- Email: [email protected]
A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia
A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia Winfred C. Wang, MD, Lynn W. Wynn, RN, Zora R. Rogers, MD, J. Paul Scott, MD, Peter A. Lane, MD, and Russell E. Ware, MD, PhD Objective: Hydroxyurea improves hematologic values and decreases vasoocclusive complications in adults and children with sickle cell anemia (SCA), but has not been tested in infants before the onset of chronic organ dysfunction. We conducted a collaborative pilot trial of hydroxyurea in infants with SCA to assess its (1) feasibility of administration, (2) toxicity, (3) hematologic effects, and (4) effect on spleen function. Study design: Patients with hemoglobin (Hb) SS or Sβ0 thalassemia (n = 28, median age 15 months) received hydroxyurea for 2 years at 20 mg/kg/day. Hydroxyurea was temporarily discontinued for predefined toxicity. Results: Seven patients exited the study early: five for noncompliance or refusal to continue, one for mild stroke, and one for fatal splenic sequestration. The predominant toxicity was transient neutropenia, which was usually associated with a viral-like illness. After 2 years of treatment, mean Hb level = 8.8 g/dL and Hb F = 20.3%, both higher than predicted age-specific levels. Radionuclide splenic uptake was absent in 47% of patients at study completion, compared with predicted functional asplenia in 80% of the patients. Conclusions: Hydroxyurea therapy for infants with SCA is feasible and well tolerated, has hematologic efficacy, and may delay functional asplenia. The potential for hydroxyurea to preserve organ function in SCA should be further evaluated. (J Pediatr 2001;139:790–6)
Because hemoglobin (Hb) F inhibits polymerization of deoxygenated sickle Hb, induction of Hb F synthesis in patients with sickle cell anemia (SCA) has become an important therapeutic goal for physicians.1 High levels of Hb F are
known to ameliorate major vaso-occlusive complications.2,3 Hydroxyurea, an inhibitor of ribonucleotide reductase, stimulates Hb F synthesis, perhaps by recruitment of early red cell progenitors with intrinsic high Hb F production.4
From St. Jude Children’s Research Hospital, Memphis, Tennessee, the University of Texas Southwestern Medical Center, Dallas, Medical College of Wisconsin, Milwaukee, the University of Colorado School of Medicine, Denver, and Duke University Medical Center, Durham, North Carolina.
Supported in part by the American Lebanese Syrian Associated Charities and by General Clinical Research Center grant Nos. M01RR00058 and M01RR00069, National Center for Research Resources, National Institutes of Health. Submitted for publication Mar 7, 2001; revision received May 16, 2001; accepted Aug 14, 2001. Reprint requests: Winfred C. Wang, MD, Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Room R-6002, 332 N Lauderdale, Memphis, TN 38105. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/119590 doi:10.1067/mpd.2001.119590
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Treatment of adults with SCA with hydroxyurea resulted in fewer episodes of pain and acute chest syndrome, fewer transfusions, and a reduced number of hospitalizations.5 For school-aged children, hematologic response and lack of significant toxicity were demonstrated in a recent Phase I-II pediatric safety
See editorial, p 763 and related article, p 785. trial.6 Several small trials have also documented a decrease in acute vaso-occlusive events,7-14 which suggests that hydroxyurea has clinical efficacy in pediatric patients similar to that in adults. ALT ANC CSSCD
Alanine aminotransferase Absolute neutrophil count Cooperative Study of Sickle Cell Disease Hb Hemoglobin HIV Human immunodeficiency virus HUG-KIDS Phase I-II trial of hydroxyurea in children MCV Mean cell volume MRI/MRA Magnetic resonance imaging/angiography MSH Multi-Center Study of Hydroxyurea NCHS National Center for Health Statistics SCA Sickle cell anemia SJCRH St. Jude Children’s Research Hospital WBC White blood cell
Morbidity and mortality of SCA result not only from acute events, but also from chronic organ damage that affects the spleen, brain, lungs, kidneys, and liver. For example, functional asplenia occurs early in life and leaves young patients at high risk for overwhelming infection.15,16 Hydroxyurea has not previously been tested in very young children with SCA before the onset of
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VOLUME 139, NUMBER 6 chronic organ dysfunction. Theoretically, hydroxyurea administration at an early age might maintain Hb F at a high enough level to preserve organ function. We performed a collaborative pilot trial by using a fixed dose of hydroxyurea in unselected infants with SCA. Our primary objectives were to (1) examine the feasibility of hydroxyurea administration in this very young population, (2) determine the toxicity of hydroxyurea, (3) assess the effects of hydroxyurea on fetal Hb levels and blood counts, and (4) obtain pilot data regarding the potential of hydroxyurea to preserve splenic function.
MATERIAL AND METHODS Patient Selection and Treatment All patients had a confirmed diagnosis of Hb SS or Hb Sβ0 thalassemia and previous compliance with scheduled clinic visits. Patients were excluded from the study for significant nonsickle cell-related medical problems, HIV seropositivity, a recent red blood cell transfusion that resulted in an Hb A level above 10%, renal or hepatic dysfunction, iron deficiency, or concomitant medication that might interact with hydroxyurea. Enrollment was not made on the basis of clinical history or laboratory evidence of disease severity. Patients were enrolled over an 8-month period from November 1996 through June 1997. This open-label trial of hydroxyurea used a fixed dose of 20 mg/kg/day. Each child received hydroxyurea for 2 years. Hydroxyurea was administered as a liquid in flavored syrup at a concentration of 100 mg/mL and dispensed as a 4-week supply. The dose of hydroxyurea was rounded to the nearest 0.1 mL (10 mg) and adjusted for weight every 8 weeks. The study was independently reviewed and approved by the institutional review board at each participating
institution. Written informed consent that included the unknown potential for carcinogenicity with long-term use of hydroxyurea was obtained from parents or guardians.
Patient Evaluation and Monitoring Physical examination was performed before treatment and every 8 weeks thereafter. Serial blood counts were performed locally every 2 to 4 weeks. Measurements of Hb F and F cells were performed at Duke University Medical Center, Durham, NC, at 0, 8, 16, 32, 52, 80, and 104 weeks after initiation of treatment. The percentage of Hb F levels were measured by the 2minute alkali denaturation test, and Fcell numbers were determined with the use of an immunostaining technique.17 Serum alanine amino transferase (ALT) and creatinine were measured quarterly and ferritin semiannually at local centers. Families were considered noncompliant and removed from the study if they missed >3 clinic visits, did not obtain hydroxyurea refills, or reported that they failed to administer hydroxyurea on a regular basis.
