Hydroxyurea Therapy for Sickle Cell Disease

HU Effects on Progression of SCD Symptoms

Sickle cell disease (SCD) is associated with specific chronic and acute patient complications, including organ and tissue damage and severe episode of sickle cell crisis (SCC), which increase the risk for premature mortality. However, research evidence suggests that HU may change the prognosis for patients with SCD in a positive way.

Painful SCC

Darbari et al. (2014) state that “polymerization of HbS occurs during deoxygenation and causes erythrocyte rigidity and sickling” (p. 341). The given pathophysiological process largely contributes to microcirculatory obstruction and the occurrence of painful SCC in patients with SCD. HU is the primary drug clinically used to reduce the incidence and prevent the symptoms of SCC, including pain in different parts of the body, headaches, severe tiredness, and others.

The questions posed by researchers included the HU-related reduction in SCC in different population groups (Darbari et al., 2014) and examination of clinical biomarkers in on-HU patients (Araujo et al., 2016). The sizes of employed samples varied from 50 to 299 SCD patients. The study by Darbari et al. (2014) showed results in support of HU effectiveness in the reduction of SCC, while Araujo et al. (2016) did not observe a significant difference in this regard between on-HU and off-HU patients. It could be caused by the inability of researchers to track the severity of SCD and the level of patients’ adherence across all study participants.

Hospitalizations

Severe SCC is among the primary reasons for hospitalizations (Araujo et al., 2016). The evidence shows that HU treatment can help reduce the number of hospitalizations by over 50% (Keikhaei, Yousefi, & Bahadoram, 2016; Wang et al., 2013), as well as their duration (Adewoyin, Oghuvwu, & Awodu, 2017). The results related to this sub-concept were obtained in research papers aimed to evaluate the clinical effects and economic benefits of HU. While Wang et al. (2013) and Keikhaei et al. (2016) focused on the assessment of the pediatric population (n=48 and n=193 respectively), Adewoyin et al. (2017) examined adults with SCD (n=60). Regarding future research, Keikhaei et al. (2016) suggested comparing the efficacy of multiple SCD treatment means to increase the credibility of obtained positive results.

Organ Damage

SCC exacerbates the pro-inflammatory environment supported by sickle red blood cells (RBCs). As a result, acute crises may lead to the development of chronic problems, including organ dysfunction. Fitzhugh et al. (2015), who assessed 383 adults with homozygous SCD, concluded that HU is not associated with a pronounced improvement in organ function over time. However, a randomized control study conducted by Wang et al. (2011) on young children with the disorder (n=193) revealed an insignificant improvement in spleen function.

The findings indicate that HU may not be effective in reversing and preventing organ dysfunction in adults, conversely to its significant effect in the alleviation of acute SCD-related problems. To further explore this problem and address possible study limitations (such as low sample randomization), Fitzhugh et al. (2015) recommended evaluating the links between HU dosage and changes in organ damage over time.

Pathophysiological Mechanisms of HU

The intake of HU helps individuals with SCD prevent RBC malformations. Although the drug is proved to be effective in reducing patient morbidity and mortality, the knowledge about the mechanisms of its beneficial impact on patient condition remains limited.

Fetal Hemoglobin

Improved production of fetal hemoglobin (HbF) due to HU intake was mentioned in all the reviewed studies. According to Silva-Pinto et al. (2013), by blocking the formation of abnormal erythrocytes, enhanced secretion of HbF supports the decrease in HbS polymerization − the major factor defining SCC development. It is also observed that compared to off-HU patients, individuals taking the drug regularly show significant increases in HbF (Araujo et al., 2016; Fitzhugh et al., 2015).

Researchers aimed to reveal the physiological ways through which HU benefits patients with SCD and describe their clinical and laboratory characteristics. Araujo et al. (2016) examined a small and non-randomly selected sample comprised of 50 patients (aged 20-50), which limits the generalization of findings. The researchers concluded that HU remains an effective therapeutic measure as it enhances laboratory parameters and reduces SCD-related complications. At the same time, Fitzhugh et al. (2015) revealed that a positive HbF response provoked by HU intake was correlated with reduced patient morbidity. Conclusions by Silva-Pinto et al. (2013), who evaluated a sample comprised of 37 patients, are consistent with the findings obtained by other researchers.

