Chlormethine Gel Versus Chlormethine Ointment for Treatment of Patients with Mycosis Fungoides: A Post-Hoc Analysis of Clinical Trial Data.
Journal
American journal of clinical dermatology
ISSN: 1179-1888
Titre abrégé: Am J Clin Dermatol
Pays: New Zealand
ID NLM: 100895290
Informations de publication
Date de publication:
Jul 2022
Jul 2022
Historique:
accepted:
17
03
2022
pubmed:
11
5
2022
medline:
2
8
2022
entrez:
10
5
2022
Statut:
ppublish
Résumé
Chlormethine gel was approved for treatment of mycosis fungoides, the most common cutaneous T-cell lymphoma, on the basis of results from study 201 and study 202. A post-hoc analysis of study 201 found interesting trends regarding improved efficacy of chlormethine gel vs ointment and noted a potential association between dermatitis and clinical response. To expand these results by performing a post-hoc analysis of study 202. Patients received chlormethine gel or ointment during study 201 (12 months) and higher-concentration chlormethine gel during study 202 (7-month extension). Response was assessed using Composite Assessment of Index Lesion Severity (CAILS). Associations between treatment frequency, response, and skin-related adverse events (AEs) were assessed using multivariate time-to-event analyses. Time-to-response and repeated measures analyses were compared between patients who only used chlormethine gel and those who switched from ointment to gel. No associations were seen between treatment frequency and improved skin response (CAILS) or AE occurrence within the 201/202 study populations. However, an association was observed specifically between contact dermatitis and improved CAILS response at the next visit (p < 0.0001). Patients who used chlormethine gel during both studies had a significantly (p < 0.05) shorter time to response and higher overall response rates than patients who initiated treatment with ointment. This post-hoc analysis shows that patients who initiated treatment using chlormethine gel had faster and higher responses compared with patients who initially used chlormethine ointment for 12 months. The development of contact dermatitis may be a potential prognostic factor for response. Study 201: NCT00168064, September 14, 2002; Study 202: NCT00535470, September 26, 2007.
Sections du résumé
BACKGROUND
BACKGROUND
Chlormethine gel was approved for treatment of mycosis fungoides, the most common cutaneous T-cell lymphoma, on the basis of results from study 201 and study 202. A post-hoc analysis of study 201 found interesting trends regarding improved efficacy of chlormethine gel vs ointment and noted a potential association between dermatitis and clinical response.
OBJECTIVE
OBJECTIVE
To expand these results by performing a post-hoc analysis of study 202.
PATIENTS AND METHODS
METHODS
Patients received chlormethine gel or ointment during study 201 (12 months) and higher-concentration chlormethine gel during study 202 (7-month extension). Response was assessed using Composite Assessment of Index Lesion Severity (CAILS). Associations between treatment frequency, response, and skin-related adverse events (AEs) were assessed using multivariate time-to-event analyses. Time-to-response and repeated measures analyses were compared between patients who only used chlormethine gel and those who switched from ointment to gel.
RESULTS
RESULTS
No associations were seen between treatment frequency and improved skin response (CAILS) or AE occurrence within the 201/202 study populations. However, an association was observed specifically between contact dermatitis and improved CAILS response at the next visit (p < 0.0001). Patients who used chlormethine gel during both studies had a significantly (p < 0.05) shorter time to response and higher overall response rates than patients who initiated treatment with ointment.
CONCLUSIONS
CONCLUSIONS
This post-hoc analysis shows that patients who initiated treatment using chlormethine gel had faster and higher responses compared with patients who initially used chlormethine ointment for 12 months. The development of contact dermatitis may be a potential prognostic factor for response.
TRIAL REGISTRATION NUMBERS AND DATES OF REGISTRATION
UNASSIGNED
Study 201: NCT00168064, September 14, 2002; Study 202: NCT00535470, September 26, 2007.
Identifiants
pubmed: 35536441
doi: 10.1007/s40257-022-00687-y
pii: 10.1007/s40257-022-00687-y
pmc: PMC9334402
doi:
Substances chimiques
Gels
0
Ointments
0
Mechlorethamine
50D9XSG0VR
Banques de données
ClinicalTrials.gov
['NCT00168064', 'NCT00535470']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
561-570Informations de copyright
© 2022. The Author(s).
