Evaluation of O⁶-Benzylguanine−Potentiated Topical Carmustine for Mycosis Fungoides

Abstract

IMPORTANCE In a phase 1 trial, single-dose O 6 -benzylguanine with topical carmustine for patients with early stage (stage IA through stage IIA) cutaneous T-cell lymphoma, mycosis fungoides (MF) type, resulted in clinical responses proportional to inhibition of O 6 -alkylguanine-DNA alkyltransferase activity, but a maximum tolerated dose (MTD) was not reached. OBJECTIVE To determine whether dose escalation of carmustine in combination with dual-dose O 6 -benzylguanine to prolong alkyltransferase inhibition could reach an MTD. DESIGN, SETTING, AND PARTICIPANTSA single-arm, phase 1-2 clinical trial conducted at a university teaching hospital enrolled 17 adults with stage IA through stage IIA cutaneous T-cell lymphoma, MF type, to evaluate treatment using topical carmustine plus 2 subsequent daily doses of intravenous O 6 -benzylguanine, administered every 2 weeks for up to 24 weeks (12 cycles). All patients who received treatment were included in an intent-to-treat analysis of the response rate.

Overlapping Science in Radiation and Sulfur Mustard Exposures of Skin and Lung: Consideration of Models, Mechanisms, Organ Systems, and Medical Countermeasures: Overlapping science in radiation and sulfur mustard injuries to lung and skin

“…SM exposure activates the immune system that is constantly surveying skin and the lumen of surface blood vessels, allowing the connection of this rich microenvironment to circulation. 61,62 This activation of the immune system has led scientists to target multiprong, systemic approaches involving myeloid cells present in all organ systems of the body. 62 One therapeutic under study is high-dose vitamin D, which can induce quiescence of activated macrophages following exposure to these alkylating agents.…”

“…Laboratory animal studies including mice, 65 Yorkshire pigs and rhesus macaques, have explored the impact of vitamin D on damaging exposures to ultraviolet radiation (UV), and SM, as well as NM. Human clinical studies have also explored vitamin D treatments following carmustine, 61 or NM exposure.…”

“…SM exposure activates the immune system that is constantly surveying skin and the lumen of surface blood vessels, allowing the connection of this rich microenvironment to circulation. 61,62…”

“…In an example from a study of treatment with carmustine for lymphoma, a patient experienced a severe skin burning sensation that could have led to his removal from the study; however, administration of vitamin D3 mitigated the skin pain, allowing him to remain on the protocol. 61 SM studies using an animal skin model at Battelle have shown that vitamin D3 modulates immune activation and protects from chemical skin injuries - a single dose of vitamin D3 following a dermal exposure to SM rescued 40% of the animals. Administration of 1 dose of vitamin D or the iNOS inhibitor 1400W rescued animals, improved hematological parameters, and promoted wound healing.…”

Error in Byline and Results Section and Other Typographical Errors

“…In the Original Investigation titled “Evaluation of O 6 -Benzylguanine-Potentiated Topical Carmustine for Mycosis Fungoides: A Phase 1-2 Clinical Trial,” published online on February 15, 2017, there was an author's missing middle initial in the byline, an error in the Results section in the abstract and text, and other minor typographical errors throughout the text. This article was corrected online.…”