Figure - available from: Cancer Management and Research
This content is subject to copyright. Terms and conditions apply.
Source publication
Mycosis fungoides (MF) is a low-grade cutaneous lymphoma accounting for more than half of primary cutaneous T-cell lymphomas (CTCLs). Due to the rarity of CTCL, randomized studies are lacking, and treatment is based mainly on the recent published European Organisation for Research and Treatment of Cancer guidelines. Basically, early-stage MF is tre...
Similar publications
Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechl...
Citations
... Skin malignant T-cell infiltration represents the main characteristic of MF, which initial presentation generally involves skin patches and/or plaques which can progress to tumors or erythroderma (3,4). Diagnosis is frequently delayed and made after several biopsies, and the staging is based on the 2007 TNMB revision (5)(6)(7). ...
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.
... Mogamulizumab is an anti-C-C chemokine receptor 4 monoclonal antibody used in the treatment of refractory MF and Sézary Syndrome (SS) (3). Mechlorethamine gel is a topical nitrogen mustard approved for the treatment of early-stage MF in the United States (4). Both treatments can cause cutaneous side effects in up to 60% of patients that mimic MF clinically and histologically making it challenging to differentiate from MF progression (1,2). ...
Cutaneous adverse events of both topical and systemic drugs in patients with mycosis fungoides (MF) present a diagnostic challenge as it is often difficult to distinguish drug associated rash from disease progression in the skin. Mogamulizumab and mechlorethamine gel are approved treatments for MF, both of which can cause treatment related cutaneous adverse events. It can often be challenging to distinguish mogamulizumab associated rash (MAR) and mechlorethamine gel associated hypersensitivity dermatitis from MF progression both clinically and histologically. High-throughput sequencing (HTS) of the T-cell receptor (TCR), also known as immunosequencing, can be used to assess T-cell clonality to support a diagnosis of MF. After identification of the malignant TCR clone at baseline, immunosequencing can track the established malignant TCR sequence and its frequency over time with high sensitivity. As a result, immunosequencing clone tracking can aid in distinguishing disease progression from treatment side effects. Here, we present a case series to demonstrate how monitoring of the malignant T-cell frequency by immunosequencing can aid in diagnosis of mogamulizumab and mechlorethamine gel cutaneous adverse events.
... Mycosis fungoides (MF) is a primary cutaneous T-cell lymphoma (CTCL), characterized by the infiltration of malignant T-cells to the epidermal layer of the skin [1]. MF accounts for C 60% of CTCLs and C 50% of all cutaneous lymphomas [2]. ...
... MF accounts for C 60% of CTCLs and C 50% of all cutaneous lymphomas [2]. Although the prognosis for earlystage disease can be acceptable (5-and 10-year survival rates [ 90%), a quarter of patients are at risk of progression to advanced disease, which has a poor prognosis (survival \ 4 years) [1,3,4]. There is no cure for MF-CTCL with conventional systemic therapy; available therapeutic options focus on local treatment of lesions (for all stages), preventing disease progression (mainly in late stages), and maintaining patient quality of life (QoL) [1,5]. ...
... Although the prognosis for earlystage disease can be acceptable (5-and 10-year survival rates [ 90%), a quarter of patients are at risk of progression to advanced disease, which has a poor prognosis (survival \ 4 years) [1,3,4]. There is no cure for MF-CTCL with conventional systemic therapy; available therapeutic options focus on local treatment of lesions (for all stages), preventing disease progression (mainly in late stages), and maintaining patient quality of life (QoL) [1,5]. Skindirected therapies (SDTs) are the foundation of care for early-stage disease [6,7], and palliation at all stages, with adjunctive therapy for treatment and symptom management in more advanced MF-CTCL [5,8]. ...
Introduction:
The DNA-alkylating agent chlormethine (CL, or mechlorethamine) is approved in several countries worldwide as a 0.016% w/w topical CL gel formulation, to treat mycosis fungoides cutaneous T-cell lymphoma, with a positive benefit/risk ratio.
Methods:
Release profiles of CL from the gel and a compounded ointment-based 0.016% CL formulation were compared via in vitro release testing (IVRT), utilizing static diffusion cells, a pseudo-infinite dose, and polytetrafluoroethylene membranes, over 5 h. The percutaneous absorption profile of CL gel in ex vivo human skin was also examined, using in vitro permeation testing (IVPT) with flow-through diffusion cells, dermatomed skin (epidermis plus dermis) and epidermal membranes, a finite dose, over 24 h.
