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ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.
No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.
The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.
“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.
The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.
Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.
Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”
Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.
Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.
Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.
TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.
The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.
The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.
“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.
As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.
The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.
Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.
There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.
TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.
Abnormal transcranial Doppler findings in sickle cell disease indicates that the pediatric patient is at high risk of a primary stroke. To date, the standard of care has been lifelong transfusion for these patients.
This study indicates there may be a viable alternative to transfusions with less invasive therapy and reduced risk of iron loading. What is not addressed, however, is whether we use hydroxyurea as front line therapy for children with abnormal findings on transcranial Doppler. The study patients had been on transfusions for at least 12 months when they were enrolled in the study and had normalized velocities on transcranial Doppler.
Do we still need to screen sickle cell disease patient patients with transcranial Doppler for stroke risk? The answer is 'yes.' What if they are already on hydroxyurea? Still the answer is 'yes.'
Should transcranial Doppler screening also be linked with MRI/MRA to look at vessels? This study refers to a select group of patients with no significant vasculopathy noted on brain imaging.
So how does the community provider interpret these finding for the real-world care of a patient? How do we not over interpret or under interpret the data? In partnership with a hematologist each child should continue to get transcranial Doppler screening annually and transfusions initiated for abnormal transcranial Doppler and study methods should be followed with crossing over to hydroxyurea for patients who normalize their transcranial Doppler results at 12 months and have no evidence of significant vasculopathy on brain imaging.
Transcranial Doppler screening should continue annually per guidelines even if the patient is already on hydroxyurea for other indications or was switched to hydroxyurea from transfusions. This is a situation that is more likely to occur in the real world clinical setting as hydroxyurea use is advocated for children as early as 9 months of age.
What happens then if transcranial Doppler findings become abnormal while on hydroxyurea? If compliance is assured and the hydroxyurea dose is optimized, then we are back to square one. Primary stroke prevention with lifelong transfusion is currently the standard of care. At least until another randomized study is done to prove non inferiority.
Dr. Ifeyinwa Osunkwo is the medical director for the sickle cell program at the Levine Cancer Institute, Carolinas Healthcare Systems, Charlotte, NC. and a member of the editorial board for Hematology News.
Abnormal transcranial Doppler findings in sickle cell disease indicates that the pediatric patient is at high risk of a primary stroke. To date, the standard of care has been lifelong transfusion for these patients.
This study indicates there may be a viable alternative to transfusions with less invasive therapy and reduced risk of iron loading. What is not addressed, however, is whether we use hydroxyurea as front line therapy for children with abnormal findings on transcranial Doppler. The study patients had been on transfusions for at least 12 months when they were enrolled in the study and had normalized velocities on transcranial Doppler.
Do we still need to screen sickle cell disease patient patients with transcranial Doppler for stroke risk? The answer is 'yes.' What if they are already on hydroxyurea? Still the answer is 'yes.'
Should transcranial Doppler screening also be linked with MRI/MRA to look at vessels? This study refers to a select group of patients with no significant vasculopathy noted on brain imaging.
So how does the community provider interpret these finding for the real-world care of a patient? How do we not over interpret or under interpret the data? In partnership with a hematologist each child should continue to get transcranial Doppler screening annually and transfusions initiated for abnormal transcranial Doppler and study methods should be followed with crossing over to hydroxyurea for patients who normalize their transcranial Doppler results at 12 months and have no evidence of significant vasculopathy on brain imaging.
Transcranial Doppler screening should continue annually per guidelines even if the patient is already on hydroxyurea for other indications or was switched to hydroxyurea from transfusions. This is a situation that is more likely to occur in the real world clinical setting as hydroxyurea use is advocated for children as early as 9 months of age.
What happens then if transcranial Doppler findings become abnormal while on hydroxyurea? If compliance is assured and the hydroxyurea dose is optimized, then we are back to square one. Primary stroke prevention with lifelong transfusion is currently the standard of care. At least until another randomized study is done to prove non inferiority.
