Hydroxyurea Reduces Conversion From Conditional to Abnormal TCD Velocities In Children with Sickle Cell Anemia (SCA)
Authors: Rothman Jennifer , Burgett Shelly , Ware Russell E. , Thornburg Courtney 
Published: October 2019

Abstract 270

The use of transcranial Doppler ultrasound (TCD), a non-invasive imaging technique, is now clearly established for detecting high risk of stroke in children with sickle cell anemia (SCA). Children with TCD flow velocities ≥200 cm/s have a 10% risk of primary stroke per year. For these children, chronic blood transfusions (CBT) are recommended and have been shown to reduce the risk of primary stroke by up to 90%. The incidence of stroke has decreased to 0.06–0.17 per 100 patient-years since the institution of TCD screening (Fullerton et al. Blood 2004; Enningul-Egham et al., J Pediatr 2010). Although patients with conditional TCDs (flow velocities 170–199 cm/s) have an estimated stroke risk of 2–5% annually, and their rate of conversion from conditional to abnormal is 23% over an 18 month period (Hankins JS et al., BJH 2008), there are no clinical guidelines for primary stroke prevention in this group. We previously conducted a prospective cohort study of hydroxyurea in 37 children with SCA and TCD velocities >140 cm/sec, and demonstrated that TCD velocities decreased significantly after starting hydroxyurea (Zimmerman et al., Blood 2007; NCT00402480). In order to determine if hydroxyurea provided sustained reductions in TCD velocities, we conducted a retrospective review of these 37 children in this original cohort who had elevated TCD velocities and long-term hydroxyurea treatment. The following data were abstracted from the medical record between April 2000 and September 2009: treatment with hydroxyurea and CBT; adherence with treatments; stroke and non-stroke neurological events; and TCD time-averaged mean velocities (TAMV) immediately prior to initiation of hydroxyurea and at the end of extended follow-up. The primary outcome was comparison of pre and post TCD TAMV using a paired t-test. The mean age of enrollment on the original study was 6.8 years (1.8-14.8) and the mean age at follow-up was 12.9 years (5.3-18.5). The mean follow-up was 5.8 years (0.8-8.5) with an overall follow up of 215.1 patient years. Twenty males and 17 females were enrolled. The mean hydroxyurea dose was 25.2 ± 5.6 mg/kg/day, with one patient discontinuing therapy after 15 months. At follow-up, the mean hemoglobin was 8.9 ± 1.2 g/dL and mean HbF was 16 ± 7.2%. Sustained decreases were observed in both the right MCA (164.8 ± 25.5 cm/s to 124.9 ± 35 cm/s, p<0.001) and left MCA (167.9 ± 25.2 cm/s to 126.9 ± 30 cm/s, p<0.001) for all 37 patients. For the 15 patients with conditional TCD velocities at enrollment, 13 had maximal TAMV that reverted to and were sustained in the normal range (185.8 ± 10.0 cm/s to 132.9 ± 14.5 cm/s, p<0.001). Two converted to abnormal TCD velocities at 1.6 years and 4.5 years for a conversion rate of 13%; one was non-adherent but the other was adherent with hemoglobin of 10.8 g/dL and HbF of 23.5%. These two patients were started on CBT and remain stroke free. There were no primary stroke events observed in the 15 subjects with conditional TCD velocities over a total of 78.1 patient years. Of the 5 patients who had abnormal TCD velocities on enrollment and whose parents refused CBT, 1 patient had a stroke after 0.8 years of hydroxyurea therapy. This was the only patient who continued to have abnormal TCD velocities at MTD, 7 months after starting hydroxyurea. The remaining 4 patients continued to have TCD velocities in the normal range off transfusion therapy over 26.3 patient years. Overall, these data illustrate that treatment with hydroxyurea at MTD in children with SCA and elevated TCD velocities resulted in significantly lower and sustained improvements in TCD velocities. Additionally, for children with conditional TCD velocities, hydroxyurea resulted in a lower than expected conversion to abnormal values, thereby sparing many children from CBT without any noted increase risk of stroke. Hydroxyurea did not, however, protect fully against stroke in one patient who had persistently abnormal TCD velocities and therefore CBT remains the standard of care in this population until larger randomized trials are conducted. Further studies are required to evaluate hydroxyurea for primary stroke prevention in children prior to conversion to abnormal TCD and in children who already have abnormal TCD. The currently funded TCD With Transfusions Changing to Hydroxyurea (TWiTCH) clinical trial, which is scheduled to begin enrollment in late 2010, will help answer this important clinical question.

Disclosures:

Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.