Hydroxyurea at Escalated Dose versus Fixed Low-Dose Hydroxyurea in Adults with Sickle Cell Disease

Abstract

Hydroxyurea reduces the frequency of vaso-occlusive complications, increases hemoglobin, and decreases mortality in sickle cell disease (SCD). Although current guidelines recommend escalation to maximum tolerated dose (MTD), the use of fixed low-dose hydroxyurea is common in low-resource countries. We conducted a systematic review and meta-analysis to evaluate the efficacy of escalated doses versus fixed low-dose of hydroxyurea in adults with SCD. Nine studies were included in the quantitative synthesis, four evaluating fixed low-dose and five evaluating escalated doses of hydroxyurea. Average daily doses of hydroxyurea in the fixed low-dose and escalated dose studies were ~10 mg/kg and 22 mg/kg, respectively. There was no difference in the estimate of vaso-occlusive crisis rate between escalated and fixed low-dose studies (p=0.73). The mean difference in hemoglobin from baseline to follow-up was greater for fixed low-dose than escalated dose studies (1.07 g/dL vs. 0.54 g/dL, p=0.01). No difference was seen in the mean estimate of fetal hemoglobin. Despite limited eligible studies and substantial heterogeneity of effect between the studies for several outcomes, there appears to be clinical equipoise regarding the most appropriate hydroxyurea dosing regimen in adults with SCD. Controlled studies of hydroxyurea at MTD versus fixed low-dose in adults with SCD are required.

INTRODUCTION

Sickle cell disease (SCD) is a multisystem disease characterized by episodes of acute illness and progressive end-organ damage. Although referred to as an orphan disease in the United States (US), with a prevalence of approximately 100,000 patients and an estimated 2,600 annual affected births in North America, an estimated 230,000 children with sickle cell anemia were born in sub-Saharan Africa in 2010.(1, 2) Further, it is projected that affected births worldwide will increase by thirty percent by 2050, with most of the increase occurring in sub-Saharan Africa.(1) Multiple studies show that the survival of children with SCD has improved in resource-rich countries over the last two decades, with the vast majority of children surviving past the age of 18.(3–5) This improved survival is largely attributed to the implementation of newborn screening, use of prophylactic penicillin, and vaccinations against Haemophilus influenzae type b and Streptococcus pneumonia.(6–8) However, excess mortality in children with SCD, most of whom remain undiagnosed, remains extremely high in many low- and middle-income countries.(1, 9) As overall mortality in young children begins to fall with implementation of newborn screening and with improvements in nutrition and medical facilities, the use of disease modifying therapies will decrease disease-related morbidity and may further increase patient survival.

Hydroxyurea, now standard therapy for children as well as adults with severe sickle cell anemia in resource-rich countries, reduces the frequency of vaso-occlusive complications, increases hemoglobin, and decreases mortality.(10–13) While current treatment guidelines in the US recommend escalating hydroxyurea to maximum tolerated dose (MTD), up to a maximum of 35 mg/kg daily, for preventing vaso-occlusive complications, the use of fixed low-doses of hydroxyurea (typically at a dose of 10 mg/kg daily) remains common in low resource countries, possibly related to the cost of drug and related monitoring. Hydroxyurea at MTD has recently been shown to be superior to fixed moderate-dose hydroxyurea in decreasing vaso-occlusive complications, hospitalizations, and RBC transfusions in young children with SCD, but has not been compared with fixed low- or moderate-doses in adult patients.(14) In the present study, we have conducted a systematic review and meta-analysis to evaluate the efficacy and safety of escalated doses of hydroxyurea versus fixed low-dose in adults with SCD.

