Clinical and hematologic effects of hydroxyurea in children with sickle cell anemia
Somasundaram Jayabose, MD, Oya Tugal, MD, Claudio Sandovai, MD, Padma Patel,. MD, Douglas Puder, MD, Teresa Lin, BA, and Paul Visintainer, PhD
From the Sections of Pediatric Hematology-Oncology and General Pediatrics, and the De- partment of Quantitative Health Sciences, New York Medical College, Valhalla
Purpose: This open-label pilot study was designed (I) to determine the effect of hydroxyurea on the hemoglobin level in children with sickle cell anemia, (2) to evaluate the toxicity of hydroxyurea, and (3) to assess any impact of hydroxyurea on the frequency of vaso-occlusive crises (VOCs). Patients and methods: Ten children (group I) with three or more VOCs of the ex- tremities or two or more VOCs of the lungs (acute chest syndrome) in the preced- ing 12 months, and five children (group 2) with hemoglobin levels less than 70 gm/L were treated with hydroxyurea in doses of 20 to 35 mg/kg per day. The frequency of VOCs before hydroxyurea therapy was compared with the frequency during therapy, and the peak hemoglobin levels during hydroxyurea therapy were compared with the pretreatment values. Results: One patient in group I was removed from the study within I month be- cause of nausea. Seven of the remaining nine patients in group I had a decrease in the frequency of VOCs. The number of VOCs per patient-year for all 14 patients decreased from 2.5 before hydroxyurea therapy to 0.87 during hydroxyurea ther- apy, a decrease of 65% (p <0.00001). Two of five patients in group 2 had an in- crease in hemoglobin of 27 gm/L and 34 gm/L over the baseline. The median rise in hemoglobin was 19 gm/L (range, 7 to 37) for all 14 patients. Nine patients are still receiving hydroxyurea for a median period of 23 months (range, 18 to 59). Conclusions: Hydroxyurea decreases the severity of anemia in some patients, and it may decrease the frequency of VOC. Its short-term hematologic toxicity is min- irnal. (J Pediatr 1996; 129:559-65)
Pain crisis and anemia are the most conspicuous features of
sickle cell anemia. ~ Vaso-occlusive crisis is the most com-
mon reason for hospitalization in patients with SCA, 2 and the frequency of crises has prognostic significance for life
expectancy. Only 40% of the young adults with more than
Supported in part by a grant from Healix Health Care Inc. Presented in part at the twentieth annual meeting of the National Sickle Cell Disease Program, Boston, Mass., March 18-21, 1995 (abstract 1751).
Extr, VOC of extremities. *Number of VOCs per patient-year. ?Average number of VOCs per patient-year.
improves their exercise capacity. 8 The degree of growth de-
lay in these patients may also correlate with the severity of anemia. 9
It is well known that HbF reduces the rate of sickle poly-
mer formation in vitro, and patients with SCA and high lev-
els of HbF frequently have milder disease. 1°13
Hydroxyurea has been shown to increase the level of HbF, the percentage of F reticulocytes and F cells, the HbF/F cell ratio, and the hemoglobin levels in patients with SCA. 14,15
In addition, a recent double-blind study in adults with SCA
has shown that hydroxyurea decreases the frequency of VOC
by 44% in comparison with the untreated group.16 No such
data are available on children.
We began an open-label pilot study in October 1990 to determine the effect of hydroxyurea on the hemoglobin lev-
els in children with SCA, to evaluate the toxicity of hydrox- yurea, and to assess any impact of hydroxyurea on the fre-
quency of VOC. Herein we present the results of this study.
