Efficacy and safety of long-term sirolimus therapy for asian patients with lymphangioleiomyomatosis

Toshinori Takada, Ayako Mikami, Nobutaka Kitamura, Kuniaki Seyama, Yoshikazu Inoue, Katsura Nagai, Masaru Suzuki, Hiroshi Moriyama, Keiichi Akasaka, Ryushi Tazawa, Toyohiro Hirai, Michiaki Mishima, Mie Hayashida, Masaki Hirose, Chikatoshi Sugimoto, Toru Arai, Noboru Hattori, Kentaro Watanabe, Tsutomu Tamada, Hirohisa YoshizawaKohei Akazawa, Takahiro Tanaka, Keita Yagi, Lisa R. Young, Francis X. McCormack, Koh Nakata

Research output: Contribution to journalArticlepeer-review

39 Citations (Scopus)


Rationale: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. Objectives: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. Methods: We conducted a single-arm, open-label, investigatorinitiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. Measurements and Main Results: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. Conclusions: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

Original languageEnglish
Pages (from-to)1912-1922
Number of pages11
JournalAnnals of the American Thoracic Society
Issue number11
Publication statusPublished - 2016 Nov


  • Adverse events
  • Lymphangioleiomyomatosis
  • Sirolimus
  • Tolerability


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