Laboratory Toxicity and Adverse Events Hematologic toxicity was defined as an absolute neutrophil count <1.5 109/L, platelet count <80 109/L, decline in Hb >20% from the baseline, or Hb <5.0 g/dL. Nonhematologic toxicity included an increase in serum creatinine by >50% or ALT >2 the upper limit of normal. If toxicity was identified, hydroxyurea was discontinued. When the laboratory abnormality resolved, hydroxyurea was resumed at the previous dose. If toxicity lasted for more than 2 weeks or reoccurred after the medication was resumed, the dose was permanently decreased by 2.5 mg/kg/day. An adverse event was defined as death or a life-threatening clinical event likely to interfere either temporarily or permanently with the pa-
tient’s ability to continue to tolerate hydroxyurea therapy. Adverse events were reported to the institutional review board of each participating institution. An advisory committee of 4 pediatric hematologists with expertise in sickle cell disease critically reviewed the progress of the study annually.
Organ Function and Toxicity Spleen function was assessed by Tc 99m sulfur-colloid uptake performed locally at study entry and exit. All scans were interpreted by a pediatric radiologist who was blinded to patient status. Splenic uptake was compared with hepatic uptake and classified as normal, slightly decreased, markedly decreased, or absent as previously described.18 Paired scans then were reviewed to assess any change in splenic uptake. Sixteen children at 2 institutions (St. Jude Children’s Research Hospital, n = 10; Duke University Medical Center, n = 6) had magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at study entry and exit. Neuropsychometric development was assessed with the Bayley Scales of Infant Development at study entry and either the Bayley examination (≤36 months) or the McCarthy Scales of Children’s Abilities at exit. Transcutaneous oxygen saturation measured by pulse oximetry was used as an indirect indicator of pulmonary function and performed quarterly at each institution. Growth was assessed by serial height and weight measurements, which were plotted on standard growth curves and monitored every 6 months for changes in growth velocity. Growth was examined retrospectively among an age- and genotype-matched comparison group from all 4 centers. Head circumference percentile measurements were determined by using National Center for Health Statistics standards.
Statistical Analyses Statistical distributions of the outcomes were examined using quantile791
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Table I. Hematologic toxicity associated with hydroxyurea
Patients n
Episodes n (%)
Blood counts n (%)*
17 15 6 6 16 8 2 1 7 1
57 (100) 35 (61) 14 (25) 8 (14) 42 12 2 1 7 1
76 (10) 50 (7) 18 (2) 8 (1)
Neutropenia (ANC <1.5 109/L) Nadir of ANC: 1.0–1.499 109/L 0.5–0.999 109/L <0.5 109/L Time to recovery:1 wk 2 wk 3 wk 4 wk Anemia exacerbation (≥20% decline) Thrombocytopenia (platelets <80 109/L)
9 (1) 1 (0.1)
*Percentage of total complete blood counts performed (n = 769).
quantile plots. Hematologic results were compared with results from the Cooperative Study of Sickle Cell Disease (CSSCD) by using hematologic values for children with SCA from birth to 5 years.19 For each of the 21 patients who completed 104 weeks of therapy, 3 control patients from the CSSCD were selected according to hemoglobinopathy diagnosis, gender, and availability of age-matched hematologic data. Because F-cell measurements were not performed by the CSSCD, age-matched values measured in the Duke University Hematology Research Laboratory17 were compared. Hematologic values and organ function at study entry and exit were compared using the 2-sided paired t test. The Wilcoxon/Mann-Whitney test and Wilcoxon signed rank test were used for comparisons of the absolute neutrophil count (ANC). Height and weight measurements were compared by using a quadratic regression model and estimation of polynomial coefficients.20
RESULTS Enrollment and Retention Twenty-eight children were enrolled in the study and received treatment. All were black with a diagnosis of Hb SS (n = 27) or Hb Sβ0 thalassemia (n = 1). Their median age at entry was 15 792
months (range, 6-28 months); 16 were boys. Twenty-one patients (75%) completed 104 weeks of follow-up at a median age of 39 months (range, 30-52 months). Seven patients did not complete the study: 2 were removed for noncompliance (after 7 and 14 months, respectively), the parents of 3 patients elected to discontinue participation, 1 patient was placed on chronic transfusions after a mild stroke, and one died from splenic sequestration. No significant differences were identified in the enrollment laboratory values for these 7 patients compared with the patients who completed 2 years of hydroxyurea therapy.
Toxicity Toxicity from hydroxyurea was primarily hematologic (Table I). Neutropenia occurred 57 times in 17 patients and was present in 10% of all blood counts. Neutropenia occurred a median of twice per patient (range, 110 episodes) with a median duration of 1 week (range, 1-4 weeks), and was associated with an intercurrent illness (usually an upper respiratory tract infection) in 40 episodes (70%). Neutropenia was never associated with an invasive bacterial infection; in 4 episodes, patients with an ANC <500 109/L were hospitalized because of
fever. Severe anemia occurred 7 times in 7 patients, was associated with acute illness on 4 occasions, and required transfusion in one patient. Thrombocytopenia (platelet count 76 109/L) occurred once in association with a viral illness. Elevation of serum ALT (167 IU/L) occurred once without explanation and resolved within 1 week. Mean levels of serum ALT and creatinine were unchanged throughout the study. Three patients had hydroxyurea dose reductions for persistent or recurrent neutropenia, to 17.5 mg/kg/day in two, and to 12.5 mg/kg/day in one. These 3 infants had an average (mean ± SD) ANC of 2.5 ± 1.1 109/L before beginning hydroxyurea, compared with a pretreatment mean ANC of 4.6 ± 2.4 109/L in patients who did not require dose modification (P = .11). Two patients had an accidental overdose of hydroxyurea. One ingested 15 his daily dose; ipecac was used to induce emesis, and hydroxyurea was withheld for 21 days. Weekly ANC values were 1350, 1281, and 1656 109/L after the ingestion. The second patient ingested 2.5 his normal daily dose, and hydroxyurea was held for 11 days. His ANC values were 840 and 1694 109/L on days 7 and 11. Neither patient had clinical symptoms.