Results:
In IVRT experiments, the mean ± SD CL release rate was significantly higher for the gel versus the ointment (5.70 ± 0.73 versus 2.38 ± 1.03 μg/cm2/√h); the formulations were inequivalent per the US Food and Drug Administration scale-up and postapproval changes for nonsterile semisolid dosage forms (FDA SUPAC-SS) criteria. Mean IVPT cumulative CL (gel) permeating through epidermal membrane was higher than for dermatomed skin (4.6% versus 2.5% of applied dose). Mean residual CL on the epidermal membrane surface was 1.3% of the applied dose.
Conclusions:
CL gel (0.016%) and ointment were inequivalent, with an optimized release profile, suggesting minimal passage of CL gel through human epidermal tissue to the dermis.
... It acts by inducing cell differentiation, apoptosis, and inhibiting metastasis [10]. Food and Drug Administration (FDA) approved BEX for treating cutaneous lymphoma [11][12][13][14]. BEX molecule was also found to be neuroprotective against myriad of neurological diseases, for instance, Alzheimer's disease, traumatic brain injury, and ischemic stroke [15][16][17]. ...
The present study is focused on the use of solid dispersion technology to triumph over the solubility-related problems of bexarotene which is currently used for treating various types of cancer and has shown potential inhibitory action on COVID-19 main protease and human ACE2 receptors. It is based on comparison of green locust bean gum and synthetic poloxamer as polymers using extensive mechanistic methods to explore the mechanism behind solubility enhancement and to find suitable concentration of drug to polymer ratio to prepare porous 3rd generation solid dispersion. The prepared solid dispersions were characterized using different studies like X-ray diffraction (XRD), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), differential scanning calorimetry (DSC), and particle size analysis in order to determine the exact changes occurred in the product which are responsible for enhancing solubility profiles of an insoluble drug. The results showed different profiles for particle size, solubility, dissolution rate, porosity, BET, and Langmuir specific surface area of prepared solid dispersions by using different polymers. In addition to the comparison of polymers, the BET analysis deeply explored the changes occurred in all dispersions when the concentration of polymer was increased. The optimized solid dispersion prepared with MLBG using lyophilization technique showed reduced particle size of 745.7±4.4 nm, utmost solubility of 63.97%, pore size of 211.597 Å, BET and Langmuir specific surface area of 5.6413 m2/g and 8.2757 m2/g, respectively.
... 5 Diagnosis is frequently made after several biopsies and the staging is based on the classical tumor, nodes, metastases (TNM) with the addition of blood involvement (B). 6,7 MF histologically shows epidermal infiltration of atypical T lymphocytes with cerebriform nuclei and βF1 + , CD3 + , CD4 + , CD5 + , CD8 À , CD45RO + immunophenotype. Its incidence in United States of America (USA) is about 5.9 cases every million people, with an average age at diagnosis of 60 years and male prevalence (men/women = 1.4). ...
... 8 Several therapies are available, especially for early stages, but none has an exclusive indication for MF. 7,9 Treatment selection needs to be continuously tailored on patient characterization comprehensive of age, sex, stage, anatomical localization of lesions, comorbidities and patient logistic. 1 For instance, phototherapy, radiotherapy and photopheresis need a frequent presence of the patient in the hospital with impact on quality of life, work productivity, and commuting costs. ...
... 11 In 2013, the American Food and Drug Administration approved the use of chlormethine 0.016% w/w gel for patients affected by stage IA and IB of MF, who resulted no responsive to the first line therapies. 7,13 In 2017 a gel preparation of this molecule (0.02% chlormethine HCl) was approved for MF by the European Medicines Agency, admitting the use for cutaneous lesions even in patients with advanced stages of the disease. 11 Bioanalytical results demonstrate lack of systemic absorption of CG in plasma samples collected and tested up to 6 months after treatment initiation. ...
Background:
Gel formulation of chlormethine (CG) has gained a preeminent role among therapies available for mycosis fungoides (MF).
Objectives:
To evaluate the frequency of use of CG for MF treatment and to determine the limits and potentialities of CG in a real-world setting.
