Table 1.
Characteristics of children treated with everolimus.
| Author, Year |
Localization of the Largest or Symptomatic CR | initial Size of the Largest or Symptomatic CR | CR Clinical Symptoms/Reason to Start mTORi | Age at mTORi Introduction | Treatment Duration | Initial mTORi Dose | Follow-Up of mTORi Serum Level | Effect of mTORi on CRs Volume | Effect of mTORi on Clinical Symptoms | Follow-Up Period after mTORi Withdrawal | CRs Volume at the End of Follow-Up | CR Clinical Manifestations at the End of Follow-Up |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Aw et al., 2017 [24]; Goyer et al., 2015 [53]; Mlczoch et al., 2015 [34] | ||||||||||||
| 1 | LV | 8 × 7 mm | significant pressure gradient in the LV outflow tract | 1 day | 36 days | 0.1 mg/day (4.5 mg/m2/week), targeted level 5–15 ng/mL | after 10 days; drug level—10.2 ng/mL |
After 36 days; 50% reduction of the largest CR, other 3 disappeared |
no cardiological symptoms | at least 18 months | progressive increase in CR size: on day 112: CR size was 3.2 × 2.7 mm on day 576: CR size was 6.6 × 4.1 mm |
no clinical symptoms |
| 2 | LV | 15 × 9 mm | no clinical symptoms, multiple tumors occupying LV and concern about possible outflow tract obstruction |
4 days | 46 day | 0.1 mg/day (4.5 mg/m2/week); targeted level 5–15 ng/mL |
after 6 days; drug level—11 ng/mL |
After 22 days; 50% reduction of CR size |
remained asymptomatic | at least 7 months | progressive increase in CR size On the 48th day of life—12.4 × 7.8 mm On the 268th day of life–17.5 × 13.2 mm |
remained asymptomatic |
| 3 | RV | 11 × 6 mm | SEGA, CR were asymptomatic | 9 days | no data | 0.1 mg/day (4.5 mg/m2/week); targeted level 5–15 ng/mL |
after 13 days; drug level −5.4 ng/mL |
After 11 days; CR size was 6.5 × 3.1 mm (30–50% reduction) After 1 month; CR was undetectable |
remained asymptomatic | still treated with everolimus | - | - |
| 4 | RV | no data | duct dependent RVOT obstruction, heart failure | 21 days | planned for 1 year | 3 mg/m2; targeted level of 4–5 ng/mL |
no data | after 28 days; CR regression (no detailed data) |
after 3 months; a significant improvement, no obstruction in RVOT |
2 weeks | CR dramatically increased in size (everolimus was re-introduced) | do data |
| Bornaun et al., 2016 [25] | LV, RV | 1.3 cm2 | cyanosis, hypotonia, LV hypertrophy, obstruction of LVOT, mild obstruction of RVOT, inoperable CR | 7 days | overall 6 months | 2 × 0.25 mg twice a week; targeted level 2.6–6.1 ng/mL |
drug level varied from 0.4 to 2.6 ng/mL | (1) after 28 days; significant reduction of CR (everolimus was ceased) (2) after 180 days of everolimus reintroduction; marked decrease of CR size |
after 4 weeks; resolution of LV outflow tract obstruction |
(1) 10 days (after 1st drug withdrawal) (2) 12 months (after 2nd drug withdrawal) |
(1) significant regrowth of all CR (2) stable CR size |
no data |
| Castro-Monsalve et al., 2018 [47] | IVS | no data | cardiac arrest, severe hemodynamic instability, cardiac failure | neonate | no data | 0.1 mg/day | drug level between 5–8 ng/mL | After 31 days; 60% reduction of CR size After 60 days; resolution of CR |
no data | no data | no data | no data |
| Choudhry et al., 2015 [48] | RV, LV | from 3 to 12 mm | SEGA; CR were asymptomatic | neonate | no data | no data | no data | after 30 days; the apparent resolution of all CR (no detailed data) |
remained asymptomatic | no data | no data | remained asymptomatic |
| Colaneri et al., 2016 [49] | LV | 40 × 35 × 40 mm (transverse diameter in thorax MRI—35 × 25 mm) |
severe reduction of LV volume resulting in duct dependent heart disease, sporadic ventricular extrasystoles, large renal angiomyolipoma; surgery was contraindicated | 7 days | 10 weeks | 0.25 mg/day (0.11 mg/kg; 1.5 mg/m2), targeted level 5–15 ng/mL |
after 5 days; drug level—9.1 ng/mL; |
After 70 days; CR size—23 × 9 mm in thorax MRI (30–50 % reduction) |
after 10 days; extrasystoles disappeared after 3 weeks; normal ventricular function |
9 months | Stable | no clinical symptoms |
| Demir et al., 2012 [50]; | RV, IVS, LV | CR sizes ranged from 5 to 25 mm | cyanosis, RV heart failure, obstruction of RV inflow, CR ineligible for surgery | neonate | 2.5 months | 0.25 mg every 6 h 2 days per week; targeted level 5–15 ng/mL |
after 4 doses drug level was 83.5 ng/mL | After 70–75 days; CR remarkably decreased in size (no detailed data) |
after 2.5 months; hemodynamic instability improved |
2 months | no data | no clinical symptoms |
| Dogan et al., 2015 [51] | LV | 24 × 21 mm and 22 × 20 mm | cyanosis, LV obstruction, inoperable tumors | neonate | 3 months | 0.25 mg two times per day, 2 days per week; targeted level of 5–15 ng/mL | drug level ranged from 3.6 to 7.8 ng/mL | After 60 days; significant CR reduction |
After 2 months; no hemodynamic instability, relief of LV obstruction |
