Additive value of transarterial embolization to systemic sirolimus treatment in kaposiform hemangioendothelioma

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor in children, which can be accompanied by life‐threatening thrombocytopenia, referred to as Kasabach‐Merritt phenomenon (KMP). The mTOR inhibitor sirolimus is emerging as targeted therapy in KHE. As the sirolimus effect on KHE occurs only after several weeks, we aimed to evaluate whether additional transarterial embolization is of benefit for children with KHE and KMP. Seventeen patients with KHE and KMP acquired from 11 hospitals in Germany were retrospectively divided into two cohorts. Children being treated with adjunct transarterial embolization and systemic sirolimus, and those being treated with sirolimus without additional embolization. Bleeding grade as defined by WHO was determined for all patients. Response of the primary tumor at 6 and 12 months assessed by magnetic resonance imaging (MRI), time to response of KMP defined as thrombocyte increase >150 × 103/μL, as well as rebound rates of both after cessation of sirolimus were compared. N = 8 patients had undergone additive embolization to systemic sirolimus therapy, sirolimus in this group was started after a mean of 6.5 ± 3 days following embolization. N = 9 patients were identified who had received sirolimus without additional embolization. Adjunct embolization induced a more rapid resolution of KMP within a median of 7 days vs 3 months; however, tumor response as well as rebound rates were similar between both groups. Additive embolization may be of value for a more rapid rescue of consumptive coagulopathy in children with KHE and KMP compared to systemic sirolimus only.

to evaluate whether additional transarterial embolization is of benefit for children with KHE and KMP. Seventeen patients with KHE and KMP acquired from 11 hospitals in Germany were retrospectively divided into two cohorts. Children being treated with adjunct transarterial embolization and systemic sirolimus, and those being treated with sirolimus without additional embolization. Bleeding grade as defined by WHO was determined for all patients. Response of the primary tumor at 6 and 12 months assessed by magnetic resonance imaging (MRI), time to response of KMP defined as thrombocyte increase >150 × 10 3 /μL, as well as rebound rates of both after cessation of sirolimus were compared. N = 8 patients had undergone additive embolization to systemic sirolimus therapy, sirolimus in this group was started after a mean of 6.5 ± 3 days following embolization. N = 9 patients were identified who had received sirolimus without additional embolization. Adjunct embolization induced a more rapid resolution of KMP within a median of 7 days vs 3 months; however, tumor response as well as rebound rates were similar between both groups. Additive embolization may be of value for a more rapid rescue of consumptive coagulopathy in children with KHE and KMP compared to systemic sirolimus only. Kasabach-Merritt phenomenon (KMP). 1,3 Different from disseminated intravascular coagulation (DIC), intratumoral platelet trapping through activated endothelium carrying a partial lymphatic phenotype results in severe thrombocytopenia. 4 This intratumoral coagulopathy accounts for a high mortality in KHE of 10% to 30% in KHE patients. 5 As curative surgical resection of KHE is frequently not possible and is additionally associated with a high mortality, 6 various systemic treatment options have been suggested including corticosteroids, vincristine, 7 interferon-alpha and platelet inhibition. 8,9 In 2013, a consensus document recommended intravenous vincristine and either oral prednisolone or intravenous methylprednisolone as first-line treatment of KHE associated with KMP, 10 while two more recent meta-analyses have identified vincristine as safer and more effective compared to corticosteroids. 7 Image-guided embolization has been shown to induce a rapid decrease of the tumor mass, but the effect is considered to be only temporary. 10,11 Besides the aforementioned approaches, the mammalian target of rapamycin (mTOR) inhibitor sirolimus, a substrate for CYP3A4, targeting the PI3K-Akt-mTOR pathway is emerging as novel treatment option in KHE. 12,13 While traditionally used to inhibit the activation of T-lymphocytes in transplant rejection, multiple reports have recently shown the efficiency of sirolimus in treating both KHE and the associated KMP. 14 In addition, sirolimus seems equally effective for initial therapy 15 and for steroid-resistant KHE 16 showing low rates of recurrence, 17 although relapse after cessation of sirolimus treatment has been observed. 18 Sirolimus treatment on the one hand initiates shrinkage and remission of the tumor and similarly it addresses KMP over time, leading to a normalization of thrombocyte counts within a period of approximately 20 days. [15][16][17]19 Therapy of complicated KHE thus aims at (a) remission of the pri-

| Patients and disease manifestation
Demographic, clinical, laboratory and procedural data were retrieved from electronic patient records. Two of the patients reported have been previously published, including additional information about the cases. 20,21 Clinical evaluation included assessment of tenderness of the lesion, expansive character of the mass, skin temperature and discoloration, pulsations/AV-shunting, hemorrhage and associated lymphedema.
Bleeding grade associated with KHE was classified according to the World Health Organization (WHO) scheme. 22

| Treatment and response assessment
In patients receiving additive embolization, the procedure was carried out under general anesthesia via a 4F groin access. Transarterial embolization was performed either using particles or ethylene vinyl alcohol copolymer. The procedure was considered technically successful if Tumors. As KHE leaves residual scar tissue both at the skin and within connective tissue, CR was defined as the absence of viable tumor on contrast-enhanced MRI, without taking nonenhancing residual scar tissue into account. Rebound of KHE and KMP after sirolimus discontinuation was defined as a switch to progressive disease either from SD, PR or CR after cessation of sirolimus treatment, defined either by an increase in tumor size or a decrease of platelet counts <150 × 10 3 /μL.

| Data analysis and statistics
Data are shown as mean ± SE, median or as relative percentages.

| Treatment and response
Embolization was performed in n = 8/17 (47%) of the patients; sirolimus without additional embolization was used in n = 9/17 (53%) patients. Embolization with devascularization of >80% of tumor vasculature was technically successful in 100%, without major periprocedural complications, especially no arterial thrombosis or dissection occurred. In 2 of 8 patients, two subsequent embolization procedures were performed, while in 6 of 8 patients one treatment cycle was sufficient to complete the procedure. Sirolimus was applied with a mean dose of 0.46 ± 0.1 mg/kg/m 2 and was given for 278 ± 56 days in the embolization group, and with a mean dose of 0.58 ± 0.2 mg/kg/m 2 given for 434 ± 69 days in the group without embolization (P = .677 for dose, P = .107 for time period differences). In the embolization group, sirolimus was started 6.5 ± 3 days following the embolization procedure.
Tumor response to therapy revealed no statistically significant differences between the two groups (Table 1) tive multicenter studies recommend sirolimus as a potential first-line treatment alone or as part of a multimodal approach. 14 Sirolimus has been shown to provide recovery from life-threatening KMP after a period of 3 weeks of oral application. [15][16][17]19 With respect to this period of severe coagulopathy, our aim was to evaluate whether

ACKNOWLEDGMENT
Open access funding enabled and organized by Projekt DEAL.