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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, I2?=?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, I2?=?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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7023761 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis.

Wang Qi Q Luo Mengqi M Xiang Bo B Chen Siyuan S Ji Yi Y

Respiratory research 20200214 1

<h4>Background</h4>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.<h4>Methods</h4>PubMed (Medline), EMBASE, Cochrane Library, Web ...[more]

PMID: 32059669

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Project description:BackgroundLymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.MethodsWe conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).ResultsDuring the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.ConclusionsIn patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

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.

Project description:Chagas disease remains a neglected tropical disease, causing significant burden in the Americas and countries that receive immigrants from endemic nations. Current pharmaceutical treatments are suboptimal, not only varying drastically in efficacy, depending on the stage of disease, but also presenting significant risk of adverse events. The objective of this review is to provide a timely update on the efficacy and safety of current trypanocidals. Eligible studies published from January 2015 to December 2020 were retrieved by one reviewer from six electronic databases. Ana-lysis was done with review management software and risk of bias was assessed using tools appropriate for the type of study (i.e., experimental or observational). Thirteen studies (10 observational and three RCTs) were included in the analysis. All 13 studies tested Benznidazole (BNZ) or Nifurtimox (NFX), and two studies also tested Posaconazole (POS) or E1224 (Ravucanazole). BNZ was found to be the most efficacious trypanocidal drug compared to Nifurtimox, POS, and E1224; it also resulted in the highest percentage of adverse effects (AEs) and treatment discontinuation due to its toxicity. Adults experienced higher frequency of neurological AEs while taking BNZ or NFX compared to children. Children had a higher frequency of general AEs compared to adults while taking BNZ. Overall, BNZ is still the most efficacious, but development of new, less toxic drugs is paramount for the quality of life of patients. Studies testing combination therapies and shorter regimens are needed, as is the devising of better clinical parameters and laboratory biomarkers to evaluate treatment efficacy. Considering the variability in methodology and reporting of the studies included in the present analysis, we offer some recommendations for the improvement and replicability of clinical studies investigating pharmacological treatment of Chagas disease. These include full disclosure of methodology, standardization of outcome measures, and always collecting and reporting data on both the efficacy of trypanocidals and on safety outcomes.

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The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis.

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The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis.

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