Everolimus
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Various toxicities following off-label use: case report A 12-year-old girl developed hypersialorrhea, leukopenia, neutropenia, epistaxis, fever, rhinorrhoea, fluctuating behaviour, diarrhoea, alopecia, asthenia, facial and forearm acne during off-label treatment with everolimus for refractory epilepsy. The girl was diagnosed with severe syndromic hypomelanosis of Ito (HMI). Anamneses revealed that she had a history of left corporal hemihypertrophy, linear hypomelanosis along Blaschko’s lines, hemimegalencephaly, hypotonia and spina bifida occulta. She also had a developmental delay with autistic-like behaviour, retinitis pigmentosa, peripheral hypothyroidism and peripheral premature puberty. At the age of 3 years, she had tonic-clonic seizures, which was treated with various drugs. Her epilepsy remained well-controlled till the age of 8 years. Afterwards, her seizure frequencies increased. Therefore, she had received treatment with various antiepileptic drugs. However, her epilepsy remained refractory to the treatment. At the age of 10 years, she had highly intractable epilepsy with a deterioration of neurological status. Further examination indicated migration disorders. Indepth whole-exome sequencing revealed mosaic de novo missense change of MTOR in 21 of 74 reads, and dermal fibroblasts analysis revealed mTOR signaling upregulation with elevated phosphorylation of p70 ribosomal protein S6 and kinase protein kinase B (AKT). Based on findings (at the current presentation), she started receiving off-label treatment with everolimus at 5 mg/day [route not stated], which was progressively increased to 12.5 mg/day to achieve blood levels between 5 and 15 µg/L. Sixteen days after the initiation of everolimus, her everolimus dose was increased to 7.5 mg/day. Subsequently, she developed mild grade I asthenia. On day 26, she developed grade I facial acne, asthenia, hypersialorrhea, mild leucopenia and neutropenia. On day 45, her everolimus dose was further increased to 10 mg/day. Subsequently, she developed grade I acne on forearms and face. The girl’s neutropenia and leucopenia became stable on day 60. Her everolimus blood level was 10.4 µg/L. On day 75, the everolimus dose was increased to 12.5 mg/day. Subsequently, she developed mild grade I alopecia, acne, epistaxis, fever, asthenia, diarrhoea and rhinorrhea. On day 90, she developed fluctuating behaviour, asthenia and worsening of alopecia. On day 120, her everolimus drug level was 18 µg/L, which was more than the expected drug level. Also, the worsening of alopecia persisted. Hence, everolimus was stopped on day 150, and subsequently, her complete blood count became normal. After five months of everolimus treatment, she had increased in duration and frequency of seizures. No changes in EEG findings after everolimus were noted. During everolimus treatment, she had received lacosamide and lamotrigine concomitantly. At the end of 3 months of everolimus treatment, she had received a 7-day course of salbutamol and amoxicillin for suspected pneumonia [aetiology not s
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