Hematologic and Biochemical Results Study patients had similar hematologic values at study entry compared with case control patients (Table II). At Week 104, treated patients had increases in average Hb, mean cell volume (MCV), Hb F, and F cell levels, as well as declines in mean white blood cell (WBC) and platelet counts. Most of these values were significantly different than those from control patients (Table II). Most of the infants had an upward trend in Hb, MCV, and Hb F levels compared with the expected agerelated changes documented in the CSSCD (Fig 1). Serial hematologic data indicated that these effects of hydroxyurea were generally apparent by
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VOLUME 139, NUMBER 6 Table II. Comparison of expected and observed hematologic results at study entry and exit for patients who completed 2 years of treatment (n = 21)
Entry (wk 0) Result Hb (g/dL) MCV (fL) Hb F (%) F cells (%) WBC (109/L) Platelets (109/L)
Exit (wk 104)
Observed n ± SD
Expected* n ± SD
Significance (P value)
Observed n ± SD
Expected* n ± SD
8.5 ± 1.4 81.7 ± 8.0 21.8 ± 7.8 80.6 ± 14.1 12.6 ± 4.4 410 ± 169
8.5 ± 1.2 79.0 ± 7.9 21.3 ± 11.2 80.5 ± 12.4 12.5 ± 3.6 336 ± 130
.91 .25 .84 .98 .90 .026
8.8 ± 1.2 90.0 ± 9.6 20.3 ± 4.9 76.2 ± 12.4 10.1 ± 3.2 352 ± 125
7.7 ± 1.0 84.1 ± 10.1 10.9 ± 7.9 65.4 ± 11.2 14.3 ± 2.4 436 ± 185
Significance (P value) .004 .069 < .001 .006 < .001 .057
*Calculated on the basis of data extracted from the CSSCD19 (see “Material and Methods”) and from the Duke University Pediatric Hematology Research Laboratory (for F cells).17
Table III. Time course for hematologic effects of hydroxyurea
Mean values (n)
Wk 0 (28)
Wk 8 (27)
Wk 16 (26)
Wk 32 (24)
Wk 52 (22)
Wk 80 (21)
Wk 104 (21)
Hb (g/dL) MCV (fL) Hb F(%) F cells (%) WBC (109/L) ANC (109/L) Platelets (109/L)
8.5 81.6 21.9 80.6 12.7 4.5 410
8.5 86.7 22.6 85.8 11.3 3.7 342
9.0 86.3 23.1 87.4 10.5 3.5 391
9.0 88.4 22.6 86.1 10.9 4.3 375
9.2 90.7 23.5 85.1 10.6 3.4 372
8.9 90.9 19.1 83.4 9.7 3.6 347
8.8 90.0 20.3 76.2 10.1 4.2 352
Change in mean value* +0.3 +8.4 –1.6 –4.4 –2.6 –0.3 –58
*Values at week 104 compared with those at week 0.
weeks 8 through 16 of therapy (Table III).
Organ Function Four patients had surgical splenectomy before entry; 17 patients had liverspleen scans performed at both study entry and exit. At entry, mildly decreased splenic uptake was observed in 8 patients, markedly decreased uptake in five, and absent uptake in four. Direct comparison of liver-spleen scans before and after 2 years of treatment showed no change in eleven, greater uptake in one, and less uptake in five. Splenic uptake was absent in eight of 17 children (47%) at week 104, including the 4 patients with absent uptake at study entry. Small areas of increased signal intensity on T-2 weighted images, consistent with silent brain infarcts, were seen in
two of 16 MRI scans at week 0 and 4 scans at week 104. No brain atrophy was seen, and MRA showed no stenoses or occlusions. On neurodevelopmental examination of patients (n = 10), the mean developmental score was 93.7 at week 0 and 89.5 at week 104 (P = .56). All transcutaneous oxygen saturation levels were >95% throughout the study. Mean oxygen saturation was 98.6% ± 1.3% initially and 98.2% ± 1.6% at week 104. No patient had decreased growth velocity. No significant differences in height or weight were found between patients and untreated age-matched control patients with Hb SS. Mean head circumference measurements were 46.9 cm at entry and 50.3 cm at exit; National Center for Health Statistics percentiles were unchanged for both boys and girls.
Clinical Adverse Events Two patients developed splenic sequestration; neither had an enlarged spleen at the onset of the study. One 25-month-old girl developed acute splenomegaly that was palpable 6 cm below the costal margin with an Hb of 4.0 g/dL (previously 9.9 g/dL). She was transfused, had an elective laparoscopic splenectomy, and remained on hydroxyurea therapy. The second patient was a 14-month-old boy whose Hb level dropped from 8.4 g/dL to 6.0 g/dL associated with fever and mild splenomegaly. His Hb level increased to 7.7 g/dL without transfusion, and he continued to receive hydroxyurea for the next 2 months. He then experienced a fatal episode of splenic sequestration, characterized by rapid onset of lethargy and fever, massive splenomegaly, and an Hb level of 2.4 g/dL. 793
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DISCUSSION
Figure. Comparison of initial (week 0) and final (week 104) hematologic values for 21 patients who completed 2 years of hydroxyurea treatment. Changes in Hb (A), MCV (B), and Hb F levels (C) are depicted.Values at week 0 are indicated with circles and at week 104 with triangles.The “background” lines in each figure delineate the 5th, 50th, and 95th percentiles for subjects from the CSSCD.19
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In this pilot study conducted at 4 institutions, administration of hydroxyurea to young infants with SCA was found to be feasible. The liquid formulation of hydroxyurea was well accepted by parents and children; 21 of 28 patients who began the study completed the full 2 years of therapy. Toxicity related to hydroxyurea was predominantly mild and reversible neu-
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VOLUME 139, NUMBER 6 tropenia. Most episodes of neutropenia were associated with presumed viral infections and lasted only 1 week; no invasive infections occurred during these episodes. Persistent or recurrent neutropenia required a decrease in the dose of hydroxyurea in only 3 patients. The higher frequency of neutropenia in our patients (10% of blood counts), compared with the 5.2% rate observed in school-aged children,6 is likely because of a lower baseline neutrophil count and a higher incidence of viral illnesses. Anemia and thrombocytopenia were rare, and no significant renal or hepatic toxicity was observed. The 2 patients who received accidental overdoses of hydroxyurea had only mild transient neutropenia. No adverse effects on growth were observed in our patients compared with untreated control patients, which further suggests that hydroxyurea can be administered safely in this very young population. Finally, no clear neurologic toxicity was observed, although MRI, MRA, and neurodevelopmental testing are difficult to interpret because of the limited data for untreated patients in this age range.21 A recent abstract22 suggests adverse effects of hydroxyurea on brain development in infant mice, but the small numbers of animals, very high dose of drug, and different route of administration limit the relevance of the results to humans. The risks and benefits of hydroxyurea therapy in the setting of cerebrovascular disease in SCA remain unclear,23,24 and a larger controlled trial will be required to fully address this question. Hematologic responses to hydroxyurea therapy mimicked responses observed in older patients,5,6 although the responses must be interpreted in light of the physiologic changes that occur normally in very young children with SCA. The maintenance of relatively stable Hb and Hb F levels of the infants in our study demonstrates a clear response to hydroxyurea when compared with the expected declines in those levels.19,25 Changes in the number of F