Dr. Ifeyinwa Osunkwo is the medical director for the sickle cell program at the Levine Cancer Institute, Carolinas Healthcare Systems, Charlotte, NC. and a member of the editorial board for Hematology News.
Abnormal transcranial Doppler findings in sickle cell disease indicates that the pediatric patient is at high risk of a primary stroke. To date, the standard of care has been lifelong transfusion for these patients.
This study indicates there may be a viable alternative to transfusions with less invasive therapy and reduced risk of iron loading. What is not addressed, however, is whether we use hydroxyurea as front line therapy for children with abnormal findings on transcranial Doppler. The study patients had been on transfusions for at least 12 months when they were enrolled in the study and had normalized velocities on transcranial Doppler.
Do we still need to screen sickle cell disease patient patients with transcranial Doppler for stroke risk? The answer is 'yes.' What if they are already on hydroxyurea? Still the answer is 'yes.'
Should transcranial Doppler screening also be linked with MRI/MRA to look at vessels? This study refers to a select group of patients with no significant vasculopathy noted on brain imaging.
So how does the community provider interpret these finding for the real-world care of a patient? How do we not over interpret or under interpret the data? In partnership with a hematologist each child should continue to get transcranial Doppler screening annually and transfusions initiated for abnormal transcranial Doppler and study methods should be followed with crossing over to hydroxyurea for patients who normalize their transcranial Doppler results at 12 months and have no evidence of significant vasculopathy on brain imaging.
Transcranial Doppler screening should continue annually per guidelines even if the patient is already on hydroxyurea for other indications or was switched to hydroxyurea from transfusions. This is a situation that is more likely to occur in the real world clinical setting as hydroxyurea use is advocated for children as early as 9 months of age.
What happens then if transcranial Doppler findings become abnormal while on hydroxyurea? If compliance is assured and the hydroxyurea dose is optimized, then we are back to square one. Primary stroke prevention with lifelong transfusion is currently the standard of care. At least until another randomized study is done to prove non inferiority.
Dr. Ifeyinwa Osunkwo is the medical director for the sickle cell program at the Levine Cancer Institute, Carolinas Healthcare Systems, Charlotte, NC. and a member of the editorial board for Hematology News.
ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.
No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.
The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.
“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.
The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.
Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.
Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”
Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.
Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.
Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.
TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.
The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.
The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.
“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.
As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.
The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.
Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.
There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.
TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.
ORLANDO – Oral hydroxyurea is as good as chronic red blood cell transfusions for prevention of primary stroke in children at high-risk for this devastating complication of sickle cell disease, results of the TWiTCH study show.
No child suffered a stroke with either hydroxyurea or monthly transfusions and transcranial doppler (TCD) velocities were maintained in both arms.
The study was stopped early, however, after noninferiority was shown for the primary end point of TCD mean velocities on the index side at 24 months, with a post-hoc analysis suggesting hydroxyurea may even be superior, study author Dr. Russell E. Ware, director of hematology at Cincinnati (Ohio) Children’s Hospital Medical Center, reported during the plenary session at the annual meeting of the American Society of Hematology.
“Hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke,” he said during a press briefing.
The final mean TCD velocities were 143 cm/second in the transfusion arm and 138 cm/sec in the hydroxyurea arm, resulting in P values of 8.82 x 10-16 for non-inferiority by intention-to-treat analysis and 0.023 for superiority in a post-hoc analysis.
Hydroxyurea also had the added benefit of improving iron overload status more than monthly transfusions based on a greater average change in serum ferritin (-1,085 ng/mL vs. -38 ng/mL; P less than .001) and liver iron concentrations (-1.9 mg/g vs. +2.4 mg/g; P = .001), according to their report.
Press briefing moderator Dr. Alexis Thompson, of the Ann & Robert H. Lurie Children’s Hospital of Chicago, commented, “This truly is one of the abstracts that are being presenting at the meeting today that can be defined as practice changing. There are many families who have great difficulty accepting the reality, prior to the TWiTCH study, of their children having to be transfused lifelong.”
