Non-melanoma Skin Cancers in Patients on Hydroxyurea for Philadelphia Chromosome-Negative Myeloproliferative Neoplasms: A Systematic Review

Abstract

Hydroxyurea (HU) or hydroxycarbamide is a cytotoxic antimetabolite widely used to treat Philadelphia chromosome-negative Myeloproliferative Neoplasms (Ph-MPN) like Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF). Patients with Ph-MPN are at an increased risk of Non-melanoma skin cancers (NMSC). The cause of this finding remains uncertain. In this systematic review, we would like to know if chronic use of HU in this population is responsible for the sudden onset of NMSC. The results obtained will help the patients and clinicians with early diagnosis of cutaneous lesions and in optimizing the current treatment options for MPN. We conducted a multi-database literature search, applied eligibility criteria and quality assessment tools to the studies extracted, with an intention to include only fair to high-quality articles. We analyzed six observational studies and four traditional reviews. Two out of 10 studies concluded that no relationship exists between the incidence of NMSC and HU. The remaining eight studies indicated the association. According to these studies, the possible risk factors include old age, excessive exposure to sunlight, higher doses, and prolonged HU therapy duration. Ultraviolet (UV) radiation and HU play a combined role in carcinogenesis. Periodic dermatologic screening is essential in these patients. Prompt biopsy and accurate diagnosis can prevent the progression of cancer and decrease the associated morbidity and mortality. True incidence and causation cannot be ascertained due to the scarcity of research on this topic. Multi-center prospective studies in large groups of Ph-MPN patients are recommended to determine the temporal relationship between NMSC and HU treatment.

Cutaneous involvement in Ph‐negative myeloproliferative neoplasms: from extramedullary hematopoiesis to myeloid metastasis with histiocytic differentiation. A systematic review of the literature

“…A potential clinical and histopathological pitfall is the presence of numerous degranulated mast cells in skin biopsies of MPN patients with itchy lesions, which should not be misdiagnosed as mastocytosis 77 . Concerning therapy‐related lesions, treatment with hydroxyurea is known to produce skin lesions such as ulcers, actinic keratosis/squamous cell carcinoma, and skin and nail hyperpigmentation in around 5% of patients, which are clinically and histopathologically different from neoplastic cutaneous involvement in MPNs 78 …”

“…77 Concerning therapy-related lesions, treatment with hydroxyurea is known to produce skin lesions such as ulcers, actinic keratosis/ squamous cell carcinoma, and skin and nail hyperpigmentation in around 5% of patients, which are clinically and histopathologically different from neoplastic cutaneous involvement in MPNs. 78…”

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety

“…Among patients treated with ruxolitinib in JUMP, NMSCs were the most common secondary malignancies and were reported in 2.7% of patients treated with ruxolitinib [ 7 ]. By comparison, a recent systematic review of patients with MPNs treated with HU in observational studies reported NMSC rates of 0.29% (10/3411 patients in a retrospective Italian study; median age, ≈63 years), 9.6% (127/1316 in an Italian case-control study; median HU exposure, 3 years), 13.6% (9/66 in a retrospective Czech study; median age, 64 years), and 34.2% (51/149 patients in a retrospective Australian study; median HU exposure, 4 years; median age, 66 years) [ 47 ]. Finally, in a noninterventional postauthorization safety study of 462 patients with MF that included prevalent or new users of ruxolitinib, a nonsignificant trend toward increased risk of NMSC with increasing ruxolitinib exposure was observed (hazard ratio [HR] corresponding to risk with each additional year of ruxolitinib, 1.2 [95% CI 0.9, 1.6]) [ 16 ].…”

Second Cancer Onset in Myeloproliferative Neoplasms: What, When, Why?

“…In fact, it increases the number of DNA breaks, causing the strands to remain open longer, and decreases the DNA polymerase activity, thereby slowing the polymerization rate at the repair sites [ 13 , 14 ]. Furthermore, HU and exposure to UV radiation play a combined role in skin cancers onset; in fact, UV-B rays promote the proliferation of TP53 mutant keratinocytes (seen in the dermo-epidermal junction and hair follicles) and enable them to colonize the adjacent compartment [ 15 , 16 ]. In the basal layer of the epidermis, the high keratinocyte turnover with HU impaired DNA synthesis and repair are the causes of skin tumors onset [ 61 ].…”