sirolimus versus sirolimus plus prednisolone for kaposiform hemangioendothelioma

Conditions: Kaposiform Hemangioendothelioma; Kasabach Merritt Phenomenon

Summary: kaposiform hemangioendothelioma (khe) is a rare vascular neoplasm that occurs predominantly in infancy or early childhood. khe has a nearly equal sex ratio. the annual incidence of khe has been estimated at 0.071 per 100,000 children. khe presents with intermediate-malignant and locally aggressive characteristics but without distant metastases. this pilot trial studies sirolimus versus sirolimus plus pednisolone in treating patients diagnosed with kaposiform hemangioendothelioma (khe) and kasabach-merritt phenomemon (kmp) that cannot be removed by surgery. the purpose of this study is to compare the efficacy and safety of orally administered sirolimus versus sirolimus plus pednisolone in the treatment of khe associated with kmp.

kasabach-merritt phenomemon (kmp) is a profound thrombocytopenia resulting from intralesional platelet trapping. it is now clear that kmp occurs with khe and tufted angioma, not with infantile or congenital hemangiomas. kmp is typically associated with more aggressive lesions and poorer outcomes. clinically significant kmp is a severe thrombocytopenia, generally below 30× 109/l. severe thrombocytopenia may indicate a severer tumor, a progressive tumor, partially or totally insensitive to therapy. in addition to severe, persistent thrombocytopenia characteristic of kmp, patients often manifest elevated d-dimer and low fibrinogen. coagulopathy in addition to thrombocytopenia is associated with more aggressive presentations and may indicate current infection or inflammation. additionally, kmp may be complicated by severe anemia due to blood sequestration and intra-lesional hemorrhaging. khe with kmp have notably high morbidity and mortality rates, resulting predominantly from rapid tumor growth and infiltration, compression or destruction of vital structures, and hemodynamic instability. consensus treatment guidelines from a multidisciplinary expert panel were published in 2013. medical treatments with corticosteroids and/or vincristine have been recommended for the management of khe. however, first-line treatment with corticosteroids is successful in only 10-27% of all cases, and treatment with vincristine is successful in 60-70% of patients. moreover, vincristine monotherapy has not been confirmed to provide significant benefits in critically ill patients. sirolimus (also known as rapamycin) is an inhibitor of the mammalian target of rapamycin (mtor). in recent studies, sirolimus was shown to be effective in patients with complex vascular anomalies, including khe. our multicenter, retrospective study demonstrated that oral sirolimus is an effective and safe option for the treatment of progressive khe. additionally, our data emphasized that the khe treatment regimen should be tailored to individual patients and guided by specific clinical circumstances. in cases of severe kasabach-merritt phenomenon (kmp), sirolimus in combination with the short-term administration of prednisolone is recommended for controlling life-threatening conditions.

Eligibility criteria:
inclusion criteria: * presenting a khe with the following characteristics: 1. clinical features and histological findings consistent with progressive, non-resectable khe associated with kmp. 2. patients must be 0 - 18 years of age at the time of study entry. 3. without functional impairment requiring treatment of corticosteroid. * organ function requirements: 1 adequate liver function: 1. total bilirubin less than or equal to 1.5 x upper limit of normal (uln)for age, and 2. alt and ast less than or equal to 2.5 x upper limit normal (uln) for age. 2 adequate renal function: 1. 0-5 years of age maximum serum creatinine (mg/dl) of 0.8 2. 6-10 years of age maximum serum creatinine (mg/dl) of 1.0 3. 11-15 years of age maximum serum creatinine (mg/dl) of 1.2 4. 16-18 years of age maximum serum creatinine (mg/dl) of 1.5 * adequate bone marrow function: absolute neutrophil count (anc) greater than or equal to 1 x 10 to the ninth/liter. * consent of parents (or the person having parental authority in families): signed and dated written informed consent. exclusion criteria: * allergy to sirolimus or other rapamycin analogues. * any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of randomization. * patients must not be known to be human immunodeficiency virus positive or known immunodeficiency. testing is not required unless a condition is suspected. * other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration). * impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus. * patients who have a history of malignancy. * patients with an inability to participate or to follow the study treatment and assessment plan.

Keywords: kaposiform hemangioendothelioma kasabach merritt phenomenon sirolimus prednisolone