Intralesional injection of bleomycin in the management of low flow vascular malformations: Results and factors affecting the outcome.

OBJECTIVE: Ethanol has been a commonly used sclerosant for low-flow vascular malformations, but it carries a high risk of complications. Bleomycin has been recently introduced as a potentially effective treatment. The aim of this study was to evaluate the safety and efficacy of bleomycin intralesional injection for the treatment of low-flow vascular malformations and determine the different factors affecting the outcome. PATIENTS AND METHODS: A total of fifty patients with low-flow vascular malformations were enrolled in the study between April 2020 and March 2022. All patients underwent preoperative duplex ultrasound and magnetic resonance angiography. The procedure was performed under ultrasound and fluoroscopic guidance. All patients were assessed for the objective improvement, ultrasound assessment, and patient-reported outcome. RESULTS: The overall rate of objective improvement was 79.53% (78.05% in venous and 87.5% in lymphatic malformations), whereas 81.25% of the patients showed a degree of size reduction or complete obliteration on postoperative ultrasound. The patient-reported outcome analysis showed a statistically significant improvement in the mean score for the pain, overall symptoms, and self-confidence. On regression analysis, the only factor associated with poor objective outcome was diffuse lesions (ill-defined or extending in more than one body region or one compartment). No major complications were recorded. CONCLUSIONS: Bleomycin intralesional injection is a safe and effective treatment for low-flow vascular malformations.

A Brazilian case of exudative perifoveal vascular anomalous complex responsive to aflibercept intravitreal injections.

PURPOSE: To report a case of exudative perifoveal exudative vascular anomalous complex (ePVAC) in a Brazilian healthy patient that underwent a complete resolution after aflibercept intravitreal injections. CASE DESCRIPTION: A 41-year-old healthy Brazilian man complained of acute central vision loss in his right eye (RE). Fundus examination showed a perifoveal hemorrhagic aneurysmal lesion, accompanied by several hard exudates in RE. On fluorescein angiography, these abnormalities showed a progressive hyperfluorescence with surrounding leakage. Optical coherence tomography (OCT) revealed a deep, perifoveal hyporeflective cystic space with a hyperreflective wall and hyperreflective material inside of fibrin-like aspect. Around this aneurism, intraretinal hyporeflective spaces suggestive of exudation were detected. Nor pathological flow signal, or telangiectatic dilations were evidenced on OCT-angiography. Therefore, a diagnosis of exudative ePVAC in RE was hypothesized. After an initial observation, the patient underwent three monthly aflibercept intravitreal injections (0.05 ml/2 mg), with a significative anatomical and functional improvement after two weeks from first dose. On last follow-up at five months from baseline, patient experienced no evidence of new exudation and a stable visual acuity. DISCUSSION: Placental growth factor (PlGF) may impact on pericytes' dropout, and thus on ePVAC development. In contrast to the other anti-VEGF drugs, aflibercept is the only molecule contrasting PlGF. Therefore, aflibercept would act on ePVAC not as an anti-VEGF drug, but rather as an anti-PlGF one. CONCLUSION: This report encouraged the use of aflibercept as a therapeutic option for ePVAC. Further studies are required to confirm our result and the impact of PlGF on ePVAC pathogenesis.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations.

BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.

Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study.

Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.

Foam Sclerotherapy in the Treatment of Hemangiomas and Venous Malformations.

BACKGROUND: Sclerotherapy has achieved great success in treating most venous malformation (VM) lesions. OBJECTIVE: To compare the effects of foam sclerotherapy on infantile hemangioma and pyogenic granuloma (PG). In addition, we analyzed the data and outcomes of foam sclerotherapy for the VM. MATERIALS AND METHODS: Thirty-nine patients with hemangiomas and 83 patients with VMs were treated, and clinical outcomes, resolution, and complication rates were compared. Sclerotherapy data from the VM group were also analyzed. RESULTS: The average age of the patients and the distribution and tissue involvement of lesions among the 3 groups were significantly different ( p < .001). The average amount of sclerosing foam administered per session in VMs was significantly higher than that in the other 2 groups ( p < .0001) (whereas that in the PG group was lower than that in the infantile hemangioma group [ p < .0001]). However, the overall therapeutic efficacy and side effects in the 3 groups were not significantly different. For VMs, the frequency of ultrasound guided foam sclerotherapy and use of 3% polidocanol increased from superficial to deep lesions, whereas the use of 1% POL decreased ( p < .0001). CONCLUSION: Infantile hemangioma and PG treatments presented good results and minor adverse reactions comparable with those of VMs.

Sclerotherapy Improves Symptoms in Patients with Small and Moderate Diameter Low-Flow Vascular Malformations: A Prospective Cohort Study.

