Efficacy And Safety Of Sirolimus For The Treatment Of Refractory Vascular Anomalies

Objective To explore the efficacy and safety of sirolimus for the treatment of refractory vascular anomalies.Method Children with vascular diseases who failed to respond to standard treatment were collected from March 2017 to September 2020.The initial oral sirolimus dose was 0.8mg/m2/d.Each course was 28 days.The efficacy and safety of sirolimus treatment were analyzed by observing the changes of lesions before and after treatment.Result 1.Efficacy evaluation:A total of 25 children with refractory vascular disease were ultimately included in the analysis,including 16 children with vascular tumor and 9 patients with vascular malformation.The average volume reduction ratio is 67.8±25.7%after 12 courses sirolimus treatment.13 cases(52%)achieved CR,11 cases(44.0%)were PR.The ORR was 96.0%.There was no significant difference in CR rate and mean volume reduction ratio for patients diagnosed as vascular tumor or vascular malformation(P=1.00,P=0.89).In the first 6 courses of sirolimus treatment,the volume gradually decreased with the accumulation of treatment time.After 6 courses of treatment,the trend of volume reduction was slower than before.T Among children who eventually achieved CR and PR,the mean time to onset of response was 4.3±3.0 courses.2.Adverse events:A total of 63 cases of sirolimus-related adverse events were experienced in 25 children,all of which were mild adverse events of grade Ⅰ to Ⅱ,and no adverse events of grade Ⅲ or above occurred.The most common adverse event was bone marrow suppression,with 12 children(48.0%)having neutropenia.The remaining adverse events were 2 cases(8.0%)of oral mucositis,4 cases(16.0%)of hypercholesterolemia,5 cases(20.0%)of hypertriglyceridemia,and 6 cases(24.0%)of hypercholesterolemia.3.Efficacy and safety of sirolimus in different trough concentration ranges:In order to explore the relationship between the efficacy and safety of blood trough concentration of sirolimus,we divided the patients into high concentration group(≥10 ng/mL)and low concentration group(<10 ng/mL)according to the average blood trough concentration.Among them,11 cases(44.0%)were in the high concentration group and 14 cases(56.0%)were in the low concentration group.The CR rate in the high concentration group was significantly higher than that in the low concentration group(72.4%vs 21.4%,P=0.017).Only one case of SD was in the low concentration group.The average volume reduction ratio of the high concentration group was significantly higher than the low one(80.9±22.9%vs 57.5±23.5%,P=0.015).The high-concentration group has a shorter onset time.But there was no significant difference between the two groups in statistical analysis(4.9±3.5 courses vs 3.5±2.1 courses,P=0.424).No adverse events of grade Ⅲ or above occurred in the low-concentration group and the high-concentration group.The incidence of adverse events below grade Ⅲ in the high concentration group was significantly higher than that in the low concentration group(81.8%vs 35.7%,P=0.021).But 2 cases of oral mucositis only occurred in the low concentration group.The incidence of bone marrow suppression was higher in the high-concentration group than in the low-concentration group.Among the adverse events associated with lipid metabolism,only 1(7.1%)cases of hypercholesterolemia and 1(7.1%)of hypertriglyceridemia were in the low concentration group,while in the high concentration group there were 3(27.3%)cases of hypercholesterolemia and 4(36.4%)cases of hypertriglyceridemia.The incidence of adverse events in lipid metabolism was higher in the high concentration group,but there was no statistical difference(P=0.173,P=0.07).Among the adverse events associated with liver function,only 1 case(7.1%)had hyperbilirubinemia in the low concentration group and 5 cases(45.5%)in the high concentration group,and there was a statistical difference between the two groups(P=0.026).Conclusion Sirolimus is effective in all types of refractory vascular disease in children.Children benefit from 6 courses sirolimus treatment or less.Sirolimus-related adverse events are controlled.Higher sirolimus trough concentration is more effective,but the incidence of adverse events is higher.