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Clinical Lymphoma, Myeloma & Leukemia Jan 2024Chlormethine (CL) gel was approved for treatment of mycosis fungoides based on the pivotal 201 trial (NCT00168064). Data visualization from individual patients is a...
Evaluating Response Trends of Chlormethine/Mechlorethamine Gel in Patients With Stage I-IIA Mycosis Fungoides: Analysis of Individual Patient Data From a Randomized Controlled Phase II Study to Facilitate Optimal Treatment Experiences.
INTRODUCTION
Chlormethine (CL) gel was approved for treatment of mycosis fungoides based on the pivotal 201 trial (NCT00168064). Data visualization from individual patients is a powerful tool for discovery of hidden treatment trends. Here, we present a post hoc analysis of individual patient data from the pivotal trial to provide a more granular depiction of treatment and response changes over time, with an emphasis on end of treatment status.
MATERIALS AND METHODS
Individual patient response data were plotted over a 12-month treatment period to visualize patient experiences while using CL gel. Responder status was assigned according to end-of-treatment Composite Assessment of Index Lesion Severity (CAILS) score, and patients were classified as early (≤4 months) or late responders based on timing of response. Baseline and active treatment characteristics were compared between early and late responders, and baseline body surface area (BSA) was compared between responders and patients with stable or progressive disease.
RESULTS
Data from 123 patients with baseline and postbaseline results were included. At the end of treatment, 64.2%/55.3% were responders, 30.9%/34.1% had stable disease, and 4.9%/10.6% had progressive disease by CAILS and mSWAT, respectively. Among patients who responded to treatment, 64.6% and 35.4% were early and late responders, respectively. Response pattern analysis also identified patients with an intermittent response or initial progressive disease. Baseline BSA was not associated with responder status. Late responders had longer treatment duration and higher postbaseline plaque elevation, while early responders had a higher frequency of dermatitis.
CONCLUSIONS
Results presented here can facilitate optimal treatment experiences for patients starting CL gel.
Topics: Humans; Mechlorethamine; Mycosis Fungoides; Skin Neoplasms; Randomized Controlled Trials as Topic; Clinical Trials, Phase II as Topic
PubMed: 37802679
DOI: 10.1016/j.clml.2023.08.020 -
Toxicological Sciences : An Official... Oct 2021Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory...
Sulfur mustard (SM) has been widely used as a chemical warfare agent including most recently in Syria. Mice exposed to SM exhibit an increase in pro-inflammatory cytokines followed by immune cell infiltration in the lung, however, the mechanisms leading to these inflammatory responses has not been completely elucidated. Mast cells are one of the first responding innate immune cells found at the mucosal surfaces of the lung and have been reported to be activated by SM in the skin. Therefore, we hypothesized that nitrogen mustard (NM: a surrogate for SM) exposure promotes activation of mast cells causing chronic respiratory inflammation. To assess the role of mast cells in NM-mediated pulmonary toxicity, we compared the effects of NM exposure between C57BL/6 and B6.Cg-KitW-sh/HNihrJaeBsmJ (KitW-sh; mast cell deficient) mice. Lung injury was observed in C57BL/6J mice following NM exposure (0.125 mg/kg) at 72 h, which was significantly abrogated in KitW-sh mice. Although both strains exhibited damage from NM, C57BL/6J mice had higher inflammatory cell infiltration and more elevated prostaglandin D2 (PGD2) present in bronchoalveolar lavage fluid compared with KitW-sh mice. Additionally, we utilized murine bone marrow-derived mast cells to assess NM-induced early and late activation. Although NM exposure did not result in mast cell degranulation, we observed an upregulation in PGD2 and IL-6 levels following exposure to NM. Results suggest that mast cells play a prominent role in lung injury induced by NM and may contribute to the acute and potentially long-term lung injury observed caused by SM.
