Lack of Systemic Absorption of Topical Mechlorethamine Gel in Patients with Mycosis Fungoides Cutaneous T-Cell Lymphoma

Abstract

Primary cutaneous T-cell lymphomas are a heterogeneous group of lymphoproliferative disorders. The most common type is mycosis fungoides (MF), which often presents with persistent patches and plaques (Willemze et al., 2019Willemze R. Cerroni L. Kempf W. Berti E. Facchetti F. Swerdlow S.H. et al.The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.Blood. 2019; 133: 1703-1714Crossref PubMed Scopus (277) Google Scholar). The recommended therapeutic options for patients with MF are based on international guidelines. For patients with early stage (IA–IIA) MF, skin-directed therapies are recommended as first-line treatment. Mechlorethamine is a skin-directed therapy that has been used for MF for decades (Vonderheid et al., 1989Vonderheid E.C. Tan E.T. Kantor A.F. Shrager L. Micaily B. Van Scott E.J. Long-term efficacy, curative potential, and carcinogenicity of topical mechlorethamine chemotherapy in cutaneous T cell lymphoma.J Am Acad Dermatol. 1989; 20: 416-428Abstract Full Text PDF PubMed Scopus (206) Google Scholar). Early formulations of mechlorethamine were aqueous or ointment-based. More recently, a topical mechlorethamine 0.016% w/w gel was specifically developed for treatment of MF and has been endorsed by international guidelines (National Comprehensive Cancer Network, 2020National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology (NCCN Guidelines®). Primary cutaneous lymphomas. Version 2.2020.https://www.nccn.org/professionals/physician_gls/default_nojava.aspxDate: 2020Date accessed: August 21, 2020Google Scholar; Trautinger et al., 2017Trautinger F. Eder J. Assaf C. Bagot M. Cozzio A. Dummer R. et al.European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – update 2017.Eur J Cancer. 2017; 77: 57-74Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar; Willemze et al., 2018Willemze R. Hodak E. Zinzani P.L. Specht L. Ladetto M. ESMO Guidelines CommitteePrimary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2018; 29: iv30-iv40Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Mechlorethamine gel was approved for treatment of patients with stage IA–IB MF in the United States in 2013 on the basis of the 201 registration study (NCT00168064) and the 202 extension study (NCT00535470), in 2016 in Israel, and in 2017 in the Europe (European Medicines Agency, 2017European Medicines AgencyLedaga: summary of product characteristics.https://www.ema.europa.eu/en/documents/product-information/ledaga-epar-product-information_en.pdfDate: 2017Date accessed: August 21, 2020Google Scholar; Kim et al., 2014Kim Y.H. Duvic M. Guitart J. Lessin S. Efficacy and safety of mechlorethamine (MCH) 0.04% gel in mycosis fungoides (MF) after treatment with topical MCH 0.02%.J Clin Oncol. 2014; 32: 9093Crossref Google Scholar; Lessin et al., 2013Lessin S.R. Duvic M. Guitart J. Pandya A.G. Strober B.E. Olsen E.A. et al.Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.JAMA Dermatol. 2013; 149: 25-32Crossref PubMed Scopus (79) Google Scholar; US Food and Drug Administration, 2020US Food and Drug AdministrationValchlor (mechlorethamine) gel: prescribing information.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202317s009lbl.pdfDate: 2020Date accessed: August 21, 2020Google Scholar). The pivotal 201 study compared 0.02% mechlorethamine gel with equal-strength compounded ointment and demonstrated that the gel met all prespecified criteria for noninferiority compared with the ointment (Lessin et al., 2013Lessin S.R. Duvic M. Guitart J. Pandya A.G. Strober B.E. Olsen E.A. et al.Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.JAMA Dermatol. 