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

Jeremie H. Estepp; Matthew P. Smeltzer; Guolian Kang; Chen Li; Winfred C. Wang; Christina Abrams; Banu Aygun; Russell E. Ware; Kerri Nottage; Jane S. Hankins

doi:10.1002/ajh.24906

Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽

10.1182/asheducation-2015.1.436 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 436-443 ◽

Cited By ~ 19

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.

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Optimizing hydroxyurea therapy for sickle cell anemia

Hematology ◽

10.1182/asheducation.v2015.1.436.3917688 ◽

2015 ◽

Vol 2015 (1) ◽

pp. 436-443 ◽

Cited By ~ 8

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.

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

Blood ◽

10.1182/blood.v106.11.3171.3171 ◽

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.

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

Blood ◽

10.1182/blood-2004-12-4973 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2269-2275 ◽

Cited By ~ 161

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.

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

Blood ◽

10.1182/blood.v124.21.85.85 ◽

2014 ◽

Vol 124 (21) ◽

pp. 85-85 ◽

Cited By ~ 2

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.

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

Blood ◽

10.1182/blood-2011-07-364190 ◽

2011 ◽

Vol 118 (18) ◽

pp. 4985-4991 ◽

Cited By ~ 89

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

Blood ◽

10.1182/blood.v99.1.10 ◽

2002 ◽

Vol 99 (1) ◽

pp. 10-14 ◽

Cited By ~ 106

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.

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Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Blood ◽

10.1182/blood-2011-08-374447 ◽

2012 ◽

Vol 119 (8) ◽

pp. 1915-1921 ◽

Cited By ~ 21

Author(s):

Jeffrey D. Lebensburger ◽

Thad Howard ◽

Yunming Hu ◽

Tamara I. Pestina ◽

Geli Gao ◽

...

Keyword(s):

Sickle Cell ◽

Sickle Cell Anemia ◽

Vascular Inflammation ◽

Pneumococcal Infection ◽

Fetal Hemoglobin ◽

Neutrophil Extravasation ◽

Hydroxyurea Treatment ◽

Inflammatory State ◽

The Impact ◽

Hydroxyurea Therapy

Abstract Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte–endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis.

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