Strokes occur in up to 10% of children with sickle cell disease (SCD). Transfusions are effective for stroke prophylaxis in this setting, but have to be continued lifelong and can lead to iron overload and other complications.
Based on the participating sites, at least 80% of children with abnormal TCD velocities currently on blood transfusions to prevent stroke would be eligible for treatment with hydroxyurea, Dr. Ware said.
Hydroxyurea increases the amount of fetal hemoglobin and fetal red blood cells and was approved more than a decade ago to ameliorate the acute and chronic complications of SCD. Its use could provide dramatic cost savings for families since a transfusion costs about $1,000 to $2,000 every month, whereas hydroxyurea costs less than a dollar a day, Dr. Ware said in an interview.
TWiTCH (TCD with Transfusions Changing to Hydroxyurea) was conducted at 26 pediatric programs and used TCD to identify 121 children with SCD who were at elevated risk of stroke based on abnormally high cerebral artery flow velocities of at least 200 cm/sec. The children were evenly randomized to 24 months of treatment. TCD velocities were obtained every 12 weeks and reviewed centrally, with local investigators blinded to the results. All children had received transfusions for at least 12 months, but had not developed severe vasculopathy.
The transfusion arm was maintained at a target hemoglobin S level of less than 30% and chelation used to manage elevated liver concentrations. Transfusions were allowed in the hydroxyurea arm until a stable maximum tolerated dose (MTD) of hydroxyurea was reached, and were then replaced by serial phlebotomy to reduce iron overload. The MTD was reached after 6 months at an average dose of about 25 mg/kg/day.
The transfusion overlap with hydroxyurea was designed as a safety measure to avoid strokes if monthly transfusions were abruptly discontinued in the hydroxyurea arm before the children had time to achieve MTD.
“The fact that that overlap was about 6 months and the fact we had about 24 months of follow-up tracking the TCD velocities over time, we feel that doesn’t affect the end statistical analysis,” Dr. Ware said.
As for whether hydroxyurea is superior to monthly transfusions, he noted that the trial was not designed for superiority and superiority was seen in a post-hoc analysis. “What we can say with certainty is that it’s non-inferior to the standard treatment,” Dr. Ware said.
The final analysis was based on 42 patients randomized to the transfusion arm who completed all 24 months of treatment, 11 with truncated treatment, and 8 withdrawals, and 41 patients assigned to the hydroxyurea arm who completed all treatment, 13 with truncated treatment and 6 withdrawals.
Sickle cell-related serious adverse events were more common in the hydroxyurea arm than the transfusion arm (23 vs. 15), but none were related to the study drug or procedures.
There were 29 new centrally adjudicated neurological events including 3 transient ischemic attacks in each arm. In the transfusion arm, one child was withdrawn per protocol after developing TCD velocities exceeding 240 cm/sec and a second developed new vasculopathy. The safety of long-term hydroxyurea has been established in multiple pediatric studies, Dr. Ware said.
TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.
AT ASH 2015
Key clinical point: Hydroxyurea can substitute for chronic transfusions to prevent primary stroke in children with sickle cell disease and abnormal transcranial doppler velocities.
Major finding: Mean TCD velocities were 143 cm/sec with transfusions vs. 138 cm/sec with hydroxyurea (P less than 8.82 x 10-16 for noninferiority; P = .023 for superiority).
Data source: Phase III, noninferiority study in 121 children with sickle cell disease.
Disclosures: TWiTCH was funded by the National Heart, Lung and Blood Institute and sponsored by Cincinnati Children’s Hospital Medical Center. Dr. Ware reported serving as a data safety monitoring board member for Eli Lilly, consultancy for Bayer, and research funding from Bristol Myers Squibb. Dr. Thompson disclosed research funding from Amgen, Baxalta, bluebird bio, Celgene, Eli Lilly, GlaxoSmithKline, Mast, and Novartis, and consultancy for ApoPharma, bluebird bio, and Novartis.