cells paralleled the changes in the percentage of Hb F, providing additional evidence for hematologic efficacy. The declines in WBC count and platelet count, at a time when both would be expected to increase also may be clinically relevant. An elevated WBC count has been implicated as a risk factor for a number of vaso-occlusive complications of SCA,26,27 and suppression of neutrophil formation may partially explain the clinical benefits of hydroxyurea.28 Our data suggest a beneficial effect of hydroxyurea on the preservation of splenic function, although the limited number of patients precluded demonstration of statistical significance. After 2 years of hydroxyurea treatment, 47% of children had functional asplenia at an age when about 80% would be expected to have asplenia by red cell pit counts.19 Anecdotal splenic regeneration has been reported in 2 young adults treated with hydroxyurea, one of whom later required splenectomy.29 It is possible that hydroxyurea may delay the development of functional asplenia but prolong the period of risk for acute splenic sequestration, a complication that occurred in two of our patients. Despite the effects of hydroxyurea in preventing the expected decline of Hb F levels in our patients, they experienced a number of clinical adverse events, including death in one. The scope of our study, the limited period of drug exposure (47 patient-years), and the use of a hydroxyurea dose lower than the predicted maximum tolerated dose prevent valid comparisons of the incidence of vaso-occlusive events in our patients with those reported by the CSSCD,30 although no striking differences in approximate incidence are apparent. Dose escalation to maximum tolerated dose should be tested in future trials to fully assess the clinical efficacy of this intervention. Hydroxyurea might also be considered for infants with a high risk for severe complications of sickle cell disease, such as those recently identified by the CSSCD.31
In summary, our pilot study has shown that administration of a liquid preparation of oral hydroxyurea to very young children with SCA is feasible and well tolerated, and is associated with limited and manageable hematologic toxicity. When used in a fixed dose, hydroxyurea treatment resulted in the maintenance of a 20% Hb F level over a 2-year period. On the basis of these pilot data, future researchers should seek definitive evidence of benefit from hydroxyurea in the preservation of the function of the spleen and other organs. A large Phase III trial addressing this question has been initiated by the National Heart, Lung, and Blood Institute. Our data provide a solid foundation for this trial and are relevant for questions of dosing, monitoring, and end point determination. We are indebted to Sara Day, Amy Walker, Evelyn Brown, Gwendolyn Lea, Juanita Dale, Bonita Williams, Lelia Nelson, and Bertha Davis for nursing and data coordination; Drs Joan Hu and Ming Tan for biostatistical analysis; Drs James Langston, Kathleen Helton, and Thomas Hay for review of diagnostic imaging; Drs William Crom and John Rodman for pharmatherapeutic support; Drs Vanessa Elliott and Ray Mulhern for neuropsychometric evaluation; Dianne Gallagher for liaison with the CSSCD; and Patsy Burnside for word processing. We are especially grateful to Drs Scott Miller, Michael DeBaun, Doris Wethers, and Sharada Sarnaik for serving as an advisory committee to this study.
REFERENCES 1. Noguchi CT, Rodgers GP, Serjeant G, Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle-cell disease. N Engl J Med 1988;318:96-9. 2. Powars DR, Weirs JN, Chan LS, Schroeder WA. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle-cell anemia? Blood 1984;63:921-6. 3. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E. Pain in sickle-cell disease. N Engl J Med 1991;325:11-6. 4. Charache S. Hydroxyurea as treatment for sickle-cell anemia. Hematol Oncol Clin North Am 1991;5:571-83. 795
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5. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, et al. Effect of hydroxyurea on the frequency of painful crises in sickle-cell anemia. N Engl J Med 1995;332:131722. 6. Kinney TR, Helms RW, O’Branski EE, Ohene-Frempong K, Wang W, Daeschner C, et al. Safety of hydroxyurea in children with sickle-cell anemia: Results of the HUG-KIDS Study, a Phase I/II trial. Blood 1999;94:1550-4. 7. Scott JP, Hillery CA, Brown ER, Misiewicz V, Labotka RJ. Hydroxyurea therapy in children severely affected with sickle-cell disease. J Pediatr 1996;6:820-8. 8. Ferster A, Vermylen C, Cornu G, Buyse M, Corazza F, Devalck C, et al. Hydroxyurea for treatment of severe sickle-cell anemia: a pediatric clinical trial. Blood 1996;88:1960-4. 9. Jayabose S, Tugal O, Sandoval C, Patel P, Puder D, Lin T, et al. Clinical and hematologic effects of hydroxyurea in children with sickle-cell anemia. J Pediatr 1996;129:559-65. 10. de Montalembert M, Belloy M, Bernaudin F, Gouraud F, Capdeville R, Mardini R, et al. Three-year followup of hydroxyurea treatment in severely ill children with sickle-cell disease. J Pediatr Hematol Oncol 1997;19:313-8. 11. Ohene-Frempong K, Smith-Whitley K. Use of hydroxyurea in children with sickle-cell disease: what comes next? Semin Hematol 1997;34:30-41. 12. Vichinsky EP. Hydroxyurea in children: present and future. Semin Hematol 1997;34:22-9. 13. Rogers ZR. Hydroxyurea therapy for diverse pediatric populations with sickle-cell disease. Semin Hematol 1997;34:42-7.
