What is Hydroxyurea? Unravelling the Benefits

Sickle Cell Disease (SCD) is a complex condition characterised by affecting multiple organs, producing acute and chronic complications, which have significant implications for survival, quality of life and economic costs. It impacts education, work productivity and household activities. Another important aspect of the natural history of SCD is that the rate and spectrum of complications vary throughout the patient’s lifespan, and the patient receives different types of medical care, for example, paediatric versus adult care with a difficult transition period or primary care versus speciality care. Apart from some promising new therapeutic offers, three well-established therapies modify the disease course of Sickle Cell Disease/Anaemia: Hydroxyurea, Erythrocyte Transfusion and Hematopoietic Stem Cell Transplantation.


Hydroxyurea (HU) is an antimetabolite S-phase specific drug that reversibly inhibits ribonucleotide diphosphate reductase enzyme. Such enzyme inhibitory effect of hydroxyurea is limited to the “de novo” synthesis of DNA and DNA repair; it does not affect RNA or protein synthesis. It is recommended for nearly all SCD patients, although the beneficial response may be limited in some patients, usually because of adherence to treatment but also due to pharmacogenomic reasons. HU is underutilised in low-medium and high-resource countries, contributing to disproportionate perceptions of potential side effects, especially carcinogenicity, teratogenicity, and reduced fertility, which have not been a problem in long-term follow-up studies. Before its use in SCD, this medication has been indicated to treat people with myeloproliferative disorders.


How Hydroxyurea Works?


Oral hydroxyurea is well absorbed through the gastrointestinal tract and distributed rapidly and widely in the body, with peak plasma concentrations reaching 1 to 4 hours after dosing. The drug is eliminated mainly through urine after being metabolised in the liver.


HU has multiple physiological effects. The primary mechanism of action and significant benefit of hydroxyurea is the upregulation of the gamma-globin gene expression in erythroid cells; subsequently, such gamma-globin chains can combine with normal alpha-globin in red blood cells to form Foetal Haemoglobin (HbF), which inhibits erythrocyte sickling, but the drug also has beneficial effects on leucocytes, reticulocytes and the activated vascular endothelium. When HU is escalated to the maximum tolerated dose, it improves laboratory variables and reduces clinical complications. The red blood cells with a higher proportion of HbF (20-25%) are known as F cells, and hydroxyurea has been shown to enhance the F cell percentage. Such induction of HbF retards the polymerisation of deoxygenated-HbS and reduces the sickling of erythrocytes mentioned above.


According to Steinberg, MH. (2020), Yasara, N. et al. (2021) and others, HbF induction by HU depends in part on a proliferating erythroid bone marrow, which is most vigorous in childhood (all children seem to respond to hydroxyurea). When HU was started early (9 months of age) at a dose of approximately 27 mg/Kg/day, the HbF levels were 33.3 % +/-9.1 %, well over 20 %, which is considered efficacious. HU reduces the morbidity and mortality of SCD primarily mediated by its induction of HbF ((although perhaps not exclusively).


According to Princez, T., and Lettre, G. (2023), hydroxyurea’s beneficial effect on stroke in children, which is at least partly mediated by HbF and obtaining higher HbF levels, should provide increased protection.


Several studies have shown that hydroxyurea inhibits ineffective erythropoiesis, causing intermittent suppression of erythroid progenitors due to its cytotoxicity and stimulating cell stress signalling, promoting the release of erythroid progenitors containing high HbF. Also, it has been shown to improve the haemoglobin level, haematocrits, mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH). The improvement of erythrocyte hydration with hydroxyurea due to the increment in MCV is identified as one of the mechanisms causing improved red blood cell deformability (improves cell hydration and deformability decreases viscosity).


Recently, research by Minniti, CP. et al. (2021) found in their cohort of patients with SCD and COVID-19 that treatment with hydroxyurea was more common in non-hospitalised patients than hospitalised; furthermore, they found that among the patients (n=10) with SCD chronically prescribed hydroxyurea who continued hydroxyurea during their hospitalisation, there were no deaths, ICU admissions or need for invasive ventilation. In contrast, all patients with SCD who died were not receiving disease-modifying therapy with hydroxyurea before hospitalisation; continuation of HU was encouraged during hospital stay.


HU reduces the level of lactate dehydrogenase (LDH) and arginase 1. LDH is an indicator of intravascular haemolysis. The levels of both proteins are high in SCD due to increased haemolysis. Another clinical advantage of hydroxyurea is a sustainable early reduction in erythrocyte adhesion.


What is hydroxyurea used for in Sickle Cell Disease/Anaemia?


There is a significant phenotypic variability among persons with SCD; these phenotypes have particular characteristics; for example, they may change with ageing, overlap, and are not mutually exclusive.


Recurrent episodes of ischemia due to vaso-occlusion by sickled erythrocytes are the hallmarks of SCD. Patients experience an array of disease symptoms and complications, including periods of acute pain, chronic pain and multi-organ injury characterised by haemolysis and vaso-occlusion. This multisystem organ injury begins in early infancy and accumulates over the lifetime of the patient, but because of phenotypic variability, some patients develop particular complications and others different ones; some have frequent or severe related organ damage and very early mortality, whereas others with the same genotype have fewer manifestations and a longer lifespan although not typical.


