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Expert Review of Clinical Pharmacology Sep 2014Mycosis fungoides (MF) is an extranodal non-Hodgkins lymphoma of T-cell origin. MF is the most common type and can be stratified as early (IA-IIA) or late (IIB or...
Mycosis fungoides (MF) is an extranodal non-Hodgkins lymphoma of T-cell origin. MF is the most common type and can be stratified as early (IA-IIA) or late (IIB or greater) stage disease. Patients with patch disease usually have a benign, chronic course. Patients with plaques have a worse prognosis and need more aggressive therapy. Topical nitrogen mustard ([NM]; mechlorethamine hydrochloride) has been used for MF since the 1950s. Complete response rates reported for stage IA are 76-80% and 35-68% for stage IB. Most common toxicities reported are irritant contact dermatitis, allergic reaction and hyperpigmentation. There is a potential for risk of non-melanoma skin cancers reported with NM use in patients who used multiple skin damaging therapies. This article focuses on the clinical trial that led to the US FDA approval of VALCHLOR for stage IA and IB MF in 2013 after one prior treatment (excluding NM within 2 years or carmustine therapy ever).
Topics: Administration, Cutaneous; Antineoplastic Agents, Alkylating; Clinical Trials as Topic; Drug Approval; Gels; Humans; Mechlorethamine; Mycosis Fungoides; Neoplasm Staging; Prognosis; Skin Neoplasms; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 25068889
DOI: 10.1586/17512433.2014.944500 -
Acta Dermato-venereologica Sep 2021Mycosis 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...
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 the 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.
Topics: Antineoplastic Agents, Alkylating; Humans; Mechlorethamine; Mycosis Fungoides; Skin Neoplasms; Universities
PubMed: 34436621
DOI: 10.2340/00015555-3911 -
Clinical Lymphoma, Myeloma & Leukemia Feb 2021The pivotal 201 Study investigated chlormethine/mechlorethamine gel treatment for patients with early stage disease mycosis fungoides and demonstrated the treatment was...
Evaluating the Treatment Patterns of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: By-time Reanalysis of a Randomized Controlled Phase 2 Study.
BACKGROUND
The pivotal 201 Study investigated chlormethine/mechlorethamine gel treatment for patients with early stage disease mycosis fungoides and demonstrated the treatment was not inferior to chlormethine ointment. However, overall response rates do not provide information about response patterns. The study objective was to assess the value of by-time analysis of clinical response data in visualizing response over time.
METHODS
This post hoc analysis re-evaluated chlormethine efficacy using a by-time approach that investigated the trend to treatment response and permitted assessment of response, both monthly between 1 and 6 months, and once every 2 months between 7 and 12 months, over the course of 1 year. In addition, very good partial response was redefined as a ≥ 75% response.
RESULTS
By-time analyses of Composite Assessment of Index Lesion Severity (CAILS) and modified severity-weighted assessment tool (mSWAT) showed response rates at 1 month (respectively, 8.5% and 5.9%) that increased over time to peak at 10 months (78.9% and 54.4%). Early, intermittent, and late response patterns were observed. In total, 32.5% of patients experienced very good partial response over 2 consecutive visits, indicating that ∼ 33% of patients could expect to have very good to complete response within 1 year.
CONCLUSION
By-time analysis for clinical response provides complementary information to traditional overall response rate data regarding response peak time and changes over time.
Topics: Antineoplastic Agents, Alkylating; Clinical Trials, Phase II as Topic; Gels; Humans; Mechlorethamine; Mycosis Fungoides; Neoplasm Staging; Randomized Controlled Trials as Topic; Skin Neoplasms; Time Factors; Treatment Outcome
PubMed: 33358692
DOI: 10.1016/j.clml.2020.11.022 -
Medical and Pediatric Oncology Aug 2000
Topics: Antineoplastic Agents; Folic Acid Antagonists; History, 20th Century; Humans; Lymphoma; Mechlorethamine; United States
PubMed: 10918248
DOI: 10.1002/1096-911x(200008)35:2<157::aid-mpo20>3.0.co;2-q -
International Journal of Radiation... Dec 1996This study describes and characterizes the interactions of nitrogen mustard mechlorethamine (HN2) with guanine and the radiation sensitivity of guanine in the presence...
