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Narin Apisarnthanarax, MD; Gary S. Wood, MD; Seth R. Stevens, MD; Sean Carlson, DO; Derek V. Chan, MD, PhD; Lili Liu, MD, PhD; Sarolta K. Szabo, MD; Pingfu Fu, PhD; Anita C. Gilliam, MD, PhD; Stanton L. Gerson, MD; Scot C. Remick, MD; Kevin D. Cooper, MD

Arch Dermatol. Published online January 16, 2012. doi:10.1001/archdermatol.2011.2797

Objectives  To evaluate the toxic effects and maximum tolerated dose of topical carmustine [1,3-bis (2-chloroethyl)-1-nitrosourea] following intravenous O6-benzylguanine in the treatment of cutaneous T-cell lymphoma (CTCL), and to determine pharmacodynamics of O6-alkylguanine DNA alkyltransferase activity in treated CTCL lesions.

Design  Open-label, dose-escalation, phase I trial.

Setting  Dermatology outpatient clinic and clinical research unit at a university teaching hospital.

Patients  A total of 21 adult patients (11 male, 10 female) with early-stage (IA-IIA) refractory CTCL, mycosis fungoides type, treated with topical carmustine following intravenous O6-benzylguanine.

Intervention  Treatment once every 2 weeks with 120 mg/m² intravenous O6-benzylguanine followed 1 hour later by whole-body, low-dose topical carmustine starting at 10 mg, with 10-mg incremental dose-escalation in 3 patient cohorts. Cutaneous T-cell lymphoma lesional skin biopsy specimens were taken at baseline and 6 hours, 24 hours, and 1 week after the first O6-benzylguanine infusion for analysis of O6-alkylguanine-DNA alkyltransferase activity.

Main Outcome Measures  Clinical response measured by physical examination and severity-weighted assessment tool measurements, safety data acquired by review of adverse events at study visits, and O6-alkylguanine-DNA alkyltransferase activity in treated lesion skin biopsy specimens.

Results  A minimal toxic effect was observed through the 40-mg carmustine dose level with 76% of adverse events being grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events. Mean baseline O6-alkylguanine-DNA alkyltransferase activity in CTCL lesions was 3 times greater than in normal controls and was diminished by a median of 100% at 6 and 24 hours following O6-benzylguanine with recovery at 1 week. Clinical disease reduction correlated positively with O6-alkylguanine-DNA alkyltransferase activity at 168 hours (P = .02) and inversely with area under the curve of O6-alkylguanine-DNA alkyltransferase over 1 week (P = .01). Twelve partial responses and 4 complete responses were observed (overall response, 76% [95% CI, 0.55-0.89]). Five patients discontinued therapy owing to adverse events with a possible, probable, or definite relationship to the study drug.

Conclusion  O6-benzylguanine significantly depletes O6-alkylguanine-DNA alkyltransferase in CTCL lesions and in combination with topical carmustine is well tolerated and shows meaningful clinical responses in CTCL at markedly reduced total carmustine treatment doses.

Trial Registration  clinicaltrials.gov Identifier: NCT00003613

Author Affiliations: Departments of Dermatology (Drs Apisarnthanarax, Wood, Stevens, Carlson, Chan, Szabo, Gilliam, and Cooper) and Internal Medicine, Case Comprehensive Cancer Center, Developmental Therapeutics Program, Seidman Cancer Center (Drs Liu, Gerson, and Remick), University Hospitals Case Medical Center, and Department of Epidemiology and Biostatistics (Dr Fu), Case Western Reserve University, Cleveland, Ohio; and Dermatology Service, Louis Stokes Department of Veterans Affairs Medical Center, Cleveland (Drs Wood, Stevens, and Cooper). Dr Apisarnthanarax is now with Clear Lake Dermatology, Webster, Texas); Dr Wood is now with the Department of Dermatology, University of Wisconsin and Middleton Department of Veterans Affairs Medical Center, Madison; Dr Stevens is now with Kaiser Permanente Woodland Hills Medical Center, Woodland Hills, California; Dr Carlson is now with the Department of Radiology, Aultman Hospital, Canton, Ohio; Dr Chan is now with the Division of Dermatology, Department of Medicine, Ohio State University, Columbus, Ohio; Dr Szabo is now with Alta Vista Dermatology, Highlands Ranch, Colorado; Dr Gilliam is now with the Department of Dermatology, Palo Alto Medical Foundation, Palo Alto, California; and Dr Remick is now with the Mary Babb Randolph Cancer Center, West Virginia University, Morgantown.

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