METHODS

We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA), to evaluate if clinical and laboratory outcomes differ between adults with SCD treated with hydroxyurea administered with an escalated dosing strategy (dose starting at 15 – 20 mg/kg daily with variable degrees of dose escalation regardless of whether MTD was attained) versus those treated with a fixed low-dosing strategy (treatment with a daily dose of 500 mg or 10 mg/kg without dose escalation).(15) The exposure variable for the evaluation was dosing strategy (escalated dose vs. fixed low-dose). The primary outcome variables evaluated included the number or rate of vaso-occlusive crisis, acute chest syndrome, hospitalizations, red blood cell transfusions, and stroke. Secondary outcomes assessed were hemoglobin concentration, fetal hemoglobin levels, absolute neutrophil count, reticulocyte count, and platelet count.

Data Sources and Selection

The search strategy aimed to identify articles that compared the efficacy of hydroxyurea at escalated and fixed low-doses in adults with SCD. With the aid of two health sciences librarians, the literature search was conducted in these databases: PubMed/Medline, Embase.com, Cochrane Library, and Scopus. Search terms were tailored for each database using thesaurus terms such as Medical Subject Headings (MeSH) for Medline and EMTREE for Embase where applicable and keywords or text words. Based on the predetermined research question, two search concepts were identified to construct the database search strategy. For sickle cell disease, the search words included “anemia, sickle cell”[MeSH] OR “sickle cell anemia”[Text Word] OR “sickle cell disease”[Text Word]; and the search words for hydroxyurea included “hydroxyurea”[MeSH] OR “hydroxyurea”[Text Word] OR “hydroxyureas”[Text Word] “Hydroxyurea/therapeutic use”[MeSH]. The full search strategy for PubMed/Medline is shown in Supplementary Table 1.

Inclusion and Exclusion Criteria

Quantitative studies (randomized controlled trials, observational studies like case-control and cross-sectional studies, and meeting abstracts) were included if they were published between January 1, 1995, and May 31, 2020. Case-reports, case-series, and non-English language articles were excluded. Multiple publications from the same patient population were narrowed down to the single publication with the most complete information.

Study Selection

Abstracts and full text articles were reviewed to identify articles that met inclusion criteria (Supplementary Figure 1). Following the initial search, 2524 citations were retrieved and screened. After eliminating 385 duplicates, 2139 citations remained. Seventeen full-text articles were then assessed for eligibility, of which 9 were included in the quantitative synthesis. Five blinded co-authors (UOO, KP, MNN, KIA, MPS) used the Rayyan Systematic Review Screening Software to independently check the titles and abstracts based on pre-decided exclusion criteria. This was followed by a full text review of selected articles, and any conflicts were resolved by consensus.

Data extraction

Using a standardized spreadsheet customized for this study, two co-authors (UOO, MNN) systematically extracted data. The information recorded included the following: title, study ID, general information (name of person extracting data, date of completion, journal details, author’s contact, publication type, funding source), eligibility (population description, type of intervention, type of outcome, setting, inclusion criteria, method of recruitment), methods (aim of study, design, unit of allocation, start date, end date, duration of participation), risk of bias assessment (blinding), participants (number randomized, withdrawals, exclusions, age, sex, race, severity of illness, comorbidities), intervention group (group name, number randomized, duration of treatment, timing, delivery, providers, economic variables), outcomes (outcome name, time-points measured, time-points reported, outcome definition, person measuring outcome, unit of measurement), results (baseline data, results in intervention group, results in control group, statistical analysis), applicability (exclusion of important populations, if the intervention was aimed at disadvantaged groups, if study directly addressed the review question), and other information (key conclusions, references to other relevant studies).