This study describes and characterizes the interactions of nitrogen mustard mechlorethamine (HN2) with guanine and the radiation sensitivity of guanine in the presence of HN2. Briefly, in an equimolar solution (0.5 mmol dm-3) the pH-dependence (pH 3.0-12.0) and time-dependence (0-36 h) of alkylation of guanine at room temperature were determined using a reverse-phase high-performance liquid chromatography (hplc) column. Based on the hplc peak areas of the product and intact guanine, the optimal pH for alkylation was determined to be 8.0. Similarly, the optimal time required for alkylation was 10 h. Two products, i.e. alkylated guanines, were detected (10:1, peak areas measured at 260 nm) and purified. Structural studies of the products were performed by direct insertion probe-electron impact mass spectrometry. These products were identified as N-(2-chloroethyl)-N-[2-(7-guanyl)ethyl]-methylamine (product 2). At optimal conditions, samples of either guanine or an equimolar solution of guanine and HN2 were 60Co irradiated (gamma-ray) at 25 Gy min-1 at doses up to 400 Gy. Both sets of samples were analysed by hplc. In each case, the sole radiation product observed and characterized was 8-hydroxy-guanine. Dose-yield plots were linear and showed that HN2 enhanced the radiation sensitivity of guanine. This increase in radiation sensitivity is attributed to the differences in electrophilic properties between nitrogen mustard and guanine.
Topics: Chromatography, High Pressure Liquid; DNA Adducts; Drug Interactions; Guanine; Hydrogen-Ion Concentration; Mechlorethamine; Radiation Tolerance
PubMed: 8980671
DOI: 10.1080/095530096144626 -
Chemical Research in Toxicology Jun 2019Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2), and sulfur mustard are potent vesicants that modify and disrupt cellular macromolecules including...
Nitrogen mustard, mechlorethamine (bis(2-chloroethyl)methylamine; HN2), and sulfur mustard are potent vesicants that modify and disrupt cellular macromolecules including DNA leading to cytotoxicity and tissue injury. In many cell types, HN2 upregulates DNA damage signaling pathways including ataxia telangiectasia mutated (ATM), ataxia telangiectasia mutated- and Rad3-related (ATR) as well as DNA-dependent protein kinase (DNA-PK). In the present studies, we investigated crosstalk between the HN2-induced DNA damage response and cell cycle progression using human A549 lung epithelial cells. HN2 (1-20 μM; 24 h) caused a concentration-dependent arrest of cells in the S and G2/M phases of the cell cycle. This was associated with inhibition of DNA synthesis, as measured by incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into S phase cells. Cell cycle arrest was correlated with activation of DNA damage and cell cycle checkpoint signaling. Thus, HN2 treatment resulted in time- and concentration-dependent increases in expression of phosphorylated ATM (Ser1981), Chk2 (Thr68), H2AX (Ser139), and p53 (Ser15). Activation of DNA damage signaling was most pronounced in S-phase cells followed by G2/M-phase cells. HN2-induced cell cycle arrest was suppressed by the ATM and DNA-PK inhibitors, KU55933 and NU7441, respectively, and to a lesser extent by VE821, an ATR inhibitor. This was correlated with abrogation of DNA damage checkpoints signaling. These data indicate that activation of ATM, ATR, and DNA-PK signaling pathways by HN2 are important in the mechanism of vesicant-induced cell cycle arrest and cytotoxicity. Drugs that inhibit activation of DNA damage signaling may be effective countermeasures for vesicant-induced tissue injury.
Topics: A549 Cells; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Proliferation; Chemical Warfare Agents; DNA Damage; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Mechlorethamine; Signal Transduction; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured
PubMed: 30964658
DOI: 10.1021/acs.chemrestox.8b00417 -
Journal of the American Academy of... Oct 1988One hundred seventeen patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride. The probability of achieving a clinically apparent...
