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

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Russell E. Ware ◽  
Barry Eggleston ◽  
Rupa Redding-Lallinger ◽  
Winfred C. Wang ◽  
Kim Smith-Whitley ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Reticulocyte Count ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
School Aged Children ◽  
Baseline Values ◽  
Wbc Count ◽  
Hydroxyurea Therapy ◽  
Baseline Hemoglobin

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.

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

Blood ◽  
2005 ◽  
Vol 106 (7) ◽  
pp. 2269-2275 ◽  
Author(s):  
Jane S. Hankins ◽  
Russell E. Ware ◽  
Zora R. Rogers ◽  
Lynn W. Wynn ◽  
Peter A. Lane ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
White Blood Cells ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Extension Study ◽  
Acute Chest Syndrome ◽  
Event Rates ◽  
Hydroxyurea Therapy

AbstractThe 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/β0-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.

scholarly journals Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

scholarly journals Absolute Reticulocyte Count Acts as a Surrogate for Fetal Hemoglobin in Infants and Children with Sickle Cell Anemia

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0136672 ◽  
Author(s):  
Emily Riehm Meier ◽  
Colleen Byrnes ◽  
Maxine Weissman ◽  
Y. Terry Lee ◽  
Jeffery L. Miller
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Reticulocyte Count ◽  
Fetal Hemoglobin ◽  
Infants And Children ◽  
In Infants And Children

scholarly journals Clinical and Hematological Evaluation of Patients with Sickle Cell Anemia Before and After Four Years of Using Hydroxyurea

10.3823/2469 ◽  
2017 ◽  
Vol 10 ◽  
Author(s):  
Ieda Maria Gonçalves Pacce Bispo ◽  
Maria Lúcia Ivo ◽  
Valter Aragão do Nascimento ◽  
Alexandra Maria Almeida Carvalho de Pinto ◽  
Olinda Maria Rodrigues de Araújo ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Hematological Parameters ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Teaching Hospitals ◽  
Acute Chest Syndrome ◽  
Mean Values ◽  
Significant Difference ◽  
Before And After

Objective: Evaluating clinical and hematological-clinical parameters of patients with sickle cell anemia (SCA) before and after four years of using hydroxyurea (HU).  Method: A retrospective cohort study implementing a quantitative, descriptive and analytical approach developed in two public teaching hospitals located in the Central-West region of Brazil, from November 2010 to October 2011. Data collection was performed through medical records of 32 patients with SCA to assess clinical and hematological parameters before and after HU treatment. The study was approved by the UFMS Ethics Committee under protocol number 1890/2010. Results: All of the 32 patients were homozygous with a mean age in the prescription of hydroxyurea of 19.72±7.58 years, an initial dose of 15.59±4.27 mg/kg/day, and 22.48±5.35 mg/kg/day in the fourth year of treatment. Regarding the use of HU, average values of some hematological parameters presented a significant difference in the fourth year compared to the mean values prior to HU use, such as fetal hemoglobin (14.49±7.52%), red blood cells (2.54±0.38x1012/L), hematocrit (25.30±4.03%) and hemoglobin (9.22±3.34g/dL).  Conclusion: Treatment with hydroxyurea showed a significant increase in fetal hemoglobin levels, increased hemoglobin, hematocrit and average corpuscular hemoglobin concentration, with reduced episodes of pain, infection and acute chest syndrome in such a way as to reaffirm its efficiency in treating these patients. Keywords: Hemoglobin; Sickle Cell Anemia; Hydroxyurea.

Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 436-443 ◽  
Author(s):  
Russell E. Ware
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Sub Saharan Africa ◽  
Future Research ◽  
Published Evidence ◽  
Treatment Indications ◽  
Hydroxyurea Treatment ◽  
Hydroxyurea Therapy

Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.

