Efficacy and Safety of Sirolimus in the Treatment of Complicated Vascular Anomalies

Abstract

Background and objectives: Complicated vascular anomalies have limited therapeutic options and cause significant morbidity and mortality. This Phase II trial enrolled patients with complicated vascular anomalies to determine the efficacy and safety of treatment with sirolimus for 12 courses; each course was defined as 28 days.

Methods: Treatment consisted of a continuous dosing schedule of oral sirolimus starting at 0.8 mg/m(2) per dose twice daily, with pharmacokinetic-guided target serum trough levels of 10 to 15 ng/mL. The primary outcomes were responsiveness to sirolimus by the end of course 6 (evaluated according to functional impairment score, quality of life, and radiologic assessment) and the incidence of toxicities and/or infection-related deaths.

Results: Sixty-one patients were enrolled; 57 patients were evaluable for efficacy at the end of course 6, and 53 were evaluable at the end of course 12. No patient had a complete response at the end of course 6 or 12 as anticipated. At the end of course 6, a total of 47 patients had a partial response, 3 patients had stable disease, and 7 patients had progressive disease. Two patients were taken off of study medicine secondary to persistent adverse effects. Grade 3 and higher toxicities attributable to sirolimus included blood/bone marrow toxicity in 27% of patients, gastrointestinal toxicity in 3%, and metabolic/laboratory toxicity in 3%. No toxicity-related deaths occurred.

Conclusions: Sirolimus was efficacious and well tolerated in these study patients with complicated vascular anomalies. Clinical activity was reported in the majority of the disorders.

Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

Copyright © 2016 by the American Academy of Pediatrics.

Figures

FIGURE 1

Macrocystic and microcystic lymphatic malformation with airway compromise. A, Coronal short-tau inversion-recovery magnetic resonance images of a young boy with a large focal macrocystic and microcystic lymphatic malformation; images were obtained before therapy initiation (left, at 6 weeks of age) and at the time of therapy cessation (right, 13 months later). The pretherapy image shows a large, infiltrating, multicystic mass of the left scalp, face, neck, and chest. The mass was causing airway compromise (not shown). With sirolimus therapy alone, the mass decreased markedly in size. B, Clinical examination revealed interval decrease in the size of the lesions, with decreased tumor bulk and firmness resulting in “saggy” tissue with less mass effect.

FIGURE 2

KHE with KMP. A, Radiographic imaging of a patient with KHE and KMP. Coronal short-tau inversion-recovery magnetic resonance images of a young girl with a left chest wall KHE; images were obtained 18 days before therapy initiation and at the time of study conclusion. The pretherapy image shows a poorly defined, irregular mass of increased signal intensity infiltrating multiple tissue planes of the superficial and deep left lateral chest wall. The posttherapy image shows a marked interval decrease in the size of the mass. B, KHE with KMP functional impairment score/skin. Skin at prestudy and end of study. Physical examination at study conclusion revealed less purpura, petechiae, decreased warm, and softer cutaneous manifestations with improved range of motion.

FIGURE 3

Generalize lymphatic anomaly with bone involvement. Coronal short-tau inversion-recovery magnetic resonance images of a young boy with generalized lymphatic anomaly obtained before therapy initiation (left, at 29 months of age) and at the time of therapy cessation (right, 11 months later). The pretherapy image shows numerous well-circumscribed, bright (fluid-signal intensity) lesions throughout the visualized bones of the pelvis and proximal right femur. The posttherapy image shows minimal residual osseous abnormality at these sites with no discrete cystic lesions.