Topics: Animals; Chemical Warfare Agents; Cytokines; Lipids; Lung; Mast Cells; Mechlorethamine; Mice; Mice, Inbred C57BL; Mustard Gas
PubMed: 34453837
DOI: 10.1093/toxsci/kfab107 -
Advances in Therapy Jun 2021Chlormethine gel is a skin-directed therapy recommended for patients with early-stage mycosis fungoides (MF) cutaneous T cell lymphoma.
INTRODUCTION
Chlormethine gel is a skin-directed therapy recommended for patients with early-stage mycosis fungoides (MF) cutaneous T cell lymphoma.
METHODS
Herein, we present three cases of patients with stage IB-IIB MF who were treated with chlormethine gel and concomitant therapies.
RESULTS
All patients responded well to treatment with chlormethine gel; complete responses were observed with improvements in Modified Severity-Weighted Assessment Tool scores and severity of lesions; one patient reported an improvement in quality of life. While adverse events did occur after treatment initiation, they were skin related and could be effectively managed through reductions in treatment frequency and the addition of emollients and topical steroids.
CONCLUSION
The cases presented here illustrate that chlormethine gel is an effective and safe treatment option for patients with MF who had received prior therapies that had proved ineffective. Chlormethine gel could be combined with other skin-directed or systemic therapies for optimal benefit. Incidences of dermatitis were seen to be successfully managed and quality of life benefits were also reported.
Topics: Humans; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mycosis Fungoides; Quality of Life; Skin Neoplasms
PubMed: 33928511
DOI: 10.1007/s12325-021-01721-x -
Frontiers in Pharmacology 2020Quinazoline derivatives display multiple pharmacological activities and target various biological receptors. Based on the skeleton of quinazoline core, we designed and...
Synthesis of a New Phenyl Chlormethine-Quinazoline Derivative, a Potential Anti-Cancer Agent, Induced Apoptosis in Hepatocellular Carcinoma Through Mediating Sirt1/Caspase 3 Signaling Pathway.
Quinazoline derivatives display multiple pharmacological activities and target various biological receptors. Based on the skeleton of quinazoline core, we designed and synthesized three new quinazoline-phenyl chlormethine conjugates (I-III) bearing a Schiff base (C = N) linker, and investigated their anti-tumor effects on HepG2-xenografted tumor and human cancer cell line HepG2. Among these compounds, compound II showed better inhibitory effect against HepG2 cells. In the present study, TUNEL staining, western blot, molecular docking, and siRNA were used to investigate the inhibitory mechanism of compound II towards hepatoma. Compound II inhibited HepG2-xenografted tumor growth in nude mice. Moreover, Compound II not only up-regulated Bax/Bcl-2 ratio and active-caspase 3 level, but also down-regulated Sirt1 expression and its activity, as well as PGC-1α expression. Furthermore, compound II also significantly suppressed the promotion of HepG2 cell proliferation, as evidenced by MTT assay and lactate dehydrogenase (LDH) release assay. Of note, the cytotoxicity of Compound II on HepG2 cells mainly regulating Sirt1/caspase 3 signaling pathway, consisting with the results . Intriguingly, z-DEVD-FMK, a caspase 3 inhibitor, almost abolished the inhibitory effects of compound II. Of note, knockdown of caspase 3 by siRNA significantly reversed the inhibitory effect of compound II on HepG2. Interestingly, compound II directly bonded to Sirt1, indicating that Sirt1 might be a promising therapeutic target of compound II. In summary, our findings reveal that compound II, a new synthetical phenyl chlormethine-quinazoline derivative, contributes to the apoptosis of HepG2 cells both and through mediating Sirt1/caspase 3 singling pathway. These findings demonstrate that compound II may be a new potent agent against hepatocellular carcinoma.
PubMed: 32670058
DOI: 10.3389/fphar.2020.00911 -
Frontiers in Medicine 2021Topical chlormethine yields high response rates in mycosis fungoides cutaneous T-cell lymphoma with early discontinuation often attributed to skin reactions. We...
A Little Experience Goes a Long Way: Chlormethine/Mechlorethamine Treatment Duration as a Function of Clinician-Level Patient Volume for Mycosis Fungoides Cutaneous T-Cell Lymphoma (MF-CTCL)-A Retrospective Cohort Study.