Références
Willemze R, Hodak E, Zinzani PL, Specht L, Ladetto M, ESMO Guidelines Committee. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29:30–40. https://doi.org/10.1093/annonc/mdy133 .
doi: 10.1093/annonc/mdy133
Kim EJ, Hess S, Richardson SK, Newton S, Showe LC, Benoit BM, et al. Immunopathogenesis and therapy of cutaneous T cell lymphoma. J Clin Invest. 2005;115:798–812. https://doi.org/10.1172/JCI24826 (Erratum in: J Clin Invest. 2007;117:836).
doi: 10.1172/JCI24826
pubmed: 15841167
pmcid: 1070436
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. Eur J Cancer. 2017;77:57–74. https://doi.org/10.1016/j.ejca.2017.02.027 .
doi: 10.1016/j.ejca.2017.02.027
pubmed: 28365528
Gilson D, Whittaker SJ, Child FJ, Scarisbrick JJ, Illidge TM, Parry EJ, et al. British association of dermatologists and U.K. Cutaneous Lymphoma Group guidelines for the management of primary cutaneous lymphomas 2018. Br J Dermatol. 2019;180:496–526. https://doi.org/10.1111/bjd.17240 .
doi: 10.1111/bjd.17240
pubmed: 30561020
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines (NCCN Guidelines
Haserick JR, Richardson JH, Grant DJ. Remission of lesions in mycosis fungoides following topical application of nitrogen mustard: a case report. Cleve Clin J Med. 1959;26:144–7.
doi: 10.3949/ccjm.26.3.144
Valchlor (mechlorethamine) [prescribing information]. Iselin, NJ: Helsinn Therapeutics (U.S.), Inc.; 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202317s009lbl.pdf . Accessed 10 Nov 2021.
Ledaga [prescribing information]. Jerusalem, Israel: Rafa Laboratories Ltd.; 2020. https://mohpublic.z6.web.core.windows.net/IsraelDrugs/Rishum_17_462433720.pdf . Accessed 10 Nov 2021.
Ledaga [summary of product characteristics]. Dublin, Ireland: Helsinn Birex Pharmaceuticals Ltd.; 2017. https://www.ema.europa.eu/en/documents/product-information/ledaga-epar-product-information_en.pdf . Accessed 10 Nov 2021.
Chang YT, Ignatova D, Hoetzenecker W, Pascolo S, Fassnacht C, Guenova E. Increased chlormethine-induced DNA double-stranded breaks in malignant T cells from mycosis fungoides skin lesions. JID Innov. 2021;2: 100069. https://doi.org/10.1016/j.xjidi.2021.100069 .
doi: 10.1016/j.xjidi.2021.100069
pubmed: 34977846
pmcid: 8683611
Querfeld C, Geskin LJ, Kim EJ, Scarisbrick JJ, Quaglino P, Papadavid E, et al. Lack of systemic absorption of topical mechlorethamine gel in patients with mycosis fungoides cutaneous T-cell lymphoma. J Invest Dermatol. 2021;141:1601-1604.e2. https://doi.org/10.1016/j.jid.2020.12.009 .
doi: 10.1016/j.jid.2020.12.009
pubmed: 33347924
pmcid: 8641791
Lessin SR, Duvic M, Guitart J, Pandya AG, Strober BE, Olsen EA, 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;149:25–32. https://doi.org/10.1001/2013.jamadermatol.541 .
doi: 10.1001/2013.jamadermatol.541
pubmed: 23069814
pmcid: 3662469
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29:2598–607. https://doi.org/10.1200/JCO.2010.32.0630 .
doi: 10.1200/JCO.2010.32.0630
pubmed: 21576639
pmcid: 3422534
Querfeld C, Scarisbrick JJ, Assaf C, Guenova E, Bagot M, Ortiz-Romero PL, et al. 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. Dermatology. 2021. https://doi.org/10.1159/000516138 .
doi: 10.1159/000516138
pubmed: 34091453
Querfeld C, Kim YH, Guitart J, Scarisbrick J, Quaglino P. Use of chlormethine 0.04% gel for mycosis fungoides after treatment with topical chlormethine 0.02% gel: a phase 2 extension study. J Am Acad Dermatol. 2021. https://doi.org/10.1016/j.jaad.2021.06.896 .