Statistical Analysis

Results were stratified by escalated dose vs. fixed low-dose of hydroxyurea. Study outcomes were treated as continuous or dichotomous measures, depending on how they were reported in the primary studies. Both primary and secondary outcomes were measured at baseline and end of study for the studies included. The number of participants in each of the two groups (baseline and end of study), their mean responses, and the standard deviation (SD) of the responses were used to perform the meta-analysis. Average effects across studies were estimated using means for random-effect meta-analysis. For studies where means were unavailable, we used medians instead and calculated standard deviations from interquartile range (IQR) (difference between Q3 and Q1), using the formula: SD = IQR/1.35 or range/4. We calculated the difference in means by: MD_i = m_1i – m_2i with standard error SE {MD_i} = √ (sd_1i² / n_1i) + (sd_2i² / (n_2i) [where MD = mean difference, m = difference in means of individual study, sd = standard deviation, n = sample size, and I = number of studies]. For dichotomous variables we report odds ratios (OR) with 95% confidence intervals (CI). The significance of the combined overall effect (escalated and fixed low-dose) was tested using a Z test and group differences between escalated and fixed doses were compared using a chi-squared test. Additionally, I² index was used to evaluate the amount of heterogeneity between the study groups, classifying 25% as low heterogeneity, 50% as moderate heterogeneity, and more than 75% as high heterogeneity. Meta-analyses were conducted for outcomes in which mean differences or odds ratios were estimable or reported in at least two studies. Analysis was conducted in Review Manager (RevMan) Version 5.4 (The Cochrane Collaboration, 2020) and a p-value of <0.05 was considered statistically significant.

RESULTS

Nine studies were included in the quantitative synthesis, of which five evaluated the effect of hydroxyurea at escalated dose, while four were studies of fixed low-dose hydroxyurea (Table 1).(10, 12, 16–22)

Table 1:

Characteristics of Studies Evaluating Hydroxyurea at Escalated Dose and Fixed Low-Dose

Author (publication year)	Country	Dosing Strategy	Number of patients (female)	Patient Age	Hydroxyurea Dose (Mean or Actual Dose)	Duration of Treatment	Study Endpoints	Study Outcomes
Singh, 2010	India	Initial fixed dose with escalation (no attempt to reach MTD)	27 (11)	Mean age 19.85 years (18.59 – 21.11)	Initial dose 20 mg/kg/day; increased by 5 mg/kg if judged appropriate by the treating clinician. (Mean dose of 22 mg/kg/day) No fixed guidelines for dose escalation and dose modification as long as the patient was found to be adequately controlled by the treating physician Never any attempt to reach a ‘maximal tolerated dose’	1 year	Number of VOC Number of hospitalizations	Decreased overall sickle cell crisis and associated increase in Hb F% Decreased hospital admissions
Voskaridou, 2010	Greece	Initial fixed dose, escalated if lack of effectiveness	330 (194)	Median age 42 years (20–76 years)	Starting dose of HU 20 mg/kg/day If no response to HU therapy after 3 months with starting dose, dose was gradually increased to 35 mg/kg/day (increment of 5–10 mg/month)	17 years	Clinical and laboratory outcomes	Increased total Hb and Hb F Decreased frequency of severe painful crises Decreased transfusion requirements Decreased hospital admissions Decreased incidence of chest syndrome Decreased leukocyte counts, platelet and reticulocyte counts, serum bilirubin, and LDH levels
Dehury, 2015	India	Fixed low-dose	104 (33)	Two groups of patients: Group I - 37 pediatric cases, mean age 9.0 +/− 4.9 years, Group II - 67 adult cases, mean age 27.7 +/− 8.1 years)	10 mg/kg/day	At least 24 months	Reduction in frequency of painful crises Reduction in blood transfusion requirements	Decreased pain crises, hospitalization rates and duration of hospital stay Increased Hb F level, hemoglobin, MCV and MCH Decreased Hb S, WBC, platelet count, serum- bilirubin and LDH levels Decreased transfusion requirements
Patel, 2012	India	Fixed low-dose	118 (36)	3–60 years of age (Two groups of patients: Group I - 27 pediatric cases, 3–14 years old, mean age 9.3 +/− 4.1 years Group II - 91 adult cases, 15–45 years old, mean age 27.3 +/− 8.7 years)	10 mg/kg/day	24 months	Reduction in frequency of painful crises Reduction in blood transfusion requirements	Decreased frequency of painful crises in pediatric and adult cases Increased Hb F, total Hb, MCV, MCH and MCHC levels Decreased WBC, platelet count and total serum bilirubin values Decreased transfusion requirements
Sethy, 2018	India	Fixed low-dose	128 (46)	≥ 18 years	10mg/kg/day	1 year	VOC Transfusion needs	Decreased VOC Decreased severity and frequency of VOC Decreased rate of transfusion
Charache, 1995	United States, Canada	Escalation to maximum tolerated dose	299 (151)	≥ 18 years	15mg/kg/day, dose increased by 5mg/kg/day every 12 weeks unless marrow suppression (range 0–35 mg/kg/day)	2 years	Painful crisis (pain crisis, ACS, priapism, hepatic sequestration) Transfusion needs	Decreased annual rates of crisis Increased median time to first and second crisis Decreased ACS Decreased transfusions
Tayo, 2018	Nigeria	Fixed low-dose	53 (20)	≥ 18 years median (interquartile range) age of 24 years (22–27)	500 mg/day The median (range) dose per body weight of HU was 9.6 mg/kg per day (8.8–10.3)	52 weeks	Severe cytopenia Development of malaria/TB CBC Hb F	2 patients with severe thrombocytopenia (<50k) 1 patient - recrudescent TB Increased Hb, hematocrit, MCV; decrease WBC (neutrophil) and platelet Increased Hb F
Ferster, 2001	Belgium	Initial fixed dose followed by escalation (no attempt to reach MTD)	93 (44)	8 months - 45 years (median 7 years)	Initial dose 20 mg/kg/day; increased by 5 mg/kg if judged appropriate by the treating clinician No fixed guidelines for dose escalation and dose modification as long as patient was found to be adequately controlled by the treating physician Never any attempt to reach a ‘maximal tolerated dose’	5 years	No. of hospitalizations/ year No. of days in hospital	Decreased no. of hospitalizations Decreased days in hospital
Lima, 1997	Brazil	Initial fixed dose followed by escalation	10 (4)	20–44 years (mean: 24 years; median: 21 years)	10mg/kg/day (initial) escalated by 5mg/kg/day every 8 weeks to 20mg/kg/day (maximum)	6–19 months	VOC	Decreased frequency or severity of VOC