Influence of Globin Gene Modifiers on Baseline and Hydroxyurea-Induced Fetal Hemoglobin Levels in Children with Sickle Cell Anemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3171-3171
Author(s):  
Russell E. Ware ◽  
Barry Eggleston ◽  
Tatiana Abramova ◽  
Sherri A. Zimmerman ◽  
Alice Lail ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Globin Gene ◽  
Fetal Hemoglobin ◽  
Globin Genes ◽  
Beta Globin ◽  
Gene Number ◽  
Gamma Globin ◽  
Alpha Globin ◽  
Hydroxyurea Therapy

Abstract Fetal hemoglobin (HbF) is recognized as a major determinant of clinical disease severity in children and adults with sickle cell anemia (SCA). Patients with elevated HbF levels have a milder disease course, and many current therapeutic protocols for SCA include pharmacological induction of HbF. However, baseline and treatment HbF levels vary widely due to presumed genetic and environmental factors. Recognized globin gene modifiers of HbF include the beta globin haplotype and a potential contribution from concomitant alpha thalassemia. To characterize more fully the influence of globin gene modifiers on both baseline and treatment HbF levels, we retrospectively determined the beta globin haplotype (Benin, CAR, Senegal, Cameroon, or Arab-Indian) by selective gamma globin gene nucleotide sequencing and the alpha globin gene number (2, 3, or 4) by PCR for 67 African-American children with SCA receiving hydroxyurea therapy at stable maximal tolerated dose (MTD). The four beta globin haplotypes and frequencies identified in our cohort of children include Benin (0.61), CAR (0.17), Senegal (0.12), and Cameroon (0.10). The number of alpha globin genes and frequencies identified were 4 genes (0.72), 3 genes (0.25) and 2 genes (0.03). Baseline and MTD HbF levels were analyzed according to each variable. The average baseline HbF value for the entire cohort of children was 7.7 ± 4.4% (median 7.6%, range 1.3 – 19.3%), while the average treatment HbF value was 23.9 ± 7.2 % (median 22.9%, range 10.2 – 40.7%). All 67 children increased their HbF in response to hydroxyurea therapy (median 16.7%, range 5.0 – 28.8%). There was a modest but statistically significant correlation between the baseline and treatment HbF (r=0.66, p<.0001). The estimated effect of one unit change in baseline HbF on treatment HbF was 1.11 (95% CI of 0.78, 1.43). When baseline %HbF was analyzed according to the beta globin haplotype, the overall ANOVA had a p-value of 0.02, indicating a statistically significant influence. Further analysis confirmed associations previously identified in adults with SCA, i.e. children with at least one copy of the CAR haplotype had a lower baseline HbF (5.9% vs 8.4%, p=.05), while those with at least one copy of the Senegal haplotype had a higher baseline HbF (11.1% vs 6.7%, p<.001). When hydroxyurea MTD (treatment) HbF values were analyzed according to beta globin haplotype while adjusting for baseline HbF, however, the effect of beta globin haplotype was not statistically significant (p=.13). Analyses of HbF according to alpha globin gene number revealed no statistically significant effects on either baseline or treatment HbF values. Taken together, these data support the hypothesis that beta globin haplotype significant influences baseline HbF values for children with SCA, but has no significant effects on hydroxyurea MTD HbF values. Accordingly, children with SCA should be offered hydroxyurea based solely on clinical indications, without consideration of baseline HbF or beta globin haplotype. Even children with low baseline HbF values or the CAR beta globin haplotype can respond to hydroxyurea therapy with an elevated %HbF. Future studies designed to identify genetic modifiers of treatment HbF values should focus on sequence polymorphisms in non-globin genes that have trans-acting effects on gamma globin gene expression.

scholarly journals Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 212-216 ◽  
Author(s):  
EP Orringer ◽  
DS Blythe ◽  
AE Johnson ◽  
G Jr Phillips ◽  
GJ Dover ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Water Content ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Fetal Hemoglobin ◽  
Hemoglobin Concentration ◽  
Mean Corpuscular Hemoglobin ◽  
Cell Disease ◽  
Hemoglobin F ◽  
The Mean