15 months | no data | severe mitral insufficiency, moderate LV dilatation, WPW in ECG |
| Garg et al., 2018 [52] | RV | 40 × 37 × 30 mm | ventricular tachycardia, hypotension, mild/moderate tricuspid insufficiency; high risk of surgery | neonate (around 4–5th day of life) | no data | 0.08 mg/day (0.3 mg/m2/day) | no data | After 14 days; a slight decrease of CR size After 30 days rapid involution of the CR |
Significant clinical improvement after a few days of treatment | still treated, but the dose was not weight-adjusted | - | - |
| Hoshal et, 2015 [26] | LV, intrapericardial tumor extending along the aortic root | no data | circulatory collapse, RVOT obstruction, cardiac enlargement, disqualification from the surgery | neonate or infant | more than 10 months | 0.5 mg/day | no data | After 60 days; regression of CR After 300 days; CR almost disappeared |
after 2 months; improvement after 10 months; normal LV ejection fraction |
no data | no data | no data |
| Kim et al., 2019 [27] | no data | 45 mm | hemodynamically unstable arrhythmia and SEGA | older than 15 months | no data | no data | no data | After 150 days; complete regression of CR |
no data | no data | no data | no data |
| Martínez-García et al., 2018 [33] | LV | 47 × 40 mm | Giant CR occupying almost whole LV resulting in duct dependent heart disease, cardiomegaly, incomplete left bundle branch block with severe repolarization disorder | 36 days | no data | 0.25 mg two times per day only 2 days a week | no data | After 90 days; CR size 22 × 29 mm (30–50% reduction) |
after 3 months; normal ejection fraction |
no data | no data | no data |
| Mohamed et al. 2014 [35] | IVS, RV | 16 × 11 mm | RVOT obstruction with heart failure; high risk of surgery, additional duct dependent heart defect | 20 days | 34 days | 0.1 mg/day (about 4.5 mg/m2/week) targeted level of 5–15 ng/mL |
after 11 days; drug level 11 ng/mL |
After 34 days; significant reduction of CR |
after 34 days; no obstruction of RV outflow tract (the child underwent surgical intervention on the 88th day of life due to a structural heart defect) |
12 months | stable | no clinical symptoms |
| Öztunç et al., 2015 [38] | LV, RV, IVS | no data | pharmacoresistant supraventricular tachycardia | neonate | 4 weeks | 0.25 mg 2 times per day twice a week | no data | After 15 days; CR started to shrink | after 8 days; the frequency and duration of tachycardia diminished |
6 months | stable | no clinical symptoms |
| Prasad et al. 2020 [41] | LV | 31 × 41 mm | congestive heart failure, respiratory dysfunction, LV dysfunction | neonate | 16 weeks | 4.5 mg/kg/m2 weekly | no data | After 70 days; CR size was 9 × 11 mm (>50% reduction) |
improvement of respiratory function | no data | no data | no clinical symptoms |
| Saffari et al., 2016 [42] (study reported 8 patients with CR treated with mTORi) | no data | no data | (6 children) symptomatic CR—obstruction of cardiac outflow or arrhythmia; (1 child) SEGA and symptomatic CR; (1 child) SEGA and asymptomatic CR |
median age 10.5 days (2 days—5 months); neonates—5 children; infants— 3 children |
no data | Infants up to 3 months—doses ranging from 0.05–0.3 mg; infants > 5 months—doses ranging from 1 to 5 mg/day |
In 1 patient toxic drug level of around 100 ng/mL after initial dose of 0.4–0.45 mg (1.5–2 mg/m2) | In all patients CR decreased in size | clinical improvement | no data | no data | In one patient recurrence of potentially life-threatening arrhythmia after everolimus cessation. The reintroduction of the drug controlled the arrhythmia |
| Shibata et al., 2019 [43] | RV | 35 × 21 mm | duct dependent obstruction of the LVOT | 4 days | less than 35 days | 0.2 mg/kg/day; targeted level 5–15 ng/mL |
on 4th day; drug level: 76.1 ng/mL, drug was transiently withdrawn |
After 16 days; CR size—28 × 15 mm (<30% reduction) After 38 days; CR size—24 × 11 mm (30–50% reduction) |
after 4 days; resolution of duct dependent heart disease |
no data | no data | no data |
| Tibero et al., 2011 [44] | LV | no detailed data | SEGA, CR were asymptomatic | 5 years | 13 months | no data | drug level between 2.3 and 7.1 ng/mL | After13 months; near-resolution of CR |
remained asymptomatic | no data | no data | remained asymptomatic |
| Wagner et al., 2015 [45] | LV | 21 × 37 × 21 mm | LVOT obstruction (partially duct dependent) | 2 days | 19 days | 1.5–2 mg/m2; targeted level 5–15 ng/mL |
after 4 days; drug level of 108 ng/mL; the drug was stopped for 4 days |
After 21 days; CR size—10 × 28 × 13 mm (30–50% reduction) |
improvement—prostaglandin infusion was ceased after 2 days of therapy | 5 months | stable | no clinical symptoms |
Abbreviations: CR—cardiac rhabdomyoma(s), IVS—intraventricular septum, LV—left ventricle, LVOT—left ventricle outflow tract, mTORi—mTOR inhibitor, RA—right atrium, RV—right ventricle, RVOT—right ventricle outflow tract.