Materials and methods:
A systematic review of articles published prior to October 2021 was performed. Articles were included in the review if a full-text English version was available. MEDLINE (PubMed), Scopus and Web of Science were each queried from their date of inception with the following terms: "mechlorethamine gel", "chlormethine gel" and "mycosis fungoides". The reference lists of the studies retrieved were searched manually. Moreover, this study included all consecutive patients with different stages of MF (from IA to IIB) who started treatment with CG gel between July 2020 and May 2021. Data of the literature were compared to our single-center real-life experience.
Results:
Of the surveyed literature, 11 publications were included in the final analysis describing a total of 548 patients with MF. 11 patients with a median (standard deviation) age of 66 years (15.1) were enrolled and followed up, receiving CG (0.02% chlormethine HCl). Response to treatment resulted higher (90.1%) in our study population than in other real-world experiences published in literature.
Conclusion:
This systematic review supports the role of CG for MF treatment, showing its limits and potentialities. Our single-center real-life experience revealed an elevated percentage of clinical response with high safety and tolerance, demonstrating its versatile use with dose and application rate adaptability.
... Insgesamt besteht eine sehr lange Erfahrung mit dem Wirkstoff Chlormethin. Die Substanz wurde in den USA erstmals 1949 in magistraler Zubereitung zur Therapie der MF angewendet -zunächst in wässriger Lösung, dann in Salbenform [10]. Um die Stabilität des Alkylans zu gewährleisten und die Anwendbarkeit zu verbessern, erfolgte zuletzt die Entwicklung von Chlormethin-Gel als Fertigprodukt. ...
Hintergrund:
Chlormethin-Gel ist in Europa zur Therapie von Patienten mit Mycosis fungoides in allen Krankheitsstadien zugelassen. Die optimalen Behandlungsregime hinsichtlich Frequenz, Dosierung, Kombinations- oder Erhaltungstherapien sind noch nicht vollständig etabliert.
Methodik:
Zehn in der Erforschung und Behandlung kutaner T-Zell-Lymphome erfahrene Experten aus Deutschland, Österreich und der Schweiz (DACH-Region) wurden schriftlich zu Indikation, Anwendungsfrequenz, Beurteilung des Therapieerfolgs, Begleittherapie, Nebenwirkungen, Kombinationstherapien in späteren Krankheitsstadien, Erhaltungstherapie und Adhärenz im Rahmen der Therapie der Mycosis fungoides mit Chlormethin-Gel befragt. Die strukturiert aufbereiteten Ergebnisse der Umfrage wurden in einer Konsensuskonferenz diskutiert und Empfehlungen zum Management der Therapie mit Chlormethin-Gel entwickelt.
Ergebnisse:
Wesentlich für die Therapie mit Chlormethin-Gel ist ein individuelles, symptomorientiertes Therapiemanagement. Systemische Nebenwirkungen des Wirkstoffs sind wegen der fehlenden systemischen Verfügbarkeit bei topischer Anwendung unwahrscheinlich. Die häufig auftretende allergische oder irritativ-toxische Kontaktdermatitis kann durch eine Anpassung des Therapieregimes, Therapiepausen sowie nebenwirkungsspezifische und unterstützende Maßnahmen häufig beherrscht werden. Ein einschleichender Therapiebeginn mit Anwendung von Chlormethin-Gel jeden zweiten Tag kann die Tolerabilität wesentlich verbessern, insbesondere wenn die Therapie alternierend mit topischen Kortikosteroiden erfolgt.
Schlussfolgerungen:
Die Anwendung von Chlormethin-Gel bei Mycosis fungoides wird durch die begleitende Kontaktdermatitis häufig eingeschränkt. Mit einem geeigneten Therapie- und Nebenwirkungsmanagement können vermeidbare Therapieabbrüche verhindert werden und mehr Patienten von der Therapie profitieren.
... Overall, experience with the agent chlormethine is extensive. In 1949, the substance was used for the first time as extemporaneous preparation in the USA -initially in aqueous solution, then in ointment form [10]. To ensure stability of the alkylating agent and to improve its application, chlormethine gel was finally developed as an approved pharmaceutical product. ...
Background:
In Europe chlormethine gel is licensed for the management of patients with mycosis fungoides of all stages. However, the optimal regimen regarding frequency and dosing as well as combination and maintenance therapy is not well established.
