Background
Results
Cohort
Patient # | Sex | Age at inclusion [y] | Age at Diagnosis [d] | Mutation | sporadic / familial | First clinical manifestation | Reason for mTOR inhibition | Further manifestations |
---|---|---|---|---|---|---|---|---|
1 | f | 4.3 | 210 |
TSC2
| sporadic | Epilepsy | SEGA | Neuro: tubers, SEN, migration lines, DD |
2 | m | 6.2 | prenatal |
TSC2
| sporadic | CR | Congenital focal lymphedema | Skin: subungual fibromas Neuro: Epilepsy, tubers, SEN, DD Other: lumbar scoliosis, aneurysms, renal artery stenosis |
3 | f | 0 | prenatal | NA | familial | CR | SEGA | Skin: angiofibromas, white spots, Shagreen patch Neuro: Epilepsy, tubers, DD |
4 | m | 0.1 | 49 | NA | sporadic | CR | SEGA | Skin: angiofibromas, white spots Neuro: Epilepsy, tubers, DD |
5 | m | 1.5 | 60 | NA | sporadic | CR | Epilepsy | Skin: white spots Neuro: tubers, SEN, DD Other: retinal hamartomas |
6 | m | 0 | prenatal |
TSC2
| familial | CR | CR | None |
7 | f | 3.1 | prenatal |
TSC2
| sporadic | CR | CR | Skin: white spots Neuro: Epilepsy, tubers, SEN, DD |
8 | f | 5.1 | prenatal | NA | sporadic | CR | SEGA | Skin: white spots Neuro: Epilepsy, tubers, SEN, white matter lesions, DD Other: retinal hamartomas |
9 | m | 4 | prenatal |
TSC2
| sporadic | CR | CR / SEGA | Skin: white spots Neuro: Epilepsy, tubers, SEN, migration lines, DD |
10 | m | 4.1 | 30 | NA | sporadic | CR | Epilepsy | Skin: white spots Neuro: tubers, SEGA, aberrant gyrification Other: renal angiomyolipoma |
11 | f | 1.7 | 30 |
TSC2
| sporadic | CR | CR | Neuro: Epilepsy, tubers, SEN, DD |
12 | m | 2.1 | 0 |
TSC2
| sporadic | SEGA | SEGA | Neuro: Epilepsy, tubers, SEN, white matter lesions, DD Cardiac: CR |
13 | m | 2.6 | 15 |
TSC2
| sporadic | CR | CR | Skin: white spots Neuro: tubers, SEN, DD |
14 | m | 3.3 | prenatal |
TSC 2
| sporadic | CR | CR | Skin: white spots, angiofibromas Neuro: Epilepsy, SEN, DD |
15 | m | 0.9 | prenatal |
TSC1
| sporadic | CR | CR | None |
16 | m | 0.3 | 90 |
TSC2
| sporadic | Epilepsy | Epilepsy | Neuro: tubers, SEN, DD Cardiac: CR Other: retinal hamartomas, renal angiomyolipoma |
17 | m | 2.4 | 30 |
None
| sporadic | CR | Epilepsy | Skin: white spots Neuro: tubers, SEN, DD |
Safety profile of everolimus therapy
Patient # | Age at start of treatment | Dosages | Comedications | AE | Vaccination status before therapy | Vaccination status during therapy |
---|---|---|---|---|---|---|
1 | 19 months | 2.5 mg once daily | VGB, MAD | Recurrent URTI / LRTI Increase of cholesterol / TG | Complete | NA |
2 | 14 months | 2.5 mg 3 times per week | VGB, STM, VPA | None | Complete | No live vaccines |
3 | 15 months | 2.5 mg once daily | LTG, VGB | Transient stomatitis | Complete | NA |
4 | 17 months | 2 mg once daily | LEV, VPA | Transient stomatitis | Complete | NA |
5 | 12 months | 3 mg once daily | OXC | None | NA | No live vaccines |
6 | 14 days | 0.3 mg two times per week | flecainide, propranolol | None | Incomplete | NA |
7 | 5 months | 1 mg daily | ACTH, OXC, VGB, TMP | Transient anemia | No vaccinations | NA |
8 | 14 months | 2.5 mg daily | different AEDs, TMP | Recurrent URTI / LRTI Increase of cholesterol / TG | Complete | NA |
9 | 7 days | NA | TPM, VGB, VPA, propanolol, melatonin | Recurrent infections Reduction of phosphate Increase of cholinesterase Increase of TG Increase of LDH | NA | Vaccinations under therapy |
10 | 2 months | NA | LEV, VGB, sotalol | Recurrent infections | NA | Vaccinations during 3 months pause of therapy |
11 | 7 days | 0.05 mg every other day | VPA, VGB, TPM, propranolol, propafenone | Worsening of infantile acne Increase of phosphate Increase of cholinesterase | NA | Vaccinations under therapy |
12 | 1 month | 0.03 mg/m2twice per day | LEV, VGB | Transient neutropenia UTI | NA | NA |
13 | 3 months | 0.1 mg twice per day | VGB, flecainide, metoprolol, amiodarone, metildigoxin | Transient neutropenia Recurrent URTI | NA | NA |
14 | 2 days | 1.5-2 mg/m2 daily | VGB, LEV, digoxin, TMP/SMX, nystatin | Increase of cholesterol / TG Transient lymphopenia | NA | No live vaccines |
15 | 2 days | 0.25 mg daily | TMP/SMX, nystatin | None | NA | No live vaccines |
16 | 7 months | 0.5 mg twice per day | PB, VGB | Recurrent infections | NA | No live vaccines |