Mean Cell Volume

According to Silva-Pinto et al. (2013), “the mean cell volume (MCV) increases during the first four to six weeks of HU treatment” (p. 239). The given timeframe is correlated with HU-linked clinical improvements in patients. Moreover, among all the hematological parameters, the increase in MCV is one of the most clearly associated with the reduction of painful SCC episodes (Silva-Pinto et al., 2013; Al Hawsawi & Turkistani, 2008).

The studies related to the given sub-concept focused on the investigation of HU effects through the evaluation of lab and clinical data. Al Hawsawi and Turkistani (2008) assessed 14 pediatric patients with severe SCD (aged 5-15). Although the researchers concluded that HU was highly beneficial for patients, the investigation of children may be regarded as the limitation in terms of the proposed PICOT research project, which is focused on adults.

White Blood Cell Count

An abnormal leukocyte count is regarded as a major inflammation marker in patients with SCD and is associated with an increased frequency of SCC, total hospitalizations, and emergency department referrals (Curtis et al., 2015). In their cohort study examining 432 adult patients, Curtis et al. (2015) concluded that high white blood cell (WBC) count was present in both younger and older patients prescribed HU or other treatment methods.

Nevertheless, evidence provided by Akingbola et al. (2015), Araujo et al. (2016), Fitzhugh et al. (2015), and others demonstrated a moderate/high decrease in the WBC count in on-HU patients. The difference in findings may be explained by distinctive research questions posed by Curtis et al. (2015): they focused on the evaluation of the role of WBC in the progression of SCD and did not consider the history of patients’ adherence to HU treatment.

Factors of HU Efficacy

Evidence in selected studies revealed that the degree of favorable effects of HU might vary in different individuals. The factors defining the drug efficacy may be both external and internal. The main ones include genes, age, and duration of treatment.

Genetic Factors

Various genetic determinants can affect one’s response to HU treatment. It is observed that a small number of genetic loci are strongly correlated with higher expression of HbF in individuals, which may facilitate the favorable impact of HU (Tafrali et al., 2013; Darbari et al., 2014). The reviewed studies exploring this matter focused on the analysis of genes possibly defining the severity of SCD, as well as prediction of individual response to HU based on different genetic variations. Tafrali et al. (2013) concluded that “MAP3K5 gene expression is associated with elevated HbF levels and HU treatment” (p. 480), while Darbari et al. (2014) noted that HU-linked reduction in SCC is more pronounced in individuals with alpha-globin gene deletion.

Two studies presented in this sub-section employed relatively large samples: 299 SCD patients in research by Darbari et al. (2014) and 92 adults in research by Tafrali et al. (2013). The findings obtained by researchers indicate that further research of genes as pharmacogenomic markers for HU treatment efficacy is required.

Age

HU is considered to benefit patients of different ages. Nevertheless, the degree of treatment effect may be substantially defined by this demographic factor. Fitzhugh et al. (2015) note that in adults, HU is not associated with improvements in organ function over time; previous pediatric studies, which examined the effects of maximum drug doses on splenic regeneration, demonstrated positive results. Additionally, Steinberg et al. (2010) state that patients over 40 years old with severe SCD are the least likely to receive favorable outcomes of treatment with any HbF-stimulating drugs. Both studies employed research designs, ensuring a high level of findings credibility. Nevertheless, the results suggest that a further comparative examination of HU efficacy in different demographic groups is needed.

Treatment Duration

Irregular use may be associated with increased SCC frequency and severity. The benefits of HU intake compared to non-administration of the drug are outlined by Adewoyin et al. (2017), Akingbola et al. (2015), Araujo et al. (2016), and other studies aimed to answer the questions about clinical effects of the therapy. Moreover, the longitudinal examination of 299 patients throughout 17,5 years by Steinberg et al. (2010) revealed that the long-term HU treatment was strongly associated with reduced mortality and morbidity rates.

Compared to other articles that mentioned the problem of adherence and treatment duration, research by Steinberg et al. (2010) is characterized by greater validity and credibility as the employed sample was sufficiently randomized and large. Since the provided evidence indicates that “individuals with the greatest exposure to the drug appeared to have improved survival” (Steinberg et al., 2010, p. 408), the research of dosage-duration links must be conducted in the future.

Barriers to Patient Compliance

Although the efficacy of HU treatment in the reduction of SCC episodes and other adverse symptoms of SCD is supported by high-quality evidence, a significant number of patients do not receive the drug or fail to comply with the treatment. The main barriers to compliance identified in the literature include individual perceptions, level of knowledge, and poor clinical attendance.

