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PLENARY PAPER
From Duke University Medical Center, Durham, NC;
Children's Hospital of Boston, MA; Children's Hospital of
Philadelphia, PA; Oakland Children's Hospital, CA; East Carolina
University, Greenville, NC; St Jude Children's Research Hospital,
Memphis, TN; the University of North Carolina at Chapel Hill, and Rho
Federal Systems Division, Inc, Chapel Hill, NC.
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.
(Blood. 2002;99:10-14) The level of fetal hemoglobin (HbF) expression is
one of the most important modifiers of disease expression for patients
with sickle cell anemia.1 The percentage of HbF (%HbF)
influences both laboratory values and clinical features of children and
adults with sickle cell anemia. For example, an elevated %HbF has been significantly associated with fewer painful vasoocclusive
events,2 fewer episodes of acute chest
syndrome,3 and reduced early mortality.4,5
Pharmacologic enhancement of HbF expression has been accomplished by
using myelosuppressive agents, cytokines, and short-chain fatty
acids.6-8 To date, however, the prototypic agent for
increasing HbF expression is hydroxyurea, based on its ease of oral
administration, modest toxicity profile, and rarity of serious side
effects. A phase I/II trial of hydroxyurea for adults with sickle cell
anemia demonstrated a significant increase in HbF expression,
accompanied by a significant increase in hemoglobin concentration and
significant decreases in reticulocytes, neutrophils, and
platelets.9 The Multicenter Study of Hydroxyurea (MSH), a
double-blinded, placebo-controlled phase III trial for adults with
sickle cell anemia, demonstrated that hydroxyurea therapy significantly
reduced the number of painful events, episodes of acute chest syndrome,
transfusions, and hospitalizations.10
Experience to date with hydroxyurea for children with sickle cell
anemia suggests that it is also effective in this younger population.
Several small trials have reported that hydroxyurea has both laboratory
and clinical efficacy in the pediatric age group.11-15 The
recently completed multicenter phase I/II pediatric hydroxyurea
trial (HUG-KIDS) confirmed that hydroxyurea at a maximally tolerated
dose (MTD) has a similar efficacy and toxicity profile for children
with sickle cell anemia as observed for adults.16 For all
participants in HUG-KIDS, the mean %HbF increased significantly from
7.3% at entry to 17.8% after 12 months of hydroxyurea therapy. There
was, however, a wide variability in the HbF response; a few children
who reached MTD had %HbF levels that were persistently below 10%,
whereas several others had levels that exceeded 25%. To investigate
this variable HbF response, we examined a variety of clinical,
laboratory, and treatment characteristics of children enrolled in
HUG-KIDS to identify factors that significantly influence the HbF response.
Study overview
The hydroxyurea dose was given orally once a day, initially at 15 mg/kg/d, then escalated every 8 weeks as tolerated to the MTD or
maximum dose of 30 mg/kg/d. Dose escalation was limited by predefined
hematologic toxicities, which included a hemoglobin concentration less
than 5 g/dL, absolute neutrophil count less than
2.0 × 109/L, absolute reticulocyte count less than
80 × 109/L (unless the hemoglobin concentration was
> 9 g/dL), or platelet count less than 80 × 109/L.