BACKGROUND: Vascular malformations are rare diseases and treatment remains controversial. Sclerotherapy is accepted as a minimally invasive treatment with good results; however, some patients do not report good response to sclerotherapy, and it is not clear which variables influence treatment outcome, preventing optimal patient selection. We hypothesized that large diameter lesions have reduced efficacy and satisfaction with sclerotherapy. Therefore, we prospectively evaluated the clinical response of low-flow vascular malformations treated with 1% polidocanol foam sclerotherapy and determined the correlation of symptom improvement with clinical variables. METHODS: Prospective cohort study of patients with symptomatic low flow vascular malformations treated at the Hospital das Clínicas between December 2016 and November 2018. Lesions were classified according to location, extension, diameter, type of vessels, margins, and symptoms. Sclerotherapy was performed by direct injection of 1% polidocanol foam, with a maximum volume of 10 ml per session. Symptom improvement was evaluated using the visual analog scale and patient-reported quality of life was assessed by the Short-form 6 dimensions (SF-6D) questionnaire. Follow-up was performed every 3 months after treatment. RESULTS: Forty lesions were treated in 38 patients, with 19 women and 19 men; median age was 20.5 years (range 4 months to 63 years). Most lesions (80%) were venous, and most commonly in the lower limbs (47.5%); 27.5% were superficial, 35% were deep, and 37.5% affected both compartments. The most common clinical presentations were deformity (95%), pain (78%), and functional limitation (58%); deep compartment lesions were more associated with functional limitation (69% vs. 27%; P = 0.030). Fifty-three per cent of lesions were >10 cm and were associated with increased numbers of psychosocial symptoms (P = 0.038). Two-hundred and forty-two sessions of sclerotherapy were performed, with 6 mean treatments per lesion (range 1-15). The mean follow-up time was 23 months (range 2-23 months). The most common complications were pain and local edema, without any major complications; some patients reported symptom recurrence (15% pain, 10% deformity, and 12% functional limitation). Sclerotherapy was associated with significant improvement of all symptoms (P < 0.001). However, lesions >10 cm were associated with poor improvement in deformity (P = 0.003). Quality of life improved for most patients (60%) and treatment satisfaction was high (82%). CONCLUSIONS: Treatment of low-flow vascular malformations with 1% polidocanol foam is safe and effective; sclerotherapy improves symptoms and quality of life. Large diameter lesions (>10 cm) are associated with increased treatment failure. A small percentage of patients reported recurrent symptoms and require other modalities for successful treatment.

Activity of a TIE2 inhibitor (rebastinib) in a patient with a life-threatening cervicofacial venous malformation.

Targeted therapy has become the first therapeutic option in many patients with vascular anomalies. A male 28-year-old patient presented a severe cervicofacial venous malformation involving half-lower face, anterior neck, and oral cavity with progression despite multiple previous treatments, with a somatic variant in TEK (endothelial-specific protein receptor tyrosine kinase) (c.2740C>T; p.Leu914Phe). The patient had facial deformity, daily episodes of pain and inflammation needing massive amount of medication, and difficulty in speech and swallowing, so rebastinib (a TIE2 kinase inhibitor) was approved for compassionate use. After 6 months of treatment, venous malformation had decreased in size and lightened, as well as improved quality-of-life scores.

ErbB signaling is a potential therapeutic target for vascular lesions with fibrous component.

Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed. Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. Results: We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component. Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.

Effective long-term sirolimus treatment in hypoxemia mainly due to intrapulmonary right-to-left shunt in a patient with multiple vascular anomalies.

Pulmonary arteriovenous malformations (PAVMs), particularly where feeding artery/arteries to PAVMs ≥ 3 mm can be treated with embolization. The treatment for hypoxemia resulting from multiple small or diffuse PAVMs remains unclear.We report a girl aged 5 years and 10 months presented with cyanosis and decreased activity after exercise (83-85% of pulse oxygen saturation, SpO2). She had 1 skin lesion on her face and 1 suspected hemangioma on her left upper extremity at birth and that gradually disappeared spontaneously. Physical examination revealed clubbed fingers, and abundant vascular networks on her back. Contrast-enhanced lung CT (slice thickness:1.25 mm) with vascular three-dimensional reconstruction and abdominal CT revealed increased bronchovascular bundles, increased diameter of the pulmonary artery and ascending aorta, and intrahepatic portosystemic venous shunts due to patent ductus venosus. Echocardiography revealed increased diameter of aortic and pulmonary artery. Transthoracic contrast echocardiography was highly positive (bubble appearing in the left ventricle after 5 cardiac cycles). Abdominal doppler ultrasound revealed hepatic-portal venous shunt. Magnetic resonance imaging, artery and vein of the brain revealed multiple malformations of venous sinuses. The patient received sirolimus for 2 years and 4 months. Her condition improved significantly. SpO2 gradually increased to 98%. Her finger clubbing gradually normalized.Our report implicates sirolimus might be a potential treatment option in persistent hypoxemia mainly due to intrapulmonary right-to-left shunt even small multiple or diffusive PAVMs in pediatric patients with multiple cutaneous and visceral vascular anomalies.

