- Email: [email protected]
P239 – 1816 Safety of everolimus by age category for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex (TSC): results from the EXIST-1 trial
E U R O P E A N JO U R N A L O F PAEDIATRIC N E U R O L O G Y
crocephaly from our neurogenetics cohort and performed whole exome sequencing. Results: We identified novel mutations in four previously described microcephaly genes including WDR62, CDK5RAP2, ASPM, NDE1. Conclusions: Genetic heterogeneity is described in microcephaly, and the microcephaly proteins take varied pathways such as centrosome-related pathways or DNA repair. We revealed novel probably population specific mutations in known microcephaly genes as described above using whole exome sequencing.
P239 - 1816 Safety of everolimus by age category for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex (TSC): results from the EXIST-1 trial Jozwiak S, Brechenmacher T, Segal S, Franz DN. The Children’s Memorial Health Institute of Warsaw, Poland – [email protected] Objective: To present a 90-day safety update by age category for patients who participated in the EXIST-1 trial (NCT00789828). EXIST-1 demonstrated that everolimus is superior to placebo for reducing SEGA volume (P<0.0001; cut-off 02 March 2011) with an adverse event (AE) profile consistent with previous reports in TSC. Material and methods: Patients (any age) with ≥1 SEGA lesion (≥1 cm in longest diameter) were randomized (2:1) to 4.5 mg/m2 /day everolimus (target blood trough 5–15 ng/mL) or placebo. AEs were graded according to Common Terminology Criteria for Adverse Events v3.0. We report safety data for everolimus patients aged <3 (n=13), ≥3 to 18 (n=55), and ≥18 years (n=10) and placebo patients aged <3 (n=7), ≥3 to 18 (n=26), and ≥18 years (n=6). Results: As of 18 July 2011 (90-day update), median treatment duration was 52 weeks for everolimus and 47 weeks for placebo. For patients <3, ≥3–18 and ≥18 years, the incidence of serious AEs was 54%, 18%, and 20% for everolimus and 29%, 12%, and 0% for placebo; incidence of drug-related grade 3–4 AEs was 46%, 13%, and 10% for everolimus and 14%, 8%, and 0% for placebo. Infections/infestations occurred in 100%, 71%, and 70% of everolimus patients and 100%, 69%, and 33% of placebo patients aged <3, ≥3–18, and ≥18 years. Stomatitis (<3 and ≥18 years) and mouth ulceration (≥3–18 years) were the most common AEs for everolimus. For everolimus vs placebo, the incidence of stomatitis was 69% vs 43% (<3 years) and 40% vs 17% (≥18 years) and mouth ulceration was 44% vs 8% (≥3–18 years). Conclusions: The safety profile of everolimus is comparable among age categories with the possible exception of infections/infestations and stomatitis in younger patients, which may be an inherent underlying characteristic of the younger age group. Small sample sizes may have limited the results.
P240 - 1817 Safety of long-term everolimus treatment in toddlers with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytomas (SEGAs) Jozwiak S, Kotulska K, Chmielewski D, Borkowska J, Łojszczyk B, ´ Kuczynski D, Kmiec´ T, Berkowitz N, Dunin-Wasowicz ˛ D. The Children’s Memorial Health Institute of Warsaw, Poland – [email protected] Objectives: TSC is a multisystem autosomal dominant disorder that manifests with growth of benign tumors in several organs. In children with TSC, SEGAs, epilepsy, and neurodevelopmental delay present the most common causes of mortality and morbidity. TSC is characterized by increased mammalian target of rapamycin (mTOR) activation, and the mTOR inhibitor, everolimus, has recently been approved for the treatment of SEGAs associated with TSC in patients older than 3 years of age. The aim of this report was to show the safety of everolimus in younger
17s (2013) S1 – S149
S119
children with TSC-associated SEGAs. Material and methods: We present locally collected safety data from 8 children under the age of 3 who participated in the EXIST-1 (Everolimus in the Treatment of Subependymal Giant Cell Astrocytomas Associated With Tuberous Sclerosis Complex) study and were treated at our center with everolimus for at least 36 months. All children had growing SEGAs, and 5 patients presented with active, drug-resistant epilepsy at baseline. Results: There were no lifethreatening or grade 4 adverse events throughout follow-up. All children are still on treatment. The incidence of adverse events and their severity were similar to that observed in older children and adults. The most common adverse events included aphthous stomatitis, upper respiratory tract infections, rash, and laboratory abnormalities. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures, and in 2 other children, at least a 50% reduction in the number of seizures was noted. Neuropsychological examination showed no significant differences between baseline and follow-up scores in the Psyche-Cattell test. Conclusions: Everolimus is a therapeutic option in patients with TSC and should be considered for treatment in children under 3 years of age.
