Several factors can contribute to hydroxyurea refractoriness. Genetic variations in enzymes involved in drug metabolism, such as UDP-glucuronosyltransferase 1A1 (UGT1A1), can alter drug clearance. Certain disease characteristics, like high baseline nucleated red blood cell counts or rapid disease progression, may also limit therapeutic benefit. Additionally, poor medication adherence, drug interactions, and inadequate dosing strategies can mimic true refractoriness.
Clinicians assess response through laboratory parameters and clinical outcomes. In sickle cell disease, a minimal increase in fetal hemoglobin or persistent pain crises signals a refractory response. In myeloproliferative disorders, inadequate suppression of leukocytosis or thrombocytosis is indicative. Thresholds for classification vary, but a Common Terminology Criteria for Adverse Events (CTCAE) grade of 2 or higher for persistence of disease-related symptoms is often used.
Management of hydroxyurea refractory patients depends on the underlying disease. Alternative therapies for sickle cell disease include crizanlizumab, voxelotor, or gene‑based approaches such as lentiviral beta‑globin gene addition. In myeloproliferative disorders, agents such as ruxolitinib or fedratinib may be employed. Dose escalation, while monitoring for toxicity, remains an option when tolerable. Emerging evidence suggests that combining hydroxyurea with therapeutic agents that inhibit nitric‑oxide or oxidative stress pathways may improve response rates.
Ongoing research focuses on identifying biomarkers predictive of response, refining pharmacogenomic profiles, and developing new drugs that target disease pathways not addressed by hydroxyurea. As such, hydroxyurea refractory remains a significant clinical challenge, underscoring the importance of individualized treatment strategies and close monitoring.