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

Abstract

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.

Conflict of interest statement

Disclosures: F. Dubos reported personal fees from Sanofi-Pasteur, MSD, and Takeda outside the submitted work. T.K. Han reported being an employee at Novartis. F. Branle reported "other" from Novartis.Pharma.AG during the conduct of the study; and is a full-time employee of Novartis.Pharma AG Switzerland. A patent application (“BYL719 [alpelisib] for use in the treatment of PIK3CA-related overgrowth spectrum”; #WO2017140828A1) has been filed by Institut National de la Santé et de la Recherche Médicale, Centre National De La Recherche Scientifique, Université Paris Descartes, and Assistance Publique-Hôpitaux De Paris for the use of BYL719 (alpelisib) in the treatment of PIK3CA-related overgrowth spectrum (PROS/CLOVES syndrome). G. Canaud is the inventor. G. Canaud receives or has received consulting fees from Novartis, Vaderis, Fresenius Medical Care, Alkermes, IPSEN, and BridgeBio. No other disclosures were reported.

© 2022 Morin et al.

Figures

Graphical abstract

Figure 1.

Changes associated with alpelisib in a 9-mo-old patient with a severe form of PROS.(A) Representative pictures of the vascular malformations of the pelvis and right leg before and then following alpelisib introduction. Lower right: Macrodactyly of the right hand before and then 12 mo after alpelisib introduction. (B) Coronal STIR-weighted MRI of the legs of patient 1 before and following alpelisib introduction (scale bar: 10 cm). (C) Growth characteristics before and after alpelisib introduction. (D) Circulating IGF1 levels before and following alpelisib introduction. The pink area shows normal values of the laboratory for the age. (E) Hemoglobin and reticulocyte levels before and after alpelisib introduction. The pink area shows normal values of the laboratory for the age. (F) HbA1c, cholesterol, and triglyceride levels before and following alpelisib introduction. The pink area shows normal values of the laboratory for the age.

Figure S1.

Radiological changes associated with alpelisib in a 9-mo-old patient with a severe form of PROS. Coronal STIR-weighted MRI with 3D reconstruction of the legs of patient 1 before and following alpelisib introduction (scale bar: 10 cm).

Figure 2.

Changes associated with alpelisib in an 8-mo-old patient with a severe form of PROS and hemimegalencephaly.(A) Representative pictures of overgrowth of the right limb and vascular malformations of the left leg before and then following alpelisib introduction. (B) Brain MRI of patient 2 before and following alpelisib introduction (scale bar: 5 cm). ASL, arterial spin labeling. (C) Growth characteristics before and after alpelisib introduction. (D) Evolution of head circumference before and after alpelisib introduction. (E) Circulating IGF1 levels before and following alpelisib introduction. The pink area shows normal values of the laboratory for the age. (F) Hemoglobin and reticulocyte levels before and after alpelisib introduction. The pink area shows normal values of the laboratory for the age. (G) HbA1C, cholesterol, and triglyceride levels before and following alpelisib introduction. The pink area shows normal values of the laboratory for the age.