Abbreviations: HU, Hydroxyurea; Hb, Hemoglobin; MCV, Mean corpuscular volume; Hct, Hematocrit; WBC, White blood cell; ANC, Absolute neutrophil count; MTD, Maximum tolerated dose; VOC, Vaso-occlusive crisis; LDH, Lactate dehydrogenase; MCH, Mean corpuscular hemoglobin; MCHC, Mean corpuscular hemoglobin concentration; ACS, Acute chest syndrome; TB, Tuberculosis; CBC, Complete blood count.

Primary Outcomes

The average daily dose of hydroxyurea in the low fixed-dose studies ranged from 9.6 to 10 mg/kg. The initial daily dose in the escalated dose studies ranged from 10 to 22 mg/kg, with an average dose of 22 mg/kg at the end of the studies. The primary clinical outcomes evaluated in this meta-analysis are summarized in Table 2. The mean difference in the vaso-occlusive crisis rate from baseline to end of study for the escalated dose studies was estimated to be −2.98 per year (95% CI: −5.43, −0.54; p=0.02) (Figure 1A). The mean difference in vaso-occlusive crisis rate from baseline to end of study for the fixed low-dose studies was estimated to be −3.43 per year (95% CI: −4.12, −2.73; p<0.00001) (Figure 1A). The mean difference in estimate for the change in vaso-occlusive crisis rate for all the studies (escalated dose and fixed low-dose) from baseline to end of study was −3.21 per year (95% CI: −4.05, −2.36; p<0.00001). However, there was no significant difference in the vaso-occlusive crisis rate from baseline to follow-up when fixed low-dose studies were compared to escalated dose studies (p=0.73).