Patient Perceptions

Patient perceptions are associated with an emotional response to disease and treatment, as well as subjective views of its efficacy. Research evidence provided by Badawy et al. (2017) makes it clear that individuals who have positive perceptions of HU effects are likely to intake the drug regularly. It is also observed that patients with mild forms of SCD and those individuals who experience fewer SCC often avoid administering HU due to perceived risks of complications (Adewoyin et al., 2017; Badawy et al., 2017).

The evidence related to this sub-concept is derived from the articles directly investigating the issue of treatment adherence and patient perceptions. They were hospital-based and employed non-randomized samples comprised of adult and pediatric patients. To address their limitations, participants for future research should be selected across multiple settings and cover the issue of whether health-related quality of life defines negative HU and SCD perceptions or vice versa.

Level of Knowledge

Limited knowledge of available treatment options and misconceptions about HU often translates into the fear of possible unfavorable effects. Misinformation and fear of HU-induced cancer are mentioned by Adewoyin et al. (2017) and Badawy et al. (2017) among the major reasons for irregular use of the drug. Moreover, Akingbola et al. (2015) state that the lack of awareness is one of the primary causes of limited HU use in the African population in general. The main limitation of the discussed studies in relation to the selected sub-concept is that they do not explore it in-depth. Evidence gaps suggest that the problem of awareness regarding HU benefits should be addressed in future research.

Poor Clinic Attendance

Poor hospital attendance among SCD patients may be associated with low levels of care satisfaction, motivation, and understanding of treatment significance, as well as minority status and low socioeconomic status. Crosby et al. (2009), who interviewed 32 SCD patients (aged 13-21), state that the lack of disease management skills, the overall health status, and quality of communication with health providers largely define one’s decision about clinical attendance. In the study by Akingbola et al. (2015), 9 out of 31 adults (aged 18-42) failed to come to the hospital to pick up the drug regularly as well. Similar to studies evaluated in the previous sub-section, in their research, Akingbola et al. (2015) utilized a small and non-randomized sample (n=31). However, compared to Crosby et al. (2009), they did not research the metrics for treatment adherence in detail, focusing primarily on hematological and clinical data of HU effects.

Risks

Some effects of HU may be dangerous for patients. Moreover, when administering it, one may take all the necessary precautions to prevent undesired outcomes.

Dosage

HU dosing may play an essential role in patient outcomes regarding the severity of SCD symptoms and the overall individual condition. According to Fitzhugh et al. (2015), the intake of a dose between 15 and 35 mg/kg/day increases patients’ prognosis for survival, while lower doses and non-administration of HU are associated with increased outcome hazards. At the same time, Adewoyin et al. (2017) raised the concern about the organ toxicity of high-dose treatment and its ability to undermine the overall effectiveness of SCD management.

Additionally, Akingbola et al. (2015) assessed 31 patients with severe SCD and concluded that lower HU doses might be effective and less hazardous for patients at high risk of infection. Overall, among all the reviewed studies, only Fitzhugh et al. (2015) evaluated the variable of dosing in detail, while other researchers merely assessed the clinical effects of HU. Further comparison of drug dosages is required.

Short-Term Adverse Effects

Regular intake of HU is considered to be relatively safe for patients of all ages, yet some researchers observed various drug-linked adverse symptoms in participants. Some studies measured the level of safety of the administered HU dose and did not reveal any remarkable unfavorable outcomes (Keikhaei et al., 2016; Al Hawsawi & Turkistani, 2008). However, Adewoyin et al. (2017) showed that from 4 patients in 60, stops taking HU because of experienced adverse effects, including fertility-related issues. Since HU is still regarded as the most efficient and safe drug for SCD, further studies investigating short-term and long-term adverse effects of HU in different patient groups are required to optimize indications for dosage and safety measures.

Long-Term Adverse Effects

Malignancy and irreversible toxic effects are regarded as possible long-term outcomes of HU treatment. The selected studies devoted to the investigation of patient adherence problems and clinical effects of HU addressed the issue only partially. For instance, Adewoyin et al. (2017) and Badawy et al. (2017) stated that the fear of possible long-term drug-linked health problems contributes to HU non-use. At the same time, the reviewed studies, including the longitudinal research by Steinberg et al. (2010), did not provide evidence supporting the risk of organ toxicity. The lack of clear findings indicates the need for detailed research of the given problem.

