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

  • Sci Transl Med. 2021 Oct 6;13(614):eabg0809. doi: 10.1126/scitranslmed.abg0809.
Florence Delestre  1  2 ,  Quitterie Venot  1  2 ,  Charles Bayard  1  2 ,  Antoine Fraissenon  2  3  4 ,  Sophia Ladraa  1  2 ,  Clément Hoguin  1  2 ,  Célia Chapelle  2  5 ,  Junna Yamaguchi  1  2 ,  Rubina Cassaca  1  2 ,  Lola Zerbib  1  2 ,  Sato Magassa  1  2 ,  Gabriel Morin  1  2 ,  Vahid Asnafi  1  6 ,  Patrick Villarese  6 ,  Sophie Kaltenbach  1  6 ,  Sylvie Fraitag  7 ,  Jean-Paul Duong  1  7 ,  Christine Broissand  8 ,  Olivia Boccara  9 ,  Véronique Soupre  10 ,  Bernard Bonnotte  11 ,  Caroline Chopinet  12 ,  Tristan Mirault  13 ,  Christophe Legendre  1  14 ,  Laurent Guibaud  3 ,  Guillaume Canaud  1  2  5  14
Affiliations
  • 1. Université de Paris, Paris, 75006, France.
  • 2. INSERM U1151, Institut Necker-Enfants Malades, Paris, 75015, France.
  • 3. Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, HCL, Bron, 69500, France.
  • 4. Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne, 42000, France.
  • 5. Unité d'hypercroissance dysharmonieuse et anomalies vasculaires, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
  • 6. Laboratoire d'Oncohématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
  • 7. Département d'Anatomopathologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
  • 8. Pharmacie, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
  • 9. Service de Dermatologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
  • 10. Service de Chirurgie Maxillo-faciale Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, 75015, Paris, France.
  • 11. Service de Médecine Interne et Immunologie Clinique, CHU Dijon Bourgogne, Dijon, 21000, France.
  • 12. Service d'Exploration Fonctionnelle Cardiovasculaire, CHU Lille, Lille, 59000, France.
  • 13. Service de Médecine Vasculaire, Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France.
  • 14. Service de Néphrologie et Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, 75015, France.
PMID: 34613809 DOI: 10.1126/scitranslmed.abg0809
Abstract

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.

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