Table 2:

Comparing primary and secondary outcomes between individuals treated with escalated dose hydroxyurea vs. fixed low-dose hydroxyurea.

Outcomes	Dosing strategy	Mean Difference or Odds Ratio (95% CI)	Z-score	P-value
Primary
Vaso-occlusive Crisis	Escalated Dose	−2.98 (−5.43, −0.54)	2.39	0.02
	Fixed Dose	−3.43 (−4.12, −2.73)	9.64	<0.00001
Acute Chest Syndrome	Escalated Dose	0.35 (0.22, 0.55)	4.54	<0.00001
	Fixed Dose	Data not available
Hospitalizations	Escalated Dose	−2.01 (−2.43, −1.58)	9.22	<0.00001
	Fixed Dose	Not estimable
Stroke	Escalated Dose	0.58 (0.25, 1.36)	1.25	0.21
	Fixed Dose	Data not available
Secondary
Hemoglobin (g/dL)	Escalated Dose	0.54 (0.30, 0.77)	4.47	<0.00001
	Fixed Dose	1.07 (0.73, 1.40)	6.26	<0.00001
Fetal Hemoglobin (%)	Escalated Dose	6.46 (3.27, 9.66)	3.96	<0.00001
	Fixed Dose	4.07 (3.03, 5.12)	7.64	<0.00001
Absolute Neutrophil Count (x109/L)	Escalated Dose	−2.28 (−3.03, −1.52)	5.89	<0.00001
	Fixed Dose	−1.00 (−1.39, −0.60)	4.93	<0.00001
Platelet Count (x109/L)	Escalated Dose	−38.51 (−107.40, 30.37)	1.1	0.27
	Fixed Dose	−52.72 (−64.91, −40.53)	8.47	<0.00001

Figure 1:

The mean difference in clinical complications from baseline to follow-up was compared between fixed low-dose and escalated dose studies. A) No significant difference in the vaso-occlusive crisis rate from baseline to follow-up was observed between fixed low-dose and escalated dose studies (p=0.73). The mean differences from baseline to end of study for the fixed low-dose studies could not be estimated for B) acute chest syndrome, C) hospitalization, and D) stroke.

We were unable to estimate mean differences from baseline to end of study for the fixed low-dose studies for acute chest syndrome, hospitalization or stroke as the data were unavailable in the individual studies. However, the odds ratio for acute chest syndrome from baseline to end of study for escalated dose studies was estimated to be 0.35 (95% CI: 0.22, 0.55; p<0.00001) (Figure 1B). The mean difference in hospitalizations from baseline to end of study for the escalated dose studies was estimated to be −2.01 per year (95% CI: −2.43, −1.58; p<0.00001) (Figure 1C). The odds ratio for stroke from baseline to follow-up for the escalated dose studies was estimated to be 0.57 (95% CI: 0.07, 4.81; p=0.60) (Figure 1D). The mean difference in blood transfusions from baseline to end of the study was not estimable for the escalated dose studies; for the fixed low-dose studies it was estimated to be −6.53 units of blood per year (95% CI: −6.82, −6.24) in one study.

Secondary Outcomes

Available laboratory data in individuals treated with hydroxyurea at escalated and fixed low-doses from eligible studies are summarized in Table 2. The mean difference in hemoglobin from baseline to end of study for the escalated dose studies was estimated to be 0.54 g/dL (95% CI: 0.30, 0.77; p<0.00001) and for the fixed low-dose studies was estimated to be 1.07 g/dL (95% CI: 0.73, 1.40; p<0.00001). The mean difference in hemoglobin for all studies (escalated dose and fixed low-dose) from baseline to end of study was 0.85 g/dL (95% CI: 0.56, 1.14; p<0.00001) (Figure 2A). The mean difference in hemoglobin from baseline to follow-up was significantly greater for the fixed dose studies compared to the escalated group (1.07 g/dL vs. 0.54 g/dL, p=0.01). The I² test statistic for this subgroup analysis was 84.8%, suggesting that there was high heterogeneity of effect between the studies (Figure 2A).