14. Olivieri NF, Vichinsky EP. Hydroxyurea in children with sickle-cell disease: impact on splenic function and compliance with therapy. J Pediatr Hematol Oncol 1998;20:26-31. 15. Pearson HA, Spencer RP, Cornelius EA. Functional asplenia in sickle-cell anemia. N Engl J Med 1969;281:923-6. 16. Wong W-Y, Overturf GD, Powars DR. Infection caused by Streptococcus pneumoniae in children with sickle-cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination. Clin Infect Dis 1992;14:1124-36. 17. Marcus SJ, Kinney TR, Schultz WH, O’Branski EE, Ware RE. Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle-cell disease. Am J Hematol 1997;54:40-6. 18. Lane PA, O’Connell JL, Lear JL, Rogers ZR, Woods GM, Hassell KL, et al. Functional asplenia in hemoglobin SC disease. Blood 1995;85:2238-44. 19. Brown AK, Sleeper LA, Miller ST, Pegelow CH, Gill FM, Waclawiw MA. Reference values and hematologic changes from birth to 5 years in patients with sickle-cell disease. Arch Pediatr Adolesc Med 1994;148:796-804. 20. Liang KL, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22. 21. Wang WC, Langston JW, Steen RG, Wynn LW, Mulhern RK, Wilimas JA, et al. Abnormalities of the central nervous system in very young children with sickle-cell anemia. J Pediatr 1998;132:994-8. 22. Horiuchi K, Golden JA, Das SK, Scully M, Liang L, Ohene-Frempong K, et al. Adverse effects of hydroxyurea on growth and development of young mice. Blood 1998;92:160a.
23. Vichinsky EP, Lubin BH. A cautionary note regarding hydroxyurea in sicklecell disease. Blood 1994;83:1124-8. 24. Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sicklecell disease. Blood 1999;94:3022-6. 25. Marcus SJ, Ware RE. Physiologic decline in fetal hemoglobin parameters in infants with sickle-cell disease: implications for pharmacological intervention. J Pediatr Hematol Oncol 1999;21:407-11. 26. Castro O, Brambilla DJ, Thorington B, Reindorf CA, Scott RB, Gillette P, et al. The acute chest syndrome in sickle-cell disease: incidence and risk factors. Blood 1994;84:643-9. 27. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle-cell disease. N Engl J Med 1994;330:1639-44. 28. Charache S, Barton FB, Moore RD, Terrin ML, Steinberg MH, Dover GJ, et al. Hydroxyurea and sickle-cell anemia: clinical utility of a myelosuppressive “switching” agent. Medicine 1996;75:300-26. 29. Claster S, Vichinsky E. First report of reversal of organ dysfunction in sickle-cell anemia by the use of hydroxyurea: splenic regeneration. Blood 1996;88:1951-3. 30. Gill FM, Sleeper LA, Weiner SJ, Brown AK, Bellevue R, Grover R, et al. Clinical events in the first decade in a cohort of infants with sickle-cell disease. Blood 1995;86:776-83. 31. Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, et al. Prediction of adverse outcomes in children with sickle-cell disease. N Engl J Med 2000;342:83-9.
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Because hemoglobin (Hb) F inhibits polymerization of deoxygenated sickle Hb, induction of Hb F synthesis in patients with sickle cell anemia (SCA) has become an important therapeutic goal for physicians.1 High levels of Hb F are
known to ameliorate major vaso-occlusive complications.2,3 Hydroxyurea, an inhibitor of ribonucleotide reductase, stimulates Hb F synthesis, perhaps by recruitment of early red cell progenitors with intrinsic high Hb F production.4
From St. Jude Children’s Research Hospital, Memphis, Tennessee, the University of Texas Southwestern Medical Center, Dallas, Medical College of Wisconsin, Milwaukee, the University of Colorado School of Medicine, Denver, and Duke University Medical Center, Durham, North Carolina.
Supported in part by the American Lebanese Syrian Associated Charities and by General Clinical Research Center grant Nos. M01RR00058 and M01RR00069, National Center for Research Resources, National Institutes of Health. Submitted for publication Mar 7, 2001; revision received May 16, 2001; accepted Aug 14, 2001. Reprint requests: Winfred C. Wang, MD, Department of Hematology/Oncology, St. Jude Children’s Research Hospital, Room R-6002, 332 N Lauderdale, Memphis, TN 38105. Copyright © 2001 by Mosby, Inc. 0022-3476/2001/$35.00 + 0 9/21/119590 doi:10.1067/mpd.2001.119590
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Treatment of adults with SCA with hydroxyurea resulted in fewer episodes of pain and acute chest syndrome, fewer transfusions, and a reduced number of hospitalizations.5 For school-aged children, hematologic response and lack of significant toxicity were demonstrated in a recent Phase I-II pediatric safety
See editorial, p 763 and related article, p 785. trial.6 Several small trials have also documented a decrease in acute vaso-occlusive events,7-14 which suggests that hydroxyurea has clinical efficacy in pediatric patients similar to that in adults. ALT ANC CSSCD
Alanine aminotransferase Absolute neutrophil count Cooperative Study of Sickle Cell Disease Hb Hemoglobin HIV Human immunodeficiency virus HUG-KIDS Phase I-II trial of hydroxyurea in children MCV Mean cell volume MRI/MRA Magnetic resonance imaging/angiography MSH Multi-Center Study of Hydroxyurea NCHS National Center for Health Statistics SCA Sickle cell anemia SJCRH St. Jude Children’s Research Hospital WBC White blood cell
Morbidity and mortality of SCA result not only from acute events, but also from chronic organ damage that affects the spleen, brain, lungs, kidneys, and liver. For example, functional asplenia occurs early in life and leaves young patients at high risk for overwhelming infection.15,16 Hydroxyurea has not previously been tested in very young children with SCA before the onset of
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VOLUME 139, NUMBER 6 chronic organ dysfunction. Theoretically, hydroxyurea administration at an early age might maintain Hb F at a high enough level to preserve organ function. We performed a collaborative pilot trial by using a fixed dose of hydroxyurea in unselected infants with SCA. Our primary objectives were to (1) examine the feasibility of hydroxyurea administration in this very young population, (2) determine the toxicity of hydroxyurea, (3) assess the effects of hydroxyurea on fetal Hb levels and blood counts, and (4) obtain pilot data regarding the potential of hydroxyurea to preserve splenic function.
MATERIAL AND METHODS Patient Selection and Treatment All patients had a confirmed diagnosis of Hb SS or Hb Sβ0 thalassemia and previous compliance with scheduled clinic visits. Patients were excluded from the study for significant nonsickle cell-related medical problems, HIV seropositivity, a recent red blood cell transfusion that resulted in an Hb A level above 10%, renal or hepatic dysfunction, iron deficiency, or concomitant medication that might interact with hydroxyurea. Enrollment was not made on the basis of clinical history or laboratory evidence of disease severity. Patients were enrolled over an 8-month period from November 1996 through June 1997. This open-label trial of hydroxyurea used a fixed dose of 20 mg/kg/day. Each child received hydroxyurea for 2 years. Hydroxyurea was administered as a liquid in flavored syrup at a concentration of 100 mg/mL and dispensed as a 4-week supply. The dose of hydroxyurea was rounded to the nearest 0.1 mL (10 mg) and adjusted for weight every 8 weeks. The study was independently reviewed and approved by the institutional review board at each participating
institution. Written informed consent that included the unknown potential for carcinogenicity with long-term use of hydroxyurea was obtained from parents or guardians.
