Lung function response and side effects to rapamycin for lymphangioleiomyomatosis: a prospective national cohort study

Abstract

A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Nottingham.NG7 2UH, U.K. simon.johnson@nottingham.ac.uk What is the key question?How can we best optimise the risk / benefit balance of mTOR inhibition for loss of lung function in individuals with LAM? What is the bottom line?Loss of lung function may continue in some individuals treated with rapamycin and a poor response to the drug is more likely in those with lower lung function and longer disease duration at the start of treatment.Lower levels of rapamycin are associated with fewer side effects but equal benefit compared with higher levels. Why read on?We have used a prospective national cohort study to understand the relationship between rapamycin levels, lung function response and side effects to improve the use of mTOR inhibitors in women with LAM. AbstractRationale mTOR inhibitors reduce loss of lung function in LAM although their benefit varies between individuals. We examined lung function response and side effects to rapamycin in a national cohort.Methods Subjects were receiving rapamycin for progressive lung disease. Clinical evaluation, detailed phenotyping, serial lung function, rapamycin and safety monitoring were performed according to a clinical protocol. Lung function change, measured as FEV1 slope (ΔFEV1), was reported for those treated for one year or longer.Results Rapamycin was associated with improved ΔFEV1 in 21 individuals where pre-treatment data were available (p<0.0001). In 47 treated for a mean duration 35.8 months, mean ΔFEV1 was +11 (SD 75) ml/yr although varied from +254 to -148 ml/yr. The quartile with the highest positive ΔFEV1 had greater pretreatment FEV1 (p=0.02) and shorter disease durations (p=0.02) than the lowest quartile. Serum rapamycin level was positively associated with side effects (p=0.02) but not ΔFEV1 over one year. Within the first month of therapy, apthous ulcers, nausea and diarrhoea were associated with higher rapamycin levels.Acne, oedema and menstrual irregularities tended to increase over the first year of therapy. At the end of observation the prevalence of side effects was 5% or less.Conclusions Rapamycin reduces lung function loss in LAM, although in some ΔFEV1 continues to fall at an accelerated rate. Poor response to rapamycin was associated with lower pre-treatment lung function and longer disease duration but not serum level. Early intervention with low dose rapamycin may preserve lung function and reduce side effects.

Rapamycin for lymphangioleiomyomatosis: optimal timing and optimal dosage

“…The safety data reported by Bee and colleagues6 were consistent with data from previous reports. Side effects of rapamycin are typically mild and tolerable.…”

“…A real-world observational study by Bee and colleagues that appears in Thorax expanded our knowledge regarding two important questions: when and how much rapamycin could be used to treat LAM 6. In a prospective cohort comprising 47 patients during a 3-year follow-up, the authors found that (1) patients with LAM with a shorter duration of disease and less severely impaired lung function responded better to rapamycin; (2) different dosages of rapamycin produced similar benefits and (3) lower doses had fewer side effects.…”

“…The dose–response curve for rapamycin remains unknown. Bee and colleagues divided patients quarterly and found that different concentration levels produced similar effects 6. Lower dosages produced similar treatment responses with fewer side effects.…”

Identification of driver genes and somatic mutations in cell‐free DNA of patients with pulmonary lymphangioleiomyomatosis

“…Loss function of TSC gene products results in hyperactivation of mTOR, which promotes the proliferation of LAM cells . Focusing on the connections of TSC gene mutations and mTOR activation, rapamycin analogues (mTOR inhibitors) have been validated an effective treatment in slowing lung function decline . However, adverse toxicity events and drug safety were still unresolved .…”

Cystic Lung Disease in Genetic Syndromes with Deficient Tumor Suppressor Gene Function

“…This study showed that sirolimus stabilizes lung function in LAM, but that continuous therapy is needed. Long-term observational studies showed that the efficacy of sirolimus is maintained over several years [85, 95, 98, 99]. One small series suggested that a low dose of sirolimus (1 mg/day) resulting in serum levels below 5 ng/mL may be sufficient to stabilize lung function [100].…”