Figure 2:

The mean difference in laboratory variables from baseline to follow-up was compared between fixed low-dose and escalated dose studies. A) The mean difference in hemoglobin from baseline to follow-up was significantly greater for fixed low-dose vs. escalated dose studies (p=0.01). B) No significant difference in the mean change of fetal hemoglobin was seen between escalated dose and fixed low-dose studies (p=0.16). C) Mean decrease in absolute neutrophil count from baseline to follow-up was significantly greater for escalated dose vs. fixed low-dose group (p=0.003). D) No significant difference in the mean estimate of platelet count was seen between escalated dose vs. fixed low-dose studies (p=0.69).

The mean difference in fetal hemoglobin levels from baseline to end of study in the escalated dose studies was 6.46% (95% CI: 3.27, 9.66; p<0.00001) and for the fixed low-dose studies were 4.07% (95% CI: 3.03, 5.12; p<0.00001). The mean difference in fetal hemoglobin for the combined escalated dose and fixed low-dose studies from baseline to end of study was 5.10% (95% CI: 3.59, 6.60; p<0.00001). There was no significant difference in the mean change of fetal hemoglobin when the escalated dose studies were compared with the fixed low-dose studies (6.46% vs. 4.07%; p=0.16) (Figure 2B).

The mean difference in absolute neutrophil count from baseline to end of study in escalated dose studies was −2.28 × 10⁹/L (95% CI: −3.03, −1.52; p<0.00001). The mean difference in absolute neutrophil count from baseline to end of study in the fixed low-dose group was −1.00 × 10⁹/L (95% CI: −1.39, −0.60; p<0.00001). The mean difference in absolute neutrophil count for the combined escalated dose and fixed low-dose studies from baseline to end of study was −1.63 × 10⁹/L (95% CI: −2.26, −1.00; p<0.00001). The mean decrease in absolute neutrophil count from baseline to follow-up was significantly greater for the escalated dose group than the fixed dose group (−2.28 [95% CI: −3.03, −1.52] vs. −1.00 [95% CI: −2.26, −1.00], p=0.003) (Figure 2C). The I² test statistic for the subgroup analysis was 88.4% (Figure 2C), suggesting that there was high heterogeneity of effect between the studies.

The mean difference in platelet count from baseline to end of study in the escalated dose studies was −38.51 × 10⁹/L (95% CI: −107.40, 30.37; p=0.27). The mean difference in platelet count from baseline to follow-up in the fixed low-dose group was −52.72 × 10⁹/L (95% CI: −64.91, −40.53; p<0.00001). For the combined escalated dose and fixed low-dose studies from baseline to end of study, the mean difference in platelet count was −53.03 × 10⁹/L (95% CI: −64.16, −41.90; p<0.00001) (Figure 2D). There was no significant difference in the mean estimate of the escalated dose studies compared with the fixed low-dose studies (p=0.69).

In the two studies with available data, the difference in the reticulocyte count from baseline to end of study in the escalated group was estimated to be −96.00 × 10⁹/L and −4.00%, respectively. Reticulocyte count was not reported in any of the fixed low-dose studies.

DISCUSSION

Current guidelines in the US recommend the use of hydroxyurea escalated to MTD to decrease vaso-occlusive complications.(23) Although hydroxyurea at MTD has been shown to be superior to fixed moderate-dose hydroxyurea in decreasing vaso-occlusive complications, hospitalizations, and RBC transfusions in young children with SCD, there are no controlled studies comparing hydroxyurea escalated to MTD with fixed doses in adult patients.(14) Despite current recommendations, increasing data show that hydroxyurea, at fixed moderate- and low-doses are safe and decrease vaso-occlusive complications in SCD.(11, 19–22) In the absence of studies directly comparing fixed low-dose with escalation to MTD, there remains uncertainty regarding the risk-benefit profile in adult patients.