Nonhematologic toxicity included an elevated serum alanine aminotransferase (twice the upper limit of normal) or a doubling of the
serum creatinine.16 MTD was defined as the dose 2.5 mg/kg below which 2 successive hematologic toxicities occurred, or when the
daily dose reached 30 mg/kg sustained without toxicity for 8 weeks.16
Patient data for analysis
The current analyses on predictors of HbF response were performed only for children who achieved MTD during the study. Of the 68 children who reached MTD, baseline and follow-up data sufficient for analysis were available for 53 patients; 15 children were excluded because of missing baseline %HbF values (n = 13) or missing %HbF values at MTD (n = 2). This patient population of 53 children included 32 boys (60%) and 21 girls (40%), with a mean age at entry of 9.5 years. The average length of time at MTD for these 53 children was 11.7 months. Each available baseline variable from these 53 children was compared with baseline data from the other 15 children who reached MTD but had missing data, using t tests for continuous variables and chi-square tests for discrete variables. No statistically significant (P < .05) differences were found, and most differences had highly nonsignificant P values, suggesting that the missing data from these 15 children were missing at random. The response variable of interest (%HbF at MTD) was calculated as the
mean of the %HbF measurements at MTD performed on each study
participant. The median number of %HbF measurements during MTD was 5, with a range of 1 to 7 measurements, although only 4 children had a
single measurement. Values of %HbF within 90 days of a blood
transfusion were not included in the analyses. The %HbF at MTD was
analyzed as a continuous response variable and also as a categorical
outcome by dividing the mean MTD %HbF into quartiles. For some
analyses, the absolute change in %HbF ( Statistical methods Clinical patient characteristics at baseline, including age and sex, were analyzed initially for statistical associations with the mean %HbF at MTD. Baseline laboratory values for hemoglobin concentration, %HbF, mean corpuscular volume (MCV), white blood cell (WBC) count, red blood cell count, absolute neutrophil count, absolute reticulocyte count, platelet count, aspartate aminotransferase, alanine aminotransferase, total bilirubin, and lactate dehydrogenase were then analyzed for an association with mean MTD %HbF. Finally, treatment characteristics (MTD dose, MTD blood counts, toxicity, and noncompliance) were studied in relationship to %HbF at MTD. Only MTD blood counts measured at least 90 days after a blood transfusion were included. Each clinical, laboratory, and treatment characteristic was analyzed as a continuous variable and also as a categorical variable by separating the values at the median into high versus low categories.Statistical associations were first assessed by computing simple
Pearson correlation coefficients (simple correlations) between mean MTD
%HbF and each continuous study variable. For some variables, simple
correlations were also computed by using the
HbF response in HUG-KIDS Figure 1 illustrates %HbF levels for the cohort of 53 HUG-KIDS children, with each child's baseline %HbF value connected by a line segment to the MTD %HbF value. At baseline, the 25%, 50%, and 75% quartile values for %HbF (indicated by arrows) were 3.5%, 5.5%, and 8.4%, respectively, with a minimum %HbF value of 1.3% and a maximum value of 19.4% HbF. At MTD, the 25%, 50%, and 75% values for %HbF (arrows) were 12.0%, 17.6%, and 21.3%, respectively, with a minimum %HbF value of 2.9% and a maximum value of 32.4%. In response to hydroxyurea therapy, most of the lines show a substantial upward trend, ie, an increase in %HbF. However, the response was highly variable, ranging from an increase in %HbF of 0.1% to 26.4% (median increase, 9.6%). No patient experienced a decline in %HbF over the treatment period, but 5 children had an increase in %HbF of less than 2.0%.
Statistical analysis using continuous variables For the entire cohort of 53 children, baseline clinical and laboratory data, as well as selected hydroxyurea treatment characteristics (MTD dose, number of toxicities, percentage of pills returned), were analyzed for associations with the %HbF at MTD (Table 1). Simple Pearson correlation coefficients revealed statistically significant positive associations between %HbF at MTD and the baseline %HbF value (P = .001), the baseline hemoglobin concentration (P = .01), and the MTD dose (P = .02), but a negative association between the %HbF at MTD and the percentage of pills returned (P = .02). These associations are illustrated by scatter diagrams in Figure 2. No other baseline value or treatment characteristic was significantly associated with MTD %HbF.
