Heterogeneity of Hydroxyurea Treatment: Effect and Determinants of Severity in Sickle Cell Anaemia

A Brief Update

Determining the severity of Sickle Cell Anaemia is challenging. Any estimate should consider the Foetal Haemoglobin level (the most prevalent haemoglobin in the last two trimesters of gestation in humans), the presence of alfa-thalassemia, and age. Hydroxyurea (HU) therapy has proven from the laboratory and clinical efficacy standpoints to ameliorate/improve the signs and symptoms of sickle cell anaemia, consequently reducing the mortality rate, primarily by increasing the level of Foetal Haemoglobin (HbF) to a range of 10 to 40%. Virtually all the patients treated will have the benefit associated with disease severity. However, significant inter-patient variability exists even if the maximum tolerated dose of HU is administered, and certain patients will have excessive myelosuppression at relatively low doses.

Some authors (McDade, J and Ware, R.E.) hypothesised in 2009 that “genetic polymorphisms may play an important role in the observed inter-patient variability for both Hydroxyurea response and toxicity”.

In 2016, Habara, A. and Steinberg, M.H. stated that the phenotypic heterogeneity of Sickle Cell Disease was only partially explained by genetic variability of the fetal haemoglobin expression and co-inheritance of alfa-thalassaemia. Work by others proposed and later demonstrated the unexpected association of the role of BCL11A in HbF gene expression.

In 2022, Sales RR. et al. published a systematic review to assess whether genetic polymorphisms affect HbF levels in patients with Sickle Cell Anaemia treated with HU. In addition, pathway analysis of single nucleotide polymorphisms (SNPs) was performed. The study was conducted at the Federal University of Minas Gerais, Belo Horizonte, Brazil. Of 1,597 articles initially identified, only seven cohort studies were included in the systematic review (five from the US and two from Brazil). The sample mean age ranged from 8.1 to 21 years. The mean dose of HU ranged from 19 to 27.1 +/- 4.3 mg/Kg, and the mean duration of treatment with HU ranged from 13.4 to 102 months.

The authors comment that “a complex regulation environment determines the HbF concentration in the blood as well as chromosome remodelling, transcription factors, erythropoiesis modulation, gene regulatory elements linked to the beta- globin gene cluster and the kinetics of erythroid cell differentiation and differential red cell survival. Consistent with this complex regulation apparatus, even with the restricted number of studies, our systematic review suggests that there is huge heterogeneity in genetic elements modulating the HbF levels in response to HU treatment”. After extensive analysis, the authors concluded: “Changes in HbF levels in response to HU therapy are likely to be regulated by genetic variations on multiple loci, and there is evidence that the BCL11A gene affects HbF changes in patients with Sickle Cell Anaemia treated with Hydroxyurea”. The induction of HbF is a powerful mechanism of action of HU; however, further research is needed to predict the success of treatment.

What is the practical application of all this genetic research in progress?

Considering that the response to treatment with HU is variable and seems to be an inherited trait, and about 25% of patients do not respond to HU treatment or are considered poor metabolisers, very recent studies evaluating the genetic determinants of response to Hydroxyurea together with the presence of variants in genes responsible not only for HU metabolism but also for regulating HbF expression and erythroid progenitor proliferation might be the answer for the differences in patient responses to HU.

Ginette, C. et al. (2023) from Portugal have published that using HU in children with Sickle Cell Anaemia should be considered safe and beneficial. “Even in children considered non/poor responders, using HbF as the main criteria, significant changes were registered in almost the same parameters identified in responders, which also denotes clinical improvement in these patients”.

Again, their conclusion was: “Several polymorphisms seem to be associated with response to Hydroxyurea treatment in Sickle Cell Anaemia patients as previously reported in other studies”.

On the other hand, apart from the co-inheritance of alfa-thalassaemia and phenotype elements determining HbF levels, environmental factors are undoubtedly crucial with socioeconomics and access to basic medical care explaining the considerable differences in outcomes between countries. In addition, studies indicate that the inflammatory profile can vary according to the genetic polymorphisms of the patient.

The healthcare system should provide the necessary infrastructure to confirm new-borns’ diagnoses and provide appropriate counselling and treatment. The early diagnosis and treatment, as well as the follow-up with a multidisciplinary team, are fundamental to the survival rate and patients’ quality of life.

As a final comment, the responsible healthcare provider should not withhold safe and effective therapy with Hydroxyurea from people with the disease while awaiting a better model to predict who will be the sickest of the sick. Every person with HbSS, as young as six to nine months of age, deserves disease-modifying therapy (Hydroxyurea); However, it can now be argued that every child with an HLA-matched sibling donor is a potential candidate for haematopoietic stem cell transplantation.

The mission of Masters Speciality Pharma, a global pharmaceutical company, is to improve the lives of patients by facilitating access to life-saving medications. We work alongside life science partners and knowledgeable pharmaceutical drug suppliers to the healthcare industry. Our primary goal is to supply people in emerging markets with essential medicines.



McDade,J. (2009).

Habara,A. and Steinberg, MH.(2016).

Sales,RR. (2022).


Prepared by: Enrique Blanco, MD. FCP.