Analysis of the MILES Cohort Reveals Determinants of Disease Progression and Treatment Response in Lymphangioleiomyomatosis
- Nishant Gupta,
- Hye-Seung Lee,
- Lisa R. Young,
- Charlie Strange,
- Joel Moss,
- Lianne G. Singer,
- Koh Nakata,
- Alan F. Barker,
- Jeffrey T. Chapman,
- Mark L. Brantly,
- James M. Stocks,
- Kevin K. Brown,
- Joseph P. Lynch,
- Hilary J. Goldberg,
- Gregory P. Downey,
- Angelo M. Taveira-DaSilva,
- Jeffrey P. Krischer,
- Kenneth Setchell,
- Bruce C. Trapnell,
- Yoshikazu Inoue and
- Francis X. McCormack
- for the NIH Rare Lung Disease Consortium
- From the University of Cincinnati (FXM, NG, BCT) and Cincinnati Children's Hospital Medical Center, Cincinnati (BCT, KS), Vanderbilt University Medical Center (LRY), National Kinki-Chou Hospital, Osaka, Japan (YI), National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda (JM. and AT-D), University of Toronto, Canada (LGS), Medical University of South Carolina, Charleston (CS), Niigata University Medical and Dental Hospital, Japan (KN), Oregon Health and Science University, Portland (AFB), Cleveland Clinic Abu Dhabi, UAE (JTC), University of Texas (JMS), University of Florida, Gainesville (MLB), University of Texas Health Sciences Center, Tyler (J.M.S.), National Jewish Health and the University of Colorado, Denver and Aurora (KKB and GPD), University of California, Los Angeles, (JPL), Harvard Medical School, Boston (HJG), and University of South Florida, Tampa (HSL, JPK)
- Nishant Gupta, M.D., 231 Albert Sabin Way, MSB Room 6053, ML 0564, Cincinnati, OH 45267-0564. E-mail: Nishant.gupta{at}uc.edu
Abstract
Rationale: The Multicenter International Lymphangioleiomyomatosis (LAM) Efficacy of Sirolimus (MILES) trial revealed that sirolimus stabilised lung function in patients with moderately-severe LAM. The purpose of this study was to further examine the MILES cohort for the effects of racial, demographic, clinical, and physiologic patient characteristics on disease progression and treatment response in LAM.
Methods: MILES subjects were stratified on the basis of menopausal status (premenopausal/postmenopausal), race (Asian/Caucasian), bronchodilator responsiveness (present/absent), initial FEV1 (51–70% versus ≤50%), and TSC-association (yes/no). Linear mixed effects model was used to compare slope differences, and non-parametric tests were used to compare medians and proportions between treatment groups in each stratum.
Results: In the MILES placebo group, premenopausal patients declined five-fold faster than postmenopausal patients (FEV1 slope −17±3 versus −3±3 mL·month−1, p=0.003). Upon treatment with sirolimus, both premenopausal (−17±3 versus −1±2 mL·month−1, p<0.0001), and postmenopausal patients (−3±3 versus 6±3 mL·month−1, p=0.04) exhibited a beneficial response in mean FEV1 slope compared with the placebo group. Race, LAM subtype, bronchodilator responsiveness, or baseline FEV1 did not impact the rate of disease progression in the placebo group, or treatment response in the sirolimus group. Menopausal status and race had differential effects on the adverse event profile of sirolimus. Baseline serum VEGF-D >600 pg·mL−1 identified subgroups of patients who were more likely to decline on placebo and respond to treatment with sirolimus.
Conclusions: In LAM patients, treatment with sirolimus is beneficial regardless of menopausal status, race, bronchodilator responsiveness, baseline FEV1, or TSC-association. Serum VEGF-D and menopausal status can help inform therapeutic decisions.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Gupta has nothing to disclose.
Conflict of interest: Dr. Lee has nothing to disclose.
Conflict of interest: Dr. Young reports other from Boehringer Ingelheim , other from UpToDate, outside the submitted work; In addition, Dr. Young has a patent Serum VEGF-D; no royalties issued.
Conflict of interest: Dr. Strange reports grants in LAM from Novartis, outside the submitted work.
Conflict of interest: Dr. Moss has nothing to disclose.
Conflict of interest: Dr. Singer has nothing to disclose.
Conflict of interest: Dr. Nakata has nothing to disclose.
Conflict of interest: Dr. Barker has nothing to disclose.
Conflict of interest: Dr. Chapman has nothing to disclose.
Conflict of interest: Dr. Brantly has nothing to disclose.
Conflict of interest: Dr. Stocks has nothing to disclose.
Conflict of interest: Dr. Brown reports grants from NHLBI, personal fees from Astra Zeneca, personal fees from Biogen, personal fees from Galecto, from Genoa, personal fees from MedImmune, personal fees from Novartis, other from Roche/Genentech, personal fees from ProMetic, personal fees from Patara, personal fees from Third Pole, personal fees from Galapagos, personal fees from Boehringer Ingelheim, personal fees from Theravance, personal fees from Three Lakes Partners, outside the submitted work.
Conflict of interest: Dr. Goldberg has nothing to disclose.
Conflict of interest: Dr. Downey has nothing to disclose.
Conflict of interest: Dr. Angelo Taveira-DaSilva has nothing to disclose.
Conflict of interest: Dr. Krischer has nothing to disclose.
Conflict of interest: Dr. Setchell has nothing to disclose.
Conflict of interest: Dr. Trapnell has nothing to disclose.
Conflict of interest: Dr. Inoue reports grants from Japanese Ministry of Health, Labour, and Welfare, during the conduct of the study.
Conflict of interest: Dr. McCormack has a patent on serum VEGF-D testing. All royalties are waived to the parent institution, the University of Cincinnati.
Conflict of interest: Dr. Lynch has nothing to disclose.
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