¹Center for Clinical Studies Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Texas A&M University College of Medicine, Temple, TX, USA
⁴University of Texas Health Science Center, Department of Dermatology, Houston, TX, USA

Conflict of interest: All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand how dermatologists can combat this issue.

Keywords: antibiotic resistance, dermatology, antibiotic, antimicrobial, infection, acne, rosacea, hidradenitis suppurativa, folliculitis decalvans, bullous pemphigoid, CARP

Introduction

There are many reasons for the development of antibiotic resistant bacteria. Aside from rampant use in agriculture settings, poor antibiotic stewardship among physicians is a major contributor. Dermatologists play an essential role in this process given the significant incidence of inflammatory dermatoses, as well as skin and soft tissue infections (SSTIs) treated with antibiotics. Furthermore, dermatologists have a higher rate of prescribing antibiotics compared to other specialists.¹ Therefore, it is crucial for dermatologists to understand strategies to combat bacterial resistance and reduce its global burden.

Combating Antibiotic Resistance in Dermatology

Molecular resistance is perpetuated through poor antibiotic stewardship. Commonly, this stems from unclear instructions on self-administration of antibiotics, use of sub-antimicrobial dosing, prescription of antibiotics for minor bacterial infections, use of antibacterial drugs for non-bacterial infections, and use of broad-spectrum antibiotics for narrow-spectrum indications.²

General methods for diminishing risk of antibiotic resistance include detailed history and physical, diagnostic laboratory and culture studies, close monitoring of clinical response, appropriate directed-therapy when the causative organism is identified, relevant empiric treatment based on local antimicrobial susceptibilities within the community, and continuing therapy for the appropriate duration.³ All of these general precautions, as well as discontinuing of antibiotics when deemed unnecessary, will aid to reduce the rate of antibiotic resistance.³

In the United States, individuals with acne vulgaris and rosacea account for 20% of the patients prescribed antimicrobials in dermatology.⁴ SSTIs account for a significant amount of the remaining portion. Specific strategies can be utilized to combat emerging resistance in the treatment of acne vulgaris, rosacea, hidradenitis suppurativa (HS), folliculitis decalvans (FD), bullous pemphigoid (BP), and confluent and reticulated papillomatosis (CARP) and SSTIs.

Acne Vulgaris

Antibiotic monotherapy is not recommended for acne vulgaris treatment. Both topical and systemic monotherapy may induce resistance among Cutibacterium acnes (C. acnes) and other organisms that comprise the commensal and transient flora.⁵ The American Academy of Dermatology (AAD) guidelines recommend coadministration of benzoyl peroxide, a topical bactericidal agent not reported to cause resistance, together with both topical and oral antibiotics.^6,7 Added to topical antibiotics, benzoyl peroxide may prevent the formation of resistance and increase treatment efficacy.⁶ Only indirect evidence supports the ability of benzoyl peroxide to limit resistance when used with oral antibiotics.^6,8 Additionally, the AAD recommends using the shortest possible courses, limiting antibiotic use to 3-4 months.⁷

Low-dose or “sub-antimicrobial” doses of doxycycline have been used in rosacea and acne vulgaris, with the intention to only derive benefits from the anti-inflammatory properties of the antibiotic.^2,9,10 However, contrary to the common belief, recent studies demonstrated that low-dose antibiotic exposure leads to the development of high-level resistance.^2,9,11

A unique method being utilized to bypass bacterial resistance in acne is the development of narrow spectrum drugs such as the new tetracycline, sarecycline. Sarecycline is a US FDA approved therapy specifically designed to treat moderate-severe acne and is the only antibiotic with a low resistance claim in its label.² It is narrow spectrum with coverage limited to clinically relevant gram-positive organisms, including C. acnes. Its structural design involves an elongated C7 moiety that extends into the 30S ribosome and directly interferes with mRNA unlike typical tetracyclines.² This newer design allows for stronger binding and increased inhibitory effects.