Topical chlormethine yields high response rates in mycosis fungoides cutaneous T-cell lymphoma with early discontinuation often attributed to skin reactions. We evaluated over 4,000 patients and found an association of clinician case volume with treatment duration and early discontinuation of chlormethine gel. The minority of clinicians with high patient volume markedly outperformed clinicians with only few patients on both outcome parameters, yet case volume as low as five patients seemed to mark a threshold for avoiding early discontinuation of treatment regimen.
PubMed: 34277658
DOI: 10.3389/fmed.2021.679294 -
International Journal of Molecular... Jul 2020Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a...
Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-β, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis.
Topics: Animals; Biomarkers; Disease Models, Animal; Extracellular Matrix Proteins; HSP90 Heat-Shock Proteins; Isoxazoles; Lung; Lung Injury; MAP Kinase Signaling System; Male; Mechlorethamine; Mice; Mice, Inbred C57BL; Pulmonary Alveoli; Pulmonary Fibrosis; Resorcinols
PubMed: 32635192
DOI: 10.3390/ijms21134740 -
Frontiers in Medicine 2023Maintenance treatment can be recommended for patients with mycosis fungoides (MF) whose disease responds to primary treatment. While positive outcomes have been observed...
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.
PubMed: 38304309
DOI: 10.3389/fmed.2023.1298988 -
American Journal of Clinical Dermatology May 2021Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel... (Observational Study)
Observational Study
The PROVe Study: US Real-World Experience with Chlormethine/Mechlorethamine Gel in Combination with Other Therapies for Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma.
BACKGROUND
Chlormethine/mechlorethamine gel is a skin-directed therapy for patients with mycosis fungoides cutaneous T-cell lymphoma. Currently, real-world data on chlormethine gel are lacking.
OBJECTIVE
Our objective was to analyze the effect of chlormethine gel in combination with other therapies on efficacy, safety, and health-related quality of life in a real-world setting.
METHODS
This prospective, observational study enrolled adult patients actively using chlormethine gel. Patients were monitored for up to 2 years during standard-of-care clinic visits. No specific visit schedules or clinical assessments, with the exception of patient-completed questionnaires, were mandated because of the expected variability in practice patterns. The primary efficacy endpoint was the proportion of patients with stage IA-IB disease receiving chlormethine + topical corticosteroids + other with ≥ 50% decrease in body surface area from baseline to 12 months. Response was assessed at each visit using by-time analysis, which investigates the trend to treatment response and allows assessment of response over time. Health-related quality of life was assessed with the Skindex-29 questionnaire.
RESULTS
In total, 298 patients were monitored. At 12 months post-treatment initiation, 44.4% (chlormethine + topical corticosteroids + other) and 45.1% (patients receiving chlormethine + other treatment) of efficacy-evaluable patients were responders. By-time analysis demonstrated that peak response occurred (chlormethine + other; 66.7%) at 18 months. There was a significant correlation between responder status and lower post-baseline Skindex-29 scores.
CONCLUSIONS
This real-world study confirmed that chlormethine gel is an important therapeutic option for patients with mycosis fungoides and contributes to reducing the severity of skin lesions and improving health-related quality of life.
Topics: Administration, Cutaneous; Administration, Oral; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Follow-Up Studies; Gels; Humans; Male; Mechlorethamine; Middle Aged; Mycosis Fungoides; Neoplasm Staging; Prospective Studies; Quality of Life; Severity of Illness Index; Skin Neoplasms; Treatment Outcome; United States
PubMed: 33656660
DOI: 10.1007/s40257-021-00591-x -
Toxicology and Applied Pharmacology Apr 2024Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung...
