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LOS ANGELES – Someday soon, physicians will probably have solid, evidence-based guidelines on how to use mTOR inhibitors in infants with tuberous sclerosis complex.
They couldn’t come soon enough. Everolimus (Afinitor) is being used off label more and more often in children under 2 years old for seizures and other manifestations of the genetic disorder, often with a decent response.
“I get emails all the time saying ‘how would you start treatment at this age?’ and we say there are no data,” he said at the American Academy of Neurology annual meeting.
Dr. Krueger presented a survey of 19 TSC centers to get the ball rolling. They reported on treating 45 children under 2 years old, at least one child at each center. The goal of the survey was to establish a baseline “to allow us to move forward with what proper studies would look like, and what needs to be done. Two-thirds of patients have seizures before their first birthday; we need to establish a safety [and efficacy] profile well before 2 years of age,” and evidence-based guidelines, he said.
On average, everolimus treatment started at 11.7 months, and continued for 27 months. Sirolimus treatment started at a mean of 16 months and continued for 16 months. Dosing ranged from once a week to daily. In contrast to case reports that skew heavily toward rhabdomyomas, most of the children were treated for epilepsy and subependymal giant cell astrocytoma (SEGA). Almost all the centers had participated in a clinical evaluation of everolimus for TSC epilepsy and SEGAs in older children, “so there was familiarity and a comfort level” for those indications, Dr. Krueger said.
Everolimus was used much more often than was sirolimus, which probably reflects ongoing clinical development of the drug. A handful of children switched between the two, probably because of side effects. Most centers reported a favorable response. The average initial daily dose of everolimus was 1.05 mg/m2; the average initial daily dose of sirolimus was 0.42 mg/m2.
Thirty-five children (78%) had an adverse event (AE), usually infections or lipid problems. Most were mild or moderate and didn’t affect treatment. Seven children (16%) had severe grade 3 events.
“The frequency of these AEs and the severity and type were not different from the earlier trials,” but almost 40% of the children discontinued treatment due to AEs, which was “much higher” than in past trials. “I think this represents the lack of real data with which to guide clinical judgment. There was a high tendency with any AE for discontinuation,” Dr. Krueger said.
There were more boys than girls among the 45 children. The majority were from the United States, and predominantly Cincinnati Children’s Hospital. Most had TSC2 mutations, which are associated with worse disease than TSC1 mutations.
Dr. Krueger reported research funding and personal compensation from Novartis, maker of everolimus. Almost all of his coinvestigators reported ties to the company. The work was supported by the Tuberous Sclerosis Alliance, which is funded in part by Novartis.
SOURCE: Krueger D et al. Neurology. 2018 Apr 90(15 Suppl.):S35.003.
LOS ANGELES – Someday soon, physicians will probably have solid, evidence-based guidelines on how to use mTOR inhibitors in infants with tuberous sclerosis complex.
They couldn’t come soon enough. Everolimus (Afinitor) is being used off label more and more often in children under 2 years old for seizures and other manifestations of the genetic disorder, often with a decent response.
“I get emails all the time saying ‘how would you start treatment at this age?’ and we say there are no data,” he said at the American Academy of Neurology annual meeting.
Dr. Krueger presented a survey of 19 TSC centers to get the ball rolling. They reported on treating 45 children under 2 years old, at least one child at each center. The goal of the survey was to establish a baseline “to allow us to move forward with what proper studies would look like, and what needs to be done. Two-thirds of patients have seizures before their first birthday; we need to establish a safety [and efficacy] profile well before 2 years of age,” and evidence-based guidelines, he said.
On average, everolimus treatment started at 11.7 months, and continued for 27 months. Sirolimus treatment started at a mean of 16 months and continued for 16 months. Dosing ranged from once a week to daily. In contrast to case reports that skew heavily toward rhabdomyomas, most of the children were treated for epilepsy and subependymal giant cell astrocytoma (SEGA). Almost all the centers had participated in a clinical evaluation of everolimus for TSC epilepsy and SEGAs in older children, “so there was familiarity and a comfort level” for those indications, Dr. Krueger said.
Everolimus was used much more often than was sirolimus, which probably reflects ongoing clinical development of the drug. A handful of children switched between the two, probably because of side effects. Most centers reported a favorable response. The average initial daily dose of everolimus was 1.05 mg/m2; the average initial daily dose of sirolimus was 0.42 mg/m2.
