Chlormethine 10mg solution for injection vials

Dear Editors, Lymphomatoid papulosis (LyP) and mycosis fungoides (MF) are both primary cutaneous T-cell lymphomas. Both entities may coexist and – owing to overlapping T-cell clones in lesions of LyP and MF within the same patient – the origin of a common progenitor cell has been postulated. Shared oncogenic alterations in both lymphoma subtypes1, 2 have been described recently.3 Lymphomatoid papulosis is an indolent primary cutaneous CD30+ lymphoproliferative disorder, which presents with recurrent, spontaneously regressing papules and nodules with predilection for limbs and trunk. Depending on disease severity and associated symptoms, therapeutic abstention may be an option for mild forms of LyP. However, in more severe cases, topical treatment with corticosteroids, phototherapy, or systemic treatment with e.g., methotrexate, bexarotene or brentuximab vedotin may represent therapeutic options.4 While topical chlormethine gel has been licensed for the treatment of MF and been implemented within clinical routine,5 its application has not been evaluated in LyP. We report on an 80-year-old woman who presented in 02/2022 with a 16-year history of MF and development of concomitant LyP that was first diagnosed in 2020. Both diseases had been confirmed histologically and similar T-cell clones with overlapping oncogenic alterations had been identified for both lymphoma subtypes and published elsewhere.3 Previous treatment modalities included stage-dependent topical (steroids, localized radiation), physical (UV-light) and systemic (methotrexate, bexarotene, brentuximab vedotin) therapies. At the time of presentation, clinical examination revealed patches on the abdomen and the lower extremities corresponding to MF (Figure 1a). Due to previous longstanding topical application of steroids, dermatoporosis was evident. Additionally, erythematous papules of concomitant LyP were present on both lower legs (Figure 1b) and the buttocks. Clinical and laboratory examination and imaging showed no signs of lymphoma manifestations other than the skin. Hence, treatment with topical chlormethine gel was initiated in incrementing application intervals – beginning twice weekly up to once daily – for MF lesions. Under this regimen, a gradual improvement of the lesions was achieved within 14 weeks (Figure 1c). As LyP lesions were mostly in close proximity to MF manifestations, topical chlormethine gel was also applied to these LyP papules in selected areas. A significant improvement and final clearing of the LyP lesions, being confined to treated areas, was observed within 21 days. Hence, topical treatment could be terminated after complete remission of the papules. However, as new LyP papules also occurred in untreated skin upon further visits, topical chlormethine gel was consecutively applied to these new LyP papules. Again, these lesions showed rapid resolution under treatment (Figure 1d). Taking together, after a 14-week treatment period with chlormethine, both MF and LyP manifestations were under good control with excellent tolerability. Lymphomatoid papulosis lesions healed with hyperpigmentation, which did not fully resolve but showed no signs of residual scarring. There were no local relapses during the follow-up at the sites treated with chlormethine gel. Only a few case reports on the topical use of alkylating agents for LyP have hitherto been published.6, 7 Chlormethine is a bifunctional alkylating agent and inhibits proliferating tumor cells by binding and crosslinking DNA strands.8 Adverse effects include irritant contact dermatitis, pruritus, and hyperpigmentation so that individualized symptom-oriented treatment algorithms with incremental dosing have been advocated.5 Chlormethine gel is recommended as first-line treatment in MF patients, but is currently not approved for other cutaneous lymphoma subtypes such as LyP. Since our patient harbored the same T-cell clone as well as overlapping somatic mutations/fusions in the coexisting MF and LyP lesions, we wondered whether chlormethine gel may not only act on MF lesions but also on neighboring LyP papules. This finding is especially relevant as chlormethine poses a possibly safe alternative to topical corticosteroids for patients with recurrent LyP who, as our patient, had experienced steroid-associated skin atrophy before. However, due to the frequent spontaneous regression of LyP lesions, a regression unrelated to chlormethine application cannot be ruled out in this case with certainty. Therefore, randomized controlled trials are warranted to gather evidence concerning the efficacy and safety of chlormethine gel in patients suffering from LyP. In conclusion, chlormethine gel is an effective off-label treatment option for LyP. Although robust data are still lacking, topical steroids remain the first-line treatment choice. This is particularly important in cases where systemic treatment options for LyP are being considered. Chlormethine gel can be a preliminary approach before initiating systemic treatment to mitigate the drug-specific side effects associated with systemic treatments. Open access funding enabled and organized by Projekt DEAL. M.W. received speaker's honoraria and participated in advisory boards of Recordati Rare Diseases. The other authors do not have any topic-related conflicts of interest.

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Topical chlormethine gel has been approved as monotherapy for treatment of adult patients with mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma. In clinical practice, chlormethine gel is often combined with other skin-directed or systemic therapies to optimize response and target recalcitrant lesions. Positive outcomes with combination regimens using chlormethine gel and topical corticosteroids, phototherapy, retinoids, methotrexate, or interferon-α have been reported in literature. However, there are no treatment guidelines on the use of combination regimens with chlormethine gel. To provide real-world evidence and guidance on the use of chlormethine gel combination regimens, several cases of patients treated with chlormethine gel combined with phototherapy ( n = 5), retinoids ( n = 16), or mogamulizumab ( n = 3) are presented. These different combination regimens showed promising results. Most patients had a complete or partial response following treatment and the combinations were well-tolerated over extended treatment periods. Patients receiving chlormethine gel with retinoids had long-term periods of remission, even after treatment discontinuation. Durations of response of up to 3 years were observed in these patients. This long-term disease control may be the result of disease-modifying effects of chlormethine. Previous studies have shown targeted reductions in malignant T-cell clones in patients treated with chlormethine gel as well as improved post-treatment responses. Further research is needed to determine the effectiveness and safety of combination treatment regimens with chlormethine gel and to assess the impact chlormethine gel has on disease control.

