Sustained Regression of Hydroxycarbamide Induced Actinic Keratoses after Switching to Anagrelide

Abstract

Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatment with HC can result in the development of confluent actinic keratoses (AK) followed by invasive keratinocytic carcinomas (“squamous dysplasia”), preferentially on sun-exposed skin. Discontinuation or dose reduction of HC may result in partial improvement. A 59-year-old farmer after 14 years on HC (2 gr/d) and acetylsalicylic acid (100 mg/d) for ET, was referred for numerous, hyperkeratotic AK on face, scalp, and hands that could not be controlled with repeated (N = 15) cryosurgery sessions in the previous 3 years. Acitretin (0.32 mg/kg daily) and topical treatments (cryosurgery with ingenol mebutate) were initiated with only marginal improvement after 3 months. Acitretin dose was doubled and HC was switched to anagrelide (0.5 mg twice daily). Within a month the AK load regressed significantly and, at 3 months follow-up, complete clinical remission was achieved and acitretin was discontinued. Twenty months later the patient is clear from AK. In conclusion, the impressive and sustainable AK remission under anagrelide draws attention to a possible role of the phosphodiesterase 3 pathway, the major pharmacological target of anagrelide, as a potential therapeutic target for keratinocytic cancers.

Skin cancer in essential thrombocythaemia and polycythaemia vera patients treated with hydroxycarbamide

“…By interfering with DNA synthesis, HC has the potential to be mutagenic and therefore provides a plausible biological mechanism for skin cancer development. By acting synergistically with ultraviolet light, HC can increase the risk of development of other non‐cancerous skin changes such as actinic keratoses (AK) [11], with case studies highlighting sustained regression of AKs after discontinuation of HC [12]. However, in our study older age, male gender, type of MPN and previous history of skin cancer were the only statistically significant prognostic risk factors for skin cancer development.…”

Anagrelide: A Clinically Effective cAMP Phosphodiesterase 3A Inhibitor with Molecular Glue Properties

“…52 Indeed, 1 has been used to successfully resolve a case of confluent actinic keratoses, a skin lesion that can progress to invasive squamous cell carcinoma. 80 As a result of the observations with velcrins, clinical applications are being explored in the context of BAY 2666605 (39), which has entered into trials in patients with metastatic melanoma and other advanced solid tumors where the downregulation of induced myeloid leukemia cell differentiation protein (Mcl-1) will be monitored as a biomarker. 81 Preclinical studies with 39 have demonstrated antitumor effects in patient-derived xenograft models of ovarian cancer and sarcoma, and since the molecule is CNS penetrant, it has been shown to have the potential to treat glioblastomas.…”

“…These data suggested that as a potential therapeutic approach, the broader cytotoxic effects of molecules with a profile similar to 20 in normal tissues would be limited . Indeed, 1 has been used to successfully resolve a case of confluent actinic keratoses, a skin lesion that can progress to invasive squamous cell carcinoma . As a result of the observations with velcrins, clinical applications are being explored in the context of BAY 2666605 ( 39 ), which has entered into trials in patients with metastatic melanoma and other advanced solid tumors where the downregulation of induced myeloid leukemia cell differentiation protein (Mcl-1) will be monitored as a biomarker .…”