Hydroxyurea Therapy for Myeloproliferative Neoplasms: Intermittent Dosage Can Circumvent Resistance/Intolerance

Twenty to 30% of patients with myeloproliferative neoplasms (MPN) are known to experience resistance or intolerance to the commonly used continuous hydroxyurea (Hu) therapy (500-1000mg daily, titrated based on response), necessitating change over to second-line therapeutic agents. At our Centre, we have used intermittent Hu therapy (20-30mg/Kg, given as a single dose twice or thrice weekly) and have observed sustained responses in 118 patients (polycythaemia vera-29, essential thrombocythemia-84, myelofibrosis-5) over a 30- year period (median 8.5 years), with notable absence of resistance or intolerance; this includes three patients who were previously considered to be Hu-resistant. Based on the pharmacokinetics of Hu and our experience, we hypothesise that the intermittent single dose regimen enables selective cytotoxicity on treatment days (attributable to high plasma level and preferential uptake by the abnormal, proliferating cells) and normal haemopoiesis on the treatment-free days (Hu has a short plasma half-life). There has been no increase in the incidence of acute leukaemia in this cohort of patients. We hope this review will encourage further evaluation of intermittent Hu therapy not only to circumvent resistance or intolerance, but also to improve the clinical outcomes in MPN patients.