The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis

Abstract

Background: Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies. Methods: PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis. Results: Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I 2 = 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I 2 = 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable. Conclusions: Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.

Tuberous sclerosis complex for the pulmonologist

“…A recent meta-analysis supports the latter findings; mTOR inhibitors were associated with improved lung function and reduced size of rAMLs [131]. Compared to sirolimus, everolimus has a shorter half-life and better bioavailability, making it an interesting option for patients awaiting transplantation [132].…”

“…Investigational treatments Doxycycline, a tetracycline antibiotic, has been studied in the treatment of LAM because of its inhibitory effects on production and activity of MMPs that promote lung destruction in LAM. However, a 2-year randomised double-blind trial of 23 female patients failed to demonstrate a difference in the decline in FEV 1 (the primary end-point), FVC, D LCO , shuttle walk distance or quality of life [132], despite a decrease in urine MMP levels [134]. The ATS/JRS guidelines advise against its use in LAM patients [98].…”

Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex

“…Following the administration of mTOR inhibitor everolimus, the patient experienced an improvement in several TSC manifestations. It is well known that hamartomas associated with TSC, such as lymphangioleiomyomatosis (LAM), AML, and subependymal giant cell astrocytomas, are caused by mTOR activation with decreased or absent expression of TSC1/2 genes [ 7 , 8 ] and can be treated with mTOR inhibitors [ [9] , [10] , [11] ]. Loss of heterozygosity for TSC1/2 genes and high expression of phospho-p70S6K and phospho-4E-BP1 proteins observed in MMPH lesions suggest the activation of mTOR pathway and plausibility of a response to mTOR inhibitors [ 2 , 12 ].…”

Use of Quantitative CT Analysis to Evaluate the Degree of Lung Destruction in Lymphangioleiomyomatosis

“…The main findings of this study are as follows: (1) the extent of pulmonary cystic damage is correlated with FEV1%pred and DLCO%pred; (2) there was a no obvious association between VEGF-D levels and cystic damage of lung in LAM patients. (3) the cyst score may be the new indicator of the degree of lung impairment with 15.80% to be the threshold of rapamycin treatment or not.…”

“…[1,2] LAM occurs sporadically (S-LAM) or is associated with tuberous sclerosis complex (TSC), and the TSC-LAM is heritable. [3] The mutation of TSC genes is involved in the pathogenesis of LAM. The inactive mutation of TSC1 or TSC2 genes results in the abnormal activation of the target of rapamycin complex 1 (mTORC1), affecting the morphology, growth, and survival of cells.…”