METHODS
Patients (Table I). From October 1990 to November 1995; a total of 15 children (male/female ratio, 10:5) were enrolled in an open-label, single-arm hydroxyurea study ap- proved by the institutional review board. The median age of the patients was 15.3 years (range, 4.4 to 18.8). Parental consent was obtained for all patients. Patients with SCA and frequent VOCs (group 1) or severe anemia (group 2) were considered eligible for study. Frequent VOC was defined as three or more hospitalizations for VOCs involving the
extremities or trunk, or two or more hospitalizations for
VOCs of the lungs (acute chest syndrome), in the preceding
12 months. Severe anemia was defined as hemoglobin lev-
els consistently less than 70 gm/L except during posttrans-
fusion periods. Ten patients were entered into group 1 and five (Nos. 10 to 14) in group 2. Of the 10 patients in group
1, only nine (Nos. 1 to 9) are evaluable because one patient had to discontinue treatment within 1 month because of se-
vere nausea. Of these nine patients, four had predominantly
VOC of the extremities and five (Nos. 1, 3, 5, 8, 9) had fre-
quent episodes of ACS.
Laboratory methods. Complete blood cell counts were
done by routine Coulter counters (Coulter Electronics, Hialeah, Fla.). Differential counts and reticulocyte counts
were done manually. All HbF determinations throughout the
course of the study were done by the same laboratory, by high-performance liquid chromatography.
Study design. Hydroxyurea therapy was started at 20
mg/kg per day, and increments of approximately 5 mg/kg were made at intervals of 4 to 8 weeks if the absolute neu- trophil count remained greater than 1.5 x 109 and the plate- let count greater than 150 x 109/L. The protocol required withholding further increases of hydroxyurea for an ANC of 1.0 to 1.5 x 109/L or a platelet count of 100 to 150 x 109/L,
and discontinuing therapy for at least a week for an ANC of less than 1.0 x 109/L or a platelet count of less than 100 x 109/L. Dosage was kept constant after a dose of 35 mg/kg per day or an absolute dose of 2000 mg/day was reached. In patients whose HbF levels rose to more than
The Journal of Pediatrics Jayabose et al. 5 6 1 Volume 129, Number 4
20%, further increases in dosage were avoided because we considered a level of more than 20% HbF to be a good re- sponse to hydroxyurea therapy and possibly sufficient to re- sult in clinical benefits. The drug was administered orally once daily. In young children, 125 mg capsules were used to make accurate dosing possible.
Monitoring compliance was attempted by using a diary system in which patients circled the dates on a calendar af- ter taking their dally medication. However, many patients failed to keep the diary. Two patients (Nos. 1 and 4) ad- mitted to frequent lapses in taking their medications. All pubertal patients were informed about the possibility of ter- atogenic effects in their offspring during therapy with hydroxyurea, and they were given counseling regarding contraception.
Baseline studies before the start of hydroxyurea therapy included complete blood cell count, reticulocyte count, de- termination of HbF level, and serum chemistry profile including aspartate aminotransferase, alanine aminotrans- ferase, total bilirubin, blood urea nitrogen, and creatinine. During follow-up, a complete blood cell count, a reticulocyte count, deteJ~nination of HbF level, and serum chemistry studies were done at 2, 4, and 8 weeks after the beginning of hydroxytucea therapy, after each dosage increase, and ev- ery 12 weeks thereafter.
We defined VOC as any painful episode involving the extremities, abdomen, back, or chest, including ACS that resulted in hospitalization. ACS itself (considered as VOC of the lungs;) was defined as an episode of respiratory dis- tress associated with infiltrates in the lung and requiring hospitalization. The institutional practice before the hydrox- yurea study was to hospitalize any patient with ACS and with other VOCs not responding to acetaminophen with codeine and oral fluids. This practice was not modified during the study period. All patients requiring intravenous administra- tion of narcotics in the emergency department were also hospitalized. Accurate records maintained for patients re- ceiving hydroxyurea therapy included the number of days in the hospital, hematologic values, and transfusion require- merits. To assess the frequency of crises before hydroxyurea therapy was assessed, we took into account the whole dura- tion of close follow-up (not just the previous 12 months) at the participating institution. For example, in patient 8 the pretreatment crisis rate was calculated as 0.6/yr for a pre- therapy follow-up period of 6.6 years, though she had two ACS episodes in the 12 months preceding hydroxyurea therapy. By including a longer period of pretreatment follow-up, one is more likely to obtain a true pretreatment crisis rate. Details of hospitalization and diagnosis of VOC and ACS before hydroxyurea therapy were obtained from hospital charts and pediatric hematology records. Episodes of crises that were not severe enough to require hospitaliza-
tion were not considered as VOCs for the study purpose and thus were not included in the analysis of the results. Hospi- talizations strictly related to febrile illnesses without associ- ated VOC were also excluded from the analysis.