Methods:
Ten experts experienced in research and management of cutaneous T-cell lymphomas from Germany, Austria, and Switzerland (DACH region) were asked in written form to report on indication for chlormethine gel, frequency of use, monitoring, concomitant therapies, adverse effects, combination therapies in later stages of the disease, maintenance therapy, and adherence to this therapy for mycosis fungoides. The structured answers were discussed in a consensus conference and recommendations were developed.
Results:
Essential for therapy with chlormethine gel is an individualized and symptom-oriented management. Because of the lack of systemic resorption of topically administered chlormethine gel, systemic adverse events are unlikely. An allergic or irritative-toxic contact dermatitis is common but manageable with adaptation of the regimen, interruption of administration, and symptom-specific supportive measurements. A step-up initial approach with application of chlormethine gel every other day is associated with a better tolerability, especially if it is alternated with topical corticosteroids.
Conclusions:
The use of chlormethine gel in the management of mycosis fungoides is often limited by a concomitant contact dermatitis. An adequate therapeutic regimen and the management of adverse effects can preclude an unnecessary withdrawal of therapy so that more patients can benefit from this treatment option.
... Mycosis fungoides (MF) is a low-grade cutaneous lymphoma encompassing more than half of primary CTCL cases, with an incidence rate of around 5.6 per million persons and a median age at diagnosis of 55-60 years. The choice of treatment depends on the patient's comorbidities and disease staging [1]. In MF-CTCL patients with limited/ localised skin involvement, the National Comprehensive Cancer Network (NCCN) Guidelines recommend topical mechlorethamine hydrochloride (MCH, or nitrogen mustard) as a primary skin-directed treatment option [2]. ...
... In MF-CTCL patients with limited/ localised skin involvement, the National Comprehensive Cancer Network (NCCN) Guidelines recommend topical mechlorethamine hydrochloride (MCH, or nitrogen mustard) as a primary skin-directed treatment option [2]. However, there is currently no curative treatment for MF-CTCL, and the main treatment objective is to reach effective palliation with symptom improvement and enhance the patient's quality of life (QoL) [1]. Indeed, patients with CTCLs experience several symptoms affecting their daily life, such as skin sensitivity, itching, annoyance about the disease, worry that it could worsen, and impairment in sexual life [3]. ...
Background:
A prospective, observational, US-based study (PROVe) used three questionnaires (Pruritus-VAS, Skindex-29, MF/SS-CTCL QoL) to assess quality of life in patients diagnosed with mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL); however, none of these studies was provided with a preference-based algorithm yielding health state utility values (HSUVs).
Objective:
This study aimed to assess the feasibility of deriving HSUVs from published mapping algorithms by comparing mapped utilities with the HSUVs reported in the MF-CTCL literature.
Methods:
We searched PubMed, the School of Health and Related Research Health Utility Database (ScHARRHUD), and the Health Economics Research Centre (HERC) database of mapping studies (version 7.0) to identify any studies mapping Pruritus-VAS, Skindex-29, or MF/SS-CTCL QoL to a preference-based instrument (ideally, EQ-5D), and any studies assessing HSUVs in MF-CTCL. Two algorithms from a recent study that mapped Pruritus-VAS onto EQ-5D-3L were applied to the PROVe patient-level data. We performed multiple imputation to handle missing VAS data, calculated average mapped utilities in the whole sample, and compared them with relevant factors using the t-test and one-way analysis of variance (ANOVA).
Results:
Overall, 298 patients provided 1441 Pruritus-VAS scores over a 2-year follow-up (1-21 visits per patient). The average mapped HSUVs ranged between 0.950 and 0.999 depending on the algorithm applied and imputation of missing data. In subgroup analysis, significant differences (p < 0.05) were observed according to age, race, and cancer stage. A few previous studies that collected HSUVs from MF-CTCL patients reported mean values of between 0.82 and 0.87 using time trade-off, 0.63 and 0.83 using EQ-5D, and 0.51 and 0.69 using the HUI3.
Conclusions:
The HSUVs derived by applying published mapping algorithms to PROVe Pruritus-VAS data appeared largely overestimated if compared with the existing literature. More research is required to understand the applicability of existing mapping algorithms and to develop new mapping algorithms in MF-CTCL.