Sirolimus treatment for paediatric head and neck lymphatic malformations: a systematic review.

PURPOSE: This PRISMA-compliant systematic review aimed to assess risks and benefits of sirolimus treatment for paediatric lymphatic malformations by focusing not only on treatment efficacy but also on possible treatment-related adverse events, and treatment combinations with other techniques. METHODS: Search criteria were applied to MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases and included all studies published up to March 2022 reporting paediatric lymphatic malformations treated with sirolimus. We selected all original studies that included treatment outcomes. After the removal of duplicates, selection of abstracts and full-text articles, and quality assessment, we reviewed eligible articles for patient demographics, lymphatic malformation type, size or stage, site, clinical response rates, sirolimus administration route and dose, related adverse events, follow-up time, and concurrent treatments. RESULTS: Among 153 unique citations, 19 studies were considered eligible, with reported treatment data for 97 paediatric patients. Most studies (n = 9) were case reports. Clinical response was described for 89 patients, in whom 94 mild-to-moderate adverse events were reported. The most frequently administered treatment regimen was oral sirolimus 0.8 mg/m2 twice a day, with the aim of achieving a blood concentration of 10-15 ng/mL. CONCLUSION: Despite promising results for sirolimus treatment in lymphatic malformation, the efficacy and safety profile of remains unclear due to the lack of high-quality studies. Systematic reporting of known side effects, especially in younger children, should assist clinicians in minimising treatment-associated risks. At the same time, we advocate for prospective multicentre studies with minimum reporting standards to facilitate improved candidate selection.

Treatment with oral or topical sirolimus in complex vascular anomalies in pediatrics. Experience in a third-level hospital. / Tratamiento con sirolimus oral o tópico en anomalías vasculares complejas en pediatría. Experiencia en un hospital terciario.

OBJECTIVE: The use of sirolimus in vascular anomalies is a special indication not authorized in its data sheet. The objective of this study was to increase the evidence of oral or topical use of sirolimus for this indication in the pediatric population. MATERIALS AND METHODS: An observational, retrospective study of patients under 18 years of age treated with oral or topical sirolimus for vascular anomalies was carried out. Diagnosis and location of lesions, administration route and dosage of sirolimus, blood levels of sirolimus in patients who received oral treatment, treatment duration, response, and toxicity were collected. RESULTS: 18 patients - 7 with oral treatment and 11 with topical treatment - were included. With oral sirolimus, the overall response rate was 85.7%. Sirolimus was discontinued in 2 cases - as a result of full resolution and progression. 57.1% of patients had adverse effects, most of which were mild. Dyslipidemia was the most frequent adverse effect. Blood levels were monitored in all patients for dose adjustment purposes. With topical treatment, the overall response rate was 72.7%. Sirolimus was discontinued in 3 cases -due to progression in 2 cases and to stability in 1. 27.3% of patients had adverse effects, with itching standing out as the most frequent one. CONCLUSIONS: The favorable results of sirolimus treatment in our patients seem to confirm its effectiveness and safety in vascular anomalies, which make it stand as a therapeutic option in pediatric patients. However, further research is required to establish the optimal treatment regimen, treatment duration, and potential long-term adverse effects.

OBJETIVO: El uso de sirolimus en anomalías vasculares es una indicación especial no autorizada en ficha técnica. El objetivo de este estudio es incrementar la evidencia del empleo por vía oral o tópica de sirolimus en esta indicación en población pediátrica. METODO: Estudio observacional retrospectivo de pacientes menores de 18 años tratados con sirolimus oral o tópico para anomalías vasculares recogiendo: diagnóstico y ubicación de lesiones, forma de administración y dosificación de sirolimus, niveles sanguíneos de fármaco en los pacientes con tratamiento oral, duración del tratamiento, respuesta y toxicidad. RESULTADOS: Se incluyeron 18 pacientes (7 con tratamiento oral y 11 tópico). Con sirolimus oral, la tasa de respuesta global fue 85,7%. Se interrumpió sirolimus en 2 casos: por resolución completa y por progresión. El 57,1% experimentó algún efecto adverso, en su mayoría leves; siendo la dislipemia el efecto adverso más frecuente. La monitorización de niveles sanguíneos fue empleada en todos los pacientes para el ajuste de dosis. Con el tratamiento tópico, la tasa de respuesta global fue 72,7%. Se interrumpió sirolimus en 3 casos: progresión en 2 casos y estabilidad en 1. El 27,3% experimentó algún efecto adverso, siendo el prurito el más frecuente. CONCLUSIONES: Los resultados favorables del tratamiento con sirolimus en nuestros pacientes parecen confirmar la efectividad y seguridad del fármaco en anomalías vasculares y lo posicionan como una opción terapéutica en pacientes pediátricos. Aun así, parece necesaria mayor investigación que trate de aclarar, entre otros, el régimen óptimo del tratamiento, la duración del mismo y los potenciales efectos adversos a largo plazo.

Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p < 0.05; however, they showed a similar decrease to children. Furthermore, the pediatric population experienced less often a sirolimus-related grade I-IV adverse event (35.9% vs. 64.1%, p > 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p < 0.05), and children responded faster (28 vs. 91 days, p < 0.05). These results suggest benefits of sirolimus in patients with slow-flow vascular malformations and support its initiation as young as possible.

No Association of Sirolimus with Wound Complications in Children With Vascular Anomalies.

INTRODUCTION: Sirolimus has demonstrated effectiveness as a treatment option for several types of vascular anomalies; however, it has a potential side effect of delayed surgical wound healing. The purpose of this study was to evaluate the association of sirolimus with postoperative complications in the pediatric vascular anomaly population. METHODS: A retrospective cohort study was performed for children with a vascular anomaly who underwent excision or debulking of the anomaly from 2015 to 2020. Patient demographics, vascular anomaly characteristics, operative variables, sirolimus dosing information, and perioperative outcomes were collected. Univariate analysis was performed to compare outcomes based on the administration of sirolimus. RESULTS: Forty-seven patients with vascular anomalies underwent 57 surgical procedures (36 without perioperative sirolimus, 21 with perioperative sirolimus). The median age at the time of surgery was seven years (IQR 1.7-14.0). The most common anomalies were lymphatic and venolymphatic malformations. Of the patients administered perioperative sirolimus, the median preoperative and postoperative sirolimus levels were comparable (preoperative 6.9 ng/mL (IQR 4.9-10.1), postoperative 6.5 ng/mL (IQR 4.7-9.4)). The rate of postoperative complications (sirolimus 19%, without sirolimus 11%; p = 0.45) and wound complications (sirolimus 14%, without sirolimus 6%; p = 0.26) were comparable between the cohorts. CONCLUSION: Our results suggest sirolimus may not significantly increase perioperative complication rates in pediatric patients undergoing resection of their vascular anomaly. LEVEL OF EVIDENCE: Level III.

Effectiveness and safety of percutaneous sclerotherapy using absolute ethanol and/or polidocanol for maxillofacial venous malformations involving the masticatory muscles: A case series.

OBJECTIVE: This study evaluated the effectiveness and safety of percutaneous sclerotherapy for maxillofacial venous malformations. STUDY DESIGN: Patients who had venous malformations involving the masticatory muscles and who underwent sclerotherapy were enrolled in this retrospective study. RESULTS: Twenty-four patients (13 female, 11 male; mean age 21 years) were analyzed. Major clinical symptoms were swelling (100%) and intralesional pain (54%). Intramuscular lesions involved the masseter muscle only in 38% of cases, both the masseter and temporalis muscles in 33%, all masticatory muscles in 21%, and the temporalis muscle only in 8%. Extramuscular involvement was observed in 58% of patients. Absolute ethanol and polidocanol were used as sclerosants. The mean number of sclerotherapy sessions per patient was 6.6 (range, 1-32). The mean follow-up duration after the first sclerotherapy session was 64.8 months (range, 6-178). The complications included paralysis of the facial nerve (25%), intraoral ulceration (8%), and hemoglobinuria (8%). The effectiveness of treatment was rated as excellent in 33% of cases, good in 46%, and fair in 21%. Better results were obtained in patients without extramuscular involvement. CONCLUSION: Percutaneous sclerotherapy can be effective and safe for maxillofacial intramuscular venous malformations, especially for localized lesions of the masseter muscle.

Repurposing alpelisib, an anti-cancer drug, for the treatment of severe TIE2-mutated venous malformations: Preliminary pharmacokinetics and pharmacodynamic data.

Extensive venous malformations involving limbs severely impact quality of life, mostly due to chronic pain and functional limitations. But patients can also display coagulopathy with associated risks of life-threatening thromboembolism and bleeding. Available pharmacological treatments (e.g., sirolimus) are not universally effective. Novel therapies are urgently needed for patients with treatment-resistant venous malformations. We report three patients with TIE-2 receptor mutations treated with alpelisib for 6 months (daily dosing: 50 mg for children weighing <50 kg and 100 mg for those >50 kg). Pain was controlled, gait improved, size of the abnormal venous network decreased, and coagulopathy dramatically improved. Drug exposure was highly variable, suggesting that alpelisib dosing should be individualized to patient's characteristics and guided by therapeutic drug monitoring.