Evaluating hydroxyurea’s photosensitizing effects: A study on cutaneous squamous cell carcinoma risk

Summary: Abstract Body: Philadelphia-chromosome–negative myeloproliferative neoplasms (Phl-MPN) are associated with increased risk of cutaneous squamous cell carcinoma (cSCC), potentially due to disease-related immunosuppression. Hydroxyurea (HU), a photosensitizing cytoreductive (CR) agent is used for Phl-MPNs and sickle cell disease (SCD)—a condition not linked to SCC. We evaluate whether HU increases cSCC risk using TriNetX Research Network. Three cohorts were analyzed: (1) Phl-MPN patients receiving HU vs no HU or other CR therapy; (2) SCD patients on HU vs no HU exposure; (3) Phl-MPN patients on HU vs alternative medications (AM) (interferon-α, anagrelide, fedratinib, ruxolitinib, pacritinib, busulfan). Propensity score matching (1:1) controlled for age, sex, race, and ethnicity. Patients with prior cSCC, immunosuppressive treatments or stem cell transplants were excluded. The primary outcome was cSCC incidence after diagnosis and drug exposure, identified via ICD-10 codes. Among 44,122 Phl-MPN patients (22,084 HU-treated, 22,084 no CR agent exposure), cSCC incidence was higher in HU users (460/21,750 vs 314/21,744; RR=1.5, CI:1.3–1.7, p<0.0001). In the SCD cohort (29,910 patients; 14,955 HU-treated, 14,955 no HU), HU was associated with significantly elevated cSCC risk (143/14,192 vs 17/14,948; RR=8.4, CI:5.1–13.9, p<0.0001). In the Phl-MPN cohort comparing HU to AM (8,280 patients; 4,140 in each group), cSCC risk was similar (RR=0.9, CI:0.7–1.2, p=0.5). HU was associated with reduced cSCC in non-sun-exposed areas (anal, hip, trunk, breast) compared to Phl-MPN patients not on CR therapy (RR=0.7, CI:0.5–0.9, p<0.03) and AM (RR=0.5, CI:0.3–1.0, p<0.04). The SCD cohort analysis for non-sun-exposed areas was inconclusive due to limited outcomes. Our findings suggest that HU-associated cSCC may be driven by photosensitization as well as immunosuppressive effects. Highlighting the importance of UV protection for HU users and the need for further research to clarify HU’s role in UV-induced cSCC. Emily R. Hunter¹, Karla L. Valdes Morales¹, Stephanie Y. Wang¹, Daniela Frankel¹, Maria Trifoi¹, Christopher J. Miller¹, Jeremy R. Etzkorn¹, Joanna Walker¹ 1. Dermatology, Hospital of the University of Pennsylvania, Philadelphia, PA, United States. Clinical Research: Epidemiology and Observational Research