Patient Evaluation and Monitoring Physical examination was performed before treatment and every 8 weeks thereafter. Serial blood counts were performed locally every 2 to 4 weeks. Measurements of Hb F and F cells were performed at Duke University Medical Center, Durham, NC, at 0, 8, 16, 32, 52, 80, and 104 weeks after initiation of treatment. The percentage of Hb F levels were measured by the 2minute alkali denaturation test, and Fcell numbers were determined with the use of an immunostaining technique.17 Serum alanine amino transferase (ALT) and creatinine were measured quarterly and ferritin semiannually at local centers. Families were considered noncompliant and removed from the study if they missed >3 clinic visits, did not obtain hydroxyurea refills, or reported that they failed to administer hydroxyurea on a regular basis.
Laboratory Toxicity and Adverse Events Hematologic toxicity was defined as an absolute neutrophil count <1.5 109/L, platelet count <80 109/L, decline in Hb >20% from the baseline, or Hb <5.0 g/dL. Nonhematologic toxicity included an increase in serum creatinine by >50% or ALT >2 the upper limit of normal. If toxicity was identified, hydroxyurea was discontinued. When the laboratory abnormality resolved, hydroxyurea was resumed at the previous dose. If toxicity lasted for more than 2 weeks or reoccurred after the medication was resumed, the dose was permanently decreased by 2.5 mg/kg/day. An adverse event was defined as death or a life-threatening clinical event likely to interfere either temporarily or permanently with the pa-
tient’s ability to continue to tolerate hydroxyurea therapy. Adverse events were reported to the institutional review board of each participating institution. An advisory committee of 4 pediatric hematologists with expertise in sickle cell disease critically reviewed the progress of the study annually.
Organ Function and Toxicity Spleen function was assessed by Tc 99m sulfur-colloid uptake performed locally at study entry and exit. All scans were interpreted by a pediatric radiologist who was blinded to patient status. Splenic uptake was compared with hepatic uptake and classified as normal, slightly decreased, markedly decreased, or absent as previously described.18 Paired scans then were reviewed to assess any change in splenic uptake. Sixteen children at 2 institutions (St. Jude Children’s Research Hospital, n = 10; Duke University Medical Center, n = 6) had magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) at study entry and exit. Neuropsychometric development was assessed with the Bayley Scales of Infant Development at study entry and either the Bayley examination (≤36 months) or the McCarthy Scales of Children’s Abilities at exit. Transcutaneous oxygen saturation measured by pulse oximetry was used as an indirect indicator of pulmonary function and performed quarterly at each institution. Growth was assessed by serial height and weight measurements, which were plotted on standard growth curves and monitored every 6 months for changes in growth velocity. Growth was examined retrospectively among an age- and genotype-matched comparison group from all 4 centers. Head circumference percentile measurements were determined by using National Center for Health Statistics standards.
Statistical Analyses Statistical distributions of the outcomes were examined using quantile791
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Table I. Hematologic toxicity associated with hydroxyurea
Patients n
Episodes n (%)
Blood counts n (%)*
17 15 6 6 16 8 2 1 7 1
57 (100) 35 (61) 14 (25) 8 (14) 42 12 2 1 7 1
76 (10) 50 (7) 18 (2) 8 (1)
Neutropenia (ANC <1.5 109/L) Nadir of ANC: 1.0–1.499 109/L 0.5–0.999 109/L <0.5 109/L Time to recovery:1 wk 2 wk 3 wk 4 wk Anemia exacerbation (≥20% decline) Thrombocytopenia (platelets <80 109/L)
9 (1) 1 (0.1)
*Percentage of total complete blood counts performed (n = 769).
quantile plots. Hematologic results were compared with results from the Cooperative Study of Sickle Cell Disease (CSSCD) by using hematologic values for children with SCA from birth to 5 years.19 For each of the 21 patients who completed 104 weeks of therapy, 3 control patients from the CSSCD were selected according to hemoglobinopathy diagnosis, gender, and availability of age-matched hematologic data. Because F-cell measurements were not performed by the CSSCD, age-matched values measured in the Duke University Hematology Research Laboratory17 were compared. Hematologic values and organ function at study entry and exit were compared using the 2-sided paired t test. The Wilcoxon/Mann-Whitney test and Wilcoxon signed rank test were used for comparisons of the absolute neutrophil count (ANC). Height and weight measurements were compared by using a quadratic regression model and estimation of polynomial coefficients.20
RESULTS Enrollment and Retention Twenty-eight children were enrolled in the study and received treatment. All were black with a diagnosis of Hb SS (n = 27) or Hb Sβ0 thalassemia (n = 1). Their median age at entry was 15 792
months (range, 6-28 months); 16 were boys. Twenty-one patients (75%) completed 104 weeks of follow-up at a median age of 39 months (range, 30-52 months). Seven patients did not complete the study: 2 were removed for noncompliance (after 7 and 14 months, respectively), the parents of 3 patients elected to discontinue participation, 1 patient was placed on chronic transfusions after a mild stroke, and one died from splenic sequestration. No significant differences were identified in the enrollment laboratory values for these 7 patients compared with the patients who completed 2 years of hydroxyurea therapy.