doi: 10.1016/j.jaad.2021.06.896
pubmed: 34333079
Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience. Arch Dermatol. 2003;139:165–73. https://doi.org/10.1001/archderm.139.2.165 .
doi: 10.1001/archderm.139.2.165
pubmed: 12588222
Talpur R, Venkatarajan S, Duvic M. Mechlorethamine gel for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma. Expert Rev Clin Pharmacol. 2014;7:591–7. https://doi.org/10.1586/17512433.2014.944500 .
doi: 10.1586/17512433.2014.944500
pubmed: 25068889
Kim EJ, Guitart J, Querfeld C, Girardi M, Musiek A, Akilov OE, et al. 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. Am J Clin Dermatol. 2021;22:407–14. https://doi.org/10.1007/s40257-021-00591-x .
doi: 10.1007/s40257-021-00591-x
pubmed: 33656660
pmcid: 8068681
Prag Naveh H, Amitay-Laish I, Zidan O, Leshem YA, Sherman S, Noyman Y, et al. Real-life experience with chlormethine gel for early-stage mycosis fungoides with emphasis on types and management of cutaneous side-effects. J Dermatolog Treat. 2021. https://doi.org/10.1080/09546634.2021.1967266 .
doi: 10.1080/09546634.2021.1967266
pubmed: 34427536
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;11:1085–106. https://doi.org/10.1007/s13555-021-00539-3 .
doi: 10.1007/s13555-021-00539-3
pubmed: 34021485
pmcid: 8322195
Klucel™ hydroxypropylcellulose. Physical and chemical properties. Ashland Inc.; 2017. https://www.ashland.com/file_source/Ashland/Product/Documents/Pharmaceutical/PC_11229_Klucel_HPC.pdf . Accessed 10 Nov 2021.
Giuliano C, Frizzarin S, Beuttel C, Powell K, Alonzi A, Stimamiglio V, et al. Percutaneous absorption of chlormethine gel in human skin: in vitro permeation testing. J Invest Dermatol. 2021;141:S171 (Abstract 134).
doi: 10.1016/j.jid.2021.08.137
Wehkamp U, Jost M, Gosmann J, Grote U, Bernard M, Stadler R. Management of chlormethine gel treatment in mycosis fungoides patients in two German skin lymphoma centers. J Dtsch Dermatol Ges. 2021;19:1057–9. https://doi.org/10.1111/ddg.14462 .
doi: 10.1111/ddg.14462
pubmed: 34288486
Pichler WJ, Hausmann O. Classification of drug hypersensitivity into allergic, p-i, and pseudo-allergic forms. Int Arch Allergy Immunol. 2016;171:166–79. https://doi.org/10.1159/000453265 .
doi: 10.1159/000453265
pubmed: 27960170
Gilmore ES, Alexander-Savino CV, Chung CG, Poligone B. Evaluation and management of patients with early-stage mycosis fungoides who interrupt or discontinue topical mechlorethamine gel because of dermatitis. JAAD Case Rep. 2020;6:878–81. https://doi.org/10.1016/j.jdcr.2020.05.031 .
doi: 10.1016/j.jdcr.2020.05.031
pubmed: 32904169
pmcid: 7452260
Alexander-Savino CV, Chung CG, Gilmore ES, Carroll SM, Poligone B. Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) establishes benefit of topical triamcinolone 0.1% ointment cotreatment in mycosis fungoides. Dermatol Ther. 2022. https://doi.org/10.1007/s13555-022-00681-6 .
doi: 10.1007/s13555-022-00681-6
Dugre F, Lefebure A, Martelli S, Pin M, Maubec E, Arnaud F. Chlormethine gel: effectiveness and tolerance to treat mycosis fungoides. Int J Clin Pharm. 2017;39:252. https://doi.org/10.1007/s11096-016-0404-4 (Abstract DI006).
doi: 10.1007/s11096-016-0404-4
Lampadaki K, Koumourtzis M, Karagianni F, Marinos L, Papadavid E. Chlormethine gel in combination with other therapies in the treatment of patients with mycosis fungoides cutaneous T cell lymphoma: three case reports. Adv Ther. 2021;38:3455–64. https://doi.org/10.1007/s12325-021-01721-x .
doi: 10.1007/s12325-021-01721-x
pubmed: 33928511
pmcid: 8190003