Abstract
Background: Mycosis Fungoides (MF) is the most frequent type of the primary cutaneous NK/T-cell lymphomas. Ingenol mebutate (IM) displays in vitro pro-apoptotic properties on neoplastic lymphocytes. Objectives: To evaluate the efficacy and safety of IM gel as topical treatment for MF. Materials and Methods: Ten male patients with longstanding classic type MF (n=9) and follicular MF (FMF; n=1), T2bN0M0B0, stage Ib, resistant to systemic methotrexate or acitretin therapies for at least 3 months, were included in this pilot study. In these patients, 11 target patch/plaque stage lesions with an area ≤ 25 cm2 were selected for IM therapy (0,05%, 2 weekly applications). The primary endpoint was the improvement of the CAILS scores. Biopsies were performed before and after treatment from 10 target lesions. Relapse rates were evaluated at 6 months. Results: The mean CAILS score of treated target lesions was reduced by 58.2%. The mean erythema, scaling and plaque elevation scores were improved by 73.6%, 93.9% and 97.9% (p<0.0001), respectively, while the lesion size remained unchanged (p=0.34). A complete or partial clearance of histological and immunohistochemical features was observed in 6/10 (60%) and 4/10 (40%) of the MF or FMF target lesions, respectively. Monoclonal TCR rearrangement was evidenced in 100% (7/7) of the patients and in 3/7 (43%) after treatment. The relapse rate at 6 months was 18%. All the patients experienced burning sensations, oozing and crusting. Conclusion: IM gel warrants further investigation and development as a potential topical treatment for localized patch/plaque stage MF and FMF.
Highlights
Ingenol Mebutate (IM) is a macrocyclic diterpene ester and originates from the plant Euphorbia peplus (PEP005, 0,015%, 0,05%, Picato° gel, Leo Pharma) [1, 2]
Immunohistology and T-Cell Receptor (TCR) Punch biopsies were obtained from 10 target lesions before IM treatment (T0) and at 2 months after treatment (T2)
The precise action mechanisms of IM on neoplastic lymphocytes should be further investigated, the IMinduced pro-inflammatory and pro-apoptotic storm [12] through activation of the Protein Kinase C (PKC) isoform PKCδ is likely to be involved in the anti-neoplastic action on Mycosis Fungoides (MF) lymphocytes [14]
Summary
Ingenol Mebutate (IM) is a macrocyclic diterpene ester and originates from the plant Euphorbia peplus (PEP005, 0,015%, 0,05%, Picato° gel, Leo Pharma) [1, 2]. For decades the sap from E. peplus has been used as traditional medicine for various types of skin cancer [1, 2] Both the EMA and the FDA recognize IM gel as a field-directed treatment for Actinic Keratosis (AK) [1, 2]. IM and other ingenol derivatives activate multiple signaling pathways in cancer cells, including the intracellular pro-apoptotic Protein Kinase C (PKC) δ, α and ε, NF-κB1, ERK, JNK and Akt pathways [10, 12]. The activation of these PKC’s leads to a rapid cancer cell apoptosis and a neutrophil-mediated immunostimulation of antibody-dependent cellular cytotoxic response [13]. Ingenol mebutate (IM) displays in vitro pro-apoptotic properties on neoplastic lymphocytes
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