A rationale for clinical trials of hydroxyurea (HU) treatment in sickle cell disease is that the agent increases red blood cell (RBC) fetal hemoglobin content. However, an additional effect of HU is to raise the mean corpuscular volume (MCV). To investigate the action of HU in a species that makes no electrophoretically distinguishable fetal hemoglobin, we treated dogs with the drug and compared their response to that of five patients with sickle cell anemia. Both dogs and patients had an increase in MCV, but the effect of HU treatment on the mean corpuscular hemoglobin concentration (MCHC), density, and water content of the RBCs differed in the two species. The dog RBCs became low in MCHC, high in ion and water content, and low in mean density. Thus, HU can raise MCV and lower MCHC without influencing fetal hemoglobin synthesis. A different pattern was seen in the sickle cell patients during HU treatment. Although the MCV of their RBCs increased, there was no change in MCHC, ion content, or mean density. A notable change in the sickle cell patients' blood was that two subpopulations of cells were nearly eliminated during HU treatment; the hypodense reticulocyte fraction and the hyperdense fraction that contains irreversibly sickled cells. These findings lead us to suggest that trials of HU in sickle cell disease must recognize the possibility that any beneficial effect of this agent might be due not only to an increase in hemoglobin F alone, but perhaps also to the associated increase in MCV or the altered RBC density profile.

scholarly journals Rapid and Automated Quantitation of Dense Red Blood Cells: A Robust Biomarker of Therapeutic Response to Early Initiation of Hydroxyurea in Young Children with Sickle Cell Anemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-17
Author(s):  
Alina Sadaf ◽  
Charles T. Quinn ◽  
Jennifer B Korpik ◽  
Amanda Pfeiffer ◽  
Mary Reynaud ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Density Gradient ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Blood Cells ◽  
Research Funding ◽  
Therapeutic Response ◽  
Hemoglobin Concentration ◽  
Gradient Fractionation ◽  
Hydroxyurea Therapy

Introduction: Hydroxyurea has well-described clinical and laboratory benefits in sickle cell anemia (SCA). Traditionally, hemoglobin concentration (Hb) and fetal hemoglobin (HbF) are used to assess treatment response, but these aggregate parameters do not fully capture the range of erythrocyte abnormalities in SCA. Dense red blood cells (DRBCs) are defined as RBCs with density >1.11 g/mL as measured by density-gradient fractionation methods, which are tedious and require technical expertise. This subpopulation of dehydrated RBCs has been associated with increased SCA severity but has not been extensively studied in children. Here we describe the utility of rapid, automated DRBC quantitation and show that the percent of DRBCs (%DRBCs) is a robust biomarker of hydroxyurea response in children with SCA. Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154) was a single-center prospective study that demonstrated individualized, pharmacokinetic (PK)-guided hydroxyurea dosing in young patients (mean age 12.1 months at initiation) results in robust and sustained HbF levels >30-40% for most adherent patients. The longitudinal follow-up phase of TREAT aims to comprehensively evaluate hematologic parameters and organ function to demonstrate the long-term benefits of this treatment strategy. During clinic visits (every 3-6 months), TREAT participants had complete blood counts (CBCs) with the ADVIA® 2120i system. This automated analyzer quantifies hyperchromic RBCs within seconds by directly measuring cell hemoglobin concentration, where DRBCs are known to correspond to RBCs with a measured MCHC >41 g/dL. Data were analyzed at baseline and after at least 6 months of hydroxyurea therapy (M≥6). α- and β-globin genotypes were determined for all patients. Results: Thirty-three TREAT participants had ADVIA data available for analysis (Table). All had homozygous SCA except one with sickle-β0-thalasemia; 17 (51.5%) were male. The median age at hydroxyurea initiation was 10.3 months (mean 26.1 months; range 6 months - 17 years). The median duration of hydroxyurea therapy was 27.7 months (mean 31.5). At baseline, median %DRBCs was 2.1%. Baseline %DRBCs were directly correlated with age at initiation of hydroxyurea (p=0.022) and inversely correlated with baseline HbF (p=0.001). After initiation of hydroxyurea (M≥6), there was a 47.6% reduction in %DRBCs (p=0.001). Median %DRBCs at M≥6 was directly correlated with absolute reticulocyte (ARC) (p=0.002), absolute neutrophil (ANC) (p=0.003) and platelet counts (p<0.001) and inversely correlated with Hb (p=0.013) and hematocrit (Hct) (p=0.019), consistent with the laboratory benefits of hydroxyurea. In bivariate analysis, the change in %DRBCs from baseline was directly correlated with baseline %DRBCs (p<0.001) and inversely correlated with baseline HbF (p=0.005). In multivariate analysis, baseline %DRBCs was the only biologic parameter that independently predicted %DRBC change (β=-0.86, p<0.001, model r2=0.91; Figure). Even when baseline %DRBCs were only mildly increased (as low as 1.5%), participants had a marked decline in %DRBC with hydroxyurea. When baseline %DRBCs were very low at baseline (<1.5%), they remained low after treatment. Of note, there was no correlation between %DRBC change and α-thalassemia status. Conclusions: DRBCs can be rapidly quantified without the tedium of classical density-gradient fractionation methods using the automated ADVIA 2120i hematology analyzer, which directly measures hyperchromic RBCs. These data from TREAT demonstrate the feasibility of serial %DRBC measurements in clinical trials and clinical practice. TREAT participants had low baseline DRBCs compared to untreated adult SCA patients (reported mean ≈12%), reflecting the young age of these patients. Nevertheless, there was a significant decline in %DRBCs with treatment that correlated strongly with the known laboratory benefits of hydroxyurea. In conclusion, automated DRBC measurements are a robust biomarker that can be incorporated in a panel of laboratory measurements of response to hydroxyurea (and severity of SCA). A larger, multicenter study of PK-guided hydroxyurea therapy (HOPS, NCT03789591) is currently underway in 11 US sickle cell centers and will provide generalizable data on DRBC responses with optimal hydroxyurea therapy. Disclosures Malik: Aruvant Sciences, Forma Therapeutics, Inc.: Consultancy; Aruvant Sciences, CSL Behring: Patents & Royalties. Kalfa:Agios Pharmaceuticals, Inc: Consultancy, Research Funding; Forma Therapeutics, Inc: Research Funding.

