized, open-label, split-face, two-arm study in patients with stage IA and IB disease | 28 | 0.016% w/w topical chlormethine gel (once nightly) applied over a minimum of 8 cm2, over a 4-month period 0.016% w/w topical chlormethine gel (once nightly) plus triamcinolone 0.1% ointment QD applied over a minimum of 8 cm2, over a 4-month period | CAILS scores were comparable between the two arms Addition of triamcinolone ointment significantly decreased the SCORAD score (p < 0.05) | 32% developed severe contact dermatitis 31% developed ACD vs. 66% of patients from historical data using aqueous formulation 4% developed ICD |
Real-world Experience of Chlormethine Gel in the Management of Patients with MF (Table 2)
Characteristic | Penn Dermatology Cutaneous T-Cell Lymphoma Clinic, USA | Cutaneous Oncology Clinic, Columbia University, USA | Rabin Medical Center, Israel | Hôpital Saint-Louis, France |
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Number of patients with MF seen/year | ~ 200 | > 350 | 300 | ~ 320 |
Disease stage of patients with MF | Mostly early stage | Ranging from stage IA or IB to Sézary syndrome | Early stage | Early and advanced stages |
Chlormethine gel usage | Early stage: treatment after corticosteroids failure Advanced stage: adjunctive treatment to systemic therapies or other SDTs | For patients with early stage, skin-limited disease Advanced disease: in combination with systemic therapies | Second-line treatment in patients for whom at least 1 previous SDT failed (topical steroids or phototherapy) | Early stage: second-line treatment after failure of high-potency corticosteroids, mainly when phototherapy is not possible or contraindicated Late stage: in combination with systemic treatments when insufficient effect is observed on patch/plaques lesions |
Chlormethine gel initial application frequency | Alternative evenings or 2 nights/week | 1–2 times/week, alternating with topical steroids | Gradually, up to a maximum of QD, sometimes with 1–2 times/week topical steroids | 3 times/week alternating with topical steroids. If well tolerated and PR, increase to QD |
Response time | 4–6 weeks; 4–24 months to achieve CR | 1–2 months; 80% of patients respond | NA | Beginning of response: 1–2 months. CR: 9–12 months; in some patients, 12–15 months required to achieve CR |
Incidence of dermatitis | ICD/ACD: 20–25% of patients in first 6 months | ICD: ~ 30%; 10% develop severe ICD | ICD is the most commonly diagnosed AE, and is usually mild | Mostly ICD (25% of cases) Real ACD rare |
Management strategy for dermatitis | Temporary suspension of treatment Potent topical steroids BID for 2–3 weeks | ICD: application of mid-to-high-potency ophthalmic steroid (chlormethine gel discontinuation if severe ICD) ACD: discontinue chlormethine gel | Mild ICD: avoid treatment discontinuation if possible; temporary addition of topical corticosteroids Moderate-to-severe ICD: topical steroid plus temporary reduction or discontinuation (only for severe dermatitis) | Moderate-to-severe dermatitis: chlormethine gel discontinuation plus topical steroids; chlormethine gel reintroduced after reactions have disappeared; and frequency of application has progressively increased |