Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068

Transcatheter Arterial Embolization in A Newborn with Cervical Kaposiform Hemangioendothelioma and Kasabach-Merritt Phenomenon.

We report a case of a 9-day-old newborn who underwent arterial embolization for Kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP), combined with sirolimus treatment, and the outcome was favorable. To the best of our knowledge, there are no case reports of such small infants undergoing arterial embolization to treat KHE. Our successful experience of treating KHE with KMP showed that transcatheter arterial embolization is feasible and can be used as an alternative to surgical resection, even in small infants.

Characterization of platelet functionality in pediatric patients with kaposiform hemangioendothelioma / Kasabach-Merritt phenomenon

Background. Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy commonly associated with Kasabach-Merritt phenomenon (KMP) that includes thrombocytopenia and coagulation dysfunction. Platelet receptor CLEC-2 -tumor cell podoplanin interaction is considered the key mechanism of thrombocytopenia in KMP, however, the effect of long-term exposure to podoplanin on platelet function is unknown. Procedure. Here we examined blood samples from six patients with KHE and one KMP. Platelet calcium signaling and functional responses to conventional activation and CLEC-2 stimulation were analyzed by continuous and endpoint live cell flow cytometry. Platelet aggregation in response to ADP or rhodocytin was analyzed by low-angle light scattering approach (LaSca). Additionally, ex vivo thrombus formation on collagen was observed in parallel-plate flow chambers. Results. We demonstrate that in KHE/KMP platelet functional responses to strong stimulation were on the lower boundary of age-matched normal ranges, while calcium mobilization and fibrinogen binding upon stimulation with ADP alone were significantly lower than control values. Platelet di-aggregate formation in response to ADP was also diminished in most of the patients. Formation of platelet aggregates in collagen-coated parallel plate flow chambers was also noticeably lower than in the age-matched control group. Calcium mobilization in response to CLEC-2 stimulation was unaltered in the patients and could be blocked by low-molecular-weight inhibitors, 2CP and HB125. Conclusions. While platelet responsiveness in KHE/KMP is moderately altered, their CLEC-2 receptors remain functional and respond to inhibition. Therefore, our findings suggest that CLEC-2-targeting molecules are new potential agents in therapeutic management of this life-threatening condition.

Characterization of platelet functionality in pediatric patients with kaposiform hemangioendothelioma / Kasabach-Merritt phenomenon

Background. Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor of infancy commonly associated with Kasabach-Merritt phenomenon (KMP) that includes thrombocytopenia and coagulation dysfunction. Platelet receptor CLEC-2 -tumor cell podoplanin interaction is considered the key mechanism of thrombocytopenia in KMP, however, the effect of long-term exposure to podoplanin on platelet function is unknown. Procedure. Here we examined blood samples from 7 patients with KHE/KMP. Platelet calcium signaling and functional responses to conventional activation and CLEC-2 stimulation were analyzed by continuous and endpoint live cell flow cytometry. Platelet aggregation in response to ADP or rhodocytin was analyzed by low-angle light scattering approach (LaSca). Additionally, ex vivo thrombus formation on collagen was observed in parallel-plate flow chambers. Results. We demonstrate that in KHE/KMP platelet functional responses to strong stimulation were on the lower boundary of age-matched normal ranges, while calcium mobilization and fibrinogen binding upon stimulation with ADP alone were significantly lower than control values. Platelet di-aggregate formation in response to ADP was also diminished in most of the patients. Formation of platelet aggregates in collagen-coated parallel plate flow chambers was also noticeably lower than in the age-matched control group. Calcium mobilization in response to CLEC-2 stimulation was unaltered in the patients and could be blocked by low-molecular-weight inhibitors, 2CP and HB125. Conclusions. While platelet responsiveness in KHE/KMP is moderately altered, platelet CLEC-2 receptors remain functional and respond to inhibition. Therefore, our findings suggest that CLEC-2-targeting molecules are new potential agents in therapeutic management of this life-threatening condition.

