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 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 -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 -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 -related lymphatic anomalies.