Statistical methods. Data were analyzed with a standard- ized morbidity ratio 17 and a chi-squared goodness-of-fit test, which compared the observed number of posttreatment VOCs with the expected number of posttreatment VOCs. The expected number of posttreatment VOCs was computed on the basis of the pretreatment rate of VOC. Thus, if treat- ment had no effect on the disease, pretreatment and post- treatment rates of VOC would be similar, resulting in sim- ilar observed and expected posttreatment VOCs. The chi- squared goodness-of-fit test with k degree's of freedom tested whether deviations between the observed and expected number of VOCs are due to random fluctuation. The test was based on the assumption that VOCs occurred randomly dur- ing the follow-up periods. An SMR greater than t.0 indicates that the treatment increased the risk of VOCs, whereas an SMR less than 1.0 indicates that treatment was effective in decreasing VOCs.
R E S U L T S
Frequency of VOCs. When all 14 patients were consid- ered, 138 VOCs occurred before hydroxyurea therapy dur- ing 55.2 patient-years of follow-up, for an average of 2.5 VOCs per patient-year (Table I). The total number of VOCs during hydroxyurea therapy was 31 in a period of 35.7 pa- tient-years, for an average of 0.87 VOC per patient-year. This represents a 65% decrease in the frequency of VOCs and is statistically significant (p <0.00001).
Statistical analysis. On the basis of the pretreatment event rate of 2.5 events per patient-year, a total of 89.3 crises would be expected during the treatment period if the treatment had no effect on the outcome; however, only 31 events were ob- served. The resulting SMR (i.e., 31/89.3 = 0.35) and the 95% confidence interval showed a 65% reduction in the rate of VOCs during treatment (SMR=0.35; 95% confidence interval = 0.24 to 0.50). A chi-squared goodness-of-fit test confirmed the significance of the reduction of VOC (chi- square value [14 dJ] = 56.85; p <0.00001).
Seven of the nine patients entered into the study because of frequent VOCs had a decrease in the number of VOCs during hydroxyurea therapy; four of them did not have any crisis during this therapy. All five patients entered into the study because of frequent ACS episodes had a decrease in the number of crises; three of them did not have any crisis during hydroxyurea therapy. Overall, 7 of 14 patients did not have any crisis during therapy for a period of 1.2 to 4.5 years. Patient 2, who had 21 crises during a period of 7.2 years be- fore hydroxyurea therapy, has not had any crisis for a period of 4.5 years during hydroxyurea therapy, even though his
5 6 2 Jayabose et al. The Journal of Pediatrics October 1996
120
100
80 E O1
. m
-~ 6o
0
E = 40
20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 i J i i
Group I Group II Patient ID
Fig. I. Changes in hemoglobin concentration during hydroxyurea therapy. Shaded bars indicate values before therapy; striped bars indicate values during therapy.
hemoglobin concentration increased from 83 gm/L before hydroxyurea therapy to 120 gm/L during therapy.
Two patients (Nos. 6 and 7) did not show any decrease in the frequency of crises during hydroxyurea therapy. In pa- tient 6 the peak HbF value was only 13.7% with a hydrox- yurea dose of 23.5 mg/kg per day. The dose was not increased further because 6f mild hair loss. Patient 7, on the other hand, had his third crisis in the twelfth month of hy- droxyurea therapy, despite an HbF value of 24.1%.