scholarly journals Higher Fetal Hemoglobin Following Escalation of Hydroxyurea to Maximum Tolerated Dose Provides Clinical Benefit to Children with Sickle Cell Anemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 85-85 ◽  
Author(s):  
Jeremie H. Estepp ◽  
Matthew P. Smeltzer ◽  
Guolian Kang ◽  
Banu Aygun ◽  
Russell E. Ware ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Clinical Data ◽  
Sickle Cell Anemia ◽  
Clinical Benefit ◽  
Research Funding ◽  
Fetal Hemoglobin ◽  
Long Term Effects ◽  
Clinical Benefits ◽  
Hydroxyurea Therapy

Abstract Background. Hydroxyurea has proven laboratory and clinical benefits for children with sickle cell anemia (SCA); however, the benefits of escalation to a maximum tolerated dosage (MTD) over a fixed or low-dose approach to therapy, remains controversial. Clinical trials utilizing hydroxyurea at MTD reported higher fetal hemoglobin (HbF) levels (~20% versus ~15%) compared to those with a fixed lower-dose (Ware, Blood 2010). The clinical benefits gained, if any, from increasing HbF levels from 15% to 20% has not been described. The Hydroxyurea Study of Long-Term Effects (HUSTLE) provides the opportunity to examine the relationship between the magnitude and duration of pharmacologically induced HbF and clinical outcomes, specifically the number of hospitalizations for vaso-occlusive complications such as acute chest syndrome (ACS) and vaso-occlusive events (VOE). Methods. The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) with a primary goal of describing the long-term effects of HU therapy in children with SCA, using serial and longitudinal collection of laboratory and clinical data. All children (≤18 years of age) who enrolled in HUSTLE and did not receive chronic blood transfusions are included in this analysis. All participants received hydroxyurea therapy escalated to a stable MTD, which was defined by moderate myelosuppression (typically ANC of 2,000-4,000 x 106/L) and no dose-limiting toxicities. Children were initially evaluated monthly but then every 2-3 months after achieving MTD. Neutropenia was defined as an ANC of <1,000 x 106/L. For this analysis, laboratory and clinical data were abstracted over twenty-seven months following enrollment onto HUSTLE, which constituted nine consecutive three month intervals. Hospitalizations for VOE and ACS were evaluated categorically for each three month time period, and %HbF levels at the beginning of each interval were used as the representative value for that period. To account for the correlated nature of the data, with potentially multiple hospitalizations per patient and time, a generalized estimating equation model was utilized. Results. A total of 162 children with SCA (148 HbSS, 14 HbSβ0thalassemia) at a mean (SD) age of 10.7 (4.3) years were analyzed. Children were hospitalized a total of 253 (52 ACS, 201 VOE) times during the first twenty-seven months following enrollment. The Figure illustrates the number of individuals hospitalized (yes versus no), stratified by HbF category, for each consecutive 3-month interval following HUSTLE enrollment. Compared to intervals when HbF levels were >20%, those with HbF levels of ≤20% had 2.2 (95% CI: 1.2-4.0; p=0.013) higher chance of hospitalization, and intervals with HbF levels <15% had 2.6 (95% CI: 1.3-5.1; p=0.021) times higher odds of hospitalization. For every 5% decrease in HbF, the odds of hospitalization due to VOE/ACS increased by 1.3 (95% CI: 1.1-1.5; p=0.014), correlating to a 30% increase. There was no statistically significant association between hydroxyurea dose (mg/kg) and hospitalization over time. Neutropenia occurred 39 times in 22 (13.6%) children; no episodes were associated with an invasive bacterial infection. Figure Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage. Figure. Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage. Discussion. In this pediatric cohort receiving hydroxyurea therapy escalated to MTD, higher %HbF levels conferred greater protection against hospitalization for severe vaso-occlusive pain or ACS. Escalation of hydroxyurea to MTD was rarely associated with neutropenia and had no clinical implications. These prospectively collected data from HUSTLE suggest that hydroxyurea dose escalation to MTD, designed to maximize %HbF levels, provides additional clinical benefit by reducing vaso-occlusive complications in children with SCA. Disclosures Estepp: Ely Lily: Research Funding; NIH: Research Funding. Off Label Use: Hydroxyurea in children with sickle cell anemia.

scholarly journals Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia

Blood ◽  
2011 ◽  
Vol 118 (18) ◽  
pp. 4985-4991 ◽  
Author(s):  
Russell E. Ware ◽  
Jenny M. Despotovic ◽  
Nicole A. Mortier ◽  
Jonathan M. Flanagan ◽  
Jin He ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Oral Absorption ◽  
Fetal Hemoglobin ◽  
Maximum Tolerated Dose ◽  
Interpatient Variability ◽  
Nucleotide Polymorphisms ◽  
Hydroxyurea Treatment ◽  
Treatment Responses ◽  
Hydroxyurea Therapy

Abstract Hydroxyurea therapy has proven laboratory and clinical efficacies for children with sickle cell anemia (SCA). When administered at maximum tolerated dose (MTD), hydroxyurea increases fetal hemoglobin (HbF) to levels ranging from 10% to 40%. However, interpatient variability of percentage of HbF (%HbF) response is high, MTD itself is variable, and accurate predictors of hydroxyurea responses do not currently exist. HUSTLE (NCT00305175) was designed to provide first-dose pharmacokinetics (PK) data for children with SCA initiating hydroxyurea therapy, to investigate pharmacodynamics (PD) parameters, including HbF response and MTD after standardized dose escalation, and to evaluate pharmacogenetics influences on PK and PD parameters. For 87 children with first-dose PK studies, substantial interpatient variability was observed, plus a novel oral absorption phenotype (rapid or slow) that influenced serum hydroxyurea levels and total hydroxyurea exposure. PD responses in 174 subjects were robust and similar to previous cohorts; %HbF at MTD was best predicted by 5 variables, including baseline %HbF, whereas MTD was best predicted by 5 variables, including serum creatinine. Pharmacogenetics analysis showed single nucleotide polymorphisms influencing baseline %HbF, including 5 within BCL11A, but none influencing MTD %HbF or dose. Accurate prediction of hydroxyurea treatment responses for SCA remains a worthy but elusive goal.

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