Valchlor®/Ledaga®

Ledaga/Valchlor contains the active substance chlormethine (or mechlorethamine), an anti-cancer drug used on the skin to treat MF-CTCL. Chlormethine is an “alkylating agent”; it binds to DNA in dividing cells, such as cancer cells, which prevents them from multiplying and growing ¹.  The antitumor effects of chlormethine on MF skin T-cells are predominantly exerted through the induction of DNA double-stranded breaks and the increased expression of the apoptotic gene CASP3 in the subpopulation of malignant skin T-cells. In addition, recent findings showed that chlormethine decreases the expression of several alkylated nucleotide excision genes involved in DNA repair ².

References:

1. Geskin LJ, Bagot M, Hodak E, Kim EJ. Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis Fungoides Cutaneous T-Cell Lymphoma: A Narrative Review and International Experience. Dermatol Ther (Heidelb) 2021 Aug;11(4):1085-1106.


2. Chang YT, Ignatova D, Hoetzenecker W, et al. Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions. JID Innov. 2021 Nov 25;2(1):100069. 

Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is a rare malignancy characterized by the infiltration of malignant T cells into the cutaneous layer of the skin². With disease progression, malignant T cells migrate into the lower dermal layer, lymph nodes, blood and organs. Symptoms of MF-CTCL include flat, red, scaly patches, thicker raised lesions called plaques, and less frequently, nodules (or bumps) called tumors². Most patients experience patches and/or plaques with the common symptom of itching. MF-CTCL can mimic benign (non-cancerous) skin conditions such as chronic eczema, allergic contact dermatitis, or psoriasis, posing a diagnostic challenge to clinicians involved in the diagnosis².  It is not unusual for the diagnosis to remain elusive for years. Prognosis is generally good in early-stage MF-CTCL and considerably poorer in those with advanced stages³.  Quality of life is impacted in MF-CTCL, worsening with disease progression due to insomnia, depression, pruritis, and pain³.

References:

1. Chang YT, Ignatova D, Hoetzenecker W, et al. Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions. JID Innov. 2021 Nov 25;2(1):100069.


2. Geskin LJ, Bagot M, Hodak E, Kim EJ. Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis Fungoides Cutaneous T-Cell Lymphoma: A Narrative Review and International Experience. Dermatol Ther (Heidelb) 2021 Aug;11(4):1085-1106.


3. Hodak E, Geskin LJ, Guenova E, et al. Real-life Barriers to Diagnosis of Mycosis Fungoides: An International Expert Panel Discussion. Am J Clin Dermatol. 2023 Jan;24(1):5-14.

Diagnosis of early MF-CTCL is challenging and often delayed, due in part to the heterogeneity, subtlety, and location of lesions, which may mimic benign inflammatory dermatoses, but also due to a general lack of physician awareness³. Typical procedures done to diagnose MF-CTCL include a thorough physical exam (including thorough skin exam), skin and/or lymph node biopsies (removal of small piece of tissue for examination by a pathologist), blood tests and possible imaging tests². Crucially, there must be a correlation between clinical and histopathologic findings, sometimes achieved using validated scoring systems³.

References:

1. Chang YT, Ignatova D, Hoetzenecker W, et al. Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions. JID Innov. 2021 Nov 25;2(1):100069.


2. Geskin LJ, Bagot M, Hodak E, Kim EJ. Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis Fungoides Cutaneous T-Cell Lymphoma: A Narrative Review and International Experience. Dermatol Ther (Heidelb) 2021 Aug;11(4):1085-1106.


3. Hodak E, Geskin LJ, Guenova E, et al. Real-life Barriers to Diagnosis of Mycosis Fungoides: An International Expert Panel Discussion. Am J Clin Dermatol. 2023 Jan;24(1):5-14.

There is currently no cure for MF-CTCL. Therapeutic options are focused on treating lesions locally (“skin directed therapy”, for all stages) and on preventing disease progression (mainly in the late stages) and maintaining the quality-of-life for patients [Geskin ref]. Examples of skin directed therapies include creams, ointments, or gels that are applied to the skin, such as topical corticosteroids, topical chlormethine, and retinoids. Ultraviolet light (phototherapy or “medical tanning”) and radiation therapy are also types of skin directed therapy [Geskin ref]. In advanced or refractory disease, systemic therapies are used, alone or in combination with skin-directed therapies, especially for persistent skin lesions.

References:

1. Chang YT, Ignatova D, Hoetzenecker W, et al. Increased Chlormethine-Induced DNA Double-Stranded Breaks in Malignant T Cells from Mycosis Fungoides Skin Lesions. JID Innov. 2021 Nov 25;2(1):100069.


2. Geskin LJ, Bagot M, Hodak E, Kim EJ. Chlormethine Gel for the Treatment of Skin Lesions in All Stages of Mycosis Fungoides Cutaneous T-Cell Lymphoma: A Narrative Review and International Experience. Dermatol Ther (Heidelb) 2021 Aug;11(4):1085-1106.


3. Hodak E, Geskin LJ, Guenova E, et al. Real-life Barriers to Diagnosis of Mycosis Fungoides: An International Expert Panel Discussion. Am J Clin Dermatol. 2023 Jan;24(1):5-14.