Toxicity Toxicity from hydroxyurea was primarily hematologic (Table I). Neutropenia occurred 57 times in 17 patients and was present in 10% of all blood counts. Neutropenia occurred a median of twice per patient (range, 110 episodes) with a median duration of 1 week (range, 1-4 weeks), and was associated with an intercurrent illness (usually an upper respiratory tract infection) in 40 episodes (70%). Neutropenia was never associated with an invasive bacterial infection; in 4 episodes, patients with an ANC <500 109/L were hospitalized because of
fever. Severe anemia occurred 7 times in 7 patients, was associated with acute illness on 4 occasions, and required transfusion in one patient. Thrombocytopenia (platelet count 76 109/L) occurred once in association with a viral illness. Elevation of serum ALT (167 IU/L) occurred once without explanation and resolved within 1 week. Mean levels of serum ALT and creatinine were unchanged throughout the study. Three patients had hydroxyurea dose reductions for persistent or recurrent neutropenia, to 17.5 mg/kg/day in two, and to 12.5 mg/kg/day in one. These 3 infants had an average (mean ± SD) ANC of 2.5 ± 1.1 109/L before beginning hydroxyurea, compared with a pretreatment mean ANC of 4.6 ± 2.4 109/L in patients who did not require dose modification (P = .11). Two patients had an accidental overdose of hydroxyurea. One ingested 15 his daily dose; ipecac was used to induce emesis, and hydroxyurea was withheld for 21 days. Weekly ANC values were 1350, 1281, and 1656 109/L after the ingestion. The second patient ingested 2.5 his normal daily dose, and hydroxyurea was held for 11 days. His ANC values were 840 and 1694 109/L on days 7 and 11. Neither patient had clinical symptoms.
Hematologic and Biochemical Results Study patients had similar hematologic values at study entry compared with case control patients (Table II). At Week 104, treated patients had increases in average Hb, mean cell volume (MCV), Hb F, and F cell levels, as well as declines in mean white blood cell (WBC) and platelet counts. Most of these values were significantly different than those from control patients (Table II). Most of the infants had an upward trend in Hb, MCV, and Hb F levels compared with the expected agerelated changes documented in the CSSCD (Fig 1). Serial hematologic data indicated that these effects of hydroxyurea were generally apparent by
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VOLUME 139, NUMBER 6 Table II. Comparison of expected and observed hematologic results at study entry and exit for patients who completed 2 years of treatment (n = 21)
Entry (wk 0) Result Hb (g/dL) MCV (fL) Hb F (%) F cells (%) WBC (109/L) Platelets (109/L)
Exit (wk 104)
Observed n ± SD
Expected* n ± SD
Significance (P value)
Observed n ± SD
Expected* n ± SD
8.5 ± 1.4 81.7 ± 8.0 21.8 ± 7.8 80.6 ± 14.1 12.6 ± 4.4 410 ± 169
8.5 ± 1.2 79.0 ± 7.9 21.3 ± 11.2 80.5 ± 12.4 12.5 ± 3.6 336 ± 130
.91 .25 .84 .98 .90 .026
8.8 ± 1.2 90.0 ± 9.6 20.3 ± 4.9 76.2 ± 12.4 10.1 ± 3.2 352 ± 125
7.7 ± 1.0 84.1 ± 10.1 10.9 ± 7.9 65.4 ± 11.2 14.3 ± 2.4 436 ± 185
Significance (P value) .004 .069 < .001 .006 < .001 .057
*Calculated on the basis of data extracted from the CSSCD19 (see “Material and Methods”) and from the Duke University Pediatric Hematology Research Laboratory (for F cells).17
Table III. Time course for hematologic effects of hydroxyurea
Mean values (n)
Wk 0 (28)
Wk 8 (27)
Wk 16 (26)
Wk 32 (24)
Wk 52 (22)
Wk 80 (21)
Wk 104 (21)
Hb (g/dL) MCV (fL) Hb F(%) F cells (%) WBC (109/L) ANC (109/L) Platelets (109/L)
8.5 81.6 21.9 80.6 12.7 4.5 410
8.5 86.7 22.6 85.8 11.3 3.7 342
9.0 86.3 23.1 87.4 10.5 3.5 391
9.0 88.4 22.6 86.1 10.9 4.3 375
9.2 90.7 23.5 85.1 10.6 3.4 372
8.9 90.9 19.1 83.4 9.7 3.6 347
8.8 90.0 20.3 76.2 10.1 4.2 352
Change in mean value* +0.3 +8.4 –1.6 –4.4 –2.6 –0.3 –58
*Values at week 104 compared with those at week 0.
weeks 8 through 16 of therapy (Table III).
Organ Function Four patients had surgical splenectomy before entry; 17 patients had liverspleen scans performed at both study entry and exit. At entry, mildly decreased splenic uptake was observed in 8 patients, markedly decreased uptake in five, and absent uptake in four. Direct comparison of liver-spleen scans before and after 2 years of treatment showed no change in eleven, greater uptake in one, and less uptake in five. Splenic uptake was absent in eight of 17 children (47%) at week 104, including the 4 patients with absent uptake at study entry. Small areas of increased signal intensity on T-2 weighted images, consistent with silent brain infarcts, were seen in
two of 16 MRI scans at week 0 and 4 scans at week 104. No brain atrophy was seen, and MRA showed no stenoses or occlusions. On neurodevelopmental examination of patients (n = 10), the mean developmental score was 93.7 at week 0 and 89.5 at week 104 (P = .56). All transcutaneous oxygen saturation levels were >95% throughout the study. Mean oxygen saturation was 98.6% ± 1.3% initially and 98.2% ± 1.6% at week 104. No patient had decreased growth velocity. No significant differences in height or weight were found between patients and untreated age-matched control patients with Hb SS. Mean head circumference measurements were 46.9 cm at entry and 50.3 cm at exit; National Center for Health Statistics percentiles were unchanged for both boys and girls.
