Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum

Victoria Parker 1 Kim Keppler-Noreuil 2 Laurence Faivre 3, 4, 5 Maxime Luu 6 Neal Oden 7 Leena de Silva 1 Julie Sapp 2 Katrina Andrews 1 Marc Bardou 6 Kong Chen 8 Thomas Darling 9 Elodie Gautier 4, 3, 5 Barry Goldspiel 10 Smail Hadj-Rabia 11, 12, 13 Julie Harris 1 Georgios Kounidas 1 Parag Kumar 10 Marjorie Lindhurst 2 Romaric Loffroy 14 Ludovic Martin 15 Alice Phan 16 Kristina Rother 8 Brigitte Widemann 17 Pamela Wolters 17 Christine Coubes 18 Lucile Pinson 18 Marjolaine Willems 18 Catherine Vincent-Delorme 19 - Promise Working Group Pierre Vabres 3, 4, 5 Robert Semple 1, 20, * Leslie Biesecker 2
Abstract : Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS
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https://hal-univ-bourgogne.archives-ouvertes.fr/hal-02000984
Contributeur : Lnc - Université de Bourgogne <>
Soumis le : jeudi 31 janvier 2019 - 09:10:26
Dernière modification le : vendredi 2 août 2019 - 14:48:04

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Victoria Parker, Kim Keppler-Noreuil, Laurence Faivre, Maxime Luu, Neal Oden, et al.. Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum. Genetics in Medicine, Nature Publishing Group, In press, ⟨https://www.nature.com/articles/s41436-018-0297-9⟩. ⟨10.1038/s41436-018-0297-9⟩. ⟨hal-02000984⟩

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