A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose‐dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long‐term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient‐years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow‐up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso‐occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 10⁶/L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.     

Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy.

In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P =.001), baseline hemoglobin concentration (P =.01), MTD dose (P =.02), and compliance (P =.02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P =.05) and baseline WBC count (P =.05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD.     

Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia

This study evaluated the oxidative stress and antioxidant capacity markers in sickle cell anemia (SCA) patients with and without treatment with hydroxyurea. We assessed GSTT1, GSTM1 and GSTP1 polymorphisms in patients and a control group. The study groups were composed of 48 subjects without hemoglobinopathies and 28 SCA patients, 13 treated with HU [SCA (+HU)], and 15 SCA patients not treated with HU [SCA (-HU)]. We observed a significant difference for GSTP1 polymorphisms in SCA patients with the V/V genotype that showed higher glutathione (GSH) and Trolox equivalent antioxidant capacity (TEAC) (p=0.0445 and p=0.0360), respectively, compared with the I/I genotype. HU use was associated with a 35.2% decrease in the lipid peroxidation levels of the SCA (+HU) group (p<0.0001). Moreover, the SCA (+HU) group showed higher TEAC as compared to the control group (p=0.002). We did not find any significant difference in glutathione-S-transferase (GST) activity between the groups (p=0.76), but the catalase (CAT) activity was about 17% and 30% decreased in the SCA (+HU) and SCA (-HU) groups, respectively (p<0.00001). Whereas the plasma GSH levels were ~2 times higher in the SCA patients than the control group (p=0.0005). HU use has contributed to higher CAT activity and TEAC, and lower lipid peroxidation in patients under treatment. These findings may explain the influence of HU in ameliorating oxidative stress on SCA subjects.     

Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia

Hydroxyurea is FDA-approved and now increasingly used for children with sickle cell anemia (SCA), but dosing strategies, pharmacokinetic (PK) profiles, and treatment responses for individual patients are highly variable. Typical weight-based dosing with step-wise escalation to maximum tolerated dose (MTD) leads to predictable laboratory and clinical benefits, but often takes 6 to 12 months to achieve. The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center study designed to prospectively validate a novel personalized PK-guided hydroxyurea dosing strategy with a primary endpoint of time to MTD. Enrolled participants received a single oral 20 mg/kg dose of hydroxyurea, followed by a sparse PK sampling approach with three samples collected over three hours. Analysis of individual PK data into a population PK model generated a starting dose that targets the MTD. The TREAT cohort (n = 50) was young, starting hydroxyurea at a median age of 11 months (IQR 9-26 months), and PK-guided starting doses were high (27.7 ± 4.9 mg/kg/d). Time to MTD was 4.8 months (IQR 3.3-9.3), significantly shorter than comparison studies (p < 0.0001), thus meeting the primary endpoint. More remarkably, the laboratory response for participants starting with a PK-guided dose was quite robust, achieving higher hemoglobin (10.1 ± 1.3 g/dL) and HbF (33.3 ± 9.1%) levels than traditional dosing. Though higher than traditional dosing, PK-guided doses were safe without excess hematologic toxicities. Our data suggest early initiation of hydroxyurea, using a personalized dosing strategy for children with SCA, provides laboratory and clinical response beyond what has been seen historically, with traditional weight-based dosing.     

Long-term hydroxyurea treatment in children with sickle cell disease: tolerance and clinical outcomes

Two hundred twenty-five SCD children have been enrolled in a study assessing the tolerability of hydroxyurea treatment. Mean age at inclusion was 9.2+/-4.4 years, median duration of treatment was 3.8 years. Ten and 75 patients have been treated respectively for more than 10 and 5 years. No severe side effect was related to hydroxyurea treatment, which was discontinued in 81 children mainly for treatment failure (30 cases) or non-compliance (17 cases). Treatment was also withdrawn in 5 of 6 children who had developed hypersplenism, in 3 because of a pathological transcranial Doppler, and in 2 after a stroke.     

Oxymetholone treatment for sickle cell anemia

Seven patients with sickle cell anemia were treated with oxymetholone for at least 2 mo. Markedly increased basal rates of hemolysis and erythropoiesis were confirmed. The urinary erythropoietin excretion was either normal or lower than expected for the red cell mass, and an expanded blood volume was due primarily to an increased plasma volume. After androgen therapy, six patients demonstrated more than a fivefold increase in urinary erythropoietin, with an increase in red cell mass ranging from 17%-75% above the control value. All showed a decline in serum iron level to the 25-75 mug/100 ml range within 4 wk after the start of therapy. Less marked changes followed lower oxymetholone doses. Reversible hepatic toxicity, with a serum bilirubin concentration exceeding 50 mg/100 ml, occurred in one patient. Androgenic hormone therapy may be useful for selected adult patients with sickle cell disease when severe anemia contributes to disease morbidity.     

Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia

Glomerular hyperfiltration and microalbuminuria/proteinuria are early manifestations of sickle nephropathy. The effects of hydroxyurea therapy on these renal manifestations of sickle cell anemia (SCA) are not well defined. Our objective was to investigate the effects of hydroxyurea on glomerular filtration rate (GFR) measured by ^99mTc‐DTPA clearance, and on microalbuminuria/proteinuria in children with SCA. Hydroxyurea study of long‐term effects (HUSTLE) is a prospective study (NCT00305175) with the goal of describing the long‐term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. Glomerular filtration rate, urine microalbumin, and serum cystatin C were measured before initiating hydroxyurea therapy and then repeated after 3 years. Baseline and Year 3 values for HUSTLE subjects were compared using the Wilcoxon Signed Rank test. Associations between continuous variables were evaluated using Spearman correlation coefficient. Twenty‐three children with SCA (median age 7.5 years, range, 2.5–14.0 years) received hydroxyurea at maximum tolerated dose (MTD, 24.4 ± 4.5 mg/kg/day, range, 15.3–30.6 mg/kg/day). After 3 years of treatment, GFR measured by ^99mTc‐DTPA decreased significantly from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m² (P = 0.016). This decrease in GFR was significantly associated with increase in fetal hemoglobin (P = 0.042) and decrease in lactate dehydrogenase levels (P = 0.035). Urine microalbumin and cystatin C levels did not change significantly. Hydroxyurea at MTD is associated with a decrease in hyperfiltration in young children with SCA. Am. J. Hematol., 88:116–119, 2013. © 2012 Wiley Periodicals, Inc.     

Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study

The long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/beta0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P < .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function.     

Effects of hydroxyurea in a population of Brazilian patients with sickle cell anemia

Fetal hemoglobin (HbF) inhibits the polymerization of sickle hemoglobin, modulating the clinical features of sickle cell anemia (SCA). Hydroxyurea (HU) therapy can increase the HbF level, although its production can be influenced by genetic determinants. Twenty-two Brazilian SCA patients were evaluated over 5 years before and after HU use. We analyzed (1) betaS haplotype; (2) patient characteristics; and (3) toxicity. No differences between age, sex, and HU response were observed. We found 40.9% of homozygous for Bantu haplotype, and, in contrasting to other trials, we observed HbF level increase in this group (3.84-9.08 g/dL, P=0.003). Adverse effects were rare. Labyrinthitis was observed in 2 (9.10%) patients after HU use, although this complication had not been described before.     

Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload

Children with sickle cell anemia (SCA) and a primary overt stroke are at high risk of recurrent (secondary) stroke. Chronic transfusion therapy dramatically reduces but does not eliminate this high risk, and inevitably results in transfusion-related hemosiderosis. We previously reported the use of hydroxyurea/phlebotomy as an alternative to transfusions to reduce the risk of secondary stroke and improve management of iron overload in 35 children with SCA. To report long-term results, we retrospectively reviewed clinical and laboratory data through October 2008. With a median of 5.6 years and total of 219 patient-years of follow-up, 10 of 35 patients (29%) had recurrent stroke after switching to hydroxyurea; seven were previously reported and three new strokes occurred during extended follow-up. The overall secondary stroke event rate was 4.6 per 100 patient-years. Children on hydroxyurea received serial phlebotomy and had lower mean serum ferritin values than children on transfusions (591 ng/mL vs. 3410 ng/mL, P = 0.02). In this cohort, long-term hydroxyurea treatment reduced but did not eliminate the risk of stroke recurrence and, uniquely, allowed phlebotomy to reduce iron overload. Long-term assessments of this therapy should evaluate risk factors for secondary stroke and assessments of hemosiderosis, neurocognitive outcome, and health-related quality of life.     