HU is currently considered a well-studied pharmacological treatment for both children and adult patients with recurrent painful vaso-occlusive episodes (VOEs), reducing the number of VOEs (pain crisis), acute complications, pulmonary hypertension, hospitalisations and mortality. Paediatric patients maintained on the maximum tolerated dose of HU over several years showed significant reductions in VOEs, hospitalisations, end-organ damage (spleen, retina, heart, bones, kidney, liver, lungs, skin), chronic hypoxemia and stroke without significant neutropenia, growth reduction, carcinogenesis, or other organ alterations.


Studies with hydroxyurea showed a significant reduction in the duration of hospital stay due to severe painful crises and the requirement of opioids, acute chest syndrome and improvement of transfusion requirement. A large prospective trial (LaSHS, by Voskaridou, E. et al. 2010) reported significantly higher survival following Hydroxyurea treatment.


The beneficial effects of HU are extended to SCD variants like haemoglobin SC disease and sickle Beta-thalassemia, maintaining a stable haemoglobin level and decreasing the frequency of painful crises and hospitalisations.


Additionally, cell adhesion to the vascular endothelium is inhibited by HU through downregulating cell adhesive molecules in reticulocytes and mature red blood cells, as well as via the reduction of white blood cells and platelets. The beneficial effect of HU on pulmonary hypertension is through induction of nitric oxide and reduction of intravascular haemolysis, improvement of haemoglobin concentration, oxygen saturation, anaemia and prevention of vaso-occlusive events.


When and how to start Hydroxyurea in Sickle Cell Disease?


Because the focus of drug treatment should be to diminish HbS polymerisation, controlled studies have shown that hydroxyurea (which reduces acute vaso-occlusive events and haemolysis with an extension of lifespan) should be started in the first year of life (currently, experts recommend starting at 6 to 9 months of age) at incremental doses, up to the maximum tolerated dose (MTD).

Authors insist not to withhold a safe and effective therapy like hydroxyurea while waiting for the sickest of the sick. On the contrary, HU therapy represents a kind of clinical challenge because its beneficial effects are “dose-dependent”, but the optimal dose for an individual patient is the one that achieves the best HbF level without severe haematological or other toxicities. The amount is based on the patient’s weight, typically starting at 15 to 20 mg/Kg/day with subsequent dose escalation to obtain the MTD, mentioned in the literature at 35 mg/Kg/day. Several clinical trials showed that using HU at MTD, higher HbF percentages are generally reached; consequently, doses should be individualised.


It has been observed that older SCD patients are more sensitive to HU dosage, with increased rates of neutropenia; therefore, HU therapy needs careful and more frequent monitoring in older adults compared with younger patients. Steinberg, (2011) published results of a follow-up of more than 17 years in adults with Sickle Cell Anaemia (SCA) where treatment with HU started in the 4th decade of life, concluding that the drug was safe and its use also appeared to be associated with reduced mortality.


A randomised clinical trial placebo-controlled in children with SCA (The Baby Hug Study) aimed to determine the effect of HU on organ function and clinical complications in children aged 9 to 18 months, regardless of clinical severity. Hydroxyurea therapy decreased acute pain episodes, dactylitis, acute chest syndrome, hospitalisation rates and transfusions compared with placebo.


Hydroxyurea is a medication that improves Quality of Life.

Adherence to HU treatment is paramount for effectiveness, but despite proven benefits, barriers to adherence persist. Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician, and the reason may not be a sufficient benefit due to underdosing or difficulties in providing the correct dose, particularly in children. Also, there is evidence that genetic modifiers affect individual response to HU determined by the HbF percentage, responsible for reported variability.

Consequently, Quality of Life is affected.

On the hypothesis that uninformed perceptions and barriers to using HU “hinder adherence”, Treadwell, MJ. et al. (2022) conducted a real-world study on healthcare providers, children and adults on socio-demographics, hospital and emergency admissions for pain, number of severe pain episodes interfering with daily activities, medication adherence and barriers to HU. The results indicated that adults 26 years and older were least likely to be on HU, and the likelihood of being on HU decreased with one or more barriers. Patients on hydroxyurea challenge taking the medication at the right time and forgetting; such were crucial unintentional barriers to adherence.


Intentional barriers were worries about side effects, and “tried, and it did not work” were essential barriers for young adults and adult patients. For healthcare providers, there is a need to strengthen the understanding and confidence in implementing SCD guidelines, understand the choices and decisions of families, guide individualised clinical discussions regarding HU therapy and help develop tailored interventions to address barriers, including combination therapies for SCD. In summary, ‚Äútreatment at optimal effectiveness” should be the primary goal for caregivers.


Improving the well-being of children and adult patients with Sickle Cell Disease/Anaemia should be the ultimate goal when treating this complex disease; more comprehensive use of hydroxyurea and newer therapeutic approaches (stem cell transplantation and gene therapy) offer hope for decreased mortality and improved health-related quality of life.

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