An Unusual Presentation of Kaposiform Hemangioendothelioma in the Mandibular Bone

Introduction A 4-year-old child presented with neck pain for several months which progressed to jaw pain and limitation in opening of the jaw. Eventual diagnosis of Kaposiform hemangioendothelioma is notable for the later age of presentation, the involvement of bone and soft tissue and the response to therapy. Case In March of 2020 child first developed sore throat and pain in his neck which led to limitation in neck movements. An enlarged tonsil was noted and treated. Symptoms improved only to recur and worsen by August 2020. Child was waking up with pain at night. Tonsils were removed in September to address this. Shortly thereafter, his mouth wouldn't open well. They saw several physicians without a definitive diagnosis for this including pediatrician, ENT and audiology. In late February 2021 ENT was re-consulted. A lytic lesion was discovered on X-ray. MRI further elucidated this as a destructive mass within the right mandibular ramus with soft tissue extension. A biopsy then characterized it as a Kaposiform Hemangioendothelioma. The biopsy showed a cellular vascular neoplasm forming variable small lobules with intervening fibrous tissue. The cells were monotonous and flat to spindled. Slit-like spaces and glomeruloid structures were seen. CD31 and D2-40 stains highlighted the endothelial cells and SMA stain pericytes. HHV8 stain was negative. No laboratory evidence of consumptive coagulopathy was noted. there was no evidence of Kasabach Merritt syndrome (KMP) Management Given the location of tumor and risks and morbidity of surgery, child was initiated on oral sirolimus aiming for a trough between 10 and 15 ng/ml and prednisone therapy with rapid taper in 4 weeks. Significant reduction in size of tumor was noted on serial scans. It measured 3.9 cm in craniocaudal, 2.8 cm in transverse, and 3.5 cm in AP dimension at diagnosis and reduced to 3.5 x 1.9 x 2.8 cm within 6 weeks. Child had improved mobility of jaw and improved speech. Nocturnal pain resolved on steroids but recurred off steroids. Aspirin was added to the treatment when steroids were weaned and helped resolve the pain. Hypercholesterolemia was noted on sirolimus, but otherwise very well tolerated at this dose. Clinical exam and serial MRIs have shown continued response to therapy. Summary We present this case as a rare presentation in an older child with the mandibular bone as the primary site. Kaposiform hemangioendotheliomas are very rare, and usually seen in the newborn or early infancy. The occurrence later in life with bone and adjacent soft tissue primary and cervicofacial location is more rare. Although 70% of KHE are complicated by Kassabach Merritt phenomenon, the older age and location in bone are features that have been associated with lack of KMP in larger series. In many cases surgical management would be preferred, but given the location of this tumor, we opted for medical therapy with sirolimus and prednisone. The impressive response to therapy is encouraging and makes us hopeful that we may decrease size such that surgery is less morbid or avoid surgery entirely. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Kaposiform hemangioendothelioma/Kasabach–Merritt syndrome. Сlinical and laboratory characteristics. Analysis of clinical cases

Kaposiform hemangioendothelioma (KHE) is a rare, usually congenital vascular tumor. It resembles Kaposi sarcoma histologically, but etiologically it is not associated with herpes simplex virus type 8. KHE refers to tumors of intermediate malignancy degree. The most severe complication is the addition of thrombocytopenia and consumption coagulopathy, i.e. development of the Kasabach–Merritt syndrome/phenomenon (KMS), which determines the high mortality rate (up to 30%) in this histological variant. The frequency of occurrence of KMS is unknown. Over Patients with KHE/KMS have clear clinical and laboratory characteristics, which in most cases allow make to diagnose without histological confirmation. Over 7-year follow-up period 32 patients with KHE were registered in our center; in 90.6% of cases it was complicated by the development of KMS. The study was approved by the Independent Ethics Committee and Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In the most of patients the tumor was detected from birth (84%), in half of the cases (52%) hematological complications were diagnosed simultaneously with the detection of the tumor. Сommon local complications include joint contractures, destruction of bone tissue, and invasion of neighboring organs. The half of the patients had changes in the heart function: from minor cardiac pathology to congenital defects. In addition, there were clinical and instrumental changes associated with volume overload: an increase in liver size, myocardial hypertrophy. Despite the presence of clear clinical and laboratory characteristics of KMS, some cases require differential diagnosis with other vascular anomalies accompanied by thrombocytopenia and consumption coagulopathy – with congenital hemangiomas (rapidly involuting congenital hemangioma), multifocal lymphangioendotheliomatosis with thrombocytopenia, kaposiform lymphangiomatosis, venous malformations. The parents of the patients agreed to use the information, including photos of children, in scientific research and publications.