The number of hospital days (for the treatment of crises) per patient-year decreased from 13.8 (763 days for 55.2 pa- tient-years) before hydroxyurea therapy to 4.9 (!75 days for 35.7 patient-years) during hydroxyurea therapy. This repre- sents a decrease of 64%, which is statistically significant (p <0.00001). The mean duration of crisis during hydroxyurea therapy was not significantly different from the duration of crisis before therapy (5.7 vs 5.3 days).
The number of transfusions given per patient-year de- creased from 1.83 (101 transfusions for 55.2 years) before hydroxyurea therapy to 0.2 (7 for 35.2 years) during therapy. However, the indications for transfusions were not uniform for the two periods--before and during hydroxyurea ther- apy. For example, three patients (Nos. 1, 2, and 6) received monthly transfusions intermittently for variable periods be- fore hydroxyurea therapy because of frequent crises. On the other hand, transfusions were discouraged for the patients receiving hydroxyurea because increased hemoglobin levels might decrease the efficacy of hydroxynrea by inhibiting erthropoiesis. Two patients received a total of three exchange
transfusions for severe ACS during the period before hydroxyurea therapy. No patient received exchange transfu- sions during hydroxyurea therapy.
Hemoglobin levels. The median increase in hemoglobin level (Fig. 1) for all 14 patients was 19 gm/L (range, 7 to 37 gm/L), an increase of 8% to 50% over the baseline values. Two of the five patients entered into the study for severe anemia had marked increases in hemoglobin levels: 27 and 34 gm/L over the baseline level, representing an increase of 44.5% and 50%, respectively, over baseline. In seven patients the peak hemoglobin level during hydroxyurea therapy reached 90 gm/L or more.
Other laboratory data. There was a significant increase in the mean HbF values and mean MCV values during hy- droxyurea therapy (Table II). In 9 of 14 patients the HbF value rose to more than 15%, and in seven of them more than 20% (Fig. 2). The mean platelet count and the mean leuko- cyte count were significantly lower during hydroxyurea therapy. However, the ANC did not show a significant drop during hydroxyurea therapy. The mean values for reticulo- cyte count, total bilirubin concentration, and lactate dehy- drogenase activity also showed a significant decrease during hydroxyurea therapy, suggesting a decrease in hemolysis as a result of hydroxyurea therapy.
Hydroxyurea dosage and HbF level. In seven patients, an HbF level of more than 20% was achieved with hydrox- yurea doses of 20.8 to 35 mg/kg. In three patients (Nos. 1, 10, 12) the rise in HbF level was not as marked (13.7%, 11%, and 12%, respectively); their peak mean corpuscular vol-
The Journal of Pediatrics Jayabose et al. 5 6 3 Volume 129, Number 4
umes were 101,120, and 108 fl, respectively. In patient 6 the maximum dose could not be maintained because of hair loss. The median hydroxyurea dose was 25.9 mg/kg (range, 20 to 35 mg/kg).
Toxicity, One patient had severe nausea, which did not improve with antiemetics including orally administered on- dansetron, and discontinued therapy within a month. Patient 6 had mild hair loss at a hydroxyurea dosage of 23.5 mg/kg per day; the hair toss subsided after the dosage was decreased to 18.75 mg/kg per day. Patient 2 had asymptomatic neutro- penia (AN(;: 0.840 x 109/L), which resolved without any decrease in the dosage. This patient also had varicella dur- ing the second year of hydroxyurea therapy; he was treated with orally administered acyclovir and recovered from the illness without any complications. No patient had thromb- ocytopenia during therapy.
Other events during hydroxyurea therapy. One patient (No. 4) had bilateral osteonecrosis of the femoral head in the third year of hydroxyurea therapy, and the osteonecrosis has progressed during hydroxyurea therapy. Another patient (No. 2), who had bilateral osteonecrosis of the femoral head 2 years before hydroxyurea therapy was begun, has stable disease with minimal symptoms. No patient had a stroke, priapism, or renal complications hydroxyurea therapy. No deaths occurred in the patients treated with hydroxyurea.
