Hydroxyurea was non-inferior, and possibly superior, to chronic transfusions for primary stroke prevention in pediatric patients with sickle cell anemia, according to results from the TCD with Transfusions Changing to Hydroxyurea (TWiTCH) study presented at the 2015 ASH Annual Meeting in Orlando, Florida.
“Stroke in sickle cell anemia is a huge problem – particularly in pediatrics,” said Russell E. Ware, MD, from Cincinnati Children’s Hospital Medical Center in Ohio, co-principal investigator of the TWiTCH study. “Up to 10 percent of children will develop a stroke, and it is one of the most severe clinical events that occurs in children.”
Although lifelong transfusions can be used to help prevent stroke in patients, transfusions have significant associated morbidities (including iron overload) and alternative treatment strategies are needed, he added.
In the TWiTCH study, Dr. Ware and investigators hypothesized that daily oral hydroxyurea (which is used to treat painful crises of sickle cell anemia) might lower the velocity of blood in cranial vessels as well as transfusions. To test their hypothesis, the researchers used transcranial Doppler (TCD) to identify patients at high risk for developing a stroke (determined by abnormal TCD velocities), then randomized patients to receive either monthly transfusions (n=61) or daily hydroxyurea (n=60) for 24 months.
In the transfusion arm, hemoglobin S (HbS) levels were maintained at <30 percent; if patients experienced iron overload, they received chelation. The hydroxyurea arm included an overlap period with transfusions until a stable maximum tolerated dose (MTD) of hydroxyurea was reached. Transfusions were then replaced by serial phlebotomy procedure to reduce iron overload.
TCD velocities were obtained and reviewed every 12 weeks. The investigators created a TCD alert algorithm to monitor changes from enrollment velocities.
The MTD for hydroxyurea was reached after seven months (±2 months), at an average dose of 27 mg/kg per day.
The study was terminated early, after the established non-inferiority margin had been reached.
The final analysis included 83 patients:
- 42 in the transfusion arm completed all treatment: 11 with truncated treatment, and 8 withdrawn
- 41 in the hydroxyurea arm completed all treatment: 13 with truncated treatment, and 6 withdrawn
At the end of the study, average TCD velocities were similar between both patient groups (143±1.6 cm/sec in the hydroxyurea arm and 138±1.6 cm/sec in the transfusion arm), indicating a similar risk for stroke and meeting the criteria for non-inferiority (p=8.82 x 10‐16). At post-hoc analysis, Dr. Ware added, suggesting that hydroxyurea might even have been superior (p=0.023).
In terms of safety, there were no deaths or new strokes, though there were 29 new neurologic events, including six transient ischemic attacks (3 in each arm). One child in the transfusion arm was withdrawn per the TCD alert algorithm after developing on-study TCD velocities >240 cm/sec.
There were also no new abnormalities or MRI lesions observed on study-exit brain MRI/MRA exams; one child in the transfusion arm, however, had developed a new vasculopathy.
“Sickle cell–related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 to 15),” the authors noted, “but none were related to study treatment or study procedures.” Iron overload improved more in the hydroxyurea than the transfusion arm, with a greater average change in serum ferritin (–1085 vs. –38 ng/mL; p<0.001) and liver iron concentration (average = –1.9 mg/g vs. +2.4 mg/g dry weight liver; p=0.001).
Overall, the non-inferiority and safety findings from the TWiTCH trial suggest that families could have a choice between hydroxyurea or chronic transfusions for the prevention of primary stroke for their children.
Ware RE, Davis BR, Schultz WH, et al. TCD with transfusions changing to hydroxyurea (TWiTCH): hydroxyurea therapy as an alternative to transfusions for primary stroke prevention in children with sickle cell anemia. Abstract #3. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.