Because the baseline %HbF varied widely among patients and might influence other variables, the analysis was repeated after adjustment for the baseline %HbF (Table 1, column PR). These partial correlations revealed that the MTD dose and noncompliance remained significant, but the baseline hemoglobin concentration did not. After adjustment for baseline %HbF, both the baseline reticulocyte count and WBC count were significantly associated with a higher %HbF at MTD (P = .05 for each; Table 1). Finally, the analysis was repeated after adjustment for baseline WBC and reticulocyte counts, and the %HbF at MTD remained significant in each case with the baseline %HbF, baseline hemoglobin concentration, MTD dose, and compliance. When the data were analyzed by using the Statistical analysis using %HbF quartiles For analyses using methods for categorical variables, the MTD %HbF was divided into quartiles, and baseline clinical and laboratory parameters were dichotomized at their median. Similar to the results described above using continuous variables, children with a higher baseline %HbF (ie, above the median baseline HbF value of 5.5%) reached a higher %HbF at MTD (20.0% versus 14.2%, P = .001 by t test). Children with an MTD of 30 mg/kg/d also had a higher overall mean %HbF at MTD than those children whose MTD was below 30 mg/kg/d (18.5% versus 14.8%, P = .05 by t test). Similar results were obtained when participants in the 2nd and 3rd quartiles of %HbF at MTD were excluded from these analyses, leaving only those children in the extreme quartiles (1st versus 4th).Statistical associations of HbF response with treatment parameters The next analyses were performed to determine if the %HbF response was associated with treatment variables, especially changes observed in other laboratory parameters. A higher MTD %HbF was associated with a higher MTD dose (P = .001) but not with age, sex, or number of hematologic toxicities (Table 2). Treatment blood counts were analyzed according to their absolute value at MTD as well as their change from baseline. A higher hemoglobin concentration and a higher MCV (both the absolute MTD values and the positive changes from baseline) were significantly associated with a higher MTD %HbF response. A lower reticulocyte count and WBC count (both absolute MTD values and negative changes from baseline) were significantly associated with a higher %HbF at MTD. No significant associations were noted between the %HbF response and MTD treatment values for neutrophils or platelets.
Over the past decade, hydroxyurea has emerged as a therapeutic option for both children and adults with sickle cell anemia. Early studies documented that hydroxyurea has a pronounced effect on HbF parameters, and it typically increases both the %HbF level and the percentage of F cells.9,16,18 Subsequent studies have reported additional potentially beneficial effects of hydroxyurea therapy, including diminished adhesiveness of sickle erythrocytes, improved rheology of circulating erythrocytes, and altered expression of surface adhesion markers.19-21 All studies to date have documented a variable response to hydroxyurea, however, especially with regard to elevation of %HbF. Identification of predictors of the HbF response to hydroxyurea might help clinicians maximize the efficacy of hydroxyurea therapy while possibly reducing its side effects and toxicities. In the phase III, randomized, double-blinded, placebo-controlled
MSH study, adults with sickle cell anemia who received hydroxyurea therapy at MTD had a modest but variable %HbF response. When the MSH
data were analyzed according to the intention-to-treat principle, the mean 2-year change in %HbF was only 3.6 ± 5.4%, ranging from The analyses of HbF parameters for children enrolled in the
HUG-KIDS study differ from the MSH results in several areas.
Importantly, we chose to use the %HbF at MTD as the primary response
variable rather than Analysis of treatment characteristics revealed that children who achieved a higher hydroxyurea MTD dose had higher MTD %HbF levels (Figure 2C). This observation should not be overinterpreted because all patients were escalated to MTD, but it suggests that the highest tolerated daily hydroxyurea dose may yield the greatest HbF response. Treatment-associated changes in laboratory variables also were highly predictive of the HbF response: greater positive changes in hemoglobin concentration and MCV, as well as greater negative changes in reticulocyte and WBC counts, were associated with a higher MTD %HbF (Table 2). The predictive power of most of these therapy-associated changes has been recognized previously9,16,18 and suggests that hydroxyurea dose escalation to mild myelosuppression is desirable for maximal HbF response. Our data indicate that selected baseline laboratory parameters (%HbF, reticulocyte count, and WBC count) identify the children most likely to have a robust HbF response to hydroxyurea therapy. A higher MTD dose of hydroxyurea, coupled with good compliance with the treatment regimen, will further identify children who will have the best HbF response. Finally, greater treatment-associated changes in selected laboratory variables (hemoglobin concentration, MCV, reticulocyte count, and WBC count) correlate with better HbF responses to hydroxyurea therapy. Taken together, these data demonstrate that almost all children with sickle cell anemia will respond to hydroxyurea therapy with increases in %HbF, but the response is complex and cannot be predicted accurately. Because even children with low baseline %HbF values can develop substantial increases in %HbF at MTD, however, clinicians should consider every severely affected child with sickle cell anemia to be a potential candidate for hydroxyurea therapy.