Clinical and laboratory effects of hydroxyurea in children and adolescents with sickle cell anemia: a Portuguese hospital study

Our aim was to assess the efficacy and safety of hydroxyurea (HU) in children with severe forms of sickle cell anemia followed in a Portuguese hospital. We carried out an open-label uncontrolled prospective study, which included children with severe forms of sickle cell anemia. Hydroxyurea was started at 15 mg/kg/day and increased to a maximum dose of 25 mg/kg/day. Patients were monitored to assess compliance, clinical and hematological response and toxicity. Nine children and adolescents, five girls and four boys, with a median age of 13 years (range 8 to 16) were enrolled in the study during a period of 24 months. All patients completed at least 15 months of therapy. Hb F was significantly increased, from a mean of 7.0 +/- 3.9% to 13.7 +/- 5.3% (p = 0.028). Clinically, all patients responded significantly with a reduction of 80% in the number of vaso-occlusive crises (VOC), 69% in hospital admissions, 76% in hospitalization days and 67% in transfusion requirements, without significant toxicity. We concluded that, in our population, HU proved to be effective in increasing Hb F levels, and in decreasing hospitalizations for VOC and transfusion requirements with no major side effects. Long-term clinical follow-up is important to certify benefit maintenance.     

Cardiac abnormalities in children with sickle cell anemia

The cardiac status of 64 children (ages 0.2 to 18 yr) with sickle cell anemia documented by hemoglobin electrophoresis was evaluated by echocardiography. Left atrial, left ventricular and aortic root dimensions were significantly increased in over 60 percent of these children at all ages compared to values for 99 normal black (non-SCA) control subjects. Left ventricular wall thickness was increased in only 20 percent of older children with sickle cell anemia. Estimated LV mass/m2 and left ventricular cardiac index were increased compared to control subjects (p less than 0.001). Left heart abnormalities expressed as a single composite function, derived from multivariate regression analysis, correlated well with severity of anemia expressed as grams of hemoglobin (r = -0.52, p = less than 0.001) and with percentage of hemoglobin S (r = 0.51, p less than 0.001), but not to the same extent with age. Echocardiographically assessed left ventricular function at rest was comparable to that of control subjects. These data suggest that the major cardiac abnormalities in children are related to the volume overload effects of chronic anemia, and that in this age group, there is no evidence for a distinct "sickle cell cardiomyopathy" or cardiac dysfunction.     

Cardiac abnormalities in children with sickle cell anemia

Sickle cell anemia (SCA) results in chronic volume overload of the heart due to hemodilution. Previous echocardiographic studies of cardiac function in children with SCA have not accounted for these abnormal loading conditions. The objectives of this study were to (1) determine how the degree of anemia and transfusion status relate to cardiac findings and (2) evaluate cardiac function using load-independent parameters of function. We evaluated 77 patients with SCA, ages 2 to 22 years (mean +/- SD = 11.7 +/- 4.7), using physical examination, electrocardiography, and echocardiography. We compared two groups of patients. Group 1 consisted of 57 non-transfused patients, and Group 2 consisted of 20 patients on a chronic transfusion protocol. Group 1 patients exhibited a significantly lower hemoglobin, higher cardiac output, and larger left ventricular (LV) end-diastolic dimension and LV mass than groups 2 (P < 0.05). However, the velocity of circumferential fiber shortening-wall stress index (a load-independent measure of systolic function) was normal and not statistically different between the two groups. Conversely, the LV myocardial performance index (a measure of combined systolic and diastolic function) was significantly higher in Group 2 (P < 0.001), possibly indicating impaired myocardial diastolic function. SCA in children results in a volume-overloaded heart with a significant increase in LV dimensions and mass, both proportional to the degree of anemia. Despite these abnormal loading conditions, systolic function is preserved. Patients on a chronic transfusion protocol may develop diastolic dysfunction despite iron chelation therapy.     

Genetic predictors for stroke in children with sickle cell anemia

Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A(-) variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.     

Long-term hydroxyurea treatment in young sickle cell patients

Hydroxyurea is the first drug that, under well-organized, large-scale trials in adults, has shown a beneficial effect on the clinical course of sickle cell disease. Several small-scale trials have been conducted in children, but they used different therapeutic schedules, and only one was a single-blind crossover trial. Still, children are clearly good responders to the treatment because a rapid clinical improvement was observed, with decreased frequencies of vaso-occlusive crises, acute chest syndromes, and transfusion requirements. Despite large interindividual variations, virtually all the children studied increased their fetal hemoglobin, mean corpuscular volume, and total hemoglobin. Follow-up varied from 6 months to 59 months. More than in adults, the fetal hemoglobin increase was sustained, and few side effects were observed. Large-scale, placebo-controlled studies seem no longer needed. Guidelines concerning patient selection, dosing schedules, and monitoring protocols as well as exhaustive registries for the detection of long-term side effects are necessary.