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

Open AccessPublished:December 18, 2020DOI:https://doi.org/10.1016/j.jid.2020.12.009

      Abbreviations:

      AE (adverse event), MF (mycosis fungoides)
      To the Editor
      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 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.
      ). 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 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.
      ). 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
      NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Primary cutaneous lymphomas. Version 2.2020.
      ;
      • Trautinger 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.
      ;
      • Willemze R.
      • Hodak E.
      • Zinzani P.L.
      • Specht L.
      • Ladetto M.
      ESMO Guidelines Committee
      Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ). 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
      Ledaga: summary of product characteristics.
      ;
      • Kim 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%.
      ;
      • Lessin 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.
      ;
      US Food and Drug Administration
      Valchlor (mechlorethamine) gel: prescribing information.
      ).
      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 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.
      ). 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
      Ledaga: summary of product characteristics.
      ;
      • Kim 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%.
      ;
      • Lessin 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.
      ;
      US Food and Drug Administration
      Valchlor (mechlorethamine) gel: prescribing information.
      ). 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 Testing


      Characteristics
      Study 201Study 202
      Mechlorethamine 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)
      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.
      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.
      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 202


      Testing Result
      Study 201Study 202
      Mechlorethamine Gel (n = 16)Mechlorethamine Ointment (n = 7)Mechlorethamine Gel (n = 15)
      Lower limit of analyte quantification in plasma samples, n (%)
       5.0 ng/ml
      Two analytes were tested: mechlorethamine and half-mustard.
      0015 (100)
       41.5 ng/ml16 (100)7 (100)0
      Analytic 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/H1
      One 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.
      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 Y.H.
      • Martinez G.
      • Varghese A.
      • Hoppe R.T.
      Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience.
      ;
      • Lindahl 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.
      ).
      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 C.V.
      • Bohjanen K.A.
      Skin-directed therapies in cutaneous T-cell lymphoma.
      ), which may predispose patients to myelosuppression (
      • Lovgren M.L.
      • Scarisbrick J.J.
      Update on skin directed therapies in mycosis fungoides.
      ). 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 C.V.
      • Bohjanen K.A.
      Skin-directed therapies in cutaneous T-cell lymphoma.
      ).
      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.

      Data availability statement

      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.

      Conflict of Interest

      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.

      Acknowledgments

      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.

      Author Contributions

      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

      Supplementary Material

      Supplementary Table S1Bioanalytic Testing Results for Individual Patients from Study 201
      Serial NumberAgeGenderRaceMF Stage at BaselineBody Surface Area of Disease, %Modality of ApplicationApplication Frequency During Bioanalytic Testing PeriodGel or OintmentLower Limit of Analyte Quantification in Plasma SamplesAnalytic Results for Plasma Samples Taken at Initial Application and after 1 Month
      41.5 ng/ml5.0 ng/mlH0H1H3H6Mo1
      138MaleWhiteIA3STALDailyGelxBQLBQLBQLBQLBQL
      263FemaleWhiteIA6STALDailyGelxBQLBQLBQLBQLBQL
      369MaleWhiteIB–IIA12FBADailyGelxBQLBQLBQLBQLBQL
      472MaleWhiteIB–IIA15FBADailyGelxBQLBQLBQLBQLBQL
      537MaleAsianIB–IIA31FBADailyGelxBQLBQLBQLBQLBQL
      664FemaleWhiteIA4STALDailyGelxBQLBQLBQLBQLBQL
      748FemaleWhiteIA7STALDailyGelxBQLBQLBQLBQLBQL
      831FemaleWhiteIA3STALDailyGelxBQLBQLBQLBQLBQL
      944MaleWhiteIA3STALDailyGelxBQLBQLBQLBQLBQL
      1067MaleWhiteIB–IIA26FBADailyGelxBQLBQLBQLBQLBQL
      1144FemaleAsianIB–IIA13FBADailyGelxBQLBQLBQLBQLBQL
      1256MaleWhiteIB–IIA19FBADailyGelxBQLBQLBQLBQLBQL
      1357MaleWhiteIB–IIA24FBADailyGelxBQLBQLBQLBQLBQL
      1454FemaleWhiteIA1STALDailyGelxBQLBQLBQLBQLBQL
      1555MaleWhiteIA7STALDailyGelxBQLBQLBQLBQLBQL
      1678FemaleWhiteIA8STAL1–3 times/wkGelxBQLBQLBQLBQLBQL
      1741MaleWhiteIB–IIA14FBADailyOintmentxBQLBQLBQLBQLBQL
      1867MaleWhiteIA8STALDailyOintmentxBQLBQLBQLBQLBQL
      1962MaleAfrican AmericanIA8STALDailyOintmentxBQLBQLBQLBQLBQL
      2056FemaleWhiteIB–IIA22FBADailyOintmentxBQLBQLBQLBQLBQL
      2170MaleWhiteIA2STALDailyOintmentxBQLBQLBQLBQLBQL
      2275MaleWhiteIA2STALDailyOintmentxBQLBQLBQLBQLBQL
      2374MaleWhiteIA7STALDailyOintmentxBQLBQLBQLBQLBQL
      Abbreviations: BQL, below quantification limit; FBA, full-body application; H, hour; Mo, month; MF, mycosis fungoides; STAL, spot treatment of affected lesions.
      Supplementary Table S2Bioanalytic Testing Results for Individual Patients from Study 202
      Serial NumberAgeGenderRaceMF Stage at BaselineBody Surface Area of Disease, %Modality of ApplicationApplication Frequency During Bioanalytic Testing PeriodLower Limit of Analyte
      Two analytes were tested: chlormethine and half-mustard.
      Quantification in Plasma Samples
      Analytic Results for Plasma Samples Taken at Month of Visit/Hour
      41.5 ng/ml5.0 ng/mlMo2/H0Mo2/H1Mo4/H0Mo4/H1Mo6/H0
      159FemaleWhiteIA4STALM2: Daily

      M4: 4–6 times/wk
      xBQLBQLBQL
      256MaleWhiteIB–IIA19FBA4–6 times/wkxBQLBQLBQL
      340MaleHispanicIB–IIA8FBA4–6 times/wkxBQLBQL
      479MaleWhiteIB–IIA10FBA4–6 times/wkxBQLBQLBQL
      570MaleWhiteIA3STALDailyxBQLBQLBQL
      648FemaleAfrican AmericanIB–IIA46FBAM4: 4–6 times/wk

      M6: daily
      xBQLBQLBQL
      775MaleWhiteIA7STAL4–6 times/wkxBQLBQLBQL
      859FemaleAfrican AmericanIA7STAL4–6 times/wkxBQLBQLBQL
      932FemaleAfrican AmericanIB–IIA24FBA4–6 times/wkxBQLBQLBQL
      1046MaleHispanicIB–IIA11FBA4–6 times/wkxBQLBQLBQL
      1157FemaleWhiteIA4STALDailyxBQL
      1256FemaleWhiteIA4STALDailyxBQLBQLBQL
      1350MaleWhiteIA11STAL4–6 times/wkxBQLBQL
      1441MaleWhiteIA1STALDailyxBQL
      1527MaleWhiteIA1STAL4–6 times/wkxBQLBQLBQL
      Sample was taken at H3.
      Abbreviations: BQL, below quantification limit; FBA, full-body application; H, hour; Mo, month; MF, mycosis fungoides; STAL, spot treatment of affected lesions.
      1 Two analytes were tested: chlormethine and half-mustard.
      2 Sample was taken at H3.

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