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

Description Alplesib exerts therapeutic effects in a mouse model of lymphatic anomalies and in six patients with lymphatic malformations over 6 months’ treatment. Inhibiting genetic lymphatic anomalies Gain-of-function mutations in the PIK3CA gene cause lymphatic malformations (LMs), genetic disorders characterized by vascular abnormalities causing pain, inflammation, and deformities. To identify potential treatments able to prevent LMs, Delestre et al. developed a genetic mouse model that recapitulates the main features of LMs and showed that the approved drug PIK3CA inhibitor alpelisib, used in oncology, prevented LMs, and increased survival. Alpelisib administration in six patients refractory to previous pharmacological or surgical approaches improved symptoms and reduced the volume of LMs. Although two patients developed adverse events potentially related to the treatment, the results suggest that inhibiting PIK3CA could be effective in treating LMs. 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.