Follow-up. Nine patients are continuing with hydrox- yurea therapy for a median period of 23 months (range, 18 to 59 months). Therapy was discontinued for lack of benefit in 1 (patient 6) of 9 patients entered into the study for fre- quent VOCs. Another patient (No. 5) in this group elected to discontinue therapy despite a marked decrease in the fre- quency of crises. Three of five patients (Nos. 10, 12, and 13) entered inte the study for severe anemia were removed from the study because the increase in their hemoglobin levels (20.5%, 10.2%, and 19.6% over the baseline value) were considered insufficiently high to justify continued hydrox- yurea therapy. The median duration of therapy for the five patients who have discontinued therapy was 15 months (range, 15 to 30 months).
D I S C U S S I O N
In this open-label pilot study the number of VOCs per pa- tient-year was significantly less during hydroxyurea therapy than during; the pretherapy period (0.87 vs 2.5 VOCs; p <0.00001), :representing a 65 % reduction in the frequency of crises. However, because of the open-label design of the study, a placebo effect on decreasing the frequency of crises could not be ruled out.
A double-blind study of adults has recently shown that hydroxyurea decreases the frequency of crises by 44% in comparison with the untreated group. 16 Two other open-la- bel studies in children have reported a decrease in painful
T able II. Comparison of pretreatment values with values at maximum dose of hydroxyurea
Values are expressed as mean + SD. MCV, Mean corpuscular volume; LDH, lactate dehydrogenase. *p by paired t test.
crises with hydroxyurea therapy, deMontalembert et al. is reported a decrease in the number of painful crises in 27 of 28 children who had three or more crises before therapy with hydroxyurea. In a study by Scott et al., 19 6 of 11 patients had a 67% reduction in hospitalizations. The current study shows that the number of days spent in the hospital per year was significantly less during hydroxyurea therapy. However, the average duration of individual crisis was not significantly different with therapy.
In vitro studies have shown that the extent of polymer formation is inversely proportional to the concentration of HbF. 12 Therefore it is likely that higher HbF levels may of- fer greater clinical benefit. However, a higher HbF level may not necessarily translate into clinical benefit in all patients. One patient in our study had his third crisis while his HbF value was 24.1%. An increase in the HbF level may not be the sole mechanism for the clinical benefits of hydrox- yurea. 2° Instead, other factors such as increased MCV, 21 in- creased deformability, 22 and decreased adhesion of erythro- cytes to the endothelium 15 may also play an important role. The observation that most responding patients did not have crises even during the first few months of hydroxyurea ther- apy may support these hypotheses, because peak HbF levels are not reached until a few months after the start of hydrox- yurea therapy.
Increasing the hemoglobin levels in patients with SCA who were undergoing transfusion therapy improved the exercise capacity of these patients in one study of adult pa- tients. 8 Although parameters of exercise capacity were not objectively evaluated in our study, two male adolescents with increases in their hemoglobin levels of 37 and 34 gm/L (increase of 44.5% and 50%) over their pretreatment values
5 6 4 Jayabose et al. The Journal of Pediatrics October 1996
30
25
"" 2O f -
0
o 15
"T"
" 10
1 2 3 4 5 6 7 8 9 10 11 12 13 14 * i i i
Group I Group II Patient ID
Fig. 2. Changes in fetal hemoglobin levels during therapy with hydroxyurea. Shaded bars indicate values before therapy; striped bars indicate peak levels during therapy.
, reported marked improvements in their exercise tolerance during hydroxyurea therapy. Although an increase in hemo- globin levels may improve the general well-being and exer- cise tolerance of these patients, it should be emphasized that isolated chronic anemia (excluding events such as splenic sequestration or aplastic crises) is not a major cause of mor- bidity or death in children with SCA. Therefore, until much more is known about the long-term toxic effects on growth and organ dysfunction, hydroxyurea should not be used in the clinical setting solely for the treatment of anemia.