Thirty-five children (78%) had an adverse event (AE), usually infections or lipid problems. Most were mild or moderate and didn’t affect treatment. Seven children (16%) had severe grade 3 events.
“The frequency of these AEs and the severity and type were not different from the earlier trials,” but almost 40% of the children discontinued treatment due to AEs, which was “much higher” than in past trials. “I think this represents the lack of real data with which to guide clinical judgment. There was a high tendency with any AE for discontinuation,” Dr. Krueger said.
There were more boys than girls among the 45 children. The majority were from the United States, and predominantly Cincinnati Children’s Hospital. Most had TSC2 mutations, which are associated with worse disease than TSC1 mutations.
Dr. Krueger reported research funding and personal compensation from Novartis, maker of everolimus. Almost all of his coinvestigators reported ties to the company. The work was supported by the Tuberous Sclerosis Alliance, which is funded in part by Novartis.
SOURCE: Krueger D et al. Neurology. 2018 Apr 90(15 Suppl.):S35.003.
LOS ANGELES – Someday soon, physicians will probably have solid, evidence-based guidelines on how to use mTOR inhibitors in infants with tuberous sclerosis complex.
They couldn’t come soon enough. Everolimus (Afinitor) is being used off label more and more often in children under 2 years old for seizures and other manifestations of the genetic disorder, often with a decent response.
“I get emails all the time saying ‘how would you start treatment at this age?’ and we say there are no data,” he said at the American Academy of Neurology annual meeting.
Dr. Krueger presented a survey of 19 TSC centers to get the ball rolling. They reported on treating 45 children under 2 years old, at least one child at each center. The goal of the survey was to establish a baseline “to allow us to move forward with what proper studies would look like, and what needs to be done. Two-thirds of patients have seizures before their first birthday; we need to establish a safety [and efficacy] profile well before 2 years of age,” and evidence-based guidelines, he said.
On average, everolimus treatment started at 11.7 months, and continued for 27 months. Sirolimus treatment started at a mean of 16 months and continued for 16 months. Dosing ranged from once a week to daily. In contrast to case reports that skew heavily toward rhabdomyomas, most of the children were treated for epilepsy and subependymal giant cell astrocytoma (SEGA). Almost all the centers had participated in a clinical evaluation of everolimus for TSC epilepsy and SEGAs in older children, “so there was familiarity and a comfort level” for those indications, Dr. Krueger said.
Everolimus was used much more often than was sirolimus, which probably reflects ongoing clinical development of the drug. A handful of children switched between the two, probably because of side effects. Most centers reported a favorable response. The average initial daily dose of everolimus was 1.05 mg/m2; the average initial daily dose of sirolimus was 0.42 mg/m2.
Thirty-five children (78%) had an adverse event (AE), usually infections or lipid problems. Most were mild or moderate and didn’t affect treatment. Seven children (16%) had severe grade 3 events.
“The frequency of these AEs and the severity and type were not different from the earlier trials,” but almost 40% of the children discontinued treatment due to AEs, which was “much higher” than in past trials. “I think this represents the lack of real data with which to guide clinical judgment. There was a high tendency with any AE for discontinuation,” Dr. Krueger said.
There were more boys than girls among the 45 children. The majority were from the United States, and predominantly Cincinnati Children’s Hospital. Most had TSC2 mutations, which are associated with worse disease than TSC1 mutations.
Dr. Krueger reported research funding and personal compensation from Novartis, maker of everolimus. Almost all of his coinvestigators reported ties to the company. The work was supported by the Tuberous Sclerosis Alliance, which is funded in part by Novartis.
SOURCE: Krueger D et al. Neurology. 2018 Apr 90(15 Suppl.):S35.003.
REPORTING FROM AAN 2018
Key clinical point: A survey of treatment centers has begun to plug the evidence gap for using mTOR inhibitors in infants with tuberous sclerosis.
Major finding: Adverse events don’t seem more common than in trials of adults and older children, but the discontinuation rate is much higher, at about 40%.
Study details: Review of 45 children under 2 years old.
Disclosures: The lead investigator reported research funding and personal compensation from Novartis, maker of everolimus.
Source: Krueger D et al. Neurology. 2018 Apr 90(15 Suppl.):S35.003.