17 | 10 months | 5 mg daily | OXC, VGB, KD | None | NA | No live vaccines |
Changes of cardiac manifestations and SEGA size under everolimus therapy
Patient # | Reason for therapy | Effect of therapy | Development before therapy | Development at follow-up |
---|---|---|---|---|
1 | SEGA | Decrease of SEGA | Normal | DD (not specified) |
2 | Congenital focal lymphedema | Regression of congenital focal lymphedema | DD (global) | DD (not specified)
K-ABC, WPPSI-III
|
3 | SEGA | Decrease of SEGA | DD (motor) | Normal
SON-R
|
4 | SEGA | Decrease of SEGA | DD (not specified) | DD (global)
MFED
|
5 | Epilepsy | Decrease of seizure frequency | DD (not specified) | NA |
6 | CR | Decrease of CR | Normal | Normal |
7 | CR | Decrease of CR | Normal | DD (speech)
MFED
|
8 | SEGA | No effect | DD (not specified) | DD (global)
Bayley II
|
9 | CR / SEGA | Decrease of CR / SEGA | NA | DD (global) |
10 | Epilepsy | Ongoing seizures | NA | Normal |
11 | CR / cardiac arrhythmia | Decrease of CR | NA | DD (global) |
12 | SEGA | Decrease of CR / SEGA | Normal | DD (global)
Bayley II
|
13 | CR / cardiac arrhythmia | Decrease of CR | DD (motor) | DD (motor)
Bayley II, VABS II, CBCL 1½-5, ELFRA-2
|
14 | CR | Decrease of CR | DD (global) | DD (motor) |
15 | CR | Decrease of CR | Normal | NA |
16 | Epilepsy | Decrease of seizure frequency | DD (not specified) | DD (global)
Bayley II, GMDS
|
17 | Epilepsy | Ongoing seizures | DD (motor) | DD (not specified) |
Epilepsy and neurodevelopment under everolimus therapy
Patient # | Age at start of mTOR inhibitor | AAO of IS | Previous treatment | Time to cessation of IS | Development prior to start of mTOR inhibition | Development during follow-up |
---|---|---|---|---|---|---|
1 | 19 months | 7 months | VGB | 16 months | Normal | DD (not specified) |
2 | 14 months | 5 months | VGB | 3 months | DD (global) | DD (not specified) |
3 | 15 months | 6 months | VGB | NA | DD (motor) | Normal |
7 | 5 months | NA | ACTH, VGB | 1 month | Normal | DD (speech) |
9 | 7 days | 7 months | VGB | 4 months | NA | DD (global) |
11 | 7 days | 1 month | VGB | NA | NA | DD (global) |
12 | 1 day | 5 months | VGB | 1 month | NA | DD (global) |
Discussion
Safety profile
Dosing
mTOR inhibitor | AAO of mTOR inhibitor | Dosing regimen | Dose [mg/m2/d] | Trough levels [ng/ml] | Duration | AE | Prophylaxis | Reference |
---|---|---|---|---|---|---|---|---|
EVE | NA | 0.25 mg twice per day 2 days per week | NA | 5–15 | 2.5 months | Increase of TG Self-limiting diarrhea Decreased CD/CD8 ratio lymphopenia | TMP/SMX | (Demir et al. 2012) |
Sirolimus | 10 days | 0.4 mg daily | NA | NA | 24 days | Increase of TG | TMP/SMX | (Breathnach et al. 2014) |
EVE | 20 days | 0.1 mg daily | 0.64 | 11 | 34 days | Transient hypokalemia | NA | (Mohamed et al. 2014) |
EVE | 2 days | 0.25 mg twice per day 2 days per week | NA | 3.6–7.8 | 3 months | NA | NA | (Dogan et al. 2015) |
EVE | 4 days | 0.1 mg daily | 0.64 | 11.5 | 42 days | NA | NA | (Goyer et al. 2015) |
EVE | 9 days | 0.1 mg daily | 0.64 | 10.2 | NA | NA | NA | |
EVE | 21 days | NA | 3 | 4–5 | NA | Hyponatremia | antibiotic prophylaxis | (Mlczoch et al. 2015) |
EVE | NA | 0.25 mg twice per day 2 days per week | NA | NA | 4 weeks | NA | NA | (Oztunc et al. 2015) |
EVE | 2 days | 0.15–0.2 mg daily | 1 | 10–15 | 19 days | Toxic levels of 108 ng/ml under initial dose of 0.4–0.45 mg (=1.5-2 mg/m2) | NA | (Wagner et al. 2015) |
EVE | 7 days | 0.25 mg daily | 1 | NA | 10 weeks | Mild mucositis Increase of TG | NA | (Colaneri et al. 2016) |
EVE | NA | 0.25 mg twice per day 2 days per week | NA | 5–10 | NA | NA | NA | (Emir et al. 2017) |
EVE | NA | 0.5 mg daily | NA | NA | NA | NA | NA | (Hoshal et al. 2016) |
EVE | 20 days | 0.1 mg daily | NA | 13.7 | 34 days | Suspected infection | NA | (Aw et al. 2017) |
EVE | 4 days | NA | NA | 11 | 42 days | None | NA | |
EVE | 9 days | 0.1 mg daily | NA | 10.2 | NA | Oral ulcers | NA | |
EVE | 1 day | 0.1 mg daily | NA | 10.2 | 36 days | None | NA | |
EVE | NA | 0.03125 mg daily | 0.12 | 3–7 | 2 weeks | Adenovirus pneumonia High trough levels of 20 ng/ml under 0.125 mg (0.0558 mg/m2) | NA | (Chang et al. 2017) |
EVE | NA | NA | 0.35 | 1.81 | NA | NA | NA | |
EVE | NA | 0.125 mg daily | 0.51 | NA | Na | NA | NA |