Efficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study

Abstract

INTRODUCTION: Blue rubber bleb nevus syndrome (BRBNS) is a rare systemic venous malformation (VM) disease. The characteristic gastrointestinal (GI) bleeding from multiple VM lesions causes severe chronic anemia which renders most patients depend on lifelong blood transfusion and frequent endoscopic treatment with dismayed outcomes. Although recent case reports suggest that oral sirolimus (rapamycin) is effective, a comprehensive evaluation of its efficacy and safety is in need. METHODS: A prospective study was conducted for both pediatric and adult BRBNS patients with administration of sirolimus at the dose of 1.0 mg/m2 to maintain a trough concentration of 3–10 ng/mL. Laboratory tests including complete blood count, biochemical profile, D-dimer, and whole-body magnetic resonance imaging were performed at baseline and 3, 6, and 12 months after treatment. Clinical indicators such as hemoglobin level, lesion size, and transfusion need were evaluated. Adverse effects were recorded regularly. RESULTS: A total of 11 patients (4 males and 7 females) with median age of 14 (range, 5–49) years were recruited. The average lesion size was reduced by 7.4% (P < 0.001), 9.3% (P < 0.001), and 13.0% (P < 0.05) at 3, 6, and 12 months of sirolimus treatment, respectively. Hemoglobin increased significantly after 6- and 12-month treatment (P = 0.006 and 0.019, respectively). Only 1 patient received blood transfusion once during the study. Patients' quality of life and coagulation function were improved. Grade 1–2 adverse effects including oral ulcers (81.8%), acne (27.3%), transient elevation of liver enzymes (18.2%), and hair loss (9.1%) were observed. DISCUSSION: Sirolimus reduces the size of VMs, alleviates GI bleeding, and eliminates transfusion dependence of patients with BRBNS. The drug-related adverse effects are mild and mostly self-limited. These findings support sirolimus as a first-line treatment for GI and cutaneous VMs of BRBNS (see Visual abstract, Supplementary Digital Content, http://links.lww.com/AJG/B819).

Sirolimus for management of GI bleeding in blue rubber bleb nevus syndrome: A case series

“…We propose an initial level of 5–10 ng/ml, which offers therapeutic benefit while minimizing side effects. This is corroborated by the prospective study by Zhou et al 12 . in which the level of 3–10 ng/ml was successful for 11 pediatric and adult patients with mild adverse effects.…”

“…32 Sirolimus blocks mTOR, thereby serving as a targeted therapy for BRBNS. Its efficacy was first demonstrated in 2012 31 and since then there have been multiple reports describing its use [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] (Table S1).…”

“…Steroids, interferon α‐2a, propranolol, and thalidomide have not demonstrated efficacy and exhibit unfavorable side effects 9–11 . Sirolimus has anti‐angiogenic properties, with multiple reports documenting its success in BRBNS 12–31 . To date, one prospective study exists reporting the efficacy and safety of sirolimus in BRBNS, 12 though questions remain regarding dosing, duration, and long‐term side effects.…”

“…Sirolimus has anti‐angiogenic properties, with multiple reports documenting its success in BRBNS 12–31 . To date, one prospective study exists reporting the efficacy and safety of sirolimus in BRBNS, 12 though questions remain regarding dosing, duration, and long‐term side effects. In this single‐center case series, we describe four pediatric patients with transfusion‐dependent anemia due to GI lesions who were successfully treated with sirolimus and review the existing literature in regard to sirolimus dosing, duration of therapy, and adverse effects.…”

Blue rubber bleb nevus syndrome complicated with disseminated intravascular coagulation and intestinal obstruction: A case report

“…It was first applied clinically in 2012[ 12 ]. Sirolimus reduces the size of venous hemangioma, thus alleviating GI bleeding and eliminating dependence on blood transfusions for patients with BRBNS[ 13 ]. The mean response time is 1.6 mo (95% confidence interval: 0.75-2.36 mo).…”