Rosacea

The large body of evidence supporting an inflammatory pathogenesis of rosacea not triggered by a bacterial etiology has led to rosacea management guidelines that support avoidance of antibiotics whenever possible.⁵ This includes the papulopustular subtype. Antibiotics should only be used after failure of topical and oral anti-inflammatory therapy.¹² Like acne, if antibiotics are used, the course should be as short as possible with treatment for no longer than 2 months.¹²

Hidradenitis Suppurativa (HS)

Given that topical clindamycin and oral tetracycline are firstline therapies for HS, it is not surprising that a high percentage of HS patients harbor lincosamide and tetracycline resistant bacteria.¹³ Therefore, it is recommended that antibiotics be used as adjunctive therapy with other management options, including chlorhexidine or benzoyl peroxide wash, adalimumab, smoking cessation, weight loss, and other non-antimicrobial treatments.^13,14

Folliculitis Decalvans (FD)

A small study of patients with FD who received one or more courses of antibiotic therapy demonstrated a third of patients harbored antibiotic resistant Staphylococcus aureus (S. aureus).¹⁵ The resistance rates in FD patients were significantly higher than the community reference values.¹⁵

Given FD is thought to stem from S. aureus, antibiotic therapy will likely remain the gold standard for exacerbations.¹⁵ However, treatments should be based on bacterial culture/sensitivities, with the aim to transition to nonantibiotic medical therapies (isotretinoin/dapsone/photodynamic therapy) or destructive therapies (laser hair removal/surgery) to suppress inflammation and address hair follicle structural abnormalities and biofilm formation to induce long-term remission.^15,16

Bullous Pemphigoid (BP)

Although topical and systemic steroids are considered the first-line treatment for BP, the substantial morbidity and mortality associated with these regimens presents a therapeutic challenge. Inasmuch, other treatment options are being sought. Among the plethora of agents trialed have been antibiotics, most notably tetracyclines given their anti-inflammatory properties. While some trials have concluded that systemic tetracyclines are effective in BP treatment, they are inferior in recovery rate when compared to systemic steroids.¹⁷ Moreover, those with milder BP and shorter courses of tetracyclines tend to achieve a lower proportion of remission than those with severe disease, indicating that disease severity and the potential need for prolonged treatment should to be taken into account before initiation.¹⁸ Therefore, judicious consideration is needed before placing patients on antibiotics for BP treatment. In general, tetracyclines may be appropriate in older patients with comorbidities that contraindicate systemic steroid use.¹⁸

Confluent and Reticulated Papillomatosis (CARP)

Oral tetracyclines are the most commonly cited monotherapy for CARP; minocycline is utilized most frequently, but other antibiotics used include amoxicillin and azithromycin.¹⁹ Evidence suggests dysfunctional keratinization as a cause of CARP, and this is supported by successful treatment with both topical and oral retinoids.²¹ Efficacy of this treatment is attributed to the anti-inflammatory and immunomodulating properties of retinoids and normalization of keratinization.²⁰ Advantages of retinoid therapy include higher patient compliance and decreased side effects.²⁰ Other treatment options that have demonstrated clinical effects include topical vitamin D derivatives.¹⁹

Skin and Soft Tissue Infections (SSTIs)

Resistance has emerged against many commonly used topical and oral antibiotics for SSTIs. This is likely a result of overuse and misuse.

Topical

Prophylactic use of topical antibiotics after surgical procedures is often unnecessary. A meta-analysis based on data pooled from four studies failed to demonstrate a statistically significant difference between application of topical antibiotics versus topical petrolatum/paraffin in preventing post-surgical infections after low risk office-based dermatologic procedures.^5,22 Low risk procedures include those with clean and clean-contaminated wounds, and following procedures in patients that are immunocompetent and not at high risk of infection, surgeries performed in regions above the knee, and surgeries not involving the groin, ears, or mucosal region of the nose or mouth.⁵ In cases where risk of post-operative infection is high, it is a better choice to utilize oral antibiotic prophylaxis, as topical therapy alone is not as likely to provide adequate prevention of infection.^5,23

Other prophylactic uses of topical antibiotics, such as with atopic dermatitis (AD), have not demonstrated efficacy either. When a cutaneous infection is present, antibiotic therapy is therapeutically beneficial in AD.¹⁸ However, chronic topical or oral antibiotic therapy is not advised to manage or suppress AD in the absence of a true skin infection, and it serves only to promote antibiotic resistance.¹⁸