P241 - 2093 Tuberous sclerosis complex: multiple tubers with no functional impact – a case report Chemaly N, Grevent D, Hadj Rabia S, Ouss L, Boddaert N, Desguerre I, Nabbout R. Neuropediatrics Department, Centre de référence des Épilepsies rares, Necker Enfants Malades Hospital, Paris, France – [email protected] Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Brain involvement is frequent with seizures, cognitive impairement and behavioral disorders. Cognitive outcome is correlated to the occurrence of seizures, age of onset of seizures, infantile spasms occurrence and pharmacoresistance. Relationship between the localization of tubers and cognitive outcome is stressed out in many publications and autism seems to affect more frequently patients presenting with temporal tubers. A 16 year old girl who consulted for “malignant acnea” was referred to our clinic for TSC. She presented facial angiofibromas and white spots. She had normal psychomotor development with normal scholar achievement. She had neither seizures nor other neurological symptoms. Her neurological examination was normal. Her neuropsychological test was normal for age and she presented no abnormal psychiatric behaviour. Renal ultrasound showed angiomyolipoma that were of small size and clinically asymptomatic. Cerebral MRI showed multiple cortical tubers (>16) located almost in all brain regions with both temporal areas involved. She has also sub ependymal nodules with a small size SEGA with no ventricules asymmetry or dilatation. Tractography was performed and showed loss of anisotropy with modification of white matter fibers tractus. This report shows that the number of tuber and their localization does not seem to be the only predictive factors for cognitive outcome in TSC patients. In infants with prenatal diagnosis, functional aspects could prevail, and they must be closely followed on clinical and EEG basis in order to rule out and treat as soon as possible seizures, especially infantile spasms.
crocephaly from our neurogenetics cohort and performed whole exome sequencing. Results: We identified novel mutations in four previously described microcephaly genes including WDR62, CDK5RAP2, ASPM, NDE1. Conclusions: Genetic heterogeneity is described in microcephaly, and the microcephaly proteins take varied pathways such as centrosome-related pathways or DNA repair. We revealed novel probably population specific mutations in known microcephaly genes as described above using whole exome sequencing.
P239 - 1816 Safety of everolimus by age category for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex (TSC): results from the EXIST-1 trial Jozwiak S, Brechenmacher T, Segal S, Franz DN. The Children’s Memorial Health Institute of Warsaw, Poland – [email protected] Objective: To present a 90-day safety update by age category for patients who participated in the EXIST-1 trial (NCT00789828). EXIST-1 demonstrated that everolimus is superior to placebo for reducing SEGA volume (P<0.0001; cut-off 02 March 2011) with an adverse event (AE) profile consistent with previous reports in TSC. Material and methods: Patients (any age) with ≥1 SEGA lesion (≥1 cm in longest diameter) were randomized (2:1) to 4.5 mg/m2 /day everolimus (target blood trough 5–15 ng/mL) or placebo. AEs were graded according to Common Terminology Criteria for Adverse Events v3.0. We report safety data for everolimus patients aged <3 (n=13), ≥3 to 18 (n=55), and ≥18 years (n=10) and placebo patients aged <3 (n=7), ≥3 to 18 (n=26), and ≥18 years (n=6). Results: As of 18 July 2011 (90-day update), median treatment duration was 52 weeks for everolimus and 47 weeks for placebo. For patients <3, ≥3–18 and ≥18 years, the incidence of serious AEs was 54%, 18%, and 20% for everolimus and 29%, 12%, and 0% for placebo; incidence of drug-related grade 3–4 AEs was 46%, 13%, and 10% for everolimus and 14%, 8%, and 0% for placebo. Infections/infestations occurred in 100%, 71%, and 70% of everolimus patients and 100%, 69%, and 33% of placebo patients aged <3, ≥3–18, and ≥18 years. Stomatitis (<3 and ≥18 years) and mouth ulceration (≥3–18 years) were the most common AEs for everolimus. For everolimus vs placebo, the incidence of stomatitis was 69% vs 43% (<3 years) and 40% vs 17% (≥18 years) and mouth ulceration was 44% vs 8% (≥3–18 years). Conclusions: The safety profile of everolimus is comparable among age categories with the possible exception of infections/infestations and stomatitis in younger patients, which may be an inherent underlying characteristic of the younger age group. Small sample sizes may have limited the results.