2013; 149: 25-32Crossref PubMed Scopus (79) Google Scholar). In total, 260 patients were enrolled and randomized 1:1 to receive 0.02% mechlorethamine gel or ointment. Treatment was applied once daily for up to 12 months. Study 202 was an open-label extension of study 201, evaluating treatment with 0.04% mechlorethamine gel in patients who did not have a complete response during study 201. In total, 98 patients received 0.04% mechlorethamine gel once daily for up to 7 months. No concomitant treatment was permitted during either study. The study protocols were approved by institutional review boards of participating centers; all patients provided written informed consent. Adverse events (AEs) reported in studies 201 and 202 were mainly skin-related and manageable (European Medicines Agency, 2017European Medicines AgencyLedaga: summary of product characteristics.https://www.ema.europa.eu/en/documents/product-information/ledaga-epar-product-information_en.pdfDate: 2017Date accessed: August 21, 2020Google Scholar; Kim et al., 2014Kim Y.H. Duvic M. Guitart J. Lessin S. Efficacy and safety of mechlorethamine (MCH) 0.04% gel in mycosis fungoides (MF) after treatment with topical MCH 0.02%.J Clin Oncol. 2014; 32: 9093Crossref Google Scholar; Lessin et al., 2013Lessin S.R. Duvic M. Guitart J. Pandya A.G. Strober B.E. Olsen E.A. et al.Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, gel in mycosis fungoides.JAMA Dermatol. 2013; 149: 25-32Crossref PubMed Scopus (79) Google Scholar; US Food and Drug Administration, 2020US Food and Drug AdministrationValchlor (mechlorethamine) gel: prescribing information.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202317s009lbl.pdfDate: 2020Date accessed: August 21, 2020Google Scholar). The lack of systemic AEs occurring during treatment indicates that mechlorethamine is unlikely to be systemically absorbed. To confirm the lack of systemic absorption, bioanalytic assays were performed to determine mechlorethamine concentrations in plasma. During study 201, plasma samples were collected from 23 patients, 16 from the gel arm and 7 from the ointment arm. Samples were collected predose at the baseline visit; 1, 3, and 6 hours after first application of mechlorethamine; and before application at the month 1 visit. Mechlorethamine concentrations were analyzed by high-performance liquid chromatography with ultraviolet detector (Coldstream Laboratories, Lexington, KY) with a lower limit of detection of 41.5 ng/ml. During study 202, plasma samples were collected from 15 patients before and 1 hour after gel application at the baseline visit (or month 2 or 4 if the patient had already started the trial) and before or 1 hour after application at the next visit (after 4 or 6 months of exposure). Fully validated high-performance liquid chromatography with tandem mass spectrometry methods (Frontage Laboratories, Exton, PA) were used to quantify levels of mechlorethamine and its primary degradation product (half-mustard); this more sensitive method had a lower limit of detection of 5.0 ng/ml. Hematologic and serum chemistry parameters were assessed at baseline and months 4, 8, and 12 (or at the termination visit) during study 201 and at baseline and final (or termination) visit for study 202. There was no overlap between the cohorts from study 201 and study 202. The demographics and clinical characteristics for all patients are summarized in Table 1.Table 1Demographics and Clinical Characteristics for Patients from Studies 201 and 202 Included in Bioanalytic TestingCharacteristicsStudy 201Study 202Mechlorethamine Gel (n = 16)Mechlorethamine (n = 7)Mechlorethamine Gel (n = 15)Age, y, mean (range)55 (31–78)64 (41–75)53 (27–79)Gender, n (%) Male9 (56.3)6 (85.7)9 (60.0) Female7 (43.8)1 (14.3)6 (40.0)Race, n (%) White14 (87.5)6 (85.7)10 (66.7) Asian2 (12.5)00 African American01 (14.3)3 (20.0) Hispanic002 (13.3)MF stage at baseline, n (%) IA9 (56.3)5 (71.4)9 (60.0) IB–IIA7 (43.8)2 (28.6)6 (40.0)Body surface area of disease, %, mean (range)11 (1–31)9 (2–22)11 (1–46)Dose application, n (%) Localized treatment of affected lesions9 (56.3)5 (71.4)9 (60.0) Full-body application7 (43.8)2 (28.6)6 (40.0)Application frequency, n (%) Daily15 (93.8)7 (100)4 (26.7) 1–3 times/wk1 (6.3)00 4–6 times/wk009 (60) Multiple regimens over time002 (13.3)1Patient 1: daily at month 2, 4–6 times/wk at month 4; patient 2: 4–6 times/wk at month 4, daily at month 6.Abbreviation: MF, mycosis fungoides.1 Patient 1: daily at month 2, 4–6 times/wk at month 4; patient 2: 4–6 times/wk at month 4, daily at month 6. Open table in a new tab Abbreviation: MF, mycosis fungoides. Bioanalytic