Targeted therapy for capillary-venous malformations.

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK, an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations' occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA (n = 16) or TEK (n = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

Treatment of two infants with PIK3CA-related overgrowth spectrum by alpelisib.

PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA gene. There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology, showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient 1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations and good tolerability.

Alpelisib administration reduced lymphatic malformations in a mouse model and in patients.

Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flares, esthetic deformities, and, in severe forms, life-threatening conditions. There is no approved medical therapy for patients with lymphatic malformations. In this proof-of-concept study, we developed a genetic mouse model of PIK3CA-related lymphatic malformations that recapitulates human disease. Using this model, we demonstrated the efficacy of alpelisib, an approved pharmacological inhibitor of PIK3CA in oncology, in preventing lymphatic malformation occurrence, improving lymphatic anomalies, and extending survival. On the basis of these results, we treated six patients with alpelisib, including three children, displaying severe PIK3CA-related lymphatic malformations. Patients were already unsuccessfully treated with rapamycin, percutaneous sclerotherapies, and debulking surgical procedures. We assessed the volume of lymphatic malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib administration was associated with improvements in the six patients. Previously intractable vascular malformations shrank, and pain and inflammatory flares were attenuated. MRI showed a decrease of 48% in the median volume of lymphatic malformations over 6 months on alpelisib. During the study, two patients developed adverse events potentially related to alpelisib, including grade 1 mucositis and diarrhea. In conclusion, this study supports PIK3CA inhibition as a promising therapeutic strategy in patients with PIK3CA-related lymphatic anomalies.

Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study.

BACKGROUND: Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. METHODS: Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. RESULTS: Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. CONCLUSIONS: Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.

Safety of Oral Propranolol for the Treatment of Infantile Hemangioma: A Systematic Review.

BACKGROUND AND OBJECTIVES: Given the widespread use of propranolol in infantile hemangioma (IH) it was considered essential to perform a systematic review of its safety. The objectives of this review were to evaluate the safety profile of oral propranolol in the treatment of IH. METHODS: We searched Embase and Medline databases (2007-July 2014) and unpublished data from the manufacturer of Hemangiol/Hemangeol (marketed pediatric formulation of oral propranolol; Pierre Fabre Dermatologie, Lavaur, France). Selected studies included ≥10 patients treated with oral propranolol for IH and that either reported ≥1 adverse event or effect (AE) or planned to capture AEs. Data capture was standardized and extracted study design, demographic characteristics, IH characteristics, intervention, and safety outcomes. AEs were assigned a system organ class and preferred term. RESULTS: A total of 83 of 398 identified literature records met the inclusion criteria, covering 3766 propranolol-treated patients. The manufacturer's data for 3 pooled clinical trials (435 propranolol-treated patients) and 1 Compassionate Use Program (1661 patients) were included. AE data were reported for 1945 of 5862 propranolol-treated patients. The most frequently reported AEs included a range of sleep disturbances, peripheral coldness, and agitation. The most serious AEs (atrioventricular block, bradycardia, hypotension, bronchospasm/bronchial hyperreactivity, and hypoglycemia-related seizures) were managed by decreasing doses or temporary/permanent discontinuation of propranolol. Limitations included the variety of included study designs; monitoring, collection, and reporting of AE data; small sample sizes for some articles; and the wide scope of review. CONCLUSIONS: Oral propranolol is well tolerated if appropriate pretreatment assessments and within-treatment monitoring are performed to exclude patients with contraindications and to minimize serious side effects during treatment.