Clinical Adverse Events Two patients developed splenic sequestration; neither had an enlarged spleen at the onset of the study. One 25-month-old girl developed acute splenomegaly that was palpable 6 cm below the costal margin with an Hb of 4.0 g/dL (previously 9.9 g/dL). She was transfused, had an elective laparoscopic splenectomy, and remained on hydroxyurea therapy. The second patient was a 14-month-old boy whose Hb level dropped from 8.4 g/dL to 6.0 g/dL associated with fever and mild splenomegaly. His Hb level increased to 7.7 g/dL without transfusion, and he continued to receive hydroxyurea for the next 2 months. He then experienced a fatal episode of splenic sequestration, characterized by rapid onset of lethargy and fever, massive splenomegaly, and an Hb level of 2.4 g/dL. 793
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DISCUSSION
Figure. Comparison of initial (week 0) and final (week 104) hematologic values for 21 patients who completed 2 years of hydroxyurea treatment. Changes in Hb (A), MCV (B), and Hb F levels (C) are depicted.Values at week 0 are indicated with circles and at week 104 with triangles.The “background” lines in each figure delineate the 5th, 50th, and 95th percentiles for subjects from the CSSCD.19
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In this pilot study conducted at 4 institutions, administration of hydroxyurea to young infants with SCA was found to be feasible. The liquid formulation of hydroxyurea was well accepted by parents and children; 21 of 28 patients who began the study completed the full 2 years of therapy. Toxicity related to hydroxyurea was predominantly mild and reversible neu-
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VOLUME 139, NUMBER 6 tropenia. Most episodes of neutropenia were associated with presumed viral infections and lasted only 1 week; no invasive infections occurred during these episodes. Persistent or recurrent neutropenia required a decrease in the dose of hydroxyurea in only 3 patients. The higher frequency of neutropenia in our patients (10% of blood counts), compared with the 5.2% rate observed in school-aged children,6 is likely because of a lower baseline neutrophil count and a higher incidence of viral illnesses. Anemia and thrombocytopenia were rare, and no significant renal or hepatic toxicity was observed. The 2 patients who received accidental overdoses of hydroxyurea had only mild transient neutropenia. No adverse effects on growth were observed in our patients compared with untreated control patients, which further suggests that hydroxyurea can be administered safely in this very young population. Finally, no clear neurologic toxicity was observed, although MRI, MRA, and neurodevelopmental testing are difficult to interpret because of the limited data for untreated patients in this age range.21 A recent abstract22 suggests adverse effects of hydroxyurea on brain development in infant mice, but the small numbers of animals, very high dose of drug, and different route of administration limit the relevance of the results to humans. The risks and benefits of hydroxyurea therapy in the setting of cerebrovascular disease in SCA remain unclear,23,24 and a larger controlled trial will be required to fully address this question. Hematologic responses to hydroxyurea therapy mimicked responses observed in older patients,5,6 although the responses must be interpreted in light of the physiologic changes that occur normally in very young children with SCA. The maintenance of relatively stable Hb and Hb F levels of the infants in our study demonstrates a clear response to hydroxyurea when compared with the expected declines in those levels.19,25 Changes in the number of F
cells paralleled the changes in the percentage of Hb F, providing additional evidence for hematologic efficacy. The declines in WBC count and platelet count, at a time when both would be expected to increase also may be clinically relevant. An elevated WBC count has been implicated as a risk factor for a number of vaso-occlusive complications of SCA,26,27 and suppression of neutrophil formation may partially explain the clinical benefits of hydroxyurea.28 Our data suggest a beneficial effect of hydroxyurea on the preservation of splenic function, although the limited number of patients precluded demonstration of statistical significance. After 2 years of hydroxyurea treatment, 47% of children had functional asplenia at an age when about 80% would be expected to have asplenia by red cell pit counts.19 Anecdotal splenic regeneration has been reported in 2 young adults treated with hydroxyurea, one of whom later required splenectomy.29 It is possible that hydroxyurea may delay the development of functional asplenia but prolong the period of risk for acute splenic sequestration, a complication that occurred in two of our patients. Despite the effects of hydroxyurea in preventing the expected decline of Hb F levels in our patients, they experienced a number of clinical adverse events, including death in one. The scope of our study, the limited period of drug exposure (47 patient-years), and the use of a hydroxyurea dose lower than the predicted maximum tolerated dose prevent valid comparisons of the incidence of vaso-occlusive events in our patients with those reported by the CSSCD,30 although no striking differences in approximate incidence are apparent. Dose escalation to maximum tolerated dose should be tested in future trials to fully assess the clinical efficacy of this intervention. Hydroxyurea might also be considered for infants with a high risk for severe complications of sickle cell disease, such as those recently identified by the CSSCD.31
In summary, our pilot study has shown that administration of a liquid preparation of oral hydroxyurea to very young children with SCA is feasible and well tolerated, and is associated with limited and manageable hematologic toxicity. When used in a fixed dose, hydroxyurea treatment resulted in the maintenance of a 20% Hb F level over a 2-year period. On the basis of these pilot data, future researchers should seek definitive evidence of benefit from hydroxyurea in the preservation of the function of the spleen and other organs. A large Phase III trial addressing this question has been initiated by the National Heart, Lung, and Blood Institute. Our data provide a solid foundation for this trial and are relevant for questions of dosing, monitoring, and end point determination. We are indebted to Sara Day, Amy Walker, Evelyn Brown, Gwendolyn Lea, Juanita Dale, Bonita Williams, Lelia Nelson, and Bertha Davis for nursing and data coordination; Drs Joan Hu and Ming Tan for biostatistical analysis; Drs James Langston, Kathleen Helton, and Thomas Hay for review of diagnostic imaging; Drs William Crom and John Rodman for pharmatherapeutic support; Drs Vanessa Elliott and Ray Mulhern for neuropsychometric evaluation; Dianne Gallagher for liaison with the CSSCD; and Patsy Burnside for word processing. We are especially grateful to Drs Scott Miller, Michael DeBaun, Doris Wethers, and Sharada Sarnaik for serving as an advisory committee to this study.
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14. Olivieri NF, Vichinsky EP. Hydroxyurea in children with sickle-cell disease: impact on splenic function and compliance with therapy. J Pediatr Hematol Oncol 1998;20:26-31. 15. Pearson HA, Spencer RP, Cornelius EA. Functional asplenia in sickle-cell anemia. N Engl J Med 1969;281:923-6. 16. Wong W-Y, Overturf GD, Powars DR. Infection caused by Streptococcus pneumoniae in children with sickle-cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination. Clin Infect Dis 1992;14:1124-36. 17. Marcus SJ, Kinney TR, Schultz WH, O’Branski EE, Ware RE. Quantitative analysis of erythrocytes containing fetal hemoglobin (F cells) in children with sickle-cell disease. Am J Hematol 1997;54:40-6. 18. Lane PA, O’Connell JL, Lear JL, Rogers ZR, Woods GM, Hassell KL, et al. Functional asplenia in hemoglobin SC disease. Blood 1995;85:2238-44. 19. Brown AK, Sleeper LA, Miller ST, Pegelow CH, Gill FM, Waclawiw MA. Reference values and hematologic changes from birth to 5 years in patients with sickle-cell disease. Arch Pediatr Adolesc Med 1994;148:796-804. 20. Liang KL, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13-22. 21. Wang WC, Langston JW, Steen RG, Wynn LW, Mulhern RK, Wilimas JA, et al. Abnormalities of the central nervous system in very young children with sickle-cell anemia. J Pediatr 1998;132:994-8. 22. Horiuchi K, Golden JA, Das SK, Scully M, Liang L, Ohene-Frempong K, et al. Adverse effects of hydroxyurea on growth and development of young mice. Blood 1998;92:160a.
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