Another factor to keep in mind is that topical antibiotic therapy is capable of inducing antibiotic resistance beyond areas of application.⁵ Topical erythromycin used on the face induced resistant C. acnes and staphylococci on the back and anterior nares where it was not applied.²⁴ Similar results have been demonstrated with other bacteria such as streptococci.⁵

Mupirocin resistance has reached up to 80% among bacterial strains such as S. aureus in certain communities with heavy usage.^13,25 Low resistance alternatives are fusidic acid and topical pleuromutilins.¹³ Moreover, regular local antiseptic treatment including octenidine or polyhexanide is broadly efficacious and confers a significantly lower risk of resistance relative to topical antibiotics.²⁶

Systemic

Prophylactic oral antibiotics are rarely appropriate for routine dermatologic surgery and are not indicated for patients who have prosthetic joints or vascular grafts.²³ It is recommended only for a small group of patients that have abnormal cardiac valves, and then only with surgery involving clearly infected skin or soft-tissue.²³

Controlled trials indicate that antimicrobial agents are unhelpful in treating cutaneous abscesses, inflamed epidermal cysts, uninfected atopic eczema, and cutaneous ulcers caused by venous insufficiency or diabetes in the absence of significant contiguous soft-tissue inflammation.²³

Between 5-10% of the North American population is classified as beta-lactam allergic.²⁷ However, only 10% of these can be confirmed by allergy diagnostics.²⁷ A false beta-lactam allergy diagnosis may lead to inappropriate use of broad spectrum antibiotics. Common reasons for a false beta-lactam allergy include misinterpretation of known predictable side effects, misinterpretation of infection-induced urticaria or viral exanthema as an immediate type drug reaction or drug exanthema; interpreting non-specific symptoms as an allergy, and considering known reactions in the family as signs of personal allergy.²⁷ To verify a true beta-lactam allergy, risk stratification of all patients should be performed. Patients with a questionable allergy may be excluded based on history alone.²⁷ Patients with an incomplete history or mild reaction may be tested on a case-by-case basis.²⁷ Patients with a medical history strongly suggesting a true allergy should undergo formal testing through a skin test (skin prick, intradermal/patch), lab test (specific immunoglobulin E, basophil activation test), and/or oral provocation test with fractionated administration of beta-lactam.²⁷

Future Directions

To confront the challenge of resistance, modification of existing antibiotics to improve potency and efficacy is underway.¹³ Additionally, development of new narrow spectrum agents with novel mechanisms of action is being pursued.¹³ Given that drug development is a slow process, it cannot keep up with the spread of resistant bacteria. Therefore, alternative methods are under investigation.

One promising avenue is modulation of the skin microbiome.¹³ Abnormalities in the skin microbiome have been observed in patients with acne.^13,28 Treatment with isotretinoin in these patients restored microbiomes to normal.²⁸ Thus, infectious and inflammatory dermatoses may respond to direct manipulation of the skin microbiome via live biotherapeutic products or transplantation of human skin microbiota.¹³ Recent trials have already demonstrated success in treating AD with skin microbiota transplantation.²⁹

Another alternative gaining traction is phage therapy, which uses bacteriophages to infect and lyse bacteria.^13,30 Recent studies have reported successful use of personalized bacteriophage therapy in patients with multidrug-resistant infections.³¹

Further strategies include implementation of electroporation, antimicrobial peptides, photodynamic therapy (PDT), photothermal therapy, nitrous oxide-releasing nanoparticles, cannabidiol, or combinations of these options.³² PDT is a therapeutic option for cutaneous infections immune to antibiotics. PDT use in acne results in reduced follicular obstruction and lower sebum excretion.³² At higher doses, it can destroy sebaceous glands.³² For cutaneous leishmaniasis and warts, PDT has demonstrated clearance rates of up to 100%.³² PDT has also been initiated as a treatment option for onychomycosis.³² Transdermal iontophoresis has been coupled with PDT to increase its effectiveness.³² It uses small electrical currents to permit controlled drug delivery and use of smaller drug concentrations.³² Its use has demonstrated broad spectrum antimicrobial efficacy against bacteria, fungi, and viruses.

Conclusion

Correct and appropriate use of antibiotics will help to preserve their utility in the face of increasing antibiotic resistance; however, greater awareness of the etiologies of resistance and how to combat each is required among prescribing providers.

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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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