... T opical chlormethine, otherwise known as mechlorethamine, was first introduced in the 1950s as an effective skin-directed chemotherapeutic agent for treating early-stage mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL) (1)(2)(3)(4). Systemically, mechlorethamine works as an alkylating agent affecting rapidly dividing cells. However, its mechanism of action topically is not fully understood and may also be mediated by immune mechanisms, including interactions with the epidermal cell-Langerhans cell-Tcell axis (5,6). ...
... In 2013, based on this pivotal study, the US Food and Drug Administration (FDA) approved the first topical formulation of chlormethine/mechlorethamine 0.016%, in the form of a gel (Valchlor ® ; Helsinn Therapeutics, Iselin, NJ, USA) for treating patients with stage IA and IB MF who have received prior skin-directed therapies (7,8). Chlormethine/mechlorethamine gel (CL gel) is an effective and safe therapy for limited or generalized patch and/or plaque (T1-T2) disease (1,7,8). Topical CL gel is currently endorsed by international guidelines for use as first-line therapy in adult patients with MF (European Organisation for Research and Treatment of Cancer (EORTC); European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN)). ...
... Topical CL gel is currently endorsed by international guidelines for use as first-line therapy in adult patients with MF (European Organisation for Research and Treatment of Cancer (EORTC); European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN)). Subsequent studies of CL gel have reported overall response rates between 57% and 79.2% (1). If complete remission is achieved, CL gel can continue to be used as a maintenance therapy (8). ...
Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechlorethamine, is a topical chemotherapeutic, which has been in use for over 60 years. In 2013, the US Food and Drug Administration approved chlormethine/mechlorethamine gel (Valchlor®) for treatment of stage IA and IB mycosis fungoides. Chlormethine/mechlorethamine gel is an effective therapy; however, its use may be limited by development of adverse cutaneous reactions. Off-label dosing modifications, as well as co-administration of topical steroids and an aggressive moisturization regimen can be used to reduce these side-effects. We report here 4 cases of mycosis fungoides treated with chlormethine/mechlorethamine gel at the Comprehensive Skin Cancer Center at Columbia University Irving Medical Center, which provide insights into the use of this therapy in clinical practice.
... Chlormethine (also known as mechlorethamine) is an SDT currently included in international guidelines [5][6][7] for use in adult patients with MF as first-line therapy. Chlormethine functions as an alkylating agent and induces DNA damage resulting in the inhibition of proliferating cells [9]. A topical chlormethine 0.016% w/w gel (equivalent to 0.02% chlormethine HCl) was developed and approved on the basis of results from the 201 registration study (NCT00168064) and the 202 extension study (NCT00535470) [10][11][12]. ...
Background:
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Patients can be treated using chlormethine gel, a skin-directed therapy developed and approved for MF. In the randomized, controlled 201 trial, chlormethine gel was found to be noninferior to equal-strength chlormethine ointment. However, there remains a need to gain more insight into outcome measures after treatment.
Objective:
The aim of this study was to further investigate the potential of chlormethine gel treatment through a novel post hoc analysis of the 201 trial data (NCT00168064).
Methods:
Patients were randomized to chlormethine gel or ointment; response assessments included Composite Assessment of Index Lesion Severity (CAILS) and total body surface area (BSA). In this post hoc analysis, additional subgroup response analyses were performed for stage IA/IB-IIA MF. Very good partial response (75 to <100% improvement) was included as an additional response category. Time to response and overall response trends were determined. Finally, multivariate time-to-event analyses were performed to determine whether associations were observed between treatment frequency, response, and adverse events.
Results:
Response rates were significantly higher for patients with stage IA MF for CAILS (intent-to-treat [p = 0.0014] and efficacy-evaluable [EE; p = 0.0036] populations) and BSA (EE population [p = 0.0488]) treated with gel versus ointment. Time to first CAILS response and response trends were better for all-stage gel-treated patients overall. No association was seen between treatment frequency and response or occurrence of adverse events at the following visit. An association was observed between the occurrence of contact dermatitis and improved clinical response at the next visit (p = 0.0001).
Conclusion:
This post hoc analysis shows that treatment with chlormethine gel may result in higher and faster response rates compared with chlormethine ointment, which confirms and expands results reported in the original analysis. The incidence of contact dermatitis may potentially be a prognostic indicator for clinical response; this needs to be confirmed in a larger population.
