The current standard of care for pediatric sickle cell anemia (SCA) patients is hydroxyurea therapy. The early initiation of this treatment, often at ages of less than 1 year, has become more commonplace after results from the phase III BABY HUG clinical study (NCT00006400) and recommendations from the 2014 NHLBI Guidelines.
Since the variability in hydroxyurea pharmacokinetics, treatment response (fetal hemoglobin [HbF]%), and maximum tolerated dose (MTD) is well-documented, the clinical investigators thought that individualized dosing might provide a better approach to SCA patient treatment. TREAT (Therapeutic Response Evaluation and Adherence Trial) was a prospective study that evaluated a personalized, pharmacokinetic-guided dosing model of hydroxyurea therapy for pediatric SCA patients. Results from this study were presented at the 2018 ASH Annual Meeting by Patrick T. McGann, MD, Cincinnati Children's Hospital Medical Center.
Using each participant's pharmacokinetic data and pharmacokinetic model-based Bayesian estimation, an individualized starting hydroxyurea dose was generated to target an area under the time-concentration curve (AUC) associated with an actual MTD. Clinical follow-up and subsequent dose adjustments targeted the MTD, which was usually defined as an absolute neutrophil count < 3.0x109/L.
Analysis was performed on the clinical and laboratory data for those TREAT participants who initiated hydroxyurea therapy before 2 years of age to allow for comparison to the results obtained from BABY HUG, which included a similar cohort of young patients, but with a weight-based dosing of 20 mg/kg/day. Ongoing clinical and research evaluation of organ function, including transcranial Doppler (TCD) studies, red blood cell (RBC) pit counts, and cystatin C measurements were performed for TREAT study patients.
The study was limited to patients having a sickle cell anemia diagnosis (HbSS or Hbb0) from 6 months to 21 years of age at enrollment. An additional requirement for participation was the necessity for a clinical decision by patient, family, and health care provider to initiate hydroxyurea therapy, including those who are transitioning from chronic transfusions to hydroxyurea therapy. Patients were excluded from participation if their family was unwilling to sign informed consent or comply with study treatments.
The primary outcome measure was the time to reach MTD (in months). Secondary outcome measures included the following: hydroxyurea adherence; neurological function; non-invasive transcranial cerebral oximetry; splenic, renal, and cardiac function; assessment of growth.
A total of 47 patients were enrolled in the TREAT clinical trial. Of these patients, 33 initiated hydroxyurea usage before 2 years of age, providing a total of 59.5 patient-years of hydroxyurea therapy. The mean age at hydroxyurea therapy initiation was 1.0 ± 0.4 years of age, while the average pharmacokinetics-guided, individualized starting dose was 27. 8 ± 5.3 mg/kg/day. It is of interest to note that this value is higher than conventional and BABY HUG initial dosing, which was 20 mg/kg/day. Those patients having completed 12 months of therapy (n=24) displayed remarkable results in hematologic laboratory data, with average 35.9 ± 8.9% HbF and hemoglobin concentration of 10.2 ± 1.1 g/dL after 12 months of therapy, as compared to values of 29.3 ± 8.8% and 9.2 ± 1.3 g/dL, respectively, at baseline. The majority of these patients (70%) had HbF >30 percent and almost half achieved HbF >40 percent after 12 months of hydroxyurea therapy. The hematological response observed in this study was more robust than that obtained in the BABY HUG trial, with an HbF of 22.4 percent and hemoglobin of 9.1 g/dL after 2 years of therapy (Lancet 2011;377:1663-1672).
There were no cases of acute splenic sequestration, dactylitis, or stroke in the TREAT cohort; however, participants had 111 emergency room or sick outpatient clinic visits. Only four (3.6%) of these emergency department or clinic visits without subsequent hospitalization were for pain, while the remaining 107 visits were for symptoms such as fever, upper respiratory infection symptoms, gastrointestinal illness, or other non-specific complaints unrelated to SCA.
Most of the 38 hospitalizations in 17 participants were for routine monitoring of fever (66%), with no positive blood cultures or admissions for febrile neutropenia. The average hospitalization stay was fairly short at 2.8 ± 2.4 days with 81 percent of patients being discharged within 72 hours of admission. There were three episodes of acute chest syndrome in two patients, two of whom required packed red blood cell transfusion. When one includes all types of visits, there were only six pain events, which was equivalent to 10.1 pain events per 100 patient-years. This figure is much lower than the published 94 events per 100 patient-years obtained in the hydroxyurea treatment arm of BABY HUG (Blood 2012;120:4304-4310). A total of 37 TCD exams were performed for 16 participants; all of these were normal, except for one patient who had conditional velocities that normalized upon hydroxyurea therapy. No significant differences were noted from baseline to month 12 in either RBC pit counts or cystatin C values.
The initiation of hydroxyurea therapy at an early age using pharmacokinetic-guided dosing showed significant clinical benefits for pediatric SCA patients. The results obtained for this study suggest that hydroxyurea therapy initiation at approximately 1 year of age, using a personalized dosing strategy, may provide more beneficial clinical and laboratory outcomes than starting at the conventional 20 mg/kg/day weight-based dosage.
At modest and well-tolerated doses of hydroxyurea, very high HbF levels were observed; this may have been a result of treatment being initiated prior to complete inactivation of HbF. Continuous long-term follow-up of these pediatric patients will determine whether these results will be sustained and able to prevent both long- and short-term complications associated with SCA.
Richard Simoneaux is a contributing writer.