Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth

Wenger, Tara L.; Ganti, Sheila; Bull, Catherine; Lutsky, Erika; Bennett, James T.; Zenner, Kaitlyn; Jensen, Dana M.; Dmyterko, Victoria; Mercan, Ezgi; Shivaram, Giridhar M.; Friedman, Seth D.; Bindschadler, Michael; Drusin, Madeleine A.; Perkins, Jonathan N.; Kong, Ada; Bly, Randall A.; Dahl, John P.; Bonilla-Vélez, Juliana; Perkins, Jonathan A.

doi:10.1016/j.gim.2022.07.026

Cited by 17 publications

(11 citation statements)

References 40 publications

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“…Currently, targeted drugs that inhibit molecules of the PI3K-AKT-mTOR pathway have been used in patients with FIL. A 5-year-old girl with FIL taking alpelisib showed sustained improvement over 25 months of treatment, including a reduction in the volume of lipomatosis and hyperpigmentation and a gradual recovery of her oral function, with 3D imaging showing a 14% reduction in facial volume, but the drug was ineffective for skeletal deformities [44]. Another pan-AKT inhibitor, miransertib, was administered in a 5-year-old boy with FIL and HMEG and improved the patient's intractable epilepsy and quality of life [45].…”

Section: Discussionmentioning

confidence: 99%

Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

Chen

Sun

Gao

et al. 2023

Orphanet J Rare Dis

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Background Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL. Results Eighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities. Conclusions The abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.

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Section: Discussionmentioning

confidence: 99%

Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

Chen

Sun

Gao

et al. 2023

Orphanet J Rare Dis

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“…Over the last decade, the successful use of sirolimus has been increasingly reported in children with LMs and kaposiform hemangioendotheliomas 7 . Alpelisib, a PIK3CA inhibitor that can directly target PIK3CA/Akt/mTOR signaling pathway, was also effectively used in LM 8 . Another activated pathway involved in LMs is the RAF/ERK/MEK signal pathway 9 .…”

Section: Discussionmentioning

confidence: 99%

Rapid response with good toleration of sirolimus for life‐threatening neonatal lymphatic malformations

Dong,

Li,

et al. 2023

Pediatric Investigation

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IntroductionLymphatic malformations (LMs) are rare vascular anomalies predominantly affecting infants, which can be debilitating or life‐threatening when complicated with intralesional bleeding or infection. Effective and safe management strategies are essential in such cases.Case presentationWe report a case series involving four Chinese neonates with life‐threatening LMs, initially treated with oral sirolimus. All patients achieved rapid relief and sustained remission, using a lower sirolimus dosage than previously recommended. Furthermore, adverse events were rarely recorded during follow‐up.ConclusionSirolimus can be considered a promising choice for neonates with intricate and life‐threatening LMs. Initiation with a reduced sirolimus dose is advisable.

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“…In addition, alpelisib also had a preventive and reversing effect on adipose overgrowth located in other areas of the body 20,21 . The latest conclusions showed that significant volume reduction of facial soft tissues can be seen after the administration of alpelisib for 1 month, and continuous use can achieve the outcomes of volume reduction of fat and LM, sebaceous nevus hypopigmentation, improvement of oral, and speech function, the drug is ineffective for skeletal deformities 22 . Targeted drugs offer new possibilities for the treatment of FIL: reducing soft tissue volume and infiltration through oral drugs, and then adjusting soft tissue and bone deformities together with surgery.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 The latest conclusions showed that significant volume reduction of facial soft tissues can be seen after the administration of alpelisib for 1 month, and continuous use can achieve the outcomes of volume reduction of fat and LM, sebaceous nevus hypopigmentation, improvement of oral, and speech function, the drug is ineffective for skeletal deformities. 22 Targeted drugs offer new possibilities for the treatment of FIL: reducing soft tissue volume and infiltration through oral drugs, and then adjusting soft tissue and bone deformities together with surgery. However, more prospective studies are necessary to explore adverse reactions, the optimal dosing, and treatment duration for patients of different ages, and whether recurrence occurs after drug withdrawal.…”

Section: Casementioning

confidence: 99%

Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3‐kinase catalytic subunit alpha mutation

Chen

Sun

Gao

et al. 2023

Pediatric Dermatology

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Alpelisib for the treatment of PIK3CA-related head and neck lymphatic malformations and overgrowth

Cited by 17 publications

References 40 publications

Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

Delineation of the phenotypes and genotypes of facial infiltrating lipomatosis associated with PIK3CA mutations

Rapid response with good toleration of sirolimus for life‐threatening neonatal lymphatic malformations

Facial infiltrating lipomatosis with hemimegalencephaly and lymphatic malformations caused by nonhotspot phosphatidylinositol 3‐kinase catalytic subunit alpha mutation

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