results indicate lack of systemic absorption of mechlorethamine in plasma samples from study 201; all samples tested negative (<41.5 ng/ml). Similarly, plasma samples from study 202 did not show measurable systemic absorption (<5.0 ng/ml) (Table 2). These results were consistent regardless of sex, race, disease stage, or whether patients were using localized or full-body application (Supplementary Tables S1 and S2). There was no pattern of change over time nor any abnormalities in the laboratory parameters (data on file).Table 2Bioanalytic Testing Results from Studies 201 and 202Testing ResultStudy 201Study 202Mechlorethamine Gel (n = 16)Mechlorethamine Ointment (n = 7)Mechlorethamine Gel (n = 15)Lower limit of analyte quantification in plasma samples, n (%) 5.0 ng/ml1Two analytes were tested: mechlorethamine and half-mustard.0015 (100) 41.5 ng/ml16 (100)7 (100)0Analytic results for plasma samples taken at initial application and after 1 month (range) H0BQL (BQL–BQL)BQL (BQL–BQL)NA H1BQL (BQL–BQL)BQL (BQL–BQL) H3BQL (BQL–BQL)BQL (BQL–BQL) H6BQL (BQL–BQL)BQL (BQL–BQL) Mo1BQL (BQL–BQL)BQL (BQL–BQL)Analytic results for plasma samples taken at months 2–6 (range) Mo2/H0NANABQL (BQL–BQL) Mo2/H1BQL (BQL–BQL) Mo4/H0BQL (BQL–BQL) Mo4/H12One patient sample was taken at H3.BQL (BQL–BQL) Mo6/H0BQL (BQL–BQL)Abbreviations: BQL, below quantification limit; H, hour; Mo, month; NA, not available.1 Two analytes were tested: mechlorethamine and half-mustard.2 One patient sample was taken at H3. Open table in a new tab Abbreviations: BQL, below quantification limit; H, hour; Mo, month; NA, not available. These bioanalytic data indicate that systemic absorption was not observed with mechlorethamine gel (0.02% or 0.04%) or mechlorethamine ointment (0.02%) in patients with MF. Samples were collected and tested up to 6 months after treatment initiation, indicating that there was sufficient time for the gel to have penetrated the skin if it could. The patients included in this analysis also presented with the typical skin-related AEs associated with MF and mechlorethamine treatment. These AEs, which included folliculitis, dermatitis, erythema, and eczema, can damage the integrity of the skin. In addition, there may be skin alterations owing to symptoms of MF. Despite the potential skin alterations or damage, no systemic absorption of mechlorethamine was detected. Laboratory monitoring also confirmed that hematologic parameters, including numbers of white blood cells, neutrophils, platelets, and lymphocytes, showed no systematic pattern of change over time. This is consistent with historic data, where no abnormalities related to systemic absorption of mechlorethamine following treatment with the aqueous or ointment formulations have been reported (Kim et al., 2003Kim Y.H. Martinez G. Varghese A. Hoppe R.T. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience.Arch Dermatol. 2003; 139: 165-173Crossref PubMed Scopus (137) Google Scholar; Lindahl et al., 2014Lindahl L.M. Fenger-Grøn M. Iversen L. Secondary cancers, comorbidities and mortality associated with nitrogen mustard therapy in patients with mycosis fungoides: a 30-year population-based cohort study.Br J Dermatol. 2014; 170: 699-704Crossref PubMed Scopus (25) Google Scholar). With a number of other skin-directed therapies used for MF, systemic absorption of the agents has been linked to occurrence of AEs. For example, topical carmustine has been shown to be systemically absorbed (Nguyen and Bohjanen, 2015Nguyen C.V. Bohjanen K.A. Skin-directed therapies in cutaneous T-cell lymphoma.Dermatol Clin. 2015; 33: 683-696Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar), which may predispose patients to myelosuppression (Lovgren and Scarisbrick, 2019Lovgren M.L. Scarisbrick J.J. Update on skin directed therapies in mycosis fungoides.Chin Clin Oncol. 