Dataset Information

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

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 p110? 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had ?1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently.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.

SUBMITTER: Parker VER

PROVIDER: S-EPMC6752269 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Parker Victoria E R VER Keppler-Noreuil Kim M KM Faivre Laurence L Luu Maxime M Oden Neal L NL De Silva Leena L Sapp Julie C JC Andrews Katrina K Bardou Marc M Chen Kong Y KY Darling Thomas N TN Gautier Elodie E Goldspiel Barry R BR Hadj-Rabia Smail S Harris Julie J Kounidas Georgios G Kumar Parag P Lindhurst Marjorie J MJ Loffroy Romaric R Martin Ludovic L Phan Alice A Rother Kristina I KI Widemann Brigitte C BC Wolters Pamela L PL Coubes Christine C Pinson Lucile L Willems Marjolaine M Vincent-Delorme Catherine C Vabres Pierre P Semple Robert K RK Biesecker Leslie G LG

Genetics in medicine : official journal of the American College of Medical Genetics 20181001 5

<h4>Purpose</h4>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.<h4>Methods</h4>Thirty-nine participants wi ...[more]

PMID: 30270358

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Project description:BackgroundLymphangioleiomyomatosis is a rare disease caused by unregulated activation of mammalian target of rapamycin (mTOR) signalling pathway. Sirolimus showed efficacy in a phase 3 trial of patients with lymphangioleiomyomatosis, but the optimal dose remains unclear.MethodsWe investigated the efficacy and safety of low-dose compared with conventional-dose sirolimus. Clinical data of 39 patients with lymphangioleiomyomatosis (mean age, 34.8 years; median treatment period, 29.6 months) who received sirolimus were retrospectively reviewed. Low-dose sirolimus was defined as any dose that maintained mean blood trough levels lower than those maintained with conventional doses (5-15 ng/mL).ResultsFifty-one percent of patients received low-dose therapy. The rate of decline in lung function decreased after treatment in the whole group (forced expiratory volume in 1 s [FEV1], - 0.12 ± 0.47 [before] vs. 0.24 ± 0.48% predicted/month [after], p = 0.027; diffusing capacity for carbon monoxide [DLco], - 0.33 ± 0.61 vs. 0.03 ± 0.26% predicted/month, p = 0.006) compared with before treatment. In the low-dose group, the rate of decline in FEV1 (- 0.08 ± 0.38 [before] vs. 0.19 ± 0.51% predicted/month [after], p = 0.264) and DLco (-0.13 ± 0.62 vs. 0.02 ± 0.28% predicted/month, p = 0.679) showed a numeric trend towards improvement after treatment; however, the conventional-dose group showed significant improvement in FEV1 (- 0.26 ± 0.54 [before] vs. 0.22 ± 0.38 [after] % predicted/month, p = 0.024) and DLco (- 0.55 ± 0.58 vs. 0.04 ± 0.25% predicted/month, p = 0.002) after treatment. Adverse events (AEs) occurred in 89.7% of patients and the most common AEs was hypercholesterolaemia (43.6%), followed by stomatitis (35.9%). The occurrences of AE were similar between the low- and conventional-dose groups (85.0% vs. 94.7%, p = 0.605).ConclusionsLow-dose sirolimus may stabilise lung function decline in lymphangioleiomyomatosis patients, but its efficacy appears to be inferior to that of conventional-dose sirolimus.

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Dataset Information

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

Publications

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

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