References

Adewoyin, A. S., Oghuvwu, O. S., & Awodu, O. A. (2017). Hydroxyurea therapy in adult Nigerian sickle cell disease: A monocentric survey on pattern of use, clinical effects and patient’s compliance. African Health Sciences, 17(1), 255-261.

Akingbola, T. S., Saraf, S. L., Shah, B. N., Ezekekwu, C. A., Sonubi, O., Hsu, L. L.,… Tayo, B. O. (2016). Hydroxyurea for treatment of sickle cell disease in adults in Africa. Blood, 128(22), 1305.

Al Hawsawi, Z. M., & Turkistani, A. W. (2008). Effect of hydroxyurea in children with sickle cell disease in Saudi Arabia. Journal of Taibah University Medical Sciences, 3(2), 129-134.

Araujo, A. M., Bezerra, M. L., Borjes Jr., S. P., Dias, J. S., Lopes, A. F., Neto, V. M., … Sant’Ana, P. G. (2016). Clinical and laboratory profile of patients with sickle cell anemia. Brazilian Journal of Hematology and Hemotherapy, 39(1), 40-45.

Badawy, S. M., Thompson, A. A., Jin-Shei, L., Penedo, F. J., Rychlik, K., Liem, R. I., & Lai, J. (2017). Adherence to hydroxyurea, health-related quality of life domains, and patients’ perceptions of sickle cell disease and hydroxyurea: A cross-sectional study in adolescents and young adults. Health & Quality Of Life Outcomes, 15(136), 1-10.

Crosby, L. E., Modi, A. C., Lemanek, K. L., Guilfoyle, S. M., Kalinyak, K. A., & Mitchell, M. J. (2009). Perceived barriers to clinic appointments for adolescents with sickle cell disease. Journal of Pediatric Hematology/oncology, 31(8), 571-576.

Curtis, S. A., Danda, N., Etzion, Z., Cohen, H. W., & Billett, H. H. (2015). Elevated steady state WBC and platelet counts are associated with frequent emergency room use in adults with sickle cell anemia. PLoS ONE, 10(8), e0133116.

Darbari, D. S., Nouraie, M., Taylor, J. G., Brugnara, C., Castro, O., & Ballas, S. K. (2014). Alpha-thalassaemia and response to hydroxyurea in sickle cell anaemia. European Journal of Haematology, 92(4), 341-345.

Fitzhugh, C. D., Hsieh, M. M., Allen, D., Coles, W. A., Seamon, C., Ring, M., … Taylor, J. G. (2015). Hydroxyurea-increased fetal hemoglobin is associated with less organ damage and longer survival in adults with sickle cell anemia. PLoS ONE, 10(11), e0141706.

Keikhaei, B., Yousefi, H., & Bahadoram, M. (2016). Hydroxyurea: Clinical and hematological effects in patients with sickle cell anemia. Global Journal of Health Science, 8(3), 252-256.

Silva-Pinto, A. C., Angulo, I. L., Brunetta, D. M., Neves, F. I. R., Bassi, S. C., Santis, G. C. D., & Covas, D. T. (2013). Clinical and hematological effects of hydroxyurea therapy in sickle cell patients: A single-center experience in Brazil. Sao Paulo Medical Journal, 131(4), 238-243.

Steinberg, M., McCarthy, W., Castro, O., Ballas, S., Armstrong, F., Smith, W., … Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia and MSH Patients’ Follow-up. (2010). The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up. American Journal of Hematology, 85(6), 403-408.

Tafrali, C., Paizi, A., Borg, J., Radmilovic, M., Bartsakoulia, M., Giannopoulou, E., Giannakopoulou, O.,… Patrinos, G. P. (2013). Genomic variation in the MAP3K5 gene is associated with β-thalassemia disease severity and hydroxyurea treatment efficacy. Pharmacogenomics, 14(5), 469-483.

Wang, W. C., Oyeku, S. O., Luo, Z., Boulet, S. L., Miller, S. T., Casella, J. F., … Grosse, S. D. (2013). Hydroxyurea is associated with lower costs of care of young children with sickle cell anemia. Pediatrics, 132(4), 677-683.

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, J. F., Minniti, C. P., … Thompson, B. W. (2011). A multicenter randomised controlled trial of hydroxyurea (hydroxycarbamide) in very young children with sickle cell anaemia. Lancet, 377(9778), 1663-1672.