May 13, 2011 — Hydroxycarbamide can be considered for treatment of all very young children with sickle cell anemia, according to the results of a randomized, double-blind trial reported in the May 14 issue of The Lancet.
"Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life," write Winfred C. Wang, from St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues. "Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects."
Between October 2003 and September 2009, eligible participants from 13 US centers were enrolled without regard to clinical severity. Inclusion criteria were hemoglobin SS (HbSS) or hemoglobin Sβ⁰thalassaemia, and ages 9 to 18 months when these children were randomly assigned to receive liquid hydroxycarbamide, 20 mg/kg per day, or identical-appearing and tasting placebo, for 2 years. Using a predetermined schedule, the medical coordinating center generated randomization assignments. Participants, caregivers, and staff at the coordinating center were blinded to treatment assignment. Study visits took place every 2 to 4 weeks.
The main outcomes were splenic function, measured by qualitative uptake on ⁹⁹Tc spleen scan, and kidney function, as reflected in glomerular filtration rate determined by ⁹⁹mTc-diethylenetriaminepentaacetic acid (⁹⁹mTc-DTPA) clearance. Other outcomes measured included blood counts, fetal hemoglobin concentration, blood chemistries, biomarkers of splenic function, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Analysis was by intent-to-treat.
Of 96 patients in the hydroxycarbamide group, 83 completed the study, as did 84 of 97 in the placebo group. The primary endpoints did not differ significantly between groups (19/70 patients with decreased splenic function at exit in the hydroxycarbamide group vs 28/74 patients in the placebo group, P = .21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group vs the placebo group of 2 mL/minute per 1.73 m², P = .84).
However, the hydroxycarbamide group fared better than the placebo group in decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, P = .002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, P < .0001). There was also some evidence for benefit from hydroxycarbamide in decreased acute chest syndrome, hospitalization rates, and transfusion.
Hydroxyurea was associated with increased hemoglobin and fetal hemoglobin levels and decreased white blood cell counts. Hydroxycarbamide treatment was well tolerated, with the only apparent toxicity being mild to moderate neutropenia.
"On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia," the study authors write.
Limitations of this study include small number of participants; relatively short duration; suboptimal endpoint measurements; and use of a fixed dose of hydroxycarbamide (20 mg/kg per day), which is lower than the usual maximal tolerated dose and perhaps clinically less effective.
In an accompanying comment, David Weatherall, from the University of Oxford, United Kingdom, calls these findings "extremely encouraging."
"Hydroxycarbamide is inexpensive and could certainly be made available in low-income countries in which sickle-cell anaemia is so common," Dr. Weatherall writes. "Although there is still a long way to go in the management of sickle-cell anaemia, enough can be achieved such that establishment of international partnerships between richer countries and low-income countries for the better management of sickle-cell anaemia is now vital. In view of the early deaths that result from this disease in sub-Saharan Africa, the success of this trial in early infancy is particularly encouraging."
The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development supported this study, with partial support from the Best Pharmaceuticals for Children Act and the National Institute of Child Health and Human Development. The study authors and Dr. Weatherall have disclosed no relevant financial relationships.
Lancet. 2011;377:1628-1630, 1663-1672. Abstract Extract
"Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life," write Winfred C. Wang, from St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues. "Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects."
Between October 2003 and September 2009, eligible participants from 13 US centers were enrolled without regard to clinical severity. Inclusion criteria were hemoglobin SS (HbSS) or hemoglobin Sβ⁰thalassaemia, and ages 9 to 18 months when these children were randomly assigned to receive liquid hydroxycarbamide, 20 mg/kg per day, or identical-appearing and tasting placebo, for 2 years. Using a predetermined schedule, the medical coordinating center generated randomization assignments. Participants, caregivers, and staff at the coordinating center were blinded to treatment assignment. Study visits took place every 2 to 4 weeks.
The main outcomes were splenic function, measured by qualitative uptake on ⁹⁹Tc spleen scan, and kidney function, as reflected in glomerular filtration rate determined by ⁹⁹mTc-diethylenetriaminepentaacetic acid (⁹⁹mTc-DTPA) clearance. Other outcomes measured included blood counts, fetal hemoglobin concentration, blood chemistries, biomarkers of splenic function, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Analysis was by intent-to-treat.
Of 96 patients in the hydroxycarbamide group, 83 completed the study, as did 84 of 97 in the placebo group. The primary endpoints did not differ significantly between groups (19/70 patients with decreased splenic function at exit in the hydroxycarbamide group vs 28/74 patients in the placebo group, P = .21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group vs the placebo group of 2 mL/minute per 1.73 m², P = .84).
However, the hydroxycarbamide group fared better than the placebo group in decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, P = .002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, P < .0001). There was also some evidence for benefit from hydroxycarbamide in decreased acute chest syndrome, hospitalization rates, and transfusion.
Hydroxyurea was associated with increased hemoglobin and fetal hemoglobin levels and decreased white blood cell counts. Hydroxycarbamide treatment was well tolerated, with the only apparent toxicity being mild to moderate neutropenia.
"On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia," the study authors write.
Limitations of this study include small number of participants; relatively short duration; suboptimal endpoint measurements; and use of a fixed dose of hydroxycarbamide (20 mg/kg per day), which is lower than the usual maximal tolerated dose and perhaps clinically less effective.
In an accompanying comment, David Weatherall, from the University of Oxford, United Kingdom, calls these findings "extremely encouraging."
"Hydroxycarbamide is inexpensive and could certainly be made available in low-income countries in which sickle-cell anaemia is so common," Dr. Weatherall writes. "Although there is still a long way to go in the management of sickle-cell anaemia, enough can be achieved such that establishment of international partnerships between richer countries and low-income countries for the better management of sickle-cell anaemia is now vital. In view of the early deaths that result from this disease in sub-Saharan Africa, the success of this trial in early infancy is particularly encouraging."
The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development supported this study, with partial support from the Best Pharmaceuticals for Children Act and the National Institute of Child Health and Human Development. The study authors and Dr. Weatherall have disclosed no relevant financial relationships.
Lancet. 2011;377:1628-1630, 1663-1672. Abstract Extract
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