We thank Dr Kazumi Horiuchi for measurement of %HbF levels for the HUG-KIDS trial, Marsha McMurray and Dr Sharyne Donfield for data management services, and the many patients and families who participated in this study. Investigators for the Pediatric Hydroxyurea Trial (HUG-KIDS) are listed in the Appendix.
Submitted June 6, 2001; accepted August 17, 2001.
Supported in part by Comprehensive Sickle Cell Center Awards from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (Boston P60 HL15157, Duke-UNC P60 HL28391, Philadelphia P60 HL38632, and Northern California P60 HL20985).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Russell E. Ware, PO Box 2916, DUMC, Durham, NC 27710; e-mail: ware0005{at}mc.duke.edu.
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© 2002 by The American Society of Hematology.
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  J. J. Strouse, S. Lanzkron, M. C. Beach, C. Haywood, H. Park, C. Witkop, R. F. Wilson, E. B. Bass, and J. B. Segal Hydroxyurea for Sickle Cell Disease: A Systematic Review for Efficacy and Toxicity in Children Pediatrics, December 1, 2008; 122(6): 1332 - 1342. [Abstract] [Full Text] [PDF]
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 S. Lanzkron, J. J. Strouse, R. Wilson, M. C. Beach, C. Haywood, H. Park, C. Witkop, E. B. Bass, and J. B. Segal Systematic Review: Hydroxyurea for the Treatment of Adults with Sickle Cell Disease Ann Intern Med, June 17, 2008; 148(12): 939 - 955. [Abstract] [Full Text] [PDF]
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 S. A. Zimmerman, W. H. Schultz, J. S. Davis, C. V. Pickens, N. A. Mortier, T. A. Howard, and R. E. Ware Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease Blood, March 15, 2004; 103(6): 2039 - 2045. [Abstract] [Full Text] [PDF]
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 G. R. Buchanan, M. R. DeBaun, C. T. Quinn, and M. H. Steinberg Sickle Cell Disease Hematology, January 1, 2004; 2004(1): 35 - 47. [Abstract] [Full Text] [PDF]
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M. Wadleigh, P. G. Richardson, D. Zahrieh, S. J. Lee, C. Cutler, V. Ho, E. P. Alyea, J. H. Antin, R. M. Stone, R. J. Soiffer, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation Blood, September 1, 2003; 102(5): 1578 - 1582. [Abstract] [Full Text] [PDF]
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P. Venigalla, B. Motwani, A. Nallari, S. Allen, M. Agarwal, M. Alva, M. Westerman, and L. Feldman A patient on hydroxyurea for sickle cell disease who developed an opportunistic infection Blood, June 17, 2002; 100(1): 363 - 364. [Full Text] [PDF]
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Top
Abstract
Introduction
%HbF = %HbF at MTD 
%HbF at baseline) was used as a continuous response variable.
.05
is described as significant.
300 × 109/L) and
neutrophil count (
-globin disorders.
N Engl J Med.
1993;328:81-86
Children's Hospital, Boston, MA: O. Platt, B. Gee, S. Kurth
(4); Duke University Medical Center, Durham, NC: T. Kinney, R. Ware, E. O'Branski, W. Schultz, A. Walker (17); Oakland Children's Hospital, Oakland, CA: E. Vichinsky, L. Styles, E. Hackney Stephens (18); Children's Hospital of Philadelphia, Philadelphia, PA: K. Ohene-Frempong, K. Smith-Whitley, L. Moore, L. Parkin, S. Whitehead
(24); East Carolina University, Greenville, NC: C. Daeschner, D. Gordon, C. Brown (11); University of North Carolina at Chapel Hill,
Chapel Hill, NC: R. Redding-Lallinger, S. Jones (7); St Jude
Children's Research Hospital, Memphis, TN: W. Wang, K. Cupples, L. Wynn (7).