Increasing the hemoglobin concentration of the sickle cell blood in vitro, even with normal erythrocytes, increases its viscosity and impairs its flow properties. 23 Such data provide the basis for the clinical recommendation of avoiding hematocrit levels greater than 35% when patients with SCA undergo transfusion therapy. 24 However, increased hemo- globin levels resulting from hydroxyurea therapy may not increase the risk of VOC, because the increase in hemoglo- bin is mostly caused by the increase in HbF concentration. No increase in the frequency of crises was observed in our patients who had a significant increase in hemoglobin lev- els, including the patient with a peak hematocrit of 36% who has not had a crisis in 4.5 years of hydroxyurea therapy.
Although hydroxyurea has been shown to be effective in reducing the frequency of painful crises in adults, it is un-
likely that it reverses the organ damage of SCA. 25 It is also not known whether it will prevent chronic organ damage. The occurrence of osteonecrosis of the femoral head during hydroxyurea therapy in one of our patients and in another patient reported by Berman and Chiarucci 26 suggests that hydroxyurea may not prevent the chronic organ damage of SCA. In addition, other investigators have reported fatal ep- isodes of stroke during hydroxyurea therapy. 27
This study did not establish a maximum tolerated dose of hydroxyurea, but our results do sugges t that a dosage of 20 to 35 mg/kg can result in a significant rise in HbF in most patients, without serious toxic effects. The side effects were infrequent and were limited to nausea, transient hair loss, and neutropenia. Hepatic dysfunction and renal dysfunction caused by hydroxyurea have not been reported in the liter- ature and were not seen in any of our patients.
Limited data are available regarding the long-term toxic effects of hydroxyurea in children, especially the carcino- genic or leukemogenic effects. In a French study of 64 pa- tients (aged 5 to 45 years; mean, 20.5 years) with erythro- cytosis caused by inoperable congenital heart disease, which was treated with hydroxyurea (10 to 20 mg/kg per day) for 2 to 15 years, there were no cases of malignancy or irrevers- ible toxic effects. 28 In addition, the Polycythemia Vera Study Group, which studies adults, did not find a statistically sig-
The Journal of Pediatrics Jayabose et al. 5 6 5 Volume 129, Number 4
nificant increase in the incidence of acute leukemia in the
hydroxyurea-treated patients, in comparison with phleboto-
my-treated patients. 29
In conclusion, the results of this study show that hydrox-
yurea decreases the severity of anemia in some children with
SCA, and it may decrease the frequency of their VOCs. Its
short-term hematologic toxicity is minimal. A double-bfind
study involving a larger number of children will be neces-
sary to demonstrate both its efficacy in decreasing the fre-
quency of VOCs and its safety with long-term use in chil-
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4. Alpert BS, Gilman PA, Strong WB, et al. Hemodynamic and ECG responsed to exercise in children with sickle cell anemia. Arch Pediatr Adolesc Med [Am J Dis Child] 1981:135:362-6.
5. Alpert BS, Dover EV, Srong WB, Covitz W. Longitudinal ex- ercise hemodynamics in children with sickle cell anemia. Arch Pediatr Adolesc Med [Am J Dis Child] 1984;138:1021-4.
6. Cowitz W, Eubig C, Balfour IC, et al. Excercise-induced car- diac dystuncfion in sickle cell anemia. Am J Cardiol 1983; 51:570-5.
7. Balfour IC, Covitz M, Arensman RW, Eubig C, Garrido M, Jones C. Left ventricular filling in sickle cell anemia. Am J Cardiol 1988;61:395-9.
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19. Scott JP, Misiewicz VM, Robinson E, Hillery CA, Labotka RJ. Long-term follow-up of severely affected children with sickle cell disease treated with hydroxyurea [abstract 240]. Twentieth National Sickle Cell Disease Program, March 18-21, 1995.
20. Orringer EP, Blythe DSB, Johnson AE, Phillips G Jr, Dover GJ, Parker JC. Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia. Blood 1991;78:212-6.
21. Ballas SK, Dover GJ, Charache S. The effect of hydroxyurea on the rheological properties of sickle erythrocytes in vivo. Am J Hematol 1989;32:104-11.
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