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Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), representing the majority of all lymphomas arising in the skin. The disease treatment focuses on managing symptoms and preventing disease evolution. To date, there is no gold standard for MF-CTCL treatment. Chlormethine, a DNA alkylating agent, is a long-known treatment for CTCL. The new chlormethine 0.02% gel (CL-gel) formulation provides proven efficacy and ease of application, improving patient compliance and outcome. The current consensus paper and real-world experience with CL-gel in the treatment of early-stage MF-CTCL may help meet the unmet need for treatments in Canada. A modified Delphi process comprised a virtual meeting and an online follow-up. A panel of 9 board-certified dermatologists with expertise in cutaneous lymphoma and 1 radiation oncologist discussed the systematic literature review results, drew from clinical experience and the opinion of the panel to adopt and agree on five consensus statements. The panel shared real-world patient cases to illustrate the use of chlormethine gel in a variety of patients across Canada. Five real-world patient cases were provided to illustrate the panels' use of chlormethine gel.

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As an important anticancer drug, chlormethine has been used for more than 70 years. Owing to its good efficacy and adaptable structure, chlormethine has been integrated with trackable prodrugs, for the investigation of drug control and tumor targeting. Given the increasing importance of precision medicine, with this review we collate the structure–activity and trackable strategies used for chlormethine-based prodrugs: 1) Small molecule prodrugs: structural transformation of closed spiropyran (SP) to zwitterionic merocyanin (MC), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET) and excited-state intramolecular proton transfer (ESIPT) can enable the fluorescence monitoring or quantification of chlormethine release; 2) Polymer prodrugs: using a conjugated backbone or incorporating fluorophores into side chains, polymers can regulate the emission (π-π interactions or aggregation-induced emission (AIE) mechanisms) and control the release of chlormethine; 3) Nanosystem prodrugs: drug release visualized by the triggered rupture, deformation or degradation of the nanocarrier; 4) Chlormethine-based fluorescent probes: the chlormethine moiety can enable mitochondrial DNA or tumor cells targeting, thereby providing probes for subcellular-labelling. 5) Multifunctional fluorescence prodrugs: modification of chlormethine with fluorescent photodynamic therapeutic (PDT) or photothermal therapeutic (PTT) agents, can achieve visible multimodal therapy, involving chemotherapy CT-PDT, CT-PTT and CT-PDT-PTT. These strategies have enabled the development of fluorescent prodrugs using chlormethine, and these approaches will be covered in this review. We envision that such structure–activity relationships will be particularly important for the future development of anticancer drugs suitable for precision medicine.

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Background: Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. Objectives: To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. Methods: This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. Results: A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Conclusions: Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.

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Maintenance treatment can be recommended for patients with mycosis fungoides (MF) whose disease responds to primary treatment. While positive outcomes have been observed in small studies with maintenance therapy, there is a lack of practical guidelines and agreement on when and how maintenance therapy for MF should be approached. In this article, we discuss expert opinions and clinical experiences on the topic of maintenance therapy for patients with MF, with a focus on chlormethine gel. Ideally, patients should have a durable response before initiating maintenance therapy. The definition of and required duration of durable response are topics that are open to debate and currently have no consensus. Chlormethine gel has several attributes that make it suitable for maintenance therapy; it can be easily applied at home, can be combined with other treatment options for maintenance, and has a manageable safety profile. Chlormethine gel as maintenance therapy can be applied at decreasing frequencies after active treatment with chlormethine gel or other therapies until the minimally effective dose is reached. Patients generally tend to adhere well to chlormethine gel maintenance regimens and may remain on treatment for several years. The experiences described here may be useful for clinicians when deciding on maintenance treatment regimens for their patients. Development of guidelines based on clinical trial outcomes will be important to ensure the most effective maintenance treatment strategies are used for patients with MF.

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The composite index lesion severity (CAILS) score is used to monitor disease and therapeutic response in mycosis fungoides (MF), but is limited by interobserver variability and low sensitivity. Emerging imaging techniques, such as multispectral imaging (MSI), colourimetry and laser speckle contrast imaging (LSCI), offer objective alternatives for quantifying CAILS parameters. The aim of this study was to evaluate non-invasive imaging modalities for objective and reliable quantification of disease extent in MF. Sixty-six participants were enrolled in two prospective studies: a cross-sectional discovery cohort to assess baseline characteristics of 35 MF patients (IA-IVB) and 10 healthy controls using CAILS and MSI, and a longitudinal confirmation cohort including 21 early-stage MF patients (IA-IIA) treated with chlormethine gel 0.016% for 16 weeks, in whom lesional and non-lesional skin were assessed using CAILS, MSI, colourimetry and LSCI at multiple time points. Candidate biomarkers were required to meet five clinical validation criteria: disease discrimination, repeatability, treatment responsiveness, correlation with CAILS and patient acceptability. In the discovery cohort, MSI detected significant differences in erythema, pigmentation, elevation and desquamation between healthy, non-lesional and lesional skin. In the confirmation cohort, four candidate biomarkers met all validation criteria: MSI CIELAB a*, MSI average haemoglobin, and colourimetry CIELAB a* (DSMIII) for quantifying erythema, and MSI individual typology angle (ITA) for pigmentation. These biomarkers reliably discriminated lesional from non-lesional skin (p ≤ 0.001), showed strong test-retest reliability (CV < 10%, ICC > 0.84), detected treatment effects, showed moderate concordance with CAILS, and were associated with low patient burden (mean 3.4/100). These findings show that MSI- and colourimetry-derived biomarkers can objectively monitor disease extent in MF and complement existing clinical assessments.

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