P240 - 1817 Safety of long-term everolimus treatment in toddlers with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytomas (SEGAs) Jozwiak S, Kotulska K, Chmielewski D, Borkowska J, Łojszczyk B, ´ Kuczynski D, Kmiec´ T, Berkowitz N, Dunin-Wasowicz ˛ D. The Children’s Memorial Health Institute of Warsaw, Poland – [email protected] Objectives: TSC is a multisystem autosomal dominant disorder that manifests with growth of benign tumors in several organs. In children with TSC, SEGAs, epilepsy, and neurodevelopmental delay present the most common causes of mortality and morbidity. TSC is characterized by increased mammalian target of rapamycin (mTOR) activation, and the mTOR inhibitor, everolimus, has recently been approved for the treatment of SEGAs associated with TSC in patients older than 3 years of age. The aim of this report was to show the safety of everolimus in younger
17s (2013) S1 – S149
S119
children with TSC-associated SEGAs. Material and methods: We present locally collected safety data from 8 children under the age of 3 who participated in the EXIST-1 (Everolimus in the Treatment of Subependymal Giant Cell Astrocytomas Associated With Tuberous Sclerosis Complex) study and were treated at our center with everolimus for at least 36 months. All children had growing SEGAs, and 5 patients presented with active, drug-resistant epilepsy at baseline. Results: There were no lifethreatening or grade 4 adverse events throughout follow-up. All children are still on treatment. The incidence of adverse events and their severity were similar to that observed in older children and adults. The most common adverse events included aphthous stomatitis, upper respiratory tract infections, rash, and laboratory abnormalities. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures, and in 2 other children, at least a 50% reduction in the number of seizures was noted. Neuropsychological examination showed no significant differences between baseline and follow-up scores in the Psyche-Cattell test. Conclusions: Everolimus is a therapeutic option in patients with TSC and should be considered for treatment in children under 3 years of age.
P241 - 2093 Tuberous sclerosis complex: multiple tubers with no functional impact – a case report Chemaly N, Grevent D, Hadj Rabia S, Ouss L, Boddaert N, Desguerre I, Nabbout R. Neuropediatrics Department, Centre de référence des Épilepsies rares, Necker Enfants Malades Hospital, Paris, France – [email protected] Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. Brain involvement is frequent with seizures, cognitive impairement and behavioral disorders. Cognitive outcome is correlated to the occurrence of seizures, age of onset of seizures, infantile spasms occurrence and pharmacoresistance. Relationship between the localization of tubers and cognitive outcome is stressed out in many publications and autism seems to affect more frequently patients presenting with temporal tubers. A 16 year old girl who consulted for “malignant acnea” was referred to our clinic for TSC. She presented facial angiofibromas and white spots. She had normal psychomotor development with normal scholar achievement. She had neither seizures nor other neurological symptoms. Her neurological examination was normal. Her neuropsychological test was normal for age and she presented no abnormal psychiatric behaviour. Renal ultrasound showed angiomyolipoma that were of small size and clinically asymptomatic. Cerebral MRI showed multiple cortical tubers (>16) located almost in all brain regions with both temporal areas involved. She has also sub ependymal nodules with a small size SEGA with no ventricules asymmetry or dilatation. Tractography was performed and showed loss of anisotropy with modification of white matter fibers tractus. This report shows that the number of tuber and their localization does not seem to be the only predictive factors for cognitive outcome in TSC patients. In infants with prenatal diagnosis, functional aspects could prevail, and they must be closely followed on clinical and EEG basis in order to rule out and treat as soon as possible seizures, especially infantile spasms.