Nitrogen mustard (NM) is a toxic vesicant that causes acute injury to the respiratory tract. This is accompanied by an accumulation of activated macrophages in the lung and oxidative stress which have been implicated in tissue injury. In these studies, we analyzed the effects of N-acetylcysteine (NAC), an inhibitor of oxidative stress and inflammation on NM-induced lung injury, macrophage activation and bioenergetics. Treatment of rats with NAC (150 mg/kg, i.p., daily) beginning 30 min after administration of NM (0.125 mg/kg, i.t.) reduced histopathologic alterations in the lung including alveolar interstitial thickening, blood vessel hemorrhage, fibrin deposition, alveolar inflammation, and bronchiolization of alveolar walls within 3 d of exposure; damage to the alveolar-epithelial barrier, measured by bronchoalveolar lavage fluid protein and cells, was also reduced by NAC, along with oxidative stress as measured by heme oxygenase (HO)-1 and Ym-1 expression in the lung. Treatment of rats with NAC attenuated the accumulation of macrophages in the lung expressing proinflammatory genes including Ptgs2, Nos2, Il-6 and Il-12; macrophages expressing inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and tumor necrosis factor (TNF)α protein were also reduced in histologic sections. Conversely, NAC had no effect on macrophages expressing the anti-inflammatory proteins arginase-1 or mannose receptor, or on NM-induced increases in matrix metalloproteinase (MMP)-9 or proliferating cell nuclear antigen (PCNA), markers of tissue repair. Following NM exposure, lung macrophage basal and maximal glycolytic activity increased, while basal respiration decreased indicating greater reliance on glycolysis to generate ATP. NAC increased both glycolysis and oxidative phosphorylation. Additionally, in macrophages from both control and NM treated animals, NAC treatment resulted in increased S-nitrosylation of ATP synthase, protecting the enzyme from oxidative damage. Taken together, these data suggest that alterations in NM-induced macrophage activation and bioenergetics contribute to the efficacy of NAC in mitigating lung injury.
Topics: Animals; Oxidative Stress; Acetylcysteine; Mechlorethamine; Male; Energy Metabolism; Rats; Lung Injury; Rats, Sprague-Dawley; Lung; Macrophages; Acute Lung Injury; Macrophages, Alveolar; Chemical Warfare Agents
PubMed: 38513841
DOI: 10.1016/j.taap.2024.116908 -
Toxicology and Applied Pharmacology May 2024Nitrogen mustard (NM; mechlorethamine) is a cytotoxic vesicant known to cause acute lung injury which can progress to chronic disease. Due to the complex nature of NM...
Nitrogen mustard (NM; mechlorethamine) is a cytotoxic vesicant known to cause acute lung injury which can progress to chronic disease. Due to the complex nature of NM injury, it has been difficult to analyze early responses of resident lung cells that initiate inflammation and disease progression. To investigate this, we developed a model of acute NM toxicity using murine precision cut lung slices (PCLS), which contain all resident lung cell populations. PCLS were exposed to NM (1-100 μM) for 0.5-3 h and analyzed 1 and 3 d later. NM caused a dose-dependent increase in cytotoxicity and a reduction in metabolic activity, as measured by LDH release and WST-1 activity, respectively. Optimal responses were observed with 50 μM NM after 1 h incubation and these conditions were used in further experiments. Analysis of PCLS bioenergetics using an Agilent Seahorse showed that NM impaired both glycolytic activity and mitochondrial respiration. This was associated with injury to the bronchial epithelium and a reduction in methacholine-induced airway contraction. NM was also found to cause DNA damage in bronchial epithelial cells in PCLS, as measured by expression of γ-H2AX, and to induce oxidative stress, which was evident by a reduction in glutathione levels and upregulation of the antioxidant enzyme catalase. Cleaved caspase-3 was also upregulated in airway smooth muscle cells indicating apoptotic cell death. Characterizing early events in NM toxicity is key in identifying therapeutic targets for the development of efficacious countermeasures.
Topics: Animals; Mechlorethamine; Lung; Mice; DNA Damage; Mice, Inbred C57BL; Dose-Response Relationship, Drug; Mitochondria; Chemical Warfare Agents; Glycolysis; Male; Apoptosis; Oxidative Stress; Acute Lung Injury; Epithelial Cells
PubMed: 38677601
DOI: 10.1016/j.taap.2024.116941