One hundred seventeen patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride. The probability of achieving a clinically apparent remission within 2 years of therapy was 75.8% in patients with stage I disease, 44.6% in patients with stage II disease, and 48.6% in patients with stage III disease. Patients with stage I disease achieved complete remission sooner (median, 6.5 months) than patients with stage II (median, 41.1 months) or stage III (median, 39.1 months) disease. The median time to relapse was 44.5 months. Sixty-eight patients (58.1%) developed a delayed hypersensitivity reaction, but only one patient had to discontinue therapy as a consequence. No appreciable differences were seen in the probability to achieve complete remission or time to complete remission as stratified by gender, substage, or the development of a delayed hypersensitivity reaction. Survival analysis revealed that the probability of surviving at 5 years was 89% for all patients. These findings compare favorably with results with other treatments for early stage mycosis fungoides.
Topics: Administration, Topical; Adult; Aged; Drug Hypersensitivity; Female; Humans; Hypersensitivity, Delayed; Male; Mechlorethamine; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Remission Induction; Skin Neoplasms; Time Factors
PubMed: 3183094
DOI: 10.1016/s0190-9622(88)70223-6 -
The British Journal of Dermatology Nov 1985Two groups of 20 patients with psoriasis were treated with mechlorethamine applied topically (group A) or with PUVA combined with mechlorethamine (group B). In group B... (Clinical Trial)
Clinical Trial
Two groups of 20 patients with psoriasis were treated with mechlorethamine applied topically (group A) or with PUVA combined with mechlorethamine (group B). In group B mechlorethamine was started after six PUVA treatments. Results showed a significant decrease of the incidence of contact dermatitis in group B (30%) compared with group A (75%). Allergic dermatitis, demonstrated by a positive patch test to mechlorethamine with an histology of eczema, was observed in 55% of patients in group A and 20% in group B. The incidence of irritant dermatitis was not significantly different in the two groups. Allergic dermatitis was observed later in group B: after an average of 32.2 applications of mechlorethamine compared with 25 applications in group A. Possible mechanisms responsible for these results are reduction of epidermal Langerhans cells by PUVA therapy and induction of antigen-specific suppressor T cells. Patients living far from a specialized centre might be treated initially with PUVA therapy then with mechlorethamine alone, at home. This schedule may reduce the incidence of contact dermatitis to mechlorethamine.
Topics: Adult; Aged; Dermatitis, Atopic; Dermatitis, Contact; Drug Eruptions; Drug Therapy, Combination; Female; Humans; Male; Mechlorethamine; Middle Aged; PUVA Therapy; Psoriasis
PubMed: 2933055
DOI: 10.1111/j.1365-2133.1985.tb02374.x -
Archives of Dermatology Oct 1977Six patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride for periods of two to four years. Clinical and histological studies for...
Six patients with mycosis fungoides were treated with topical mechlorethamine hydrochloride for periods of two to four years. Clinical and histological studies for radiomimetic and radiodermatitis-like effects failed to demonstrate any abnormalities. The only observed changes were generalized hyperpigmentation of the skin and melanin-containing melanophages in the papillary dermis. We consider that the long-term use of topical mechlorethamine may be a safe form of therapy, but that a continuous indefinite follow-up of patients on this medication should be mandatory.
Topics: Administration, Topical; Biopsy; DNA; Dermatitis, Contact; Humans; Mechlorethamine; Mycosis Fungoides; Pigmentation Disorders; Skin; Skin Neoplasms; Skin Pigmentation
PubMed: 911166
DOI: 10.1001/archderm.113.10.1387 -
Dermatology (Basel, Switzerland) 2022Mycosis 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... (Randomized Controlled Trial)
Randomized Controlled Trial
Post hoc Analysis of a Randomized, Controlled, Phase 2 Study to Assess Response Rates with Chlormethine/Mechlorethamine Gel in Patients with Stage IA-IIA Mycosis Fungoides.
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.
Topics: Antineoplastic Agents, Alkylating; Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mycosis Fungoides; Neoplasm Staging; Skin Neoplasms
PubMed: 34091453
DOI: 10.1159/000516138