Hydroxyurea and Newer Drug Therapies for Sickle Cell Disease

Hydroxyurea has been used safely in sickle cell disease since 1995 and remains the backbone of disease-modifying therapy. It works by increasing fetal haemoglobin, reducing neutrophil and reticulocyte counts, decreasing red cell adhesiveness, improving red cell hydration and thereby decreasing sickling, and by releasing nitric oxide, which causes vasodilation and helps relieve pain. It reduces pain crises, chest crises, blood transfusions and hospital admissions, and can be given safely long term.

When and How Hydroxyurea Is Used

Hydroxyurea is indicated for patients with more than three pain crises a year or more than two chest crises a year, and can also be considered for chronic leg ulcers, symptomatic anaemia with alloimmunisation who cannot be transfused regularly, persistent priapism not responding to standard therapy, an increased risk of haemolysis, and pulmonary hypertension. Dosing typically starts at 10 to 15 mg per kilogram, with the complete blood count and liver and kidney function monitored, and the dose gradually increased by 5 mg per kilogram every two months if required; the drug is well tolerated, and the literature supports doses as high as 35 mg per kilogram. Toxicities include gastrointestinal upset, skin hyperpigmentation and nail pigmentation; if toxicity increases, the drug is stopped, the patient is monitored for a couple of weeks, and it is resumed at a lower dose. There is some literature suggesting a possible association with malignancy, though the drug has been used safely for decades. It should ideally be stopped when a patient is planning pregnancy: in men, it can reduce sperm count and motility and is teratogenic, and women who conceive should not take it at least during the first trimester.

L-Glutamine, Crizanlizumab and Voxelotor

L-glutamine is an antioxidant that may increase the availability of reduced glutathione, reducing the oxidative stress that contributes to the disease's pathophysiology; it was approved by the FDA in 2017. Crizanlizumab is a human monoclonal antibody directed against P-selectin adhesion molecules, given as a 30-minute infusion every four weeks; the pivotal SUSTAIN trial, published in the New England Journal of Medicine in 2017, showed favourable results for high- and low-dose crizanlizumab against placebo, though most participants in that trial were also on hydroxyurea at the same time. Voxelotor, marketed as Oxbryta, is a haemoglobin oxygen modulator that increases haemoglobin and reduces haemolysis, taken orally at 1,500 mg a day; it was approved by the FDA in 2019, but the manufacturer voluntarily withdrew it in September 2024 over safety concerns.

This article is based on a Jivo Masterclass session conducted by Dr. Divya Doval, Senior Consultant, Bone Marrow Transplant & Haemato-Oncology, BLK-Max Super Speciality Hospital, New Delhi. The article has been summarised with the assistance of an AI tool from the original masterclass recording. Watch the full Masterclass recording