In children with sickle cell disease (SCD), does hydroxyurea with phlebotomy reduce the risk of secondary stroke and improve management of iron overload when compared to standard treatment (chronic transfusions with chelation)?
Among children with sickle-cell disease, hydroxyurea plus phlebotomy was inferior to transfusions plus chelation therapy in reducing rates of stroke and iron overload.
Stroke is a major complication of SCD, with a primary incidence of up to 11% in children with the disease by the time they reach age 20. The incidence of recurrent stroke ranges from 47% to 93% in untreated patients. Chronic transfusions has been the mainstay of therapy to prevent secondary stroke as it improves blood flow with non-sickled erythrocytes and suppresses endogenous hematopoiesis of erythrocytes with sickle hemoglobin (HbS). However, transfusions administered indefinitely do have several side effects, including increased risk of infection, alloimmunization, and iron overload requiring chelation therapy.
Hydroxyurea has been used clinically for acute complications of SCD and has been thought to be potentially protective against secondary stroke. Anecdotal reports using hydroxyurea in combination with phlebotomy to reduce iron burden has been shown to be a feasible alternative to chronic transfusions with chelation. The SWiTCH study was designed to compare the efficacy of hydroxyurea/phlebotomy with transfusion/chelation in preventing secondary stroke and iron overload in children with SCD.
- Multicenter, single-masked, randomized, non-inferiority trial
- Hydroxyurea and phlebotomy (n=67)
- Standard transfusion and chelation (n=66)
- Setting: 26 sickle cell centers in the US
- Study time: 30 months
- Follow-up: Interim analyses after 33% and 67% of subjects completed exit studies
- Analysis: Intention-to-treat
- Primary outcome: Composite of secondary stroke occurrence during 30-month period and quantitative liver iron change from baseline, measured by liver biopsy at 30 months or exit from the study
- Secondary outcomes: Non-stroke neurological events, non-neurological sickle cell events (splenic sequestration, vaso-occlusive pain, acute chest syndrome, priapism, hospitalization, death), transfusion-related complications, chelation-related complications, functional evaluation, neurocognitive evaluation, growth and development, hydroxyurea-related complications, phlebotomy-related complications, and liver biopsy-related complications
- Pediatric subjects with severe form of sickle cell anemia (HbSS, HbS/B-thal, HbS/Oarab)
- Age 5.0 - 18.9 years (inclusive at time of enrollment)
- Overt, primary clinical stroke after age 12 months with documented infarction on brain CT or MRI
- At least 18 months of chronic monthly erythrocyte transfusions since primary stroke
- Documented transfusional iron overload (≥5.0mg Fe per gram of dry weight liver or ferritin ≥500ng/mL on 2 separate occasions)
- Average HbS <45% while receiving transfusions, for the 6 months preceding enrollment
- Parent/guardian informed consent with verbal or written assent from the child (<18 years old) or subject able to provide consent (≥18 years old)
- Can comply with study-related treatments, evaluations, and follow-up
- Inability to tolerate chronic erythrocyte transfusions
- Inability to tolerate daily oral hydroxyurea
- Clinical and laboratory evidence of hypersplenism
- Abnormal lab values at initial evaluation
Data are from the transfusions/chelation group, whose differences are not statistically significant when compared to the hydroxyurea/phlebotomy group except where noted.
- Mean age: 13.3 years
- Male: 47%
- HbSS: 100%
- Stroke history:
- Mean age of primary stroke: 6.2 years
- Previous recurrent stroke: 6% (vs. 15%, p=0.096)
- History of TIA: 17%
- Baseline brain MRI/MRA:
- Infarction: 98%
- Vasculopathy: 82%
- Moya-moya: 8%
- Transfusion history:
- Mean duration: 7.0 years
- Simple transfusions: 62%
- RBC alloantibodies: 26%
- RBC autoantibodies: 14%
- Iron overload status:
- Liver iron concentration (mg Fe/g dry weight liver): 14.5 (9.5-23.3)
- Serum ferritin (ng/mL): 3282.0 (2321.0-3406.0)
- Previous desferrioxamine use: 70%
- Previous deferasirox: 87%
- Baseline laboratory parameters:
- Hemoglobin (g/dL): 9.2 (8.6-9.7)
- MCV (fL): 86.2 (83.6-87.7)
- HbA: 67.5% (56.3-74.5%)
- HbS: 27.0% (21.2-38.6%)
- HbF: 1.7% (1.0-2.5%)
- Absolute reticulocyte count (x10^9/L): 335.4 (246.2-391.0)
- WBC (x10^9/L): 13.2 (11.0-16.6)
- ANC (x10^9/L): 7.4 (6.2-9.2)
- ALT (U/L): 41.0 (36.0-58.0)
- Creatinine (mg/dL): 0.4 (0.3-0.5)
- Total bilirubin (mg/dL): 2.8 (1.8-3.9)
Comparisons are hydroxyurea plus phlebotomy vs. standard treatment of chronic transfusions plus iron chelation.
This study was designed as a non-inferiority trial, meaning that its purpose was to show that hydroxyurea/phlebotomy was at least not worse than standard treatment of transfusion/chelation. The non-inferiority margin of the study - the acceptable upper limit of increased stroke risk with hydroxyurea - was 0.20 (20%), but this is an arbitrary assignment based on expert opinion. Non-inferiority trials have a tendency to also bias towards equivalence between study arms.
Funding for this study was provided by National Heart, Lung, and Blood Institute grants. The authors declared no competing financial interests.