2019; 8: 7Crossref PubMed Scopus (10) Google Scholar). There are also reports that topical corticosteroid treatment can result in systemic absorption, which in turn can lead to Cushing syndrome, hyperglycemia, and unmasking of latent diabetes mellitus (Nguyen and Bohjanen, 2015Nguyen C.V. Bohjanen K.A. Skin-directed therapies in cutaneous T-cell lymphoma.Dermatol Clin. 2015; 33: 683-696Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). In conclusion, we found no measurable evidence of mechlorethamine in plasma samples from patients with MF after topical once daily application of 0.02% gel or ointment or 0.04% gel. This lack of systemic absorption also suggests that systemic drug–drug interactions are unlikely to occur when mechlorethamine gel is used concomitantly with other agents. These data, together with the lack of hematologic and systemic toxicity, confirm that mechlorethamine gel is a valuable treatment option for patients with MF that does not require blood monitoring or hospital visits. All data from the bioanalytic assessments performed are present in the manuscript and supplementary files. There are no data sets in a repository. Individual patient-level data may be shared on reasonable request. Christiane Querfeld: http://orcid.org/0000-0001-9698-5809 Larisa J. Geskin: http://orcid.org/0000-0002-0981-3513 Ellen J. Kim: http://orcid.org/0000-0001-9099-7614 Julia J. Scarisbrick: http://orcid.org/0000-0002-8011-4408 Pietro Quaglino: http://orcid.org/0000-0003-4185-9586 Evangelia Papadavid: http://orcid.org/0000-0002-8634-102X James T. Angello: http://orcid.org/0000-0002-7714-7073 Pablo L. Ortiz-Romero: http://orcid.org/0000-0003-2985-9639 CQ received a research grant from Celgene; was a clinical investigator for Celgene, Trillium, miRagen, Bioniz, Kyowa Kirin, and Actelion (Helsinn); and served on the advisory board of Helsinn/Actelion, miRagen, Bioniz, Trillium, Kyowa Kirin, Medivir, and Stemline. LJG received research support from Helsinn, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, miRagen, Galderma, Merck, BMS, and Stratpharma; was a principal investigator for Helsinn, J&J, Mallinckrodt, Kyowa Kirin, Soligenix, Innate, miRagen, Galderma, Merck, BMS, and Stratpharma; and served on the speakers’ bureau of Helsinn, J&J and on the scientific advisory board of Helsinn, J&J, Mallinckrodt, and Kyowa Kirin. EJK received research support from Actelion, Galderma, MedImmune, and Soligenix; serves as a consultant for Actelion, Almirall, Galderma, and Helsinn; was a principal investigator for Actelion, Galderma, MedImmune, and Soligenix; served as a consultant for Actelion, Almirall, Galderma, and Helsinn; served on the scientific advisory board for Helsinn, Kyowa Kirin;was a principal investigator for Innate Pharma; and received a clinical trial grant from Innate Pharma. JJS was a consultant for Takeda, Helsinn, Recordati, 4SC, Kyowa, Mallinckrodt, Miragen, and Codiak and received a research grant from Kyowa. PQ served on the advisory board of 4SC, Takeda, Actelion, Innate Pharma, Recordati Rare Diseases, Kyowa, Therakos, and Helsinn. EP was a consultant for 4SC, Helsinn, AbbVie, Janssen, Novartis, Recordati, Pfizer, and UCB. JTA was an employee of Helsinn Therapeutics (US), Inc. PLO-R served on the advisory board of 4SC, Takeda, Actelion, Innate Pharma, Recordati Rare Diseases, Kyowa, and miRagen; held a patent for PLCG1; and received research support from Meda. The authors would like to acknowledge and thank the volunteers, investigators, and study teams at the centers participating in these studies. Editorial and medical writing assistance was provided by Judith Land, PhD, from Aptitude Health, The Hague, the Netherlands, funded by Helsinn Healthcare SA. The authors are fully responsible for all content and editorial decisions for this manuscript. CQ was supported by a National Institutes of Health / National Cancer Institute grant ( R01 CA229510-01 ) and a Leukemia & Lymphoma Society Clinical Scholar Award. Conceptualization: CQ, LJG, EJK, JJS, PQ, EP, JTA, PLO-R; Writing - Original Draft Preparation: CQ, LJG, EJK, JJS, PQ, EP, JTA, PLO-R; Writing - Review and Editing: CQ, LJG, EJK, JJS, PQ, EP, JTA, PLO-R Abbreviations: BQL, below quantification limit; FBA, full-body application; H, hour; Mo, month; MF, mycosis fungoides; STAL, spot treatment of affected lesions. Abbreviations: BQL, below quantification limit; FBA, full-body application; H, hour; Mo, month; MF, mycosis fungoides; STAL, spot treatment of affected lesions.