Meta-analysis of escalated doses of hydroxyurea and fixed low-dose hydroxyurea showed no significant differences in vaso-occlusive crisis rate, although significant benefit was observed when each of the dosing regimens was evaluated. Unfortunately, we were unable to compare the effects of escalated dose and fixed low-dose hydroxyurea on acute chest syndrome, blood transfusion and stroke due to the lack of data for fixed low-dose studies. In a recent study conducted in Nigeria, no significant difference in the incidence rates of the primary outcome measures of stroke, transient ischemic attack and death was observed in children with abnormal transcranial Doppler velocities following treatment with fixed low-dose hydroxyurea versus moderate-dose hydroxyurea, although the incidence rate ratio of hospitalization was higher in the low-dose group versus the moderate-dose group.(24)

A statistically significant mean difference was observed in the hemoglobin level between the escalated dose and fixed low-dose studies, with a surprisingly higher mean increase in hemoglobin level in the fixed low-dose studies, although there was moderate heterogeneity of effect between the studies. However, no significant difference in the mean estimate of HbF was observed when escalated dose studies was compared with fixed low-dose studies. A previously published comparison of laboratory effects following 24 weeks of fixed low-dose hydroxyurea versus hydroxyurea escalated to MTD for 104 weeks in the multicenter study of hydroxyurea showed no significant differences in change from baseline for total hemoglobin or HbF.(25) Consistent with the dose-dependent myelosuppressive effects of hydroxyurea, a significantly greater mean decrease in the absolute neutrophil count was observed in the escalated dose studies than in the fixed low-dose studies.

The results of these meta-analyses must be interpreted with caution. The number of eligible studies during the search period were few, with unavailable data for several clinical and laboratory outcomes in multiple primary studies. The follow-up period also varied between studies, which could introduce bias into the comparisons of some outcomes. There was moderate or substantial heterogeneity of effect between the studies for several outcomes, suggesting that the magnitude of effects of hydroxyurea differed between studies.(26, 27) Despite escalation, doses were not always titrated to MTD in multiple escalated dose studies. Further, we were unable to ascertain the average daily dose of hydroxyurea in several of the escalated dose studies. The effect of the different dosing strategies on multiple clinical complications could not be adequately compared due to unavailable data in the individual studies.

Based on these findings, there appears to be clinical equipoise regarding the most appropriate hydroxyurea dosing regimen to decrease vaso-occlusive complications in adults with SCD. While a controlled clinical trial comparing the efficacy and safety of HU at MTD versus low fixed-dose hydroxyurea in adults with SCD is unlikely to be performed in the US where MTD is the accepted standard of care, this study is necessary in low- and middle-income countries where fixed low-dose hydroxyurea is commonly administered. The use of any hydroxyurea dosing regimen must be weighed against the cost-benefit ratio, especially in the context of resource-limited countries.

Novelty Statement:

1. What is the new aspect of your work?

This is the first study evaluating the efficacy and safety of escalated doses versus fixed low-doses of hydroxyurea in adults with sickle cell disease.

2. What is the central finding of your work?

Meta-analysis of escalated doses and fixed low-doses of hydroxyurea in adults with sickle cell disease showed no significant differences in the rate of vaso-occlusive crisis, although the mean difference in hemoglobin was greater for the fixed low-dose studies.

3. What is (or could be) the specific clinical relevance of your work?

By comparing escalated doses to fixed low-doses of hydroxyurea in adults with sickle cell disease, this study provides clinicians with data to inform them on the options for dosing hydroxyurea in adults with sickle cell disease. Unlike in young children with sickle cell disease, where dose escalation of hydroxyurea to maximum tolerated dose has been demonstrated to be beneficial, there appears to be clinical equipoise regarding the most appropriate hydroxyurea dosing regimen in adults with sickle cell disease.

Data Availability